It is important that we understand the roles and functions of receptors because most drugs interact with receptors  that will determine selective therapeutic and toxic effects of the drug. Moreover, receptors largely determine the  quantitative relations between dose of a drug and pharmacologic effect.   An agonist is defined as an agent that can bind to a receptor and elicit a biologic response. The magnitude of the  drug effect depends on the drug concentration at the receptor site, which in turn is determined by the dose of drug  administered and by factors characteristic of the drug pharmacokinetic profile, such as rate of absorption,  distribution, and metabolism.   Figure 2.6 The effect of dose on the magnitude of pharmacologic response. Panel A is a linear graph. Panel B  is a semilogarithmic plot of the same data. EC50 =drug dose that shows fifty percent of maximal response.   As the concentration of a drug increases, the magnitude of its pharmacologic effect also increases. The relationship  between dose and response is a continuous one, and it can be mathematically described for many systems by  application of the law of mass action, assuming the simplest model of drug binding:   The response is a graded effect, meaning that the response is continuous and gradual. This contrasts with a quantal  response, which describes an all-or-nothing response. A graph of this relationship is known as a graded  dosea€" response curve. Plotting the magnitude of the response against increasing doses of a drug produces a graph  that has the general shape depicted in Figure 2.6A. The curve can be described as a rec-tangular hyperbolaa€"a very  familiar curve in biology, because it can be applied to diverse biological events, such as ligand binding, enzymatic  activity, and responses to pharmacologic agents.   1. Potency: Two important properties of drugs can be determined by graded dosea€" response curves. The first is  potency, a measure of the amount of drug necessary to produce an effect of a given magnitude. For a number  of reasons, the concentration producing an effect that is fifty percent of the maximum is used to determine  potency; it commonly designated as the EC 50 . In Figure 2.6, the EC 50 for Drugs A and B are indicated. Drug A is  more potent than Drug B because less Drug A is needed to obtain 50 percent effect. Thus, therapeutic  preparations of drugs will reflect the potency. For example, candesartan and irbesartan are  angiotensinaC" receptor blockers that are used alone or in combination to treat hypertension. Candesartan is  more potent than irbesartan because the dose range for candesartan is 4 to 32 mg, as compared to a dose range  of 75 to 300 mg for irbesartan. Candesartan would be Drug A and irbesartan would be Drug B in Figure 2.6. An  important contributing factor to the dimension of the EC 50 is the affinity of the drug for the receptor.   Semilogarithmic plots are often employed, because the range of doses (or concentrations) may span several  orders of magnitude. By plotting the log of the concentration, the complete range of doses can be graphed. As  shown in Figure 2.6B, the curves become sigmoidal in shape. It is also easier to visually estimate the EC 50 .   2. Efficacy [intrinsic activity]: The second drug property that can be determined from graded dosea€" response  plots is the efficacy of the drug. This is the ability of a drug to illicit a physiologic response when it interacts  with a receptor. Efficacy is dependent on the number of druga€"receptor complexes formed and the efficiency  of the coupling of receptor activation to cellular responses. Analogous to the maximal velocity for enzyme-  catalyzed reactions, the maximal response (E max ) or efficacy is more important than drug potency. A drug with   greater efficacy is more therapeutically beneficial than one that is more potent. Figure 2. 7 shows the response  to drugs of differing potency and efficacy.   3. DrugaC" receptor binding: The quantitative relationship between drug concentration and receptor occupancy  applies the law of mass action to the kinetics of the binding of drug and receptor molecules. By making the  assumption that the binding of one drug molecule does not alter the binding of subsequent molecules, we can  mathematically express the relationship between the percentage (or fraction) of bound receptors and the drug  concentration:    where [D] =the concentration of free drug; [DR] =the concentration of bound drug; [R t ] =the total   concentration of receptors, and is equal to the sum of the concentrations of unbound (free) receptors and  bound receptors and; Kd =[D][R]/[DR], and is the dissociation constant for the drug from the receptor. The  value of Kd can be used to determine the affinity of a drug for its receptor. Affinity describes the strength of  the interaction (binding) between a ligand and its receptor. The higher the Kd value, the weaker the interaction  and the lower the affinity. The converse occurs when a drug has a low Kd. The binding of the ligand to the  receptor is strong, and the affinity is high. Equation (1) defines a curve that has the shape of a rectangular  hyperbola (Figure 2.8). As the concentration of free drug increases, the ratio of the concentrations of bound  receptors to total receptors approaches unity. Doses are often plotted on a logarithmic scale, because the range  from lowest to highest concentrations of doses often spans several orders of magnitude. It is important to note  the similarity between these curves and those representing the relationship between dose and effect.   Figure 2.7 Typical dose-response curve for drugs showing differences in potency and efficacy. (EC 50 =  drug dose that shows fifty percent of maximal response.)    4. Relationship of binding to effect: The binding of the drug to its receptor initiates events that ultimately lead to  a measurable biologic response. The mathematical model that describes drug concentration and receptor  binding can be applied to dose (drug concentration) and response (or effect), providing the following  assumptions are met: 1) The magnitude of the response is proportional to the amount of receptors bound or  occupied, 2) the E max occurs when all receptors are bound, and 3) binding of the drug to the receptor exhibits  no cooperativity. In this case,    where [E] =the effect of the drug at concentration [D] and [E max ] =the maximal effect of the drug.   Figure 2.8 The effect of dose on the magnitude of drug binding.    5. Agonists: If a drug binds to a receptor and produces a biologic response that mimics the response to the  endogenous ligand, it is known as an agonist. For example, phenylephrine is an agonist at i±L-adrenoceptors,  because it produces effects that resemble the   action of the endogenous ligand, norepinephrine. Upon binding to i±L-adrenoceptors on the membranes of  vascular smooth muscle, phenylephrine mobilizes intracellular Ca 2+ , causing contraction of the actin and myosin  filaments. The shortening of the muscle cells decreases the diameter of the arteriole, causing an increase in  resistance to the flow of blood through the vessel. Blood pressure therefore rises to maintain the blood flow. As  this brief description illustrates, an agonist may have many effects that can be measured, including actions on  intracellular molecules, cells, tissues, and intact organisms. All of these actions are attributable to interaction  of the drug molecule with the receptor molecule. In general, a full agonist has a strong affinity for its receptor  and good efficacy.    Figure 2.9 Effects of drug antagonists. EC 50 =drug dose that shows fifty percent of maximal response.    6. Antagonists: Antagonists are drugs that decrease the actions of another drug or endogenous ligand. Antagonism  may occur in several ways. Many antagonists act on the identical receptor macromolecule as the agonist.  Antagonists, however, have no intrinsic activity and, therefore, produce no effect by themselves. Although  antagonists have no intrinsic activity, they are able to bind avidly to target receptors because they possess  strong affinity. If both the antagonist and the agonist bind to the same site on the receptor, they are said to be  a€oecompetitive.a€§ For example, the antihypertensive drug prazosin competes with the endogenous ligand,  norepinephrine, at i±L-adrenoceptors, decreasing vascular smooth muscle tone and reducing blood pressure.  Plotting the effect of the competitive antagonist characteristically causes a shift of the agonist dosea€" response  curve to the right. Competitive antagonists have no intrinsic activity. If the antagonist binds to a site other than  where the agonist binds, the interaction is a€oenoncompetitivea€§ or a€oeallosterica€'- : (Figure 2.9). [Note: A  drug may also act as a chemical antagonist by combining with another drug and rendering it inactive. For  example, protamine i oni cal ly binds to heparin, rendering it inactive and antagonizing heparin's anticoagulant  effect. ]   7. Functional antagonism: An antagonist may act at a completely separate receptor, initiating effects that are  functionally opposite those of the agonist. A classic example is the antagonism by epinephrine to histamine-  induced bronchoconstriction. Histamine binds to Hi histamine receptors on bronchial smooth muscle, causing  contraction and narrowing of the bronchial tree. Epinephrine is an agonist at i 2 2 -adrenoceptors on bronchial  smooth muscle, which causes the muscles to actively relax. This functional antagonism is also known as    8. Partial agonists: Partial agonists have efficacies (intrinsic activities) greater than zero, but less than that of a  full agonist. Even if all the receptors are occupied, partial agonists cannot produce an E max of as great a  magnitude as that of a full agonist. However, a partial agonist may have an affinity that is greater than, less  than, or equivalent to that of a full agonist. A unique feature of these drugs is that, under appropriate  conditions, a partial agonist may act as an antagonist of a full agonist. Consider what would happen to the E max  of an agonist in the presence of increasing concentrations of a partial agonist (Figure 2. 10). As the number of  receptors occupied by the partial agonist increases, the E max would decrease until it reached the E max of the  partial agonist. This potential of partial agonists to act both agonistically and antagonistically may be  therapeutically exploited.   For example, aripiprazole, an atypical neuroleptic agent, is a partial agonist at selected dopamine receptors.  Dopaminergic pathways that were overactive would tend to be inhibited by the partial agonist, whereas  pathways that were underactive may be stimulated. This might explain the ability of aripiprazole to improve  many of the symptoms of schizophrenia, with a small risk of causing extrapyramidal adverse effects (see p. 33).   Another important dosea€" response relationship is that of the influence of the magnitude of the dose on the  proportion of a population that responds. These responses are known as quantal responses, because, for any  individual, the effect either occurs or it does not. Even graded responses can be considered to be quantal if a  predetermined level of the graded response is designated as the point at which a response occurs or not. For  example, a quantal dosea€" response relationship can be determined in a population for the antihypertensive drug  atenolol. A positive response is defined as at least a 5 mm Hg fall in diastolic blood pressure. Quantal  dosea€" response curves are useful for determining doses to which most of the population responds.    Figure 2.11 Cumulative percentage of patients responding to plasma levels of a drug.   The therapeutic index of a drug is the ratio of the dose that produces toxicity to the dose that produces a clinically  desired or effective response in a population of individuals:   where TD50 =the drug dose that produces a toxic effect in half the population and ED50 =the drug dose that  produces a therapeutic or desired response in half the population. The therapeutic index is a measure of a drug's  safety, because a larger value indicates a wide margin between doses that are effective and doses that are toxic.   The therapeutic index is determined by measuring the frequency of desired response, and toxic response, at various  doses of drug. By convention, the doses that produce the therapeutic effect and the toxic effect in fifty percent of  the population are employed; these are known as the ED50 and TD50, respectively. In humans, the therapeutic index  of a drug is determined using drug trials and accumulated clinical experience. These usually reveal a range of  effective doses and a different (sometimes overlapping) range of toxic doses. Although some drugs have narrow   therapeutic indices, they are routinely used to treat certain diseases. Several lethal diseases, such as Hodgkin's  lymphoma, are treated with narrow therapeutic index drugs; however, treatment of a simple headache, for  example, with a narrow therapeutic index drug would be unacceptable. Figure 2. 11 shows the responses to  warfarin, an oral anti-coagulant with a narrow therapeutic index, and penicillin, an antimicrobial drug with a large  therapeutic index.   1. Warfarin (example of a drug with a small therapeutic index); As the dose of warfarin is increased, a greater  fraction of the patients respond (for this drug, the desired response is a two-fold increase in prothrombin time)  until eventually, all patients respond (see Figure 2. 11A). However, at higher doses of warfarin, a toxic response  occurs,   namely a high degree of anticoagulation that results in hemorrhage. [Note: that when the therapeutic index is  low, it is possible to have a range of concentrations where the effective and toxic responses overlap. That is,  some patients hemorrhage, whereas others achieve the desired two-fold prolongation of prothrombin time.   Variation in patient response is, therefore, most likely to occur with a drug showing a narrow therapeutic index,  because the effective and toxic concentrations are similar. Agents with a low therapeutic indexa€"that is, drugs  for which dose is critically importanta€"are those drugs for which bioavailability critically alters the therapeutic  effects (see p. 7).   2. Penicillin (example of a drug with a large therapeutic index): For drugs such as penicillin (see Figure 2. 11B),   it is safe and common to give doses in excess (often about ten-fold excess) of that which is minimally required to  achieve a desired response. In this case, bioavailability does not critically alter the therapeutic effects.   A. If 10 mg of Drug A produces the same response as 100 mg of Drug B, Drug A is more efficacious than Drug B.   B. The greater the efficacy, the greater the potency of a drug.   C. In selecting a drug, potency is usually more important than efficacy.   E. Variation in response to a drug among different individuals is most likely to occur with a drug showing a  large therapeutic index.   2.2 Variation in the sensitivity of a population of individuals to increasing doses of a drug is best determined by  which of the following?   2.3 Which of the following statements most accurately describes a system having spare receptors?   D. Spare receptors are active even in the absence of agonist.   E. Agonist affinity for spare receptors is less than their affinity for nonspare receptors.   >Table of Contents > Unit II - Drugs Affecting theAutonomic Nervous System >Chapter 3 - The AutonomicNervous System   The autonomic nervous system, along with the endocrine system, coordinates the regulation and integration of  bodily functions. The endocrine system sends signals to target tissues by varying the levels of blood-borne  hormones. In contrast, the nervous system exerts its influence by the rapid transmission of electrical impulses over  nerve fibers that terminate at effector cells, which specifically respond to the release of neuromediator substances.  Drugs that produce their primary therapeutic effect by mimicking or altering the functions of the autonomic  nervous system are called autonomic drugs and are discussed in the following four chapters. These autonomic agents  act either by stimulating portions of the autonomic nervous system or by blocking the action of the autonomic  nerves. This chapter outlines the fundamental physiology of the autonomic nervous system, and it describes the role  of neurotransmitters in the communication between extracellular events and chemical changes within the cell.   The nervous system is divided into two anatomical divisions: the central nervous system (CNS), which is composed of  the brain and spinal cord, and the peripheral nervous system, which includes neurons located outside the brain and  spinal corda€"that is, any nerves that enter or leave the CNS (Figure 3. 1). The peripheral nervous system is  subdivided into the efferent division, the neurons of which carry signals away from the brain and spinal cord to the  peripheral tissues, and the afferent division, the neurons of which bring information from the periphery to the CNS.  Afferent neurons provide sensory input to modulate the function of the efferent division through reflex arcs, that  is, neural pathways that mediate a reflex action.   The efferent portion of the peripheral nervous system is further divided into two major functional subdivisions, the  somatic and the autonomic systems (see Figure 3.1). The somatic efferent neurons are involved in the voluntary  control of functions such as contraction of the skeletal muscles essential for locomotion. On the other hand, the  autonomic system regulates the everyday requirements of vital bodily functions without the conscious participation  of the mind. It is composed of efferent neurons that innervate smooth muscle of the viscera,   cardiac muscle, vasculature, and the exocrine glands, thereby controlling digestion, cardiac output, blood flow, and  glandular secretions.    1. Efferent neurons: The autonomic nervous system carries nerve impulses from the CNS to the effector organs by  way of two types of efferent neurons (Figure 3.2). The first nerve cell is called a preganglionic neuron, and its  cell body is located within the CNS. Preganglionic neurons emerge from the brainstem or spinal cord and make a  synaptic connection in ganglia (an aggregation of nerve cell bodies located in the peripheral nervous system).  These ganglia function as relay stations between a preganglionic neuron and a second nerve cell, the  postganglionic neuron. The latter neuron has a cell body originating in the ganglion. It is generally  nonmyelinated and terminates on effector organs, such as smooth muscles of the viscera, cardiac muscle, and  the exocrine glands.   2. Afferent neurons: The afferent neurons (fibers) of the autonomic nervous system are important in the reflex  regulation of this system (for example, by sensing pressure in the carotid sinus and aortic arch) and signaling the  CNS to influence the efferent branch of the system to respond (see below).   3. Sympathetic neurons: The efferent autonomic nervous system is divided into the sympathetic and the  parasympathetic nervous systems, as well as the enteric nervous system (see Figure 3.1). Anatomically, they  originate in the CNS and emerge from two different spinal cord regions. The preganglionic neurons of the  sympathetic system come from thoracic and lumbar regions of the spinal cord, and they synapse in two cord-like  chains of ganglia that run in parallel on each side of the spinal cord. The preganglionic neurons are short in  comparison to the postganglionic ones. Axons of the postganglionic neuron extend from these ganglia to the  tissues that they innervate and regulate (see Chapter 6). [Note: The adrenal medulla, like the sympathetic  ganglia, receives preganglionic fibers from the sympathetic system. Lacking axons, the adrenal medulla, in  response to stimulation by the ganglionic neurotransmitter acetylcholine, influences other organs by secreting  the hormone epinephrine, also known as adrenaline, and lesser amounts of norepinephrine into the blood. ]   4. Parasympathetic neurons: The parasympathetic preganglionic fibers arise from the cranium (from cranial  nerves III, VII, IX, and X) and from the sacral region of the spinal cord and synapse in ganglia near or on the  effector organs. Thus, in contrast to the sympathetic system, the preganglionic fibers are long, and the  postganglionic ones are short, with the ganglia close to or within the organ innervated. In most instances there  is a one-to-one connection between the preganglionic and postganglionic neurons, enabling the discrete  response of this division.   5. Enteric neurons: The enteric nervous system is the third division of the autonomic nervous system. It is a  collection of nerve fibers that innervate the gastrointestinal tract, pancreas, and gallbladder, and it constitutes  the a€oebrain of the gut.a€§ This system functions independently of the CNS and controls the motility, exocrine  and endocrine secretions, and microcirculation of the gastrointestinal tract. It is modulated by both the  sympathetic and parasympathetic nervous systems.   Although continually active to some degree (for example, in maintaining the tone of vascular beds), the  sympathetic division has the property of adj usting in response to stressful situations, such as trauma, fear,  hypoglycemia, cold, or exercise.   1. Effects of stimulation of the sympathetic division: The effect of sympathetic output is to increase heart rate  and blood pressure, to mobilize energy stores of the body, and to increase blood flow to skeletal muscles and  the heart while diverting flow from the skin and internal organs. Sympathetic stimulation results in dilation of  the pupils and the bronchioles (Figure 3.3). It also affects gastrointestinal motility and the function of the  bladder and sexual organs.   2. Fight or flight response: The changes experienced by the body during emergencies have been referred to as    the a€oefight or flightaCl* response (Figure 3.4). These reactions are triggered both by direct sympathetic  activation of the effector organs and by stimulation of the adrenal medulla to release epinephrine and lesser  amounts of norepinephrine. These hormones enter the bloodstream and promote responses in effector organs  that contain adrenergic receptors (see Figure 6. 6). The sympathetic nervous system tends to function as a unit,  and it   often discharges as a complete systema€"for example, during severe exercise or in reactions to fear (see Figure  3.4). This system, with its diffuse distribution of postganglionic fibers, is involved in a wide array of physiologic  activities, but it is not essential for life.    Figure 3.3 Action of sympathetic and parasympathetic nervous systems on effector organs.   The parasympathetic division maintains essential bodily functions, such as digestive processes and elimination of  wastes, and is required for life. It usually acts to oppose or balance the actions of the sympathetic division and is  generally dominant over the sympathetic system in a€oerest and digesta€§ situations. The parasympathetic system is  not a functional entity as such, and it never discharges as a complete system. If it did, it would produce massive,  undesirable, and unpleasant symptoms. Instead, discrete parasympathetic fibers are activated separately, and the  system functions to affect specific organs, such as the stomach or eye.   (discrete because postganglionic  neurons are not branched, but  are directed so a specific organ)   Figure 3.4 Sympathetic and parasympathetic actions are elicited by different stimuli.   Although the autonomic nervous system is a motor system, it does require sensory input from peripheral structures  to provide information on the state of affairs in the body. This feedback is provided by streams of afferent  impulses, originating in the viscera and other autonomically innervated structures, that travel to integrating centers  in the CNSa€"that is, the hypothalamus, medulla oblongata, and spinal cord. These centers respond to the stimuli by  sending out efferent reflex impulses via the autonomic nervous system (Figure 3.5).   1. Reflex arcs: Most of the afferent impulses are translated into reflex responses without involving consciousness.  For example, a fall in blood pressure causes pressure-sensitive neurons (baroreceptors in the heart, vena cava,  aortic arch, and carotid sinuses) to send fewer impulses to cardiovascular centers in the brain. This prompts a  reflex response of increased sympathetic output to the heart and vasculature and decreased parasympathetic  output to the heart, which results in a compensatory rise in blood pressure and tachycardia (see Figure 3. 5).  [Note: In each case, the reflex arcs of the autonomic nervsous system comprise a sensory (or afferent) arm, and  a motor (or efferent, or effector) arm.]   2. Emotions and the autonomic nervous system: Stimuli that evoke feelings of strong emotion, such as rage,  fear, or pleasure, can modify the activity of the autonomic nervous system.    Figure 3.5 Baroreceptor reflex arc responds to a decrease in blood pressure.   1. Dual innervation: Most organs in the body are innervated by both divisions of the autonomic nervous system.  Thus, vagal parasympathetic innervation slows the heart rate, and sympathetic innervation increases the heart  rate. Despite this dual innervation, one system usually predominates in controlling the activity of a given organ.    For example, in the heart, the vagus nerve is the predominant factor for controlling rate. This type of  antagonism is considered to be dynamic and is fine-tuned at any given time to control homeostatic organ  functions.   2. Organs receiving only sympathetic innervation: Although most tissues receive dual innervation, some effector  organs, such as the   adrenal medulla, kidney, pilomotor muscles, and sweat glands, receive innervation only from the sympathetic  system. The control of blood pressure is also mainly a sympathetic activity, with essentially no participation by  the parasympathetic system.   The efferent somatic nervous system differs from the autonomic system in that a single myelinated motor neuron,  originating in the CNS, travels directly to skeletal muscle without the mediation of ganglia. As noted earlier, the  somatic nervous system is under voluntary control, whereas the autonomic is an involuntary system.   Neurotransmission in the autonomic nervous system is an example of the more general process of chemical signaling  between cells. In addition to neurotransmission, other types of chemical signaling are the release of local mediators  and the secretion of hormones.    Figure 3.6 Summary of the neurotransmitters released and the types of receptors found within the autonomic   and somatic nervous systems. [Note: This schematic diagram does not show that the parasympathetic ganglia  are close to or on the surface of the effector organs and that the postganglionic fibers are usually shorter than  the preganglionic fibers. By contrast, the ganglia of the sympathetic nervous system are close to the spinal  cord. The postganglionic fibers are long, allowing extensive branching to innervate more than one organ  system. This allows the sympathetic nervous system to discharge as a unit. ]   Most cells in the body secrete chemicals that act locallya€"that is, on cells in their immediate environment. These  chemical signals are rapidly destroyed or removed; therefore, they do not enter the blood and are not distributed  throughout the body. Histamine (see p. 520) and the prostaglandins (see p. 519) are examples of local mediators.   Specialized endocrine cells secrete hormones into the bloodstream, where they travel throughout the body exerting  effects on broadly distributed target cells in the body. (Hormones are described in Chapters 23 through 26. )   All neurons are distinct anatomic units, and no structural continuity exists between most neurons. Communication  between nerve cellsa€"and between nerve cells and effector organsa€"occurs through the release of specific  chemical signals, called neurotransmitters, from the nerve terminals. This release is triggered by the arrival of the  action potential at the nerve ending, leading to depolarization. Uptake of Ca 2+ initiates fusion of the synaptic  vesicles with the presynaptic membrane and release of their contents. The neurotransmitters rapidly diffuse across  the synaptic cleft or space (synapse) between neurons and combine with specific receptors on the postsynaptic  (target) cell (Figure 3.6 and see Chapter 2).   1. Membrane receptors: All neurotransmitters and most hormones and local mediators are too hydrophilic to  penetrate the lipid bilayer of target-cell plasma membranes. Instead, their signal is mediated by binding to  specific receptors on the cell surface of target organs. [Note: A receptor is defined as a recognition site for a  substance. It has a binding specificity, and it is coupled to processes that eventually evoke a response. Most  receptors are proteins. They need not be located in the membrane (see Chapter 2). ]   Figure 3.7 Three mechanisms whereby binding of a neurotransmitter leads to a cellular effect.    2. Types of neurotransmitters: Although over fifty signal molecules in the nervous system have tentatively been  identified, six signal compoundsaC" norepinephrine (and the closely related epinephrine), acetylcholine,  dopamine, serotonin, histamine, and i 3 -aminobutyric acida€"are most commonly involved in the actions of  therapeutically useful drugs. Each of these chemical signals binds to a specific family of receptors.   Acetylcholine and norepinephrine are the primary chemical signals in the autonomic nervous system, whereas a  wide variety of neurotransmitters function in the CNS. Not only are these neurotransmitters released on nerve  stimulation, cotransmitters, such as adenosine, often accompany them and modulate the transmission process.   a. Acetylcholine: The autonomic nerve fibers can be divided into two groups based on the chemical nature of  the neurotransmitter released. If transmission is mediated by acetylcholine, the neuron   is termed cholinergic (see Chapters 4 and 5). Acetylcholine mediates the transmission of nerve impulses  across autonomic ganglia in both the sympathetic and parasympathetic nervous systems. It is the  neurotransmitter at the adrenal medulla. Transmission from the autonomic postganglionic nerves to the  effector organs in the parasympathetic system and a few sympathetic system organs also involves the release  of acetylcholine. In the somatic nervous system, transmission at the neuromuscular j unction (that is,  between nerve fibers and voluntary muscles) is also cholinergic (see Figure 3.6).   b. Norepinephrine and epinephrine: When norepinephrine or epinephrine is the transmitter, the fiber is  termed adrenergic (adrenaline being another name for epinephrine). In the sympathetic system,  norepinephrine mediates the transmission of nerve impulses from autonomic postganglionic nerves to  effector organs. Norepinephrine and adrenergic receptors are discussed in Chapters 6 and 7. A summary of  the neuromediators released and the type of receptors within the peripheral nervous system is shown in  Figure 3.6. [Note: A few sympathetic fibers, such as those involved in sweating, are cholinergic; for  simplicity, they are not shown in the figure. ]   The binding of chemical signals to receptors activates enzymatic processes within the cell membrane that ultimately  result in a cellular response, such as the phosphorylation of intracellular proteins or changes in the conductivity of  ion channels. A neurotransmitter can be thought of as a signal and a receptor as a signal detector and transducer.  Second-messenger molecules, produced in response to neurotransmitter binding to a receptor, translate the  extracellular signal into a response that may be further propagated or amplified within the cell. Each component  serves as a link in the communication between extracellular events and chemical changes within the cell (see  Chapter 2).   Neurotransmitter receptors are membrane proteins that provide a binding site that recognizes and responds to  neurotransmitter molecules. Some receptors, such as the postsynaptic receptors of nerve or muscle, are directly  linked to membrane ion channels; thus, binding of the neurotransmitter occurs rapidly (within fractions of a  millisecond) and directly affects ion permeability (Figure 3.7A). [Note: The effect of acetylcholine on these  chemically gated ion channels is discussed on p. 27. ]   Many receptors are not directly coupled to ion gates. Rather, the receptor signals its recognition of a bound  neurotransmitter by initiating a series of reactions, which ultimately results in a specific intracellular response.  Second-messenger moleculesa€"so named because they intervene between the original message (the    neurotransmitter or hormone) and the ultimate effect on the cella€"are part of the cascade of events that  translates neurotransmitter binding into a cellular response, usually through the intervention of a G protein. The  two most widely recognized   second messengers are the adenylyl cyclase system and the calcium/ phosphatidylinositol system (Figure 3. 7B and C).  [Note: G s is the protein involved in the activation of adenylyl cyclase, and G q is the subunit that activates  phospholipase C to release diacylglycerol and inositol trisphosphate (see p. 27).]   3.1 Which one of the following statements concerning the parasympathetic nervous system is correct?   B. The parasympathetic system often discharges as a single, functional system.   C. The parasympathetic division is involved in accommodation of near vision, movement of food, and  urination.   D. The postganglionic fibers of the parasympathetic division are long compared to those of the sympathetic  nervous system.   E. The parasympathetic system controls the secretion of the adrenal medulla.   3. 2 Which one of the following is characteristic of parasympathetic stimulation?   C. Contraction of sphincter muscle in the iris of the eye (miosis).   3.3 Which of the following is characteristic of the sympathetic nervous system.   > Table of Contents > Unit II - Drugs Affecting theAutonomic Nervous System > Chapter 4 - Cholinergic Agonists   Drugs affecting the autonomic nervous system are divided into two groups according to the type of neuron involved  in their mechanism of action. The cholinergic drugs, which are described in this and the following chapter, act on  receptors that are activated by acetylcholine. The second groupa€"the adrenergic drugs (discussed in Chapters 6  and 7)a€"act on receptors that are stimulated by norepinephrine or epinephrine. Cholinergic and adrenergic drugs  both act by either stimulating or blocking receptors of the autonomic nervous system. Figure 4. 1 summarizes the  cholinergic agonists discussed in this chapter.   The preganglionic fibers terminating in the adrenal medulla, the autonomic ganglia (both parasympathetic and  sympathetic), and the postganglionic fibers of the parasympathetic division use acetylcholine as a neurotransmitter  (Figure 4.2). In addition, cholinergic neurons innervate the muscles of the somatic system and also play an  important role in the central nervous system (CNS). [Note: Patients with Alzheimer's disease have a significant loss  of cholinergic neurons in the temporal lobe and entorhinal cortex. Most of the drugs available to treat the disease  are acetylcholinesterase inhibitors (see p. 102).]   Neurotransmission in cholinergic neurons involves sequential six steps. The first foura€"synthesis, storage, release,  and binding of acetylcholine to a receptora€"are followed by the fifth step, degradation of the neurotransmitter in  the synaptic gap (that is, the space between the nerve endings and adj acent receptors located on nerves or    effector organs), and the sixth step, the recycling of choline (Figure 4.3).   1. Synthesis of acetylcholine: Choline is transported from the extra-cellular fluid into the cytoplasm of the  cholinergic neuron by an energy-dependent carrier system that cotransports sodium and that can be inhibited by  the drug hemicholinium. [Note: Choline has a quaternary nitrogen and carries a permanent positive charge, and  thus, cannot diffuse through the membrane.] The uptake of choline is the rate-limiting step in acetylcholine  synthesis. Choline acetyltransferase catalyzes the reaction of choline with acetyl coenzyme A (CoA) to form  acetylcholinea€"an estera€"in the cytosol. Acetyl CoA is derived from the mitochondria and is produced by the  Krebs cycle and fatty acid oxidation.   2. Storage of acetylcholine in vesicles: The acetylcholine is packaged into presynaptic vesicles by an active  transport process coupled to the efflux of protons. The mature vesicle contains not only acetylcholine but also  adenosine triphosphate (ATP) and proteoglycan. [Note: ATP has been suggested to be a cotransmitter acting at  prejunctional purinergic receptors to inhibit the release of acetylcholine or norepinephrine.] Cotransmission  from autonomic neurons is the rule rather than the exception. This means that most synaptic vesicles will  contain the primary neurotransmitter, here acetylcholine, as well as a cotransmitter that will increase or  decrease the effect of the primary neurotransmitter. The neurotransmitters in vesicles will appear as bead-like  structures, known as varicosities, along the nerve terminal of the presynaptic neuron.   3. Release of acetylcholine: When an action potential propagated by the action of voltage-sensitive sodium  channels arrives at a nerve ending, voltage-sensitive calcium channels on the presynaptic membrane open,  causing an increase in the concentration of intracellular calcium. Elevated calcium levels promote the fusion of  synaptic vesicles with the cell membrane and release of their contents into the synaptic space. This release can  be blocked by botulinum toxin. In   contrast, the toxin in black widow spider venom causes all the acetylcholine stored in synaptic vesicles to empty  into the synaptic gap.   4. Binding to the receptor: Acetylcholine released from the synaptic vesicles diffuses across the synaptic space,  and it binds to either of two postsynaptic receptors on the target cell or to presynaptic receptors in the  membrane of the neuron that released the acetylcholine. The postsynaptic cholinergic receptors on the surface  of the effector organs are divided into two classesaC" muscarinic and nicotinic, (see Figure 4.2 and p. 46).   Binding to a receptor leads to a biologic response within the cell, such as the initiation of a nerve impulse in a  postganglionic fiber or activation of specific enzymes in effector cells as mediated by second-messenger  molecules (see p. 27 and below).   5. Degradation of acetylcholine: The signal at the postj unctional effector site is rapidly terminated, because  acetylcholinesterase cleaves acetylcholine to choline and acetate in the synaptic cleft (see Figure 4.3). [Note:  Butyrylcholinesterase, sometimes called pseudocholinesterase,   is found in the plasma, but it does not play a significant role in termination of acetylcholine's effect in the  synapse.]   Acetylcholine is rapidly  hydrolyzed by acetyl-  cholinesterase in the  synaptic cleft.    Figure 4.3 Synthesis and release of acetylcholine from the cholinergic neuron. AcCoA =acetyl coenzyme A.    6. Recycling of choline: Choline may be recaptured by a sodium-coupled, high-affinity uptake system that  transports the molecule back into the neuron, where it is acetylated into acetylcholine that is stored until  released by a subsequent action potential.   Two families of cholinoceptors, designated muscarinic and nicotinic receptors, can be distinguished from each other  on the basis of their different affinities for agents that mimic the action of acetylcholine (cholinomimetic agents or  parasympathomimetics).   These receptors, in addition to binding acetylcholine, also recognize muscarine, an alkaloid that is present in  certain poisonous mushrooms. By contrast, the muscarinic receptors show only a weak affinity for nicotine (Figure  4.4A). Binding studies and specific inhibitors, as well as cDNA characterization, have distinguished five subclasses of  muscarinic receptors: Mi, M 2 , M 3 , M 4 , and M 5 . Although five muscarinic receptors have been identified by gene  cloning, only Mi, M 2 and M 3 , receptors have been functionally characterized.   1. Locations of muscarinic receptors: These receptors have been found on ganglia of the peripheral nervous  system and on the autonomic effector organs, such as the heart, smooth muscle, brain, and exocrine glands (see  Figure 3. 3, p. 37). Specifically, although all five subtypes have been found on neurons, Mi receptors are also  found on gastric parietal cells, M 2 receptors on cardiac cells and smooth muscle, and M 3 receptors on the  bladder, exocrine glands, and smooth muscle. [Note: Drugs with muscarinic actions preferentially stimulate  muscarinic receptors on these tissues, but at high concentration they may show some activity at nicotinic  receptors.]   2. Mechanisms of acetylcholine signal transduction: A number of different molecular mechanisms transmit the  signal generated by acetylcholine occupation of the receptor. For example, when the Mi or M 3 receptors are  activated, the receptor undergoes a conformational change and interacts with a G protein, designated G q ,  which in turn activates phospholipase C . 1 This leads to the hydrolysis of   phosphatidyl i nositol- (4, 5)- bisphosphate- P 2 to yield diacylglycerol and inositol (1,4, 5) -trisphosphate (formerly   called inositol (1, 4, 5)-triphosphate), which cause an increase in intracellular Ca 2+ (see Figure 3.7C, p. 41). This  cation can then interact to stimulate or inhibit enzymes, or cause hyperpolarization, secretion, or contraction.   In contrast, activation of the M2 subtype on the cardiac muscle stimulates a G protein, designated Gj, that  inhibits adenylyl cyclase 2 and increases K + conductance (see Figure 3.7B, p. 41), to which the heart responds  with a decrease in rate and force of contraction.   3. Muscarinic agonists and antagonists: Attempts are currently underway to develop muscarinic agonists and  antagonists that are directed against specific receptor subtypes. For example, pirenzepine, a tricyclic  anticholinergic drug, has a greater selectivity for inhibiting Mi muscarinic receptors, such as in the gastric  mucosa. At therapeutic doses, pirenzepine does not cause many of the side effects seen with the non-subtype-  specific drugs; however, it does produce a reflex tachycardia on rapid infusion due to blockade of M 2 receptors  in the heart. Therefore, the usefulness of pirenzepine as an alternative to proton pump inhibitors in the  treatment of gastric and duodenal ulcers is questionable. Darifenacin is a competitive muscarinic receptor  antagonist with a greater affinity for the M 3 receptor than for the other muscarinic receptors. The drug is used  in the treatment of overactive bladder. [Note: At present, no clinically important agents interact solely with the  M 4 and M 5 receptors.]    4. Nicotinic receptors: These receptors, in addition to binding acetylcholine, also recognize nicotine but show  only a weak affinity for muscarine (see Figure 4.4B). The nicotinic receptor is composed of five subunits, and it  functions as a ligand-gated ion channel (see Figure 3.7A). Binding of two acetylcholine molecules elicits a  conformational change that allows the entry of sodium ions, resulting in the depolarization of the effector cell.  Nicotine (or acetylcholine) initially stimulates and then blocks the receptor. Nicotinic receptors are located in  the CNS, adrenal medulla, autonomic ganglia, and the neuromuscular j unction. Those at the neuromuscular  j unction are sometimes designated Nm and the others Nn. The nicotinic receptors of autonomic ganglia differ  from those of the neuromuscular j unction. For example, ganglionic receptors are selectively blocked by  hexamethonium, whereas neuromuscular j unction receptors are specifically blocked by tubocurarine.   Cholinergic agonists (also known as parasympathomimetics) mimic the effects of acetylcholine by binding directly to  cholinoceptors. These agents may be broadly classified into two groups: choline esters, which include acetylcholine  and synthetic esters of choline, such as carbachol and bethanechol . Naturally occurring alkaloids, such as  pilocarpine constitue the second group (Figure 4. 5). All of the direct-acting cholinergic drugs have longer durations  of action than acetylcholine. Some of the more therapeutically useful drugs ( pilocarpine and bethanechol )  preferentially bind to muscarinic receptors and are sometimes referred to as muscarinic agents. [Note: Muscarinic  receptors are located primarily, but not exclusively, at the neuroeffector j unction of the parasympathetic nervous  system.] Flowever, as a group, the direct-acting agonists show little specificity in their actions, which limits their  clinical usefulness.   Acetylcholine [a-se-teel-KOE-leen] is a quaternary ammonium compound that cannot penetrate membranes.   Although it is the neurotransmitter of parasympathetic and somatic nerves as well as autonomic ganglia, it is  therapeutically of no importance because of its multiplicity of actions and its rapid inactivation by the  cholinesterases. Acetylcholine has both muscarinic and nicotinic activity. Its actions include:   1. Decrease in heart rate and cardiac output: The actions of acetylcholine on the heart mimic the effects of  vagal stimulation. For example, acetylcholine, if injected intravenously, produces a brief decrease in cardiac  rate (negative chronotropy) and stroke volume as a result of a reduction in the rate of firing at the sinoatrial  (SA) node. [Note: It should be remembered that normal vagal activity regulates the heart by the release of  acetylcholine at the SA node.]    2. Decrease in blood pressure: Inj ection of acetylcholine causes vasodilation and lowering of blood pressure by an  indirect mechanism of action. Acetylcholine activates M 3 receptors found on endothelial cells lining the smooth  muscles of blood vessels. This results in the production of nitric oxide from arginine . 3 [Note: nitric oxide is also  known as endothelium-derived relaxing factor.] (See p. 341 for more detail on nitric oxide. ) Nitric oxide then  diffuses to vascular smooth muscle cells to stimulate protein kinase G production, leading to hyperpolarization  and smooth muscle relaxation. In the absence of administered cholinergic agents, the vascular receptors have  no known function, because acetylcholine is never released into the blood in any significant quantities.   Atropine blocks these muscarinic receptors and prevents acetylcholine from producing vasodilation.   3. Other actions: In the gastrointestinal tract, acetylcholine increases salivary secretion and stimulates intestinal  secretions and motility, Bronchiolar secretions are also enhanced. In the genitourinary tract, the tone of the  detrusor urinae muscle is increased, causing expulsion of urine. In the eye, acetylcholine is involved in  stimulating ciliary muscle contraction for near vision and in the constriction of the pupillae sphincter muscle,  causing miosis (marked constriction of the pupil). Acetylcholine (l%solution) is instilled into the anterior   Bethanechol [be-THAN-e-kole] is structurally related to acetylcholine, in which the acetate is replaced by  carbamate and the choline is methylated (see Figure 4. 5). Hence, it is not hydrolyzed by acetylcholinesterase (due  to the addition of carbonic acid), although it is inactivated through hydrolysis by other esterases. It lacks nicotinic  actions (due to the addition of the methyl group) but does have strong muscarinic activity. Its major actions are on  the smooth musculature of the bladder and gastrointestinal tract. It has a duration of action of about 1 hour.   1. Actions: Bethanechol directly stimulates muscarinic receptors, causing increased intestinal motility and tone. It  also stimulates the detrusor muscles of the bladder whereas the trigone and sphincter are relaxed, causing  expulsion of urine.   2. Therapeutic applications: In urologic treatment, bethanechol is used to stimulate the atonic bladder,  particularly in postpartum or postoperative, nonobstructive urinary retention. Bethanechol may also be used to  treat neurogenic atony as well as megacolon.   3. Adverse effects: Bethanechol causes the effects of generalized cholinergic stimulation (Figure 4.6). These  include sweating, salivation, flushing, decreased blood pressure, nausea, abdominal pain, diarrhea, and  bronchospasm.   Carbachol [KAR-ba-kole] has both muscarinic as well as nicotinic actions (lacks a methyl group present in  bethanechol; see Figure 4.5). Like bethanechol, carbachol is an ester of carbamic acid and a poor substrate for  acetylcholinesterase (see Figure 4.5). It is biotransformed by other esterases, but at a much slower rate. A single  administration can last as long as 1 hour.   1. Actions: Carbachol has profound effects on both the cardiovascular system and the gastrointestinal system  because of its ganglion-stimulating activity, and it may first stimulate and then depress these systems. It can  cause release of epinephrine from the adrenal medulla by its nicotinic action. Locally instilled into the eye, it  mimics the effects of acetylcholine, causing miosis and a spasm of accommodation in which the ciliary muscle of  the eye remains in a constant state of contraction   2. Therapeutic uses: Because of its high potency, receptor nonselectivity, and relatively long duration of action,  carbachol is rarely used therapeutically except in the eye as a miotic agent to treat glaucoma by causing  pupillary contraction and a decrease in intraocular pressure.   3. Adverse effects: At doses used ophthal mol ogi cal ly, little or no side effects occur due to lack of systemic  penetration (quaternary amine).   The alkaloid pilocarpine [pye-loe-KAR-peen] is a tertiary amine and is stable to hydrolysis by acetylcholinesterase  (see Figure 4. 5). Compared with acetylcholine and its derivatives, it is far less potent, but it is uncharged and will  penetrate the CNS at therapeutic doses. Pilocarpine exhibits muscarinic activity and is used primarily in  ophthalmology.   Figure 4.7 Actions of pilocarpine and atropine on the iris and ciliary muscle of the eye.    1. Actions: Applied topically to the cornea, pilocarpine produces a rapid miosis and contraction of the ciliary  muscle. The eye undergoes miosis and a spasm of accommodation; the vision is fixed at some particular distance,  making it impossible to focus (Figure 4.7). [Note the opposing effects of atropine, a muscarinic blocker, on the  eye (see p. 57).] Pilocarpine is one of the most potent stimulators of secretions (secretagogue) such as sweat,  tears, and saliva, but its use for producing these effects has been limited due to its lack of selectivity. The drug  is beneficial in promoting salivation in patients with xerostomia resulting from irradiation of the head and neck.   Sj AUgren's syndrome, which is characterized by dry mouth and lack of tears, is treated with oral pilocarpi me  tablets and cevimeline, a cholinergic drug that also has the drawback of being nonspecific.   2. Therapeutic use in glaucoma: Pilocarpine is the drug of choice in the emergency lowering of intraocular  pressure of both narrow-angle (also called closed-angle) and wide-angle (also called open-angle) glaucoma.  Pilocarpine is extremely effective in opening the trabecular meshwork around Schlemm's canal, causing an  immediate drop   in intraocular pressure as a result of the increased drainage of aqueous humor. This action lasts up to 8 hours  and can be repeated. The organophosphate echothiophate inhibits acetylcholinesterase and exerts the same  effect for a longer duration. [Note: Carbonic anhydrase inhibitors, such as acetazolamide, as well as the  i 2 -adrenergic blocker timolol, are effective in treating glaucoma chronically but are not used for emergency  lowering of intraocular pressure.]   3. Adverse effects: Pilocarpine can enter the brain and cause CNS disturbances. It stimulates profuse sweating and  salivation.   Acetylcholinesterase is an enzyme that specifically cleaves acetylcholine to acetate and choline and, thus,  terminates its actions. It is located both pre- and postsynapt ical ly in the nerve terminal, where it is membrane  bound. Inhibitors of acetylcholinesterase indirectly provide a cholinergic action by prolonging the lifetime of  acetylcholine produced endogenously at the cholinergic nerve endings. This results in the accumulation of  acetylcholine in the synaptic space (Figure 4.8). These drugs can thus provoke a response at all cholinoceptors in  the body, including both muscarinic and nicotinic receptors of the autonomic nervous system, as well as at  neuromuscular j unctions and in the brain.   Physostigmine [fi-zoe-STIG-meen] is a nitrogenous carbamic acid ester found naturally in plants and is a tertiary  amine. It is a substrate for acetylcholinesterase, and it forms a relatively stable carbamoylated intermediate with  the enzyme, which then becomes reversibly inactivated. The result is potentiation of cholinergic activity  throughout the body.   1. Actions: Physostigmine has a wide range of effects as a result of its action, and not only the muscarinic and  nicotinic sites of the autonomic nervous system but also the nicotinic receptors of the neuromuscular j unction  are stimulated. Its duration of action is about 2 to 4 hours, and it is considered to be an intermediate-acting  agent. Physostigmine can enter and stimulate the cholinergic sites in the CNS.   2. Therapeutic uses: The drug increases intestinal and bladder motility, which serve as its therapeutic action in  atony of either organ (Figure 4.9). Placed topically in the eye, it produces miosis and spasm of accommodation,  as well as a lowering of intraocular pressure. It is used to treat glaucoma, but pilocarpine is more effective.  Physostigmine is also used in the treatment of overdoses of drugs with anticholinergic actions, such as atropine,    3. Adverse effects: The effects of physostigmine on the CNS may lead to convulsions when high doses are used.  Bradycardia and a fall in cardiac output may also occur. Inhibition of acetylcholinesterase at the skeletal  neuromuscular j unction causes the accumulation of acetylcholine and, ultimately, results in paralysis of skeletal  muscle. However, these effects are rarely seen with therapeutic doses.   Neostigmine [nee-oh-STIG-meen] is a synthetic compound that is also a carbamic acid ester, and it reversibly  inhibits acetylcholinesterase in a manner similar to that of physostigmine. Unlike physostigmine, neostigmine has a  quaternary nitrogen; hence, it is more polar and does not enter the CNS. Its effect on skeletal muscle is greater  than that of physostigmine, and it can stimulate contractility before it paralyzes. Neostigmine has a moderate  duration of action, usually 30 minutes to 2 hours. It is used to stimulate the bladder and Gl tract, and it is also used  as an antidote for tubocurarine and other competitive neuromuscular blocking agents (see p. 60). Neostigmine has  found use in symptomatic treatment of myasthenia gravis, an autoimmune disease caused by antibodies to the  nicotinic receptor at neuromuscular j unctions. This causes their degradation and, thus, makes fewer receptors  available for interaction with the neurotransmitter. Adverse effects of neostigmine include those of generalized  cholinergic stimulation, such as salivation, flushing, decreased blood pressure, nausea, abdominal pain, diarrhea,  and bronchospasm. Neostigmine does not cause CNS side effects and is not used to overcome toxicity of central-  acting antimuscarinic agents such as atropine.   Pyridostigmine [peer-id-oh-STIG-meen] and ambenomium [am-be-NOE-mee-um] are other cholinesterase inhibitors  that are used in the chronic management of myasthenia gravis. Their durations of action are intermediate (3 to 6  hours and 4 to 8 hours, respectively), but longer than that of neostigmine. Adverse effects of these agents are  similar to those of neostigmine.   Demecarium [dem-e-KARE-ee-um] is another cholinesterase inhibitor used to treat chronic open-angle glaucoma  (primarily in patients refractory to other agents) closed-angle glaucoma after irredectomy. It is also used for the  diagnosis and treatment of accommodative esotropia. Demecarium is a quaternary amine that is structurally related  to neostigmine. Mechanisms of actions and side effects are similar to those of neostigmine.   The actions of edrophonium [ed-row-FOE-nee-um] are similar to those of neostigmine, except that it is more  rapidly absorbed and has a short duration of action of 10 to 20 minutes (prototype short-acting agent).   Edrophonium is a quaternary amine and is used in the diagnosis of myasthenia gravis. Intravenous inj ection of  edrophonium leads to a rapid increase in muscle strength. Care must be taken, because excess drug may provoke a  cholinergic crisis. Atropine is the antidote.   As mentioned above, patients with Alzheimer's disease have a deficiency of cholinergic neurons in the CNS. This  observation led to the development of anticholinesterases as possible remedies for the loss of cognitive function.   Tacrine [TAK-reen] was the first to become available, but it has been replaced by the others because of its  hepatotoxicity. Despite the ability of donepezil [doe-NEP-e-zil], rivastigmine [ri-va-STIG-meen], and   galantamine [gaa-LAN-ta-meen] to delay the progression of the disease, none can stop its progression.   A number of synthetic organophosphate compounds have the capacity to bind covalently to acetylcholinesterase.   The result is a long-lasting increase in acetylcholine at all sites where it is released. Many of these drugs are  extremely toxic and were developed by the military as nerve agents. Related compounds, such as parathion, are  employed as insecticides.   Figure 4.10 Covalent modification of acetylcholinesterase by echothiophate; also shown is the reactivation  of the enzyme with pralidoxime. R =(CH3)3N4-CH2-CH2-   1. Mechanism of action: Echothiophate [ek-oe-THI-oh-fate] is an organophosphate that covalently binds via its  phosphate group to the serine-OH group at the active site of acetylcholinesterase (Figure 4. 10). Once this  occurs, the enzyme is permanently inactivated, and restoration of acetylcholinesterase activity requires the  synthesis of new enzyme molecules. Following covalent modification of acetylcholinesterase, the  phosphorylated enzyme slowly releases one of its ethyl groups (see Figure 4. 10). The loss of an alkyl group,  which is called aging, makes it impossible for chemical reactivators, such as pralidoxime (see below), to break  the bond between the remaining drug and the enzyme.   2. Actions: Actions include generalized cholinergic stimulation, paralysis of motor function (causing breathing  difficulties), and convulsions. Echothiophate produces intense miosis and, thus, has found therapeutic use.  Atropine in high dosage can reverse many of the muscarinic and some of the central effects of echothiophate.   3. Therapeutic uses: An ophthalmic solution of the drug is used directly in the eye for the chronic treatment of  open-angle glaucoma. The effects may last for up to one week after a single administration. Echothiophate is  not a first-line agent in the treatment of glaucoma. In addition to its other side effects, the potential risk for  causing cataracts limits the use of echothiophate.   4. Reactivation of acetylcholinesterase: Pralidoxime can reactivate inhibited acetylcholinesterase. Flowever, it  is unable to penetrate into the CNS. The presence of a charged group allows it to approach an anionic site on  the enzyme, where it essentially displaces the phosphate group of the organophosphate and regenerates the  enzyme. If given before aging of the alkylated enzyme occurs, it can reverse the effects of echothiophate,  except for those in the CNS. With the newer nerve agents, which produce aging of the enzyme complex within  seconds, pralidoxime is less effective. Pralidoxime is a weak acetylcholinesterase inhibitor and, at higher  doses, may cause side effects similar to other acetylcholinsterase inhibitors (Figures 4.6 and 4.9).   A summary of the actions of some of the cholinergic agonists is presented in Figure 4.11.   These drugs bind preferentially  at muscarinic receptors; other drugs  act d irectly or indirectly at both  muscarinic and nicotinic receptors    These drugs are uncharged,  tertiary rsmines that  can penetrate the CNS    Topically to reduce intraocular pressure in open-  angle or narrow-angle glaucoma, particularly  In patients who have become tolerant to  pilocarpine    Although their benefit Is modest these cholin-  esterase Inhibitors remain first-line treatment for  Alzheimer’s disease. There Is no consistent evidence  to suggest treatment reduces health care costs or  prolongs time until institutionalization. When  Alzheimer's disease becomes moderate to severe.  memantine. • n N-methyl-D-aspartate antagonist  sometimes is added to therapy.   4.1 A patient with an acute attack of glaucoma is treated with pilocarpine. The primary reason for its  effectiveness in this condition is its:   C. Ability to inhibit secretions, such as tears, saliva, and sweat,   4.2 A soldier's unit has come under attack with a nerve agent. The symptoms exhibited are skeletal muscle  paralysis, profuse bronchial secretions, miosis, bradycardia, and convulsions. The alarm indicates exposure to  an organophosphate. What is the correct treatment?   A. Do nothing until you can confirm the nature of the nerve agent.   B. Administer atropine, and attempt to confirm the nature of the nerve agent.   4.3 A patient being diagnosed for myasthenia gravis would be expected to have improved neuromuscular  function after being treated with:   4.4 The drug of choice for treating decreased salivation accompanying head and neck irradiation is:   > Table of Contents > Unit II - Drugs Affecting theAutonomic Nervous System > Chapter 5 - Cholinergic Antagonists   The cholinergic antagonists (also called cholinergic blockers, parasympatholytics or anticholinergic drugs) bind to  cholinoceptors, but they do not trigger the usual receptor-mediated intracellular effects. The most useful of these  agents selectively block muscarinic synapses of the parasympathetic nerves. The effects of parasympathetic  innervation are thus interrupted, and the actions of sympathetic stimulation are left unopposed. A second group of  drugs, the ganglionic blockers, show a preference for the nicotinic receptors of the sympathetic and  parasympathetic ganglia. Clinically, they are the least important of the anticholinergic drugs. A third family of  compounds, the neuromuscular blocking agents, interfere with transmission of efferent impulses to skeletal  muscles. These agent are used as adj uvants in anesthesia during surgery. Figure 5. 1 summarizes the cholinergic  antagonists discussed in this chapter.   Commonly known as antimuscarinics, these agents (for example, atropine and scopolamine ) block muscarinic  receptors (Figure 5.2), causing inhibition of all muscarinic functions. In addition, these drugs block the few  exceptional sympathetic neurons that are cholinergic, such as those innervating salivary and sweat glands. In  contrast to the cholinergic agonists, which have limited usefulness therapeutically, the cholinergic blockers are  beneficial in a variety of clinical situations. Because they do not block nicotinic receptors, the antimuscarinic drugs  have little or no action at skeletal neuromuscular j unctions or autonomic ganglia. [Note: A number of antihistaminic  and antidepressant drugs also have antimuscarinic activity.]   Atropine [A-troe-peen], a tertiary amine belladonna alkaloid, has a high affinity for muscarinic receptors, where it    binds competitively, preventing acetylcholine from binding to those sites (Figure 5.3). Atropine acts both centrally  and peripherally. Its general actions last about 4 hours except when placed topically in the eye, where the action  may last for days.   a. Eye: Atropine blocks all cholinergic activity on the eye, resulting in persistent mydriasis (dilation of the  pupil, see Figure 4.6, p. 46), unresponsiveness to light, and cycloplegia (inability to focus for near vision). In  patients with narrow-angle glaucoma,   intraocular pressure may rise dangerously. Shorter-acting agents, such as the antimuscarinic tropicamide, or  an i±-adrenergic drug, like phenylephrine, are generally favored for producing mydriasis in ophthalmic  examinations.    b. Gastrointestinal (Gl): Atropine can be used as an antispasmodic to reduce activity of the Gl tract. Atropine  and scopolamine (which is discussed below) are probably the most potent drugs available that produce this  effect. Although gastric motility is reduced, hydrochloric acid production is not significantly affected. Thus,  the drug is not effective in promoting healing of peptic ulcer. [Note: Pirenzepine (see p. 47), an  Mi-muscarinic antagonist, does reduce gastric acid secretion at doses that do not antagonize other systems. ]   c. Urinary system: Atropine is also employed to reduce hypermotility states of the urinary bladder. It is still  occasionally used in enuresis (involuntary voiding of urine) among children, but i±-adrenergic agonists with   Figure 5.3 Competition of atropine and scopolamine with acetylcholine for the muscarinic receptor.    d. Cardiovascular: Atropine produces divergent effects on the cardiovascular system, depending on the dose  (Figure 5.4). At   low doses, the predominant effect is a decreased cardiac rate (bradycardia). Originally thought to be due to  central activation of vagal efferent outflow, the effect is now known to result from blockade of the Mi  receptors on the inhibitory prej unctional (or presynaptic) neurons, thus permitting increased acetylcholine  release. With higher doses of atropine, the M 2 receptors on the sinoatrial node are blocked, and the cardiac  rate increases modestly. This generally requires at least 1 mg of atropine, which is a higher dose than  ordinarily given. Arterial blood pressure is unaffected, but at toxic levels, atropine will dilate the cutaneous  vasculature.   e. Secretions: Atropine blocks the salivary glands, producing a drying effect on the oral mucous membranes  (xerostomia). The salivary glands are exquisitely sensitive to atropine. Sweat and lacrimal glands are also  affected. [Note: Inhibition of secretions by sweat glands can cause elevated body temperature. ]   Rapid heart rate;  palpitation; marked  dryness of the mouth;  dilation of pupil; some  blurring of near vision   a. Ophthalmic: In the eye, topical atropine exerts both mydriatic and cycloplegic effects, and it permits the  measurement of refractive errors without interference by the accommodative capacity of the eye. [Note:  Phenylephrine or similar i±-adrenergic drugs are preferred for pupillary dilation if cycloplegia is not  required. Also, individuals 40 years of age and older have decreased ability to accommodate, and drugs are  not necessary for an accurate refraction. ] Shorter-acting antimuscarinics (cyclopentolante and  tropicamide ) have largely replaced atropine due to prolonged mydriasis observed with atropine (7a€"14  days versus 6a€"24 hours with other agents). Atropine may induce an acute attack of eye pain due to sudden  increases in eye pressure in individuals with narrow-angle glaucoma.   b. Antispasmodic: Atropine is used as an antispasmodic agent to relax the Gl tract and bladder.   c. Antidote for cholinergic agonists: Atropine is used for the treatment of overdoses of cholinesterase  inhibitor insecticides and some types of mushroom poisoning (certain mushrooms contain cholinergic  substances that block cholinesterases). Massive doses of the antagonist may be required over a long period  of time to counteract the poisons. The ability of atropine to enter the central nervous system (CNS) is of  particular importance. The drug also blocks the effects of excess acetylcholine resulting from  acetylcholinesterase inhibitors, such as physostigmine.   d. Antisecretory: The drug is sometimes used as an antisecretory agent to block secretions in the upper and  lower respiratory tracts prior to surgery.   3. Pharmacokinetics: Atropine is readily absorbed, partially metabolized by the liver, and eliminated primarily in  the urine. It has a half-life of about 4 hours.   4. Adverse effects: Depending on the dose, atropine may cause dry mouth, blurred vision, a€oesandy eyes,a€§  tachycardia, and constipation.    Effects on the CNS include restlessness, confusion, hallucinations, and delirium, which may progress to  depression, collapse of the circulatory and respiratory systems, and death. Low doses of cholinesterase  inhibitors such as physostigmine may be used to overcome atropine toxicity. In older individuals, the use of  atropine to induce mydriasis and cycloplegia is considered to be too risky, because it may exacerbate an attack  of glaucoma in someone with a latent condition. In other older individuals, atropine may induce urinary  retention that is troublesome. Children are sensitive to effects of atropine a€"in particular, the rapid increases  in body temperature that it may elicit. This may be dangerous in children.    Scopolamine [skoe-POL-a-meen], another tertiary amine belladonna alkaloid, produces peripheral effects similar to  those of atropine. However, scopolamine has greater action on the CNS (unlike with atropine, CNS effects are  observed at therapeutic doses) and a longer duration of action in comparison to those of atropine. It has some  special actions as indicated below.   1. Actions: Scopolamine is one of the most effective antia€" motion sickness drugs available (Figure 5.5).  Scopolamine also has the unusual effect of blocking short-term memory. In contrast to atropine, scopolamine  produces sedation, but at higher doses it can produce excitement instead. Scopolamine may produce euphoria  and is subject to abuse.   2. Therapeutic uses: Although similar to atropine, therapeutic use of scopolamine is limited to prevention of  motion sickness (for which it is particularly effective) and to blocking short-term memory. [Note: As with all  such drugs used for motion sickness, it is much more effective prophyl act ical ly than for treating motion sickness  once it occurs. The amnesic action of scopolamine makes it an important adj unct drug in anesthetic  procedures.]   3. Pharmacokinetics and adverse effects: These aspects are similar to those of atropine.   Inhaled ipratropium [i-pra-TROE-pee-um], a quaternary derivative of atropine, is useful in treating asthma in  patients who are unable to take adrenergic agonists. Ipratropium is also beneficial in the management of chronic  obstructive pulmonary disease. It is inhaled for these conditions. Because of its positive charge, it does not enter  the systemic circulation or the CNS, isolating its effects to the pulmonary system. Important characteristics of the  muscarinic antagonists are summarized in Figures 5.6 and 5. 7.   These agents are used as ophthalmic solutions for similar conditions as atropine (mydriasis and cyclopegia). Their  duration of action is shorter than that of atropine ; tropicamide produces mydriasis for 6 hours and cyclopentolate  for 24 hours.   Ganglionic blockers specifically act on the nicotinic receptors of both parasympathetic and sympathetic autonomic  ganglia. Some also block the ion channels of the autonomic ganglia. These drugs show no selectivity toward the  parasympathetic or sympathetic ganglia and are not effective as neuromuscular antagonists. Thus, these drugs block   the entire output of the autonomic nervous system at the nicotinic receptor. Except for nicotine, the other drugs  mentioned in this category are nondepolarizing, competitive antagonists. The responses observed are complex and  unpredictable, making it impossible to achieve selective actions. Therefore, ganglionic blockade is rarely used  therapeutically. However, ganglionic blockers often serve as tools in experimental pharmacology.   To treat spastic disorders of the Gl  and lower urinary tract   A component of cigarette smoke, nicotine [NIC-oh-teen] is a poison with many undesirable actions. It is without  therapeutic benefit and is deleterious to health. [Note: Nicotine is available as patches, lozenges, gums, and other  forms. Patches are available for application to the skin. The drug is absorbed and is effective in reducing the craving  for nicotine in people who wish to stop smoking. ] Depending on the dose, nicotine depolarizes autonomic ganglia,  resulting first in stimulation and then in paralysis of all ganglia. The stimulatory effects are complex due to effects  on both sympathetic and parasympathetic ganglia. The effects include increased blood pressure and cardiac rate  (due to release of transmitter from adrenergic terminals and from the adrenal medulla) and increased peristalsis and  secretions. At higher doses, the blood pressure falls because of ganglionic blockade, and activity both in the Gl  tract and bladder musculature ceases. (See p. 118 for a full discussion of nicotine.)   Mecamylamine [mek-a-MILL-a-meen] produces a competitive nicotinic blockade of the ganglia. The duration of  action is about 10 hours after a single administration. The uptake of the drug via oral absorption is good, in contrast  to that of trimethaphan. As with trimethaphan, it is primarily used to lower blood pressure in emergency  situations.    These drugs block cholinergic transmission between motor nerve endings and the nicotinic receptors on the  neuromuscular end plate of skeletal muscle (see Figure 5.2). These neuromuscular blockers are structural analogs of  acetylcholine, and they act either as antagonists (nondepolarizing type) or agonists (depolarizing type) at the  receptors on the end plate of the neuromuscular j unction. Neuromuscular blockers are clinically useful during  surgery for producing complete muscle relaxation, without having to employ higher anesthetic doses to achieve  comparable muscular relaxation. Agents are also useful in facilitating intubation as well. A second group of muscle   relaxants, the central muscle relaxants, are used to control spastic muscle tone. These drugs include diazepam,  which binds at i 3 -aminobutyric acid (GABA) receptors; dantrolene, which acts directly on muscles by interfering  with the release of calcium from the sarcoplasmic reticulum; and baclofen, which probably acts at GABA receptors  in the CNS.   The first drug that was found to be capable of blocking the skeletal neuromuscular j unction was curare, which the  native hunters of the Amazon in South America used to paralyze game. The drug tubocurarine [too-boe-  kyoo-AR-een] was ultimately purified and introduced into clinical practice in the early 1940s. Although  tubocurarine is considered to be the prototype agent in this class, it has been largely replaced by other agents due  to side effects (see Figure 5. 10). The neuromuscular blocking agents have significantly increased the safety of  anesthesia, because less anesthetic is required to produce muscle relaxation, allowing patients to recover quickly  and completely after surgery. Note: Higher doses of anesthesia may produce respiratory paralysis and cardiac  depression, increasing recovery time after surgery. ]   a. At low doses; Nondepolarizing neuromuscular blocking drugs interact with the nicotinic receptors to prevent  the binding of acetylcholine (Figure 5.8). These drugs thus prevent depolarization of the muscle cell  membrane and inhibit muscular contraction. Because these agents compete with acetylcholine at the  receptor without stimulating the receptor, they are called competitive blockers. Their action can be  overcome by increasing the concentration of acetylcholine in the synaptic gapa€"for example, by  administration of cholinesterase inhibitors, such as neostigmine, pyridostigmine, or edrophonium.  Anesthesiologists often employ this strategy to shorten the duration of the neuromuscular blockade.    b. At high doses; Nondepolarizing blockers can block the ion channels of the end plate. This leads to further    weakening of neuromuscular transmission, and it reduces the ability of acetylcholinesterase inhibitors to  reverse the actions of nondepolarizing muscle relaxants.   2. Actions: Not all muscles are equally sensitive to blockade by competitive blockers. Small, rapidly contracting  muscles of the face and eye are most susceptible and are paralyzed first, followed by the fingers. Thereafter,  the limbs, neck, and trunk muscles are paralyzed. Then the intercostal muscles are affected, and lastly, the  diaphragm muscles are paralyzed. Those agents (for example, t ubocurarine, mivacurium, and atracurium),  which release histamine, can produce a fall in blood pressure, flushing, and bronchoconstriction.   3. Therapeutic uses: These blockers are used therapeutically as adj uvant drugs in anesthesia during surgery to  relax skeletal muscle. These agents are also used to facilitate intubation as well as during orthopedic surgery.   4. Pharmacokinetics: All neuromuscular blocking agents are inj ected intravenously, because their uptake via oral  absorption is minimal.   These agents possess two or more quaternary amines in their bulky ring structure, making them orally  ineffective. They penetrate membranes very poorly and do not enter cells or cross the blood-brain barrier.   Many of the drugs are not metabolized; their actions are terminated by redistribution (Figure 5.9). For example,  tubocurarine, pancuronium, mivacurium, metocurine, and doxacurium are excreted in the urine unchanged.  Atracurium is degraded spontaneously in the plasma and by ester hydrolysis. [Note: Atracurium has been  replaced by its isomer, cisatracurium. Atracurium releases histamine and is metabolized to laudanosine, which  can provoke seizures. Cisatracurium, which has the same pharmacokinetic properties as atracurium, is less  likely to have these effects.] The aminosteroid drugs ( vecuronium and rocuronium ) are deacetylated in the  liver, and their clearance may be prolonged in patients with hepatic disease. These drugs are also excreted  unchanged in the bile. The choice of an agent will depend on how quickly muscle relaxation is needed and on  the duration of the muscle relaxation. The onset and duration of action as well as other characteristics of the  neuromuscular blocking drugs are shown in Figure 5. 10.   5. Adverse effects: In general, agents are safe with minimal side effects. The adverse effects of the specific  neuromuscular blocking drugs are shown in Figure 5. 10.    a. Cholinesterase inhibitors: Drugs such as neostigmine, physostigmine, pyridostigmine, and edrophonium  can overcome the action of nondepolarizing neuromuscular blockers, but with increased dosage,  cholinesterase inhibitors can cause a depolarizing block as a result of elevated acetylcholine concentrations  at the end-plate membrane. If the neuromuscular blocker has entered the ion channel, cholinesterase  inhibitors are not as effective in overcoming blockade.   b. Halogenated hydrocarbon anesthetics: Drugs such as halothane act to enhance neuromuscular blockade by  exerting a stabilizing action at the neuromuscular j unction. These agents sensitize the neuromusclular   c. Aminoglycoside antibiotics: Drugs such as gentamicin or tobramycin inhibit acetylcholine release from  cholinergic nerves by competing with calcium ions. They synergize with tubocurarine and other competitive  blockers, enhancing the blockade.   d. Calcium-channel blockers: These agents may increase the neuromuscular block of tubocurarine and other  competitive blockers as well as depolarizing blockers.   1. Mechanism of action: The depolarizing neuromuscular blocking drug sued nyl choline [ suk-si n- i 1 1- KOE- leen]  attaches to the nicotinic receptor and acts like acetylcholine to depolarize the j unction (Figure 5. 11). Unlike  acetylcholine, which is instantly destroyed by acetylcholinesterase, the depolarizing agent persists at high  concentrations in the synaptic cleft, remaining attached to the receptor for a relatively   longer time and providing a constant stimulation of the receptor. [Note: The duration of action of   sued nyl choline is dependent on diffusion from the motor end plate and hydrolysis by plasma cholinesterase.]   The depolarizing agent first causes the opening of the sodium channel associated with the nicotinic receptors,  which results in depolarization of the receptor (Phase I). This leads to a transient twitching of the muscle  (fasciculations). Continued binding of the depolarizing agent renders the receptor incapable of transmitting  further impulses. With time, continuous depolarization gives way to gradual repolarization as the sodium  channel closes or is blocked. This causes a resistance to depolarization (Phase II) and a flaccid paralysis.    Tubocurarin t may induct  histamine rtltast and  promote ganglionic blockade.  The drug can also lower  blood pressure. Because of  these side effects, tubo-  curarin e is rarely used as a  therapeutic agent.   Mivacurium has an onset of action  similar to that of cisatracurium, but  recovery from blockade is more  rapid, making mivacurium useful  for short surgical procedures.    CJsatrocurium spontaneously  degrades in plasma and is the  only nondepolarizing neuro-  muscular blocking drug whose  dose need not be reduced in  patients with renal failure.   Rapid onset of action makes  rocuronium useful for tracheal  intubation in patients with  gastric contents.    Postoperative muscle pain is  common; hyperkalemia and  increased intraocular and  intragastric pressure may  occur. Drug may trigger  malignant hyperthermia.    Figure 5.10 Onset and duration of action of neuromuscular blocking drugs (center column), with a summary of  therapeutic considerations.    2. Actions: The sequence of paralysis may be slightly different, but as with the competitive blockers, the  respiratory muscles are paralyzed last. Succinyl choline initially produces short-lasting muscle fasciculations,  followed within a few minutes by paralysis. The drug does not produce a ganglionic block except at high doses,  but it does have weak histamine-releasing action. Normally, the duration of action of succinyl choline is  extremely short, because this drug is rapidly broken down by plasma cholinesterase. However, succinyl choline    that gets to the neuromusclular j unction is not metabolized by acetylcholinesterase, allowing the agent to bind  to nicotinic receptors, and redistribution to plasma is necessary for metabolism (therapeutic benefits last only  for a few minutes). [Note: Genetic variants in which plasma cholinesterase levels are low or absent leads to  prolonged neuromuscular paralysis.]   3. Therapeutic uses: Because of its rapid onset and short duration of action, sued nyl choline is useful when rapid  endotracheal intubation is required during the induction of anesthesia (a rapid action is essential if aspiration of  gastric contents is to be avoided during intubation). It is also employed during electroconvulsive shock  treatment.   4. Pharmacokinetics: Sued nyl choline is injected intravenously. Its brief duration of action (several minutes)  results from redistribution and rapid hydrolysis by plasma cholinesterase. It therefore is usually given by  continuous infusion.   Membrane depolarizes, resulting  in an initial discharge that  produces transient fasciculations  followed by flaccid paralysis.   Membrane repolarizes, but  receptor is desensitized  to the effect of acetylcholine.    a. Hyperthermia: When halothane (see p. 133) is used as an anesthetic, administration of sued nyl choline has  occasionally caused malignant hyperthermia (with muscular rigidity and hyperpyrexia) in genetically  susceptible people (see Figure 5. 10). This is treated by rapidly cooling the patient and by administration of  dantrolene, which blocks release of Ca 2+ from the sarcoplasmic reticulum of muscle cells, thus reducing  heat production and relaxing muscle tone.   b. Apnea: Administration of sued nyl choline to a patient who is genetically deficient in plasma cholinesterase  or has an atypical form of the enzyme can lead to prolonged apnea due to paralysis of the diaphragm.   c. Hyperkalemia: Sued nyl choline increases potassium release from intracellular stores. This may be  particularly dangerous in burn patients or patients with massive tissue damage in which postassium is been  rapidly lost from within cells.   5.1 A 75-year-old man who was a smoker is diagnosed with chronic obstructive pulmonary disease and suffers  from occasional bronchospasm. Which of the following would be effective in treating him?   5.2 Which of the following may precipitate an attack of open-angle glaucoma if instilled into the eye?   5.3 The prolonged apnea sometimes seen in patients who have undergone an operation in which  succinylcholine was employed as a muscle relaxant has been shown to be due to:   D. A mutation in the nicotinic receptor at the neuromuscular j unction.   5.4 A 50-year-old male farm worker is brought to the emergency room. He was found confused in the orchard  and since then has lost consciousness. His heart rate is 45, and his blood pressure is 80/40 mm Hg. He is  sweating and salivating profusely. Which of the following treatments is indicated?   > Table of Contents > Unit II - Drugs Affecting theAutonomic Nervous System > Chapter 6 - Adrenergic Agonists   The adrenergic drugs affect receptors that are stimulated by norepinephrine or epinephrine. Some adrenergic drugs  act directly on the adrenergic receptor (adrenoceptor) by activating it and are said to be sympathomimetic. Others,  which will be dealt with in Chapter 7, block the action of the neurotransmitters at the receptors (sympatholytics),  whereas still other drugs affect adrenergic function by interrupting the release of norepinephrine from adrenergic  neurons. This chapter describes agents that either directly or indirectly stimulate adrenoceptors (Figure 6.1).    Figure 6.1 Summary of adrenergic agonists. Agents marked with an asterisk  are catecholamines.   Adrenergic neurons release norepinephrine as the primary neurotransmitter. These neurons are found in the central  nervous system (CNS) and also in the sympathetic nervous system, where they serve as links between ganglia and  the effector organs. The adrenergic neurons and receptors, located either presynaptically on the neuron or  postsynaptically on the effector organ, are the sites of action of the adrenergic drugs (Figure 6.2).   Neurotransmission in adrenergic neurons closely resembles that already described for the cholinergic neurons (see  p. 43), except that norepinephrine is the neurotransmitter instead of acetylcholine, Neurotransmission takes place    at numerous bead-like enlargements called varicosities. The process involves five steps: synthesis, storage, release,  and receptor binding of norepinephrine, followed by removal of the neurotransmitter from the synaptic gap (Figure  6.3).   1. Synthesis of norepinephrine: Tyrosine is transported by a Na + - 1 i nked carrier into the axoplasm of the  adrenergic neuron, where it is hydroxylated to dihydroxyphenylalanine (DOPA) by tyrosine hydroxylase. 1 This is  the rate-limiting step in the formation of norepinephrine. DOPA is then decarboxylated by the enzyme dopa  decarboxylase (aromatic l-amino acid decarboxylase) to form dopamine in the cytoplasm of the presynaptic  neuron.   2. Storage of norepinephrine in vesicles: Dopamine is then trans-ported into synaptic vesicles by an amine  transporter system that is also involved in the reuptake of preformed norepinephrine. This carrier system is  blocked by reserpine (see p. 90). Dopamine is hydroxylated to form norepinephrine by the enzyme, dopamine  l 2 -hydroxylase. [Note: Synaptic vesicles contain dopamine or norepinephrine plus adenosine triphosphate  (ATP), and i 2 -hydroxylase, as well as other cotransmitters. ] In the adrenal medulla, norepinephrine is  methylated to yield epinephrine, both of which are stored in chromaffin cells. On stimulation, the adrenal  medulla releases about 80 percent epinephrine and 20 percent norepinephrine directly into the circulation.   3. Release of norepinephrine: An action potential arriving at the nerve j unction triggers an influx of calcium ions  from the extracellular fluid into the cytoplasm of the neuron. The increase in calcium causes vesicles inside the  neuron to fuse with the cell membrane and expel (exocytose) their contents into the synapse. This release is  blocked by drugs such as guanethi dine (see p. 91).   4. Binding to a receptor: Norepinephrine released from the synaptic vesicles diffuses across the synaptic space and  binds to either postsynaptic receptors on the effector organ or to presynaptic receptors on the nerve ending.    The recognition of norepinephrine by the membrane receptors triggers a cascade of events within the cell,  resulting in the formation of intracellular second messengers that act as links (transducers) in the  communication between the neurotransmitter and the action generated within the effector cell. Adrenergic  receptors use both the cyclic adenosine monophosphate (cAMP) second-messenger system, 2 and the  phosphatidylinositol cycle, 3 to transduce the signal into an effect.   5. Removal of norepinephrine: Norepinephrine may 1) diffuse out of the synaptic space and enter the general  circulation, 2) be metabolized to O-methylated derivatives by postsynaptic cell membranea€"associated  catechol O-methyltransferase (COMT) in the synaptic space, or 3) be recaptured by an uptake system that pumps  the norepinephrine back into the neuron. The uptake by the neuronal membrane involves a sodium/ potassium-  activated ATPase that can be inhibited by tricyclic antidepressants, such as imipramine, or by cocaine (see  Figure 6. 3). Uptake of norepinephrine into the presynaptic neuron is the primary mechanism for termination of  norepinephrine's effects.   6. Potential fates of recaptured norepinephrine: Once norepinephrine reenters the cytoplasm of the adrenergic  neuron, it may be taken up into adrenergic vesicles via the amine transporter system and be sequestered for  release by another action potential, or it may persist in a protected pool. Alternatively, norepinephrine can be  oxidized by monoamine oxidase (MAO) present in neuronal mitochondria. The inactive products of  norepinephrine metabolism are excreted in the urine as van i I lyl mandel i c acid, metanephrine, and  normetanephrine.   • Postsyrvaptic receptor  is activated by the  binding of neuro-  transmitter.    Figure 6.3 Synthesis and release of norepinephrine from the adrenergic neuron. (MAO =monoamine  oxidase.)   In the sympathetic nervous system, several classes of adrenoceptors can be distinguished pharmacologically. Two  families of receptors, designated i±and I 2 , were initially identified on the basis of their responses to the adrenergic  agonists epinephrine, norepinephrine, and isoproterenol . The use of specific blocking drugs and the cloning of  genes have revealed the molecular identities of a number of receptor subtypes. These proteins belong to a  multigene family. Alterations in the primary structure of the receptors influence their affinity for various agents.   1. i±i and i ±2 Receptors: The i±-adrenoceptors show a weak response to the synthetic agonist isoproterenol , but  they are responsive to the naturally occurring catecholamines epinephrine and norepinephrine (Figure 6.4). For   T± receptors, the rank order of potency is epinephrine a %<¥ norepinephrine »isoproterenol . The  i±-adrenoceptors are subdivided into two subgroups, I±l and i±2, based on their affinities for ilagonists and  blocking drugs. For example, the I±l receptors have a higher affinity for phenylephrine than do the i±2  receptors. Conversely, the drug clonidine selectively binds to i+2 receptors and has less effect on I±l receptors.    a. i±i Receptors: These receptors are present on the postsynaptic membrane of the effector organs and  mediate many of the classic effectsa€"originally designated asi±-adrenergica€”involving constriction of  smooth muscle. Activation of i±i receptors initiates a series of reactions through a G protein activation of  phospholipase C, resulting in the generation of inositol- 1 , 4 , 5 -trisphosphate (IP3) and diacylglycerol (DAG)   from phosphatidylinositol. IP3 initiates the release of Ca 2+ from the endoplasmic reticulum into the cytosol,  and DAG turns on other proteins within the cell (Figure 6. 5).   b. i ± 2 Receptors: These receptors, located primarily on presynaptic nerve endings and on other cells, such as  the i * 2 cell of the pancreas, and on certain vascular smooth muscle cells, control adrenergic neuromediator  and insulin output, respectively. When a sympathetic adrenergic nerve is stimulated, the released  norepinephrine traverses the synaptic cleft and interacts with the i±i receptors. A portion of the released  norepinephrine a€oecircles backa€§ and reacts with 1+2 receptors on the neuronal membrane (see Figure   6. 5). The stimulation of the T±2 receptor causes feedback inhibition of the ongoing release of norepinephrine  from the stimulated adrenergic neuron. This inhibitory action decreases further output from the adrenergic  neuron and serves as a local modulating mechanism for reducing sympathetic neuromediator output when  there is high sympathetic activity. [Note: In this instance these receptors are acting as inhibitory  autoreceptors.] T±2 Receptors are also found on presynpatic parasympathetic neurons. Norepinephrine  released from a presynaptic sympathetic neuron can diffuse to and interact with these receptors, inhibiting  acetylcholine release [Note: In these instances these receptors are behaving as inhibitory heteroreceptors. ]  This is another local modulating mechanism to control autonomic activity in a given area. In contrast to i±i  receptors, the effects of binding at T±2 receptors are mediated by inhibition of adenylyl cyclase and a fall in  the levels of intracellular cAMP.   c. Further subdivisions: The I±l and I ±2 receptors are further divided into I±la, 1±lb. I±lg and 1±ld and into  i±2A ( I±2 b< and i±2o- This extended classification is necessary for understanding the selectivity of some  drugs. For example, tamsulosin is a selective I±la antagonist that is used to treat benign prostate  hyperplasia. The drug is clinically useful because it targetsi±iA receptors found primarily in the urinary tract  and prostate gland.   2. i 2 Receptors: i 2 Receptors exhibit a set of responses different from those of the ilreceptors. These are  characterized by a strong response to isoproterenol , with less sensitivity to epinephrine and norepinephrine  (see Figure 6.4). Fori 2 receptors, the rank order of potency is isoproterenol >epinephrine >norepinephrine.   The i 2 -adrenoceptors can be subdivided into three major subgroups, i 2 i, f 2 2, and T 2 3, based on their affinities for  adrenergic agonists and antagonists, although several others have been identified by gene cloning. [It is known  that i 2 3 receptors are involved in lipolysis but their role in other specific reactions are not known] . i 2 i  Receptors have approximately equal affinities for epinephrine and norepinephrine, whereas i 2 2 receptors have a  higher affinity for epinephrine than for norepinephrine. Thus, tissues with a predominance of i 2 2 receptors  (such as the vasculature of skeletal muscle) are particularly responsive to the hormonal effects of circulating  epinephrine released by the adrenal medulla. Binding of a neurotransmitter at any of the three i 2 receptors  results in activation of adenylyl cyclase and, therefore, increased concentrations of cAMP within the cell.   Activation of the receptor increases  production of DA<ind IP 3 , leading  to an increase in intracellular  calcium ions.    Figure 6.5 Second messengers mediate the effects of itreceptors. DAG =diacylglycerol; IP 3 = inositol  trisphosphate; ATP =adenosine triphosphate; cAMP =cyclic adenosine monophosphate.    3. Distribution of receptors: Adrenergically innervated organs and tissues tend to have a predominance of one  type of receptor. For example, tissues such as the vasculature to skeletal muscle have both T±l and i 2 2 receptors,  but the I 2 2 receptors predominate. Other tissues may have one type of receptor exclusively, with practically no  significant numbers of other types of adrenergic receptors. For example, the heart contains predominantly l 2 i  receptors.    4. Characteristic responses mediated by adrenoceptors: It is useful to organize the physiologic responses to  adrenergic stimulation according to receptor type, because many drugs preferentially stimulate or block one  type of receptor. Figure 6. 6 summarizes the most prominent effects mediated by the adrenoceptors. As a  generalization, stimulation of T±l receptors characteristically produces vasoconstriction (particularly in skin and  abdominal viscera) and an increase in total peripheral resistance and blood pressure. Conversely, stimulation of  i 2 i receptors characteristically causes cardiac stimulation, whereas stimulation of i 2 2 receptors produces  vasodilation (in skeletal vascular beds) and bronchiolar relaxation.   5. Desensitization of receptors: Prolonged exposure to the catecholamines reduces the responsiveness of these  receptors, a phenomenon known as desensitization. Three mechanisms have been suggested to explain this  phenomenon: 1) sequestration of the receptors so that they are unavailable for interaction with the ligand; 2)  down-regulation, that is, a disappearance of the receptors either by destruction or decreased synthesis; and 3)  an inability to couple to G protein, because the receptor has been phosphorylated on the cytoplasmic side by  either protein kinase A or i 2 -adrenergic receptor kinase.   Most of the adrenergic drugs are derivatives of i 2 -phenylethylamine (Figure 6.7). Substitutions on the benzene ring  or on the ethylamine side chains produce a great variety of compounds with varying abilities to differentiate  between i±and i 2 receptors and to penetrate the CNS. Two important structural features of these drugs are the  number and location of OH substitutions on the benzene ring and the nature of the substituent on the amino  nitrogen.    Figure 6.7 Structures of several important adrenergic agonists. Drugs containing the catechol ring are shown  in yellow.   Sympathomimetic amines that contain the 3, 4-dihydroxybenzene group (such as epinephrine, norepinephrine,   isoproterenol , and dopamine ) are called catecholamines. These compounds share the following properties:   1. High potency: Drugs that are catechol derivatives (with a€"OH groups in the 3 and 4 positions on the benzene  ring) show the highest potency in directly activating i±or i 2 receptors.   2. Rapid inactivation: Not only are the catecholamines metabolized by COMT postsynaptically and by MAO  intraneuronally, they are also metabolized in other tissues. For example, COMT is in the gut wall, and MAO is in  the liver and gut wall. Thus, catecholamines have only a brief period of action when given parenterally, and  they are ineffective when administered orally because of inactivation.   3. Poor penetration into the CNS: Catecholamines are polar and, therefore, do not readily penetrate into the  CNS. Nevertheless, most of these drugs have some clinical effects (anxiety, tremor, and headaches) that are  attributable to action on the CNS.   Compounds lacking the catechol hydroxyl groups have longer half-lives, because they are not inactivated by COMT.   These include phenylephrine, ephedrine, and amphetamine. Phenylephrine, an analog of epinephrine, has only a  single a€"OH at position 3 on the benzene ring, whereas ephedrine lacks hydroxyls on the ring but has a methyl  substitution at the l±-carbon. These are poor substrates for MAO and, thus, show a prolonged duration of action,  because MAO is an important route of detoxification. Increased lipid solubility of many of the noncatecholamines  (due to lack of polar hydroxyl groups) permits greater access to the CNS. [Note: Ephedrine and amphetamine may  act indirectly by causing the release of stored catecholamines.]   The nature and bulk of the substituent on the amine nitrogen is important in determining the I 2 selectivity of the  adrenergic agonist. For example, epinephrine, with a a€" CH 3 substituent on the amine nitrogen, is more potent at  i 2 receptors than norepinephrine, which has an unsubstituted amine. Similarly, isoproterenol , with an isopropyl  substituent a€"CH(CFl 3)2 on the amine nitrogen (see Figure 6 . 7), is a strong I 2 agonist with little T± activity (see  Figure 6.4).   Figure 6.8 Sites of action of direct-, indirect-, and mixed-acting adrenergic agonists.   1. Direct-acting agonists: These drugs act directly on l±or I 2 receptors, producing effects similar to those that  occur following stimulation of sympathetic nerves or release of the hormone epinephrine from the adrenal  medulla (Figure 6.8). Examples of direct-acting agonists include epinephrine, norepinephrine, isoproterenol,  and phenylephrine.   2. Indirect-acting agonists: These agents, which include amphetamine, cocaine and tyramine, may block the  uptake of norepinephrine (uptake blockers) or are taken up into the presynaptic neuron and cause the release  of norepinephrine from the cytoplasmic pools or vesicles of the adrenergic neuron (see Figure 6.8). As with  neuronal stimulation, the norepinephrine then traverses the synapse and binds to the i±or i 2 receptors.  Examples of uptake blockers and agents that cause norepinephrine release include cocaine and amphetamines,  respectively.   3. Mixed-action agonists: Some agonists, such as ephedrine, pseudoephedrine and metaraminol , have the  capacity both to stimulate adrenoceptors directly and to release norepinephrine from the adrenergic neuron  (see Figure 6.8).   Direct-acting agonists bind to adrenergic receptors without interacting with the presynaptic neuron. The activated  receptor initiates synthesis of second messengers and subsequent intracellular signals. As a group, these agents are   Epinephrine [e p-i-NEF-rin] is one of four catecholaminesa€"ep/nep/ir/ne, norepinephrine, dopamine, and  dobutam/nea€"commonly used in therapy. The first three catecholamines occur naturally in the body as  neurotransmitters; the latter is a synthetic compound. Epinephrine is synthesized from tyrosine in the adrenal  medulla and released, along with small quantities of norepinephrine, into the bloodstream. Epinephrine interacts  with both i±and i 2 receptors. At low doses, i 2 effects (vasodilation) on the vascular system predominate, whereas at  high doses, T± effects (vasoconstriction) are strongest.   a. Cardiovascular: The maj or actions of epinephrine are on the cardiovascular system. Epinephrine  strengthens the contractility of the myocardium (positive inotropic: i 2 i action) and increases its rate of  contraction (positive chronotropic: i 2 i action). Cardiac   output therefore increases. With these effects comes increased oxygen demands on the myocardium.   Epinephrine constricts arterioles in the skin, mucous membranes, and viscera (T± effects), and it dilates  vessels going to the liver and skeletal muscle (T 2 2 effects). Renal blood flow is decreased. Therefore, the  cumulative effect is an increase in systolic blood pressure, coupled with a slight decrease in diastolic  pressure (Figure 6.9).   b. Respiratory; Epinephrine causes powerful bronchodilation by acting directly on bronchial smooth muscle  (T 2 2 action). This action relieves all known allergic- or histamine-induced bronchoconstriction. In the case of  anaphylactic shock, this can be lifesaving. In individuals suffering from an acute asthmatic attack,  epinephrine rapidly relieves the dyspnea (labored breathing) and increases the tidal volume (volume of  gases inspired and expired). Epinephrine also inhibits the release of allergy mediators such as histamines  from mast cells.   Figure 6.9 Cardiovascular effects of intravenous infusion of low doses of epinephrine.    c. Hyperglycemia: Epinephrine has a significant hyperglycemic effect because of increased glycogenolysis in  the liver (\ 2 3 2 effect), increased release of glucagon (T 2 2 effect), and a decreased release of insulin (i±2  effect). These effects are mediated via the cAMP mechanism.   d. Lipolysis: Epinephrine initiates lipolysis through its agonist activity on the l 2 receptors of adipose tissue,  which upon stimulation activate adenylyl cyclase to increase cAMP levels. Cyclic AMP stimulates a hormone-  sensitive lipase, which hydrolyzes triacylglycerols to free fatty acids and glycerol. 4   2. Biotransformations: Epinephrine, like the other catecholamines, is metabolized by two enzymatic pathways:  MAO, and COMT, which has S-adenosylmethionine as a cofactor (see Figure 6. 3). The final metabolites found in  the urine are metanephrine and van i I lyl mandel ic acid. [Note: Urine also contains normetanephrine, a product of  norepinephrine metabolism.]   a. Bronchospasm: Epinephrine is the primary drug used in the emergency treatment of any condition of the  respiratory tract when bronchoconstriction has resulted in diminished respiratory exchange. Thus, in  treatment of acute asthma and anaphylactic shock, epinephrine is the drug of choice; within a few minutes    after subcutaneous administration, greatly improved respiratory exchange is observed. Administration may  be repeated after a few hours. However, selective 1 2 2 agonists, such as albuterol, are presently favored in  the chronic treatment of asthma because of a longer duration of action and minimal cardiac stimulatory  effect.   b. Glaucoma: In ophthalmology, a two-percent epinephrine solution may be used topically to reduce  intraocular pressure in open-angle glaucoma. It reduces the production of aqueous humor by  vasoconstriction of the ciliary body blood vessels.   c. Anaphylactic shock: Epinephrine is the drug of choice for the treatment of Type I hypersensitivity reactions  in response to allergens.   d. Cardiac arrest: Epinephrine may be used to restore cardiac rhythm in patients with cardiac arrest regardless  of the cause.   e. Anesthetics: Local anesthetic solutions usually contain 1: 100,000 parts epinephrine. The effect of the drug  is to greatly increase the duration of the local anesthesia. It does this by producing vasoconstriction at the  site of injection, thereby allowing the local anesthetic to persist at the injection site before being absorbed  into the circulation and metabolized. Very weak solutions of epinephrine (1: 100,000) can also be used  topically to vasoconstrict mucous membranes to control oozing of capillary blood.   4. Pharmacokinetics: Epinephrine has a rapid onset but a brief duration of action (due to rapid degradation). In  emergency situations, epinephrine is given intravenously for the most rapid onset of action. It may also be given  subcutaneously, by endotracheal tube, by inhalation, or topically to the eye (Figure 6. 10). Oral administration is  ineffective, because epinephrine and the other catecholamines are inactivated by intestinal enzymes. Only  metabolites are excreted in the urine.   a. CNS disturbances: Epinephrine can produce adverse CNS effects that include anxiety, fear, tension,  headache, and tremor.   b. Hemorrhage: The drug may induce cerebral hemorrhage as a result of a marked elevation of blood pressure.   c. Cardiac arrhythmias: Epinephrine can trigger cardiac arrhythmias, particularly if the patient is receiving   a. Hyperthyroidism: Epinephrine may have enhanced cardio-vascular actions in patients with hyperthyroidism.   If epinephrine is required in such an individual, the dose must be reduced. The mechanism appears to  involve increased production of adrenergic receptors on the vasculature of the hyperthyroid individual,  leading to a hypersensitive response.   b. Cocaine: In the presence of cocaine, epinephrine produces exaggerated cardiovascular actions. This is due  to the ability of cocaine to prevent reuptake of catecholamines into the adrenergic neuron; thus, like  norepinephrine, epinephrine remains at the receptor site for longer periods of time (see Figure 6.3).   c. Diabetes: Epinephrine increases the release of endogenous stores of glucose. In the diabetic, dosages of  insulin may have to be increased.   d. l 2 -Blockers: These agents prevent epinephrine's effects on b receptors, leaving l±-receptor stimulation  unopposed. This may lead to an increase in peripheral resistance and an increase in blood pressure.   e. Inhalation anesthetics: Inhalational anesthetics sensitizethe heart to the effects of epinephrine, which may  lead to tachycardia.   Because norepinephrine [nor-ep-i-NEF-rin] is the neuromediator of adrenergic nerves, it should theoretically  stimulate all types of adrenergic receptors. In practice, when the drug is given in therapeutic doses to humans, the  i±-adrenergic receptor is most affected.    a. Vasoconstriction: Norepinephrine causes a rise in peripheral resistance due to intense vasoconstriction of  most vascular beds, including the kidney (T±l effect). Both systolic and diastolic blood pressures increase  (Figure 6. 11). [Note: Norepinephrine causes greater vasoconstriction than does epinephrine, because it  does not induce compensatory vasodilation via l 2 2 receptors on blood vessels supplying skeletal muscles, etc.  The weak i 2 2 activity of norepinephrine also explains why it is not useful in the treatment of asthma.]    b. Baroreceptor reflex: In isolated cardiac tissue, norepinephrine stimulates cardiac contractility; however, in    vivo, little if any cardiac stimulation is noted. This is due to the increased blood pressure that induces a  reflex rise in vagal activity by stimulating the baroreceptors. This reflex bradycardia is sufficient to  counteract the local actions of norepinephrine on the heart, although the reflex compensation does not  affect the positive inotropic effects of the drug (see Figure 6. 11).   c. Effect of atropine pretreatment: If atropine, which blocks the transmission of vagal effects, is given before  norepinephrine, then norepinephrine stimulation of the heart is evident as tachycardia.   2. Therapeutic uses: Norepinephrine is used to treat shock, because it increases vascular resistance and,  therefore, increases blood pressure. However, metaraminol is favored, because it does not reduce blood flow  to the kidney, as does norepinephrine. Other actions of norepinephrine are not considered to be clinically  significant. It is never used for asthma or in combination with local anesthetics. Norepinephrine is a potent  vasoconstrictor and will cause extravasation (discharge of blood from vessel into tissues) along the inj ection  site. [Note: When norepinephrine is used as a drug, it is sometimes called levarterenol [leev-are-TER-a-nole].]   3. Pharmacokinetics: Norepinephrine may be given IV for rapid onset of action. The duration of action is 1 to 2  minutes following the end of the infusion period. It is poorly absorbed after subcutaneous inj ection   and is destroyed in the gut if administered orally. Metabolism is similar to that of epinephrine.   4. Adverse effects: These are similar to those of epinephrine. In addition, norepinephrine may cause blanching  and sloughing of skin along injected vein (due to extreme vasoconstriction).   Isoproterenol [eye-soe-proe-TER-e-nole] is a direct-acting synthetic catecholamine that predominantly stimulates  both i 2 i- and T 2 2 -adrenergic receptors. Its nonselectivity is one of its drawbacks and the reason why it is rarely used  therapeutically. Its action on i±receptors is insignificant.    a. Cardiovascular: Isoproterenol produces intense stimulation of the heart to increase its rate and force of  contraction, causing increased cardiac output (Figure 6. 12). It is as active as epinephrine in this action and,  therefore, is useful in the treatment of atrioventricular block or cardiac arrest. Isoproterenol also dilates  the arterioles of skeletal muscle (T 1 2 2 effect), resulting in decreased peripheral resistance. Because of its  cardiac stimulatory action, it may increase systolic blood pressure slightly, but it greatly reduces mean  arterial and diastolic blood pressure (see Figure 6.12).    b. Pulmonary: A profound and rapid bronchodilation is produced by the drug (T 2 2 action, Figure 6. 13).   Isoproterenol is as active as epinephrine and rapidly alleviates an acute attack of asthma when taken by  inhalation (which is the recommended route). This action lasts about 1 hour and may be repeated by  subsequent doses.   c. Other effects: Other actions on i 2 receptors, such as increased blood sugar and increased lipolysis, can be  demonstrated but are not clinically significant.   2. Therapeutic uses: Isoproterenol is now rarely used as a broncho-dilator in asthma. It can be employed to  stimulate the heart in emergency situations.   3. Pharmacokinetics: Isoproterenol can be absorbed systemically by the sublingual mucosa but is more reliably  absorbed when given parenteral ly or as an inhaled aerosol. It is a marginal substrate for COMT and is stable to  MAO action.   4. Adverse effects: The adverse effects of isoproterenol are similar to those of epinephrine.   Dopamine [DOE-pa-meen], the immediate metabolic precursor of norepinephrine, occurs naturally in the CNS in the  basal ganglia, where it functions as a neurotransmitter, as well as in the adrenal medulla. Dopamine can activate i±-  and i 2 -adrenergic receptors. For example, at higher doses, it can cause vasoconstriction by activating i±i receptors,  whereas at lower doses, it stimulates i 2 i cardiac receptors. In addition, Di and D 2 dopaminergic receptors, distinct  from the i±- and i 2 -adrenergic receptors, occur in the peripheral mesenteric and renal vascular beds, where binding  of dopamine produces vasodilation. D 2 receptors are   also found on presynaptic adrenergic neurons, where their activation interferes with norepinephrine release.   a. Cardiovascular: Dopamine exerts a stimulatory effect on the l 2 i receptors of the heart, having both  inotropic and chronotropic effects (see Figure 6.13). At very high doses, dopamine activates T ±l receptors  on the vasculature, resulting in vasoconstriction.   b. Renal and visceral: Dopamine dilates renal and splanchnic arterioles by activating dopaminergic receptors,  thus increasing blood flow to the kidneys and other viscera (see Figure 6. 13). These receptors are not  affected by i±- or i 2 -blocking drugs. Therefore, dopamine is clinically useful in the treatment of shock, in  which significant increases in sympathetic activity might compromise renal function. [Note: Similar  dopamine receptors are found in the autonomic ganglia and in the CNS.]   2. Therapeutic uses: Dopamine is the drug of choice for shock and is given by continuous infusion. It raises the  blood pressure by stimulating the l 2 i receptors on the heart to increase cardiac output, and T±l receptors on  blood vessels to increase total peripheral resistance. In addition, it enhances perfusion to the kidney and  splanchnic areas, as described above. An increased blood flow to the kidney enhances the glomerular filtration  rate and causes sodium diuresis. In this regard, dopamine is far superior to norepinephrine, which diminishes  the blood supply to the kidney and may cause renal shutdown.   3. Adverse effects: An overdose of dopamine produces the same effects as sympathetic stimulation. Dopamine is  rapidly metabolized to homovanillic acid by MAO or COMT, and its adverse effects (nausea, hypertension,  arrhythmias) are therefore short-lived.    1. Actions: Dobutamine [doe-BYOO-ta-meen] is a synthetic, direct-acting catecholamine that is a l 2 i-receptor  agonist. It is available as a racemic mixture. One of the stereoisomers has a stimulatory activity. It increases  cardiac rate and output with few vascular effects.   2. Therapeutic uses: Dobutamine is used to increase cardiac output in congestive heart failure (see p. 194) as well  as for inotropic support after cardiac surgery. The drug increases cardiac output with little change in heart rate,  and it does not significantly elevate oxygen demands of the myocardiuma€"a maj or advantage over other  sympathomimetic drugs.   3. Adverse effects: Dobutamine should be used with caution in atrial fibrillation, because the drug increases  atrioventricular conduction. Other adverse effects are the same as those for epinephrine. Tolerance may  develop on prolonged use.   Oxymetazoline [ok-see-met-AZ-of-leen] is a direct-acting synthetic adrenergic agonist that stimulates both T±l- and  l± 2 -adrenergic receptors. It is primarily used locally in the eye or the nose as a vasoconstrictor. Oxymetazoline is  found in many over-the-counter short-term nasal spray   decongestant products as well as in ophthalmic drops for the relief of redness of the eyes associated with swimming,  colds, or contact lens. The mechanism of action of oxymetazoline is direct stimulation of i±receptors on blood  vessels supplying the nasal mucosa and the conj unctiva to reduce blood flow and decrease congestion.   Oxymetazoline is absorbed in the systemic circulation regardless of the route of administration and may produce  nervousness, headaches, and trouble sleeping. When administered in the nose, burning of the nasal mucosa and  sneezing may occur. Rebound congestion is observed with long-term use.   Phenylephrine [fen-ill-EF-rin] is a direct-acting, synthetic adrenergic drug that binds primarily to i±receptors and  favors ill receptors over i+? receptors. It is not a catechol derivative and, therefore, not a substrate for COMT.  Phenylephrine is a vasoconstrictor that raises both systolic and diastolic blood pressures. It has no effect on the  heart itself but rather induces reflex bradycardia when given parenteral ly. It is often used topically on the nasal  mucous membranes and in ophthalmic solutions for mydriasis. Phenylephrine acts as a nasal decongestant and  produces prolonged vasoconstriction. The drug is used to raise blood pressure and to terminate episodes of  supraventricular tachycardia (rapid heart action arising both from the atrioventricular j unction and atria). Large  doses can cause hypertensive headache and cardiac irregularities.   Figure 6.14 Onset and duration of bronchodilation effects of inhaled adrenergic agonists.   Methoxamine [meth-OX-a-meen] is a direct-acting, synthetic adrenergic drug that binds primarily to ilreceptors,  with i±i receptors favored over i +2 receptors. Methoxamine raises blood pressure by stimulating T±i receptors in the  arterioles, causing vasoconstriction. This causes an increase in total peripheral resistance. Because of its effects on  the vagus nerve, methoxamine is used clinically to relieve attacks of paroxysmal supraventricular tachycardia. It is  also used to overcome hypotension during surgery involving halothane anesthetics. In contrast to most other  adrenergic drugs, methoxamine does not tend to trigger cardiac arrhythmias in the heart, which is sensitized by  these general anesthetics. Adverse effects include hypertensive headache and vomiting.   Clonidine [KLOE-ni-deen] is an i ±2 agonist that is used in essential hypertension to lower blood pressure because of  its action in the CNS (see p. 225). It can be used to minimize the symptoms that accompany withdrawal from opiates  or benzodiazepines. Clonidine acts centrally to produce inhibition of sympathetic vasomotor centers, decreasing   Metaproterenol [met-a-proe-TER-a-nole], although chemically similar to isoproterenol , is not a catecholamine,  and it is resistant to methylation by COMT. It can be administered orally or by inhalation. The drug acts primarily at  I 2 2 receptors, producing little effect on the heart. Metaproterenol produces dilation of the bronchioles and  improves airway function. The drug is useful as a bronchodilator in the treatment of asthma and to reverse  bronchospasm (Figure 6.14).   Albuterol [al-BYOO-ter-ole], pirbuterol [peer-BYOO-ter-ole], and terbutaline [ter-BYOO-te-leen] are short-acting  i 2 2 agonists used primarily as bronchodilators and administered by a metered-dose inhaler (see Figure 6. 14).  Compared with the nonselective i 2 -adrenergic agonists, such as metaproterenol , these drugs produce equivalent  bronchodilation with less cardiac stimulation.   Salmeterol [sal-ME-ter-ole] and formoterol [for-MOH-ter-ole] are T 2 2- adrenergic selective, long-acting  bronchodilators. A single dose by a metered-dose inhalation device, such as a dry powder inhaler, provides  sustained bronchodilation over 12 hours, compared with less than 3 hours for albuterol. Unlike formoterol,  however, salmeterol has a somewhat delayed onset of action (see Figure 6. 14). These agents are not recommended  as monotherapy and are highly efficacious when combined with a corticorsteroid. Salmeterol and formoterol are  the agents of choice for treating nocturnal asthma in symptomatic patients taking other asthma medications.   Indirect-acting adrenergic agonists cause norepinephrine release from presynaptic terminals or inhibit the uptake of  norepinephrine (see Figure 6.8). They potentiate the effects of norepinephrine produced endogenously, but these  agents do not directly affect postsynaptic receptors.   The marked central stimulatory action of amphetamine [am-FET-a-meen] is often mistaken by drug abusers as its  only action. Flowever, the drug can increase blood pressure significantly by l±-agonist action on the vasculature as  well asi 2 -stimulatory effects on the heart. Its peripheral actions are mediated primarily through the blockade of  norepinephrine uptake and cellular release of stored catecholamines; thus, amphetamine is an indirect-acting  adrenergic drug. The actions and uses of amphetamines are discussed under stimulants of the CNS (see p. 121). The  CNS stimulant effects of amphetamine and its derivatives have led to their use for treating hyperactivity in  children, narcolepsy, and appetite control. Its use in pregnancy should be avoided because of adverse effects on  development of the fetus.   Tyramine [TIE-ra-meen] is not a clinically useful drug, but it is important because it is found in fermented foods,  such as ripe cheese and Chianti wine (see MAO inhibitors, p. 145). It is a normal byproduct of tyrosine metabolism.  Normally, it is oxidized by MAO in the gastrointestinal tract, but if the patient is taking MAO inhibitors, it can  precipitate serious vasopressor episodes. Like amphetamines, tyramine can enter the nerve terminal and displace  stored norepinephrine. The released catecholamine then acts on adrenoceptors.   Cocaine [koe-KANE] is unique among local anesthetics in having the ability to block the Na + /K + -activated ATPase    (required for cellular uptake of norepinephrine) on the cell membrane of the adrenergic neuron.   Consequently, norepinephrine accumulates in the synaptic space, resulting in enhancement of sympathetic activity  and potentiation of the actions of epinephrine and norepinephrine. Therefore, small doses of the catecholamines  produce greatly magnified effects in an individual taking cocaine as compared to those in one who is not. In  addition, the duration of action of epinephrine and norepinephrine is increased. Like amphetamines, it can  increase blood pressure by i±-agonist actions and P-stimulatory effects. [Note: Cocaine as a CNS stimulant and drug  of abuse is discussed on p. 118. ]   Mixed-action drugs induce the release of norepinephrine from presynaptic terminals, and they activate adrenergic  receptors on the postsynaptic membrane (see Figure 6.8).   Ephedrine [e-FED-rin], and pseudoephedrine [soo-doe-e-FED-rin] are plant alkaloids, that are now made  synthetically. These drugs are mixed-action adrenergic agents. They not only release stored norepinephrine from  nerve endings (see Figure 6.8) but also directly stimulate both i±and i 2 receptors. Thus, a wide variety of  adrenergic actions ensue that are similar to those of epinephrine, although less potent. Ephedrine and    pseudoephedrine are not catechols and are poor substrates for COMT and MAO; thus, these drugs have a long  duration of action. Ephedrine and pseudoephedrine have excellent absorption orally and penetrate into the CNS;  however, pseudoephedrine has fewer CNS effects. Ephedrine is eliminated largely unchanged in the urine, and  pseudoephedrine undergoes incomplete hepatic metabolism before elimination in the urine. Ephedrine raises  systolic and diastolic blood pressures by vasoconstriction and cardiac stimulation. Ephedrine produces  bronchodilation, but it is less potent than epinephrine or isoproterenol in this regard and produces its action more  slowly. It is therefore sometimes used prophylactically in chronic treatment of asthma to prevent attacks rather  than to treat the acute attack. Ephedrine enhances contractility and improves motor function in myasthenia gravis,  particularly when used in conj unction with anticholinesterases (see p. 50). Ephedrine produces a mild stimulation of  the CNS. This increases alertness, decreases fatigue, and prevents sleep. It also improves athletic performance.   Ephedrine has been used to treat asthma, as a nasal decongestant (due to its local vasoconstrictor action), and to  raise blood pressure. Pseudoephedrine is primarily used to treat nasal and sinus congestion or congestion of the  eustachian tubes. [Note: The clinical use of ephedrine is declining due to the availability of better, more potent  agents that cause fewer adverse effects. Ephedr/ne-containing herbal supplements (mainly ephedra-containing  products) were banned by the U.S. Food and Drug Administration in April 2004 because of life-threatening  cardiovascular reactions. Pseudoephedrine has been illegally converted to methamphet amine. Thus, products  containing pseudoephedrine have certain restrictions and must be kept behind the sales counter.]   Important characteristics of the adrenergic agonists are summarized in Figures 6. 15, 6. 16 and 6.17.   As a CNS stimulant in treatment  of children with attention  deficit syndrome, narcolepsy,  and appetite control   6.1 A 68-year-old man presents to the emergency department with acute heart failure. You decide that this  patient requires immediate drug therapy to improve his cardiac function. Which one of the following drugs   6.2 Remedies for nasal stuffiness often contain which one of the following drugs?   6.3 Which one of the following drugs, when administered intravenously, can decrease blood flow to the skin,  increase blood flow to skeletal muscle, and increase the force and rate of cardiac contraction?   6.4 The following circles represent pupillary diameter in one eye prior to and following the topical application  of Drug X:   >Table of Contents > Unit II - Drugs Affecting theAutonomic Nervous System >Chapter 7 - Adrenergic Antagonists   The adrenergic antagonists (also called blockers or sympatholytic agents) bind to adrenoceptors but do not trigger  the usual receptor-mediated intracellular effects. These drugs act by either reversibly or irreversibly attaching to  the receptor, thus preventing its activation by endogenous catecholamines. Like the agonists, the adrenergic  antagonists are classified according to their relative affinities for T± or i 2 receptors in the peripheral nervous system.  [Note: Antagonists that block dopamine receptors are most important in the central nervous system (CNS) and are  therefore considered in that section (see p. 151).] The receptor-blocking drugs discussed in this chapter are  summarized in Figure 7.1.    Figure 7.1 Summary of blocking agents and drugs affecting neurotransmitter uptake or release.   Drugs that block i±-adrenoceptors profoundly affect blood pressure. Because normal sympathetic control of the  vasculature occurs in large part through agonist actions on i±-adrenergic receptors, blockade of these receptors  reduces the sympathetic tone of the blood vessels, resulting in decreased peripheral vascular resistance. This  induces a reflex tachycardia resulting from the lowered blood pressure. [Note: P receptors, including  Pi-adrenoceptors on the heart, are not affected by i±blockade,] The i±-adrenergic blocking agents,  phenoxybenzamine and phentolamine, have limited clinical applications.   Phenoxybenzamine [fen-ox-ee-BEN-za-meen] is nonselective, linking covalently to both i±L-postsynaptic and  ii^-presynaptic receptors (Figure 7.2). The block is irreversible and noncompetitive, and the only mechanism the  body has for overcoming the block is to synthesize new adrenoceptors, which requires a day or more. Therefore,  the actions of phenoxybenzamine last about 24 hours after a single administration. After the drug is inj ected, a  delay of a few hours occurs before a blockade develops, because the molecule must undergo biotransformation to  the active form.   a. Cardiovascular effects: By blocking i± receptors, phenoxybenzamine prevents vasoconstriction of  peripheral blood vessels by endogenous catecholamines. The decreased peripheral resistance provokes a  reflex tachycardia. Furthermore, the   ability to block presynaptic inhibitory l ±2 receptors in the heart can contribute to an increased cardiac  output. [Note: These receptors when blocked will result in more norepinephrine release, which stimulates! 2  receptors on the heart to increase cardiac output]. Thus, the drug has been unsuccessful in maintaining  lowered blood pressure in hypertension and has been discontinued for this purpose.   b. Epinephrine reversal: All l±-adrenergic blockers reverse the i±-agonist actions of epinephrine. For  example, the vasoconstrictive action of epinephrine is interrupted, but vasodilation of other vascular beds  caused by stimulation of f 2 receptors is not blocked. Therefore, the systemic blood pressure decreases in  response to epinephrine given in the presence of phenoxybenzamine (Figure 7.3). [Note: The actions of  norepinephrine are not reversed but are diminished, because norepinephrine lacks significant i 2 -agonist  action on the vasculature. ] Phenoxybenzamine has no effect on the actions of isoproterenol , which is a  pure i 2 agonist (see Figure 7. 3).    2. Therapeutic uses: Phenoxybenzamine is used in the treatment of pheochromocytoma, a catecholamine-  secreting tumor of cells derived from the adrenal medulla. Prior to surgical removal of the tumor, patients are  treated with phenoxybenzamine to preclude the hypertensive crisis that can result from manipulation of the  tissue. This drug is also useful in the chronic management of these tumors, particularly when the catecholamine-  secreting cells are diffuse and, therefore, inoperable. Phenoxybenzamine or phentolamine are sometimes  effective in treating Raynaud's disease. Autonomic hyperreflexia, which predisposes paraplegics to strokes, can  be managed with phenoxybenzamine.   3. Adverse effects: Phenoxybenzamine can cause postural hypotension, nasal stuffiness, nausea, and vomiting. It  can inhibit ej aculation. The drug also may induce reflex tachycardia, mediated by the baroreceptor reflex, and  is contraindicated in patients with decreased coronary perfusion.   In contrast to phenoxybenzamine, phentolamine [fen-TOLE-a-meen] produces a competitive block of T±l and I ±2  receptors. The drug's action lasts for approximately 4 hours after a single administration. Like phenoxybenzamine,  it produces postural hypotension and causes epinephrine reversal. P/iento/am/ne-induced reflex cardiac stimulation  and tachycardia are mediated by the baroreceptor reflex and by blocking the T ±2 receptors of the cardiac  sympathetic nerves. The drug can also trigger arrhythmias and anginal pain, and it is contraindicated in patients with  decreased coronary perfusion. Phentolamine is also used for the short-term management of pheochromocytoma.  Phentolamine is now rarely used for the treatment of impotence (it can be inj ected intracavernosally to produce  vasodilation of penile arteries).    u-Adrenergic blockers  have no effect on the  actions of isoproterenol,  which Is a pure jl agonist.    Figure 7.3 Summary of effects of adrenergic blockers on the changes in blood pressure induced by  isoproterenol, epinephrine, and norepinephrine.   Prazosin [PRAY-zoe-sin], terazosin [ter-AY-zoe-sin], doxazosin [dox-AY-zoe-sin], and tamsulosin [tam-SUE-  loh-sin] are selective competitive blockers of the I±l receptor. In contrast to phenoxybenzamine and  phentolamine,   the first three drugs are useful in the treatment of hypertension. Tamsulosin and alfuzosin [al-FYOO-zoe-sin] are  indicated for the treatment of benign prostatic hypertrophy (also known as benign prostatic hyperplasia or BPH).  Metabolism leads to inactive products that are excreted in the urine except for those of doxazosin, which appear in  the feces. Doxazosin is the longest acting of these drugs.   1. Cardiovascular effects: All of these agents decrease peripheral vascular resistance and lower arterial blood  pressure by causing the relaxation of both arterial and venous smooth muscle. Tamsulosin has the least effect  on blood pressure. These drugs, unlike phenoxybenzamine and phentolamine, cause minimal changes in cardiac  output, renal blood flow, and the glomerular filtration rate.   2. Therapeutic uses: Individuals with elevated blood pressure who have been treated with one of these drugs do  not become tolerant to its action. However, the first dose of these drugs produces an exaggerated orthostatic  hypotensive response that can result in syncope (fainting). This action, termed a a€oefirst-dosea€^ effect, may  be minimized by adj usting the first dose to one-third or one-fourth of the normal dose and by giving the drug at  bedtime. An increase in the risk of congestive heart failure has been reported when i±L-receptor blockers have  been used as monotherapy in hypertension. The i±L-receptor antagonists have been used as an alternative to  surgery in patients with symptomatic BPH. Blockade of the ilreceptors decreases tone in the smooth muscle of  the bladder neck and prostate and improves urine flow. Tamsulosin is a more potent inhibitor of the I±ia  receptors found on the smooth muscle of the prostate. This selectivity accounts for tamsulosin's minimal effect  on blood pressure. [Note: Finasteride and dutasteride inhibit 5i±-reductase, preventing the conversion of  testosterone to dihydrotestosterone. These drugs are approved for the treatment of BPH by reducing prostate  volume in selected patients (see. p. 309)]   3. Adverse effects: I±l Blockers may cause dizziness, a lack of energy, nasal congestion, headache, drowsiness,  and orthostatic hypotension (although to a lesser degree than that observed with phenoxybenzamine and  phentolamine). An additive antihypertensive effect occurs when prazosin is given with either a diuretic or a  T 2 - blocker, thereby necessitating a reduction in its dose. Due to a tendency to retain sodium and fluid, prazosin  is frequently used along with a diuretic. Male sexual function is not as severely affected by these drugs as it is by  phenoxybenzamine and phentolamine ; however, by blocking a receptors in the ejaculatory ducts and impairing   smooth muscle contraction, inhibition of ejaculation and retrograde ejaculation have been reported. Figure 7.4  summarizes some adverse effects observed with i±-blockers.   Yohimbine [yo- HIM- bean] is a selective competitive i ±2 blocker. It is found as a component of the bark of the  yohimbe tree and is sometimes used as a sexual stimulant. Yohimbine works at the level of the CNS to increase  sympathetic outflow to the periphery. It directly blocks i+? receptors and has been used to relieve vasoconstriction  associated with Raynaud's disease. Yohimbine is contraindicated in CNS and cardiovascular conditions because it is a  CNS and cardiovascular stimulant.   All the clinically available f 2 - blockers are competitive antagonists. Nonselective i 2 -blockers act at both i 2 i and i 2 2  receptors, whereas cardioselective i 2 antagonists primarily block i 2 i receptors [Note: There are no clinically useful  f 2 2 antagonists]. These drugs also differ in intrinsic sympathomimetic activity, in CNS effects, and in  pharmacokinetics (Figure 7. 5). Although all T 2 - blockers lower blood pressure in hypertension, they do not induce  postural hypotension, because the i±-adrenoceptors remain functional. Therefore, normal sympathetic control of  the vasculature is maintained. l 2 -Blockers are also effective in treating angina, cardiac arrhythmias, myocardial  infarction, congestive heart failure, hyperthyroidism, and glaucoma, as well as serving in the prophylaxis of  migraine headaches. [Note: The names of all i 2 -blockers end in a€oe-olola€§ except for labetalol and carvedilol.]   Propranolol [proe-PRAN-oh-lole] is the prototype i 2 -adrenergic antagonist and blocks both l 2 i and i 2 2 receptors.   a. Cardiovascular: Propranolol diminishes cardiac output, having both negative inotropic and chronotropic  effects (Figure 7.6). It directly depresses sinoatrial and atrioventricular activity. The resulting bradycardia  usually limits the dose of the drug. Cardiac output, work, and oxygen consumption are decreased by  blockade of i 2 i receptors: these effects are useful in the treatment of angina (see p. 211). The P-blockers  are effective in attenuating supraventricular cardiac arrhythmias but generally are not effective against  ventricular arrhythmias (except those induced by exercise).   The reduction in cardiac output leads to decreased blood pressure. This hypotension triggers a reflex  peripheral vasoconstriction that is reflected in reduced blood flow to the periphery. On balance, there is a  gradual reduction of both systolic and diastolic blood pressures in hypertensive patients. No postural  hypotension occurs, because the i±L-adrenergic receptors that control vascular resistance are unaffected.   c. Bronchoconstriction: Blocking i 2 2 receptors in the lungs of susceptible patients causes contraction of the  bronchiolar smooth muscle (see Figure 7.6). This can precipitate a respiratory crisis in patients with chronic  obstructive pulmonary disease (COPD) or asthma. T 2 - Bl ockers, and in particular nonselective ones, are thus  contraindicated in patients with COPD or asthma.   d. Increased Na + retention: Reduced blood pressure causes a decrease in renal perfusion, resulting in an  increase in Na + retention and plasma volume (see Figure 7.6). In some cases, this compensatory response  tends to elevate the blood pressure. For these patients, i 2 -blockers are often combined with a diuretic to  prevent Na + retention. By inhibiting I 2 receptors, renin production is also prevented, contributing to Na +  retention.   e. Disturbances in glucose metabolism: T 2 - blockade leads to decreased glycogenolysis and decreased glucagon  secretion. Therefore, if a Type I (formerly insulin-dependent) diabetic is to be given propranolol , very  careful monitoring of blood glucose is essential, because pronounced hypoglycemia may occur after insulin  inj ection. T 2 - Blockers also attenuate the normal physiologic response to hypoglycemia.    f. Blocked action of isoproterenol: All I 2 - blockers, including propranolol , have the ability to block the actions  of isoproterenol on the cardiovascular system. Thus, in the presence of a P-blocker, isoproterenol does not  produce either the typical cardiac stimulation or reductions in mean arterial pressure and diastolic pressure    (see Figure 7.3). [Note: In the presence of a I 2 - bl ocker, epinephrine no longer lowers diastolic blood  pressure or stimulates the heart, but its vasoconstrictive action (mediated by i±receptors) remains  unimpaired. The actions of norepinephrine on the cardiovascular system are mediated primarily by l±  receptors and are, therefore, unaffected.]   a. Hypertension: Propranolol lowers blood pressure in hypertension by several different mechanisms of  action. Decreased cardiac output is the primary mechanism, but inhibition of renin release from the kidney  and decreased sympathetic outflow from the CNS also contribute to propranolol's antihypertensive effects  (see p. 220).   b. Glaucoma: P-Blockers, particularly topically applied timolol, are effective in diminishing intraocular  pressure in glaucoma. This occurs by decreasing the secretion of aqueous humor by the ciliary body. Many  patients with glaucoma have been maintained with these drugs for years. They neither affect the ability of  the eye to focus for near vision nor change pupil size, as do the cholinergic drugs. However, in an acute  attack of glaucoma, pilocarpine is still the drug of choice. The i 2 -blockers are only used to treat this disease  chronically.   c. Migraine: Propranolol is also effective in reducing migraine episodes when used prophylactically (see p.   526). T 2 - Blockers are valuable in the treatment of chronic migraine, in which they decrease the incidence  and severity of the attacks. The mechanism may depend on the blockade of catecholamine-induced  vasodilation in the brain vasculature. [Note: During an attack, the usual therapy with sumatriptan or other  drugs is used.]   d. Hyperthyroidism: Propranolol and other T 2 - blockers are effective in blunting the widespread sympathetic  stimulation that occurs in hyperthyroidism. In acute hyperthyroidism (thyroid storm), P-blockers may be  lifesaving in protecting against serious cardiac arrhythmias.   e. Angina pectoris: Propranolol decreases the oxygen requirement of heart muscle and, therefore, is  effective in reducing the chest pain on exertion that is common in angina. Propranolol is therefore   useful in the chronic management of stable angina, but not for acute treatment. Tolerance to moderate  exercise is increased, and this is measurable by improvement in the electrocardiogram. However, treatment  with propranolol does not allow strenuous physical exercise, such as tennis.   f. Myocardial infarction: Propranolol and other T 2 - blockers have a protective effect on the myocardium.   Thus, patients who have had one myocardial infarction appear to be protected against a second heart attack  by prophylactic use of P-blockers. In addition, administration of a P-blocker immediately following a  myocardial infarction reduces infarct size and hastens recovery. The mechanism for these effects may be a  blocking of the actions of circulating catecholamines, which would increase the oxygen demand in an  already ischemic heart muscle. Propranolol also reduces the incidence of sudden arrhythmic death after  myocardial infarction.   a. Bronchoconstriction: Propranolol has a serious and potentially lethal side effect when administered to an  asthmatic (Figure 7. 7). An immediate contraction of the bronchiolar smooth muscle prevents air from  entering the lungs. Deaths by asphyxiation have been reported for asthmatics who were inadvertently  administered the drug. Therefore, propranolol must never be used in treating any individual with COPD or  asthma.   b. Arrhythmias: Treatment with P-blockers must never be stopped quickly because of the risk of precipitating  cardiac arrhythmias, which may be severe. The P-blockers must be tapered off gradually for 1 week.   Long-term treatment with a P antagonist leads to up-regulation of the P-receptor. On suspension of  therapy, the increased receptors can worsen angina or hypertension.    c. Sexual impairment: Because sexual function in the male occurs through i±-adrenergic activation, T 2 - bl ockers  do not affect normal ej aculation or the internal bladder sphincter function. On the other hand, some men  do complain of impaired sexual activity. The reasons for this are not clear, and they may be independent of  P-receptor blockade.   d. Disturbances in metabolism: P-Blockade leads to decreased glycogenolysis and decreased glucagon  secretion. Fasting hypoglycemia may occur. [Note: Cardioselective P-blockers are preferred in treating  asthmatic patients who use insulin (see T 2 i-selecti ve antagonists). ]   e. Drug interactions: Drugs that interfere with the metabolism of propranolol , such as clmetldlne,  fluoxetine, paroxetine, and ritonavir, may potentiate its antihypertensive effects. Conversely, those that  stimulate its metabolism, such as barbiturates, phenytoin, and rifampin, can decrease its effects.   Figure 7.7 Adverse effects commonly observed in individuals treated with propranolol .   Timolol [TIM-o-lole] and nadolol [ NAH-doh- lole] also block i 2 i- and I 2 2 - adrenoceptors and are more potent than  propranolol. Nadolol has a   very long duration of action (see Figure 7.5). Timolol reduces the production of aqueous humor in the eye. It is  used topically in the treatment of chronic open-angle glaucoma and, occasionally, for systemic treatment of  hypertension.   C. Acebutolol, atenolol, metoprolol, and esmolol: Selective I 2 !  antagonists   Drugs that preferentially block the i 2 i receptors have been developed to eliminate the unwanted  bronchoconstrictor effect (T 2 2 effect) of propranolol seen among asthmatic patients. Cardioselective P-blockers,  such as acebutolol [a-se-BYOO-toe-lole], atenolol [a-TEN-oh- lole], and metoprolol [me-TOE-proe-lole],  antagonize i 2 i receptors at doses 50- to 100-fold less than those required to block P 2 receptors. This   cardioselectivity is thus most pronounced at low doses and is lost at high doses. [Note: Acebutolol has some intrinsic  agonist activity.]   I), and p 2 receptors partially activated  but unable to respond to more potent  catecholamines    Figure 7.8 Comparison of agonists, antagonists, and partial agonists of I 2 adrenoceptors.    1. Actions: These drugs lower blood pressure in hypertension and increase exercise tolerance in angina (see Figure    7.6). Esmolol [EZ-moe-lole] has a very short lifetime (see Figure 7.5) due to metabolism of an ester linkage. It is  only given intravenously if required during surgery or diagnostic procedures (for example, cystoscopy). In  contrast to propranolol , the cardiospecific blockers have relatively little effect on pulmonary function,  peripheral resistance, and carbohydrate metabolism. Nevertheless, asthmatics treated with these agents must  be carefully monitored to make certain that respiratory activity is not compromised.   2. Therapeutic use in hypertension: The cardioselective T 2 - blockers are useful in hypertensive patients with  impaired pulmonary function. Because these drugs have less effect on peripheral vascular P 2 receptors,  coldness of extremities, a common side effect of i 2 -blocker therapy, is less frequent. Cardioselective P-blockers  are useful in diabetic hypertensive patients who are receiving insulin or oral hypoglycemic agents.   a. Cardiovascular: Acebutolol and pindolol [PIN-doe-lole] are not pure antagonists; instead, they have the  ability to weakly stimulate both i 2 i and i 2 2 receptors (Figure 7.8) and are said to have intrinsic  sympathomimetic activity (ISA). These partial agonists stimulate the I 2 receptor to which they are bound, yet  they inhibit stimulation by the more potent endogenous catecholamines, epinephrine and norepinephrine.   The result of these opposing actions is a much diminished effect on cardiac rate and cardiac output  compared to that of l 2 -blockers without ISA.   b. Decreased metabolic effects: Blockers with ISA minimize the disturbances of lipid and carbohydrate  metabolism that are seen with other P-blockers.   2. Therapeutic use in hypertension: P-Blockers with ISA are effective in hypertensive patients with moderate  bradycardia, because a further decrease in heart rate is less pronounced with these drugs. Carbohydrate  metabolism is less affected with acebutolol and pindolol   than it is with propranolol , making them valuable in the treatment of diabetics. [Note: The b blockers with ISA  are not used as antiarrhythmic agents due to their partial agonist effect.] Figure 7.9 summarizes some of the  indications for P-blockers.    E. Labetalol and carvedilol: Antagonists of both l±- and l 2 -  adrenoceptors   Propranolol, metoprolol, timolol,  other [5-blockers reduce cardiac  output and renin secretion.    Arrhythmia prophylaxis after  myocardial infarction  Propranolol, mttoprolol, and  timolol reduce cardiac output  and renin secretion.    1. Actions: Labetalol [lah-BET-a-lole] and carvedilol [ CAR- ve-d i I -o I ] are reversible T 2 - blockers with concurrent  i±i-blocking actions that produce peripheral vasodilation, thereby reducing blood pressure. They contrast with  the other i 2 -blockers that produce peripheral vasoconstriction, and they are therefore useful in treating    hypertensive patients for whom increased peripheral vascular resistance is undesirable. They do not alter serum  lipid or blood glucose levels. Carvedilol also decreases lipid peroxidation and vascular wall thickening, effects  that have benefit in heart failure.   2. Therapeutic use in hypertension: Labetalol is useful for treating the elderly or black hypertensive patient in  whom increased peripheral vascular resistance is undesirable. [Note: In general, black hypertensive patients are  not well controlled with T 2 - blockers. ] Labetalol may be employed as an alternative to methyldopa in the  treatment of pregnancy-induced hypertension. Intravenous labetalol is also used to treat hypertensive  emergencies, because it can rapidly lower blood pressure (see p. 227).   3. Adverse effects: Orthostatic hypotension and dizziness are associated with T±i blockade. Figure 7. 10 summarizes  the receptor specificities and uses of the l 2 -adrenergic antagonists.   As noted on p. 119, some agonists, such as amphetamine and tyramine, do not act directly on the adrenoceptor.   Instead, they exert their effects indirectly on the adrenergic neuron by causing the release of neurotransmitter  from storage vesicles. Similarly, some agents act on the adrenergic neuron, either to interfere with  neurotransmitter release or to alter the uptake of the neurotransmitter into the adrenergic nerve. However, due to  the advent of newer and more effective agents, with fewer side effects, these agents are rarely used  therapeutically. These agents are included in this chapter due to their unique mechanisms of action and historical  value.   Reserpine [re-SER-peen], a plant alkaloid, blocks the Mg 2+ / adenosine triphosphatea€"dependent transport of  biogenic amines, norepinephrine, dopamine, and serotonin from the cytoplasm into storage vesicles in the  adrenergic nerves of all body tissues. This causes the ultimate depletion of biogenic amines. Sympathetic function,  in general, is impaired because of decreased release of norepinephrine. The drug has a slow onset, a long duration  of action, and effects that persist for many days after discontinuation.   Guanethidlne [gwahn-ETH-i-deen] blocks the release of stored norepinephrine as well as displaces norepinephrine  from storage vesicles (thus producing a transient increase in blood pressure). This leads to gradual depletion of  norepinephrine in nerve endings except for those in the CNS. Guanethidine commonly causes orthostatic  hypotension and interferes with male sexual function. Supersensitivity to norepinephrine due to depletion of the  amine can result in hypertensive crisis in patients with pheochromocytoma.   Although cocaine inhibits norepinephrine uptake, it is an adrenergic agonist. See page 78 for discussion.    Figure 7.10 Summary of i 2 -adrenergic antagonists. 1 Acebutolol and pindolol are partial agonists.   7.1 The graphs below depict the changes in blood pressure caused by the intravenous administration of  epinephrine before and after an unknown Drug X.   7.2 A 38-year-old male has recently started monotherapy for mild hypertension. At his most recent office visit,  he complains of tiredness and not being able to complete three sets of tennis. Which one of the following drugs  is he most likely to be taking for hypertension?   7.3 A 60-year-old asthmatic man comes in for a checkup and complains that he is having some difficulty in  aCoestarting to urinate. a€ !S Physical examination indicates that the man hasa blood pressure of 160/100 mm  Hg and a slightly enlarged prostate. Which of the following medications would be useful in treating both of  these conditions?   >Table of Contents > Unit III - Drugs Affecting the Central Nervous System >Chapter 8 - Neurodegenerative Diseases   Most drugs that affect the central nervous system (CNS) act by altering some step in the neurotransmission process.  Drugs affecting the CNS may act presynaptically by influencing the production, storage, release, or termination of  action of neurotransmitters. Other agents may activate or block postsynaptic receptors. This chapter provides an  overview of the CNS, with a focus on those neurotransmitters that are involved in the actions of the clinically useful  CNS drugs. These concepts are useful in understanding the etiology and treatment strategies of Parkinson's and  Alzheimer's diseasesa€"the two neurodegenerative disorders that respond to drug therapy (Figure 8. 1).   Figure 8.1 Summary of agents used in the treatment of Parkinson's and Alzheimer's diseases.   In many ways, the basic functioning of neurons in the CNS is similar to that of the autonomic nervous system  described in Chapter 3. For example, transmission of information in the CNS and in the periphery both involve the  release of neurotransmitters that diffuse across the synaptic space to bind to specific receptors on the postsynaptic  neuron. In both systems, the recognition of the neurotransmitter by the membrane receptor of the postsynaptic  neuron triggers intracellular changes. However, several major differences exist between neurons in the peripheral  autonomic nervous system and those in the CNS. The circuitry of the CNS is much more complex than that of the  autonomic nervous system, and the number of synapses in the CNS is far greater. The CNS, unlike the peripheral  autonomic nervous system, contains powerful networks of inhibitory neurons that are constantly active in  modulating the rate of neuronal transmission. In addition, the CNS communicates through the use of more than 10  (and perhaps as many as 50) different neurotransmitters. In contrast, the autonomic nervous system uses only two  primary neurotransmitters, acetylcholine and norepinephrine. Figure 8.2 describes some of the more important  neurotransmitters in the CNS.   Excitatory/inhibitory: Feeding behavior, control of body temperature, modulation of sensory pathways  including nociception (stimulation of pain nerve sensors), regulation of mood and emotion, and  sleep/wakefulness.   Inhibitory; Increases Cl~ flux into the postsynaptic neuron, resulting in hyperpolarization.   Generally inhibitory: Mediates analgesia as well as other central nervous system effects.   In the CNS, receptors at most synapses are coupled to ion channels; that is, binding of the neurotransmitter to the  postsynaptic membrane receptors results in a rapid but transient opening of ion channels. Open channels allow  specific ions inside and outside the cell membrane to flow down their concentration gradients. The resulting change  in the ionic composition across the membrane of the neuron alters the postsynaptic potential, producing either  depolarization or hyperpolarization of the postsynaptic membrane, depending on the specific ions that move and  the direction of their movement.    Empty receptor is inactive, and the  coupled sodium channel is closed.    Entry of Na + depolarizes the cell  and increases neural excitability.    Figure 8.3 Binding of the excitatory neurotransmitter, acetylcholine, causes depolarization of the neuron.   Neurotransmitters can be classified as either excitatory or inhibitory, depending on the nature of the action they  elicit. Stimulation of excitatory neurons causes a movement of ions that results in a depolarization of the  postsynaptic membrane. These excitatory postsynaptic potentials (EPSP) are generated by the following: 1)   Stimulation of an excitatory neuron causes the release of neurotransmitter molecules, such as glutamate or  acetylcholine, which bind to receptors on the postsynaptic cell membrane. This causes a transient increase in the  permeability of sodium (Na 4 ) ions. 2) The influx of Na + causes a weak depolarization or EPSP that moves the  postsynaptic potential toward its firing threshold. 3) If the number of stimulated excitatory neurons increases, more  excitatory neurotransmitter is released. This ultimately causes the EPSP depolarization of the postsynaptic cell to  pass a threshold, thereby generating an all-or-none action potential. [Note: The generation of a nerve impulse  typically reflects the activation of synaptic receptors by thousands of excitatory neurotransmitter molecules  released from many nerve fibers. ] (See Figure 8. 3 for an example of an excitatory pathway. )   Stimulation of inhibitory neurons causes movement of ions that results in a hyperpolarization of the postsynaptic  membrane. These inhibitory postsynaptic potentials (IPSP) are generated by the following: 1)   Stimulation of inhibitory neurons releases neurotransmitter molecules, such asl 3 -aminobutyric acid (GABA) or  glycine, which bind to receptors on the postsynaptic cell membrane. This causes a transient increase in the    permeability of specific ions, such as potassium (K"*) and chloride (Cl") ions. 2) The influx of Cl" and efflux of K +  cause a weak hyperpolarization or IPSP that moves the postsynaptic potential away from its firing threshold. This  diminishes the generation of action potentials. (See Figure 8.4for an example of an inhibitory pathway.)   Most neurons in the CNS receive both EPSP and IPSP input. Thus, several different types of neurotransmitters may  act on the same neuron, but each binds to its own specific receptor. The overall resultant action is due to the  summation of the individual actions of the various neurotransmitters on the neuron. The neurotransmitters are not  uniformly distributed in the CNS but are localized in specific clusters of neurons, the axons of which may synapse  with specific regions of the brain. Many neuronal tracts thus seem to be chemically coded, and this may offer  greater opportunity for selective modulation of certain neuronal pathways.    Empty receptor it inactive,  and the coupled chloride  channel is closed.    Entry of Cl" hyperpolarizes  the cell, making it more  difficult to depolarize and,  therefore, reducing neural  excitability.   Figure 8.4 Binding of the inhibitory neurotransmitter, i»-aminobutyric acid (GABA), causes hyperpolarization  of the neuron.   Neurodegenerative diseases of the CNS include Alzheimer's disease, Parkinson's disease, Huntington's disease, and  amyotrophic lateral sclerosis. These devastating illnesses are characterized by the progressive loss of selected  neurons in discrete brain areas, resulting in characteristic disorders of movement, cognition, or both. For example,  Alzheimer's disease is characterized by the loss of cholinergic neurons in the nucleus basalis of Maynert, whereas  Parkinson's disease is associated with a loss of dopaminergic neurons in the substantia nigra. The most prevalent of  these disorders is Alzheimer's disease, estimated to have affected some 4 million people in 2000. The number of  cases is expected to increase as the proportion of elderly in the population increases.   Parkinsonism is a progressive neurological disorder of muscle movement, characterized by tremors, muscular  rigidity, bradykinesia (slowness in initiating and carrying out voluntary movements), and postural and gait  abnormalities. Most cases involve people over the age of 65, among whom the incidence is about 1 in 100  individuals.   The cause of Parkinson's disease is unknown for most patients. The disease is correlated with destruction of  dopaminergic neurons in the substantia nigra with a consequent reduction of dopamine actions in the corpus  striatuma€"parts of the brain's basal ganglia system that are involved in motor control. The loss of dopamine neurons  in the substantia nigra is evidenced by diminished overall uptake of dopamine precursors in this region, which can  be visualized using positron-emission tomography and the dopamine analog fluorodopa (Figure 8.5). Genetic factors  do not play a dominant role in the etiology of Parkinson's disease, although they may exert some influence on an  individual's susceptibility to the disease. It appears increasingly likely that an as-yet-unidentified environmental  factor may play a role in the loss of dopaminergic neurons.   1. Substantia nigra: The substantia nigra, part of the extrapyramidal system, is the source of dopaminergic  neurons that terminate in the striatum (shown as red neurons in Figure 8.6). Each dopaminergic neuron makes  thousands of synaptic contacts within the neostriatum and, therefore, modulates the activity of a large number  of cells. These dopaminergic projections from the substantia nigra fire tonical ly rather than in response to  specific muscular movements or sensory input. Thus, the dopaminergic system appears to serve as a tonic,  sustaining influence on motor activity rather than participating in specific movements.   Figure 8.5 Positron-emission tomographic scan of the brain showing the difference in fluorodopa  (FDOPA) levels between those with and without Parkinson's disease.    2. Neostriatum: Normally, the neostriatum is connected to the substantia nigra by neurons (shown as orange in  Figure 8.6) that secrete the inhibitory transmitter GABA at their termini in the substantia nigra. In turn, cells of  the substantia nigra send neurons (show n red in Figure 8.6) back to the neostriatum, secreting the inhibitory  transmitter dopamine at their termini. This mutual inhibitory pathway normally maintains a degree of inhibition  of the two separate areas. In Parkinson's disease, destruction of cells in the substantia nigra results in the  degeneration of the nerve terminals responsible for secreting dopamine in the neostriatum. Thus, the normal  modulating inhibitory influence of dopamine on cholinergic neurons in the neostriatum is significantly  diminished, resulting in overproduction or a relative overactivity of acetylcholine by the stimulatory neurons  (shown as green in Figure 8.6). This triggers a chain of abnormal signaling, resulting in loss of the control of  muscle movements.   3. Secondary parkinsonism: Parkinsonian symptoms infrequently follow viral encephalitis or multiple small  vascular lesions. Drugs such as the phenothiazines and haloperidol, whose maj or pharmacologic action is  blockade of dopamine receptors in the brain, may also produce parkinsonian symptoms. These drugs should not  be used in parkinsonian patients.   In addition to an abundance of inhibitory dopaminergic neurons, the neostriatum is also rich in excitatory  cholinergic neurons that oppose the action of dopamine (see Figure 8.6). Many of the symptoms of parkinsonism  reflect an imbalance between the excitatory cholinergic neurons and the greatly diminished number of inhibitory  dopaminergic neurons. Therapy is aimed at restoring dopamine in the basal ganglia and antagonizing the excitatory  effect of cholinergic neurons, thus reestablishing the correct dopamine/ acetylcholine balance. Because long-term  treatment with levodopa is limited by fluctuations in therapeutic responses, strategies to maintain CNS dopamine  levels as constant as possible have been devised.   | Loss of the Inhibitory effect  I of dopamine results in more  production of acetylcholine,  which triggers a chain of  abnormal signaling leading  to impaired mobility.    Figure 8.6 Role of substantia nigra in Parkinson's disease. DA =dopamine; GABA =l»-aminobutyric acid; ACh =  acetylcholine.   Currently available drugs offer temporary relief from the symptoms of the disorder, but they do not arrest or  reverse the neuronal degeneration caused by the disease.   Levodopa [lee-voe-DOE-pa] is a metabolic precursor of dopamine (Figure 8.7). It restores dopaminergic  neurotransmission in the corpus striatum by enhancing the synthesis of dopamine in the surviving neurons of the   substantia nigra. In patients with early disease, the number of residual dopaminergic neurons in the substantia nigra  (typically about 20 percent of normal) is adequate for conversion of levodopa to dopamine. Thus, in new patients,  the therapeutic response to levodopa is consistent, and the patient rarely complains that the drug effects a€oewear  off.a€i Unfortunately, with time, the number of neurons decreases, and fewer cells are capable of taking up  exogenously administered levodopa and converting it to dopamine for subsequent storage and release.   Consequently, motor control fluctuation develops. Relief provided by levodopa is only symptomatic, and it lasts  only while the drug is present in the body.   a. Levodopa: Because parkinsonism results from insufficient dopamine in specific regions of the brain,  attempts have been made to replenish the dopamine deficiency. Dopamine itself does not cross the  blood-brain barrier, but its immediate precursor, levodopa, is actively transported into the CNS and is  converted to dopamine in the brain (see Figure 8.7). Large doses of levodopa are required, because much of  the drug is decarboxylated to dopamine in the periphery, resulting in side effects that include nausea,  vomiting, cardiac arrhythmias, and hypotension.   b. Carbidopa: The effects of levodopa on the CNS can be greatly enhanced by coadministering carbidopa    [kar-bi-DOE-pa], a dopa decarboxylase inhibitor that does not cross the blood-brain barrier. Carbidopa  diminishes the metabolism of levodopa in the gastrointestinal tract and peripheral tissues; thus, it increases  the availability of levodopa to the CNS. The addition of carbidopa lowers the dose of levodopa needed by  four- to five-fold and, consequently, decreases the severity of the side effects arising from peripherally  formed dopamine.   Figure 8.7 Synthesis of dopamine from levodopa in the absence and presence of carbidopa, an inhibitor of  dopamine decarboxylase in the peripheral tissues. Gl = gast roi ntesti nal .   2. Actions: Levodopa decreases the rigidity, tremors, and other symptoms of parkinsonism.   3. Therapeutic uses: Levodopa in combination with carbidopa is a potent and efficacious drug regimen currently  available to treat Parkinson's disease. In approximately two-thirds of patients with Parkinson's disease,  levodopaa€" carbidopa treatment substantially reduces the severity of the disease for the first few years of  treatment. Patients then typically experience a decline in response during the third to fifth year of therapy.   4. Absorption and metabolism: The drug is absorbed rapidly from the small intestine (when empty of food).   Levodopa has an extremely short half-life (1 to 2 hours), which causes fluctuations in plasma concentration. This  may produce fluctuations in motor response, which generally correlate with the plasma concentrations of  levodopa, or perhaps give rise to the more troublesome a€oeon-offa€§? phenomenon, in which the motor  fluctuations are not related to plasma levels in a simple way. Motor fluctuations may cause the patient to  suddenly lose normal mobility and experience tremors, cramps, and immobility. Ingestion of meals, particularly  if high in protein, interferes with the transport of levodopa into the CNS. Large, neutral amino acids (for  example, leucine and isoleucine) compete with levodopa for absorption from the gut and for transport across  the blood-brain barrier. Thus, levodopa should be taken on an empty stomach, typically 45 minutes before a  meal. Withdrawal from the drug must be gradual.   a. Peripheral effects: Anorexia, nausea, and vomiting occur because of stimulation of the chemoreceptor  trigger zone of the medulla. (Figure 8.8). Tachycardia and ventricular extra systoles result from  dopaminergic action on the heart. Hypotension may also develop. Adrenergic action on the iris causes  mydriasis, and in some individuals, blood dyscrasias and a positive reaction to the Coombs' test are seen.  Saliva and urine are a brownish color because of the melanin pigment produced from catecholamine  oxidation.   b. CNS effects: Visual and auditory hallucinations and abnormal involuntary movements (dyskinesias) may  occur. These CNS effects are the opposite of parkinsonian symptoms and reflect the overactivity of  dopamine at receptors in the basal ganglia. Levodopa can also cause mood changes, depression, psychosis,  and anxiety.   6. Interactions: The vitamin pyridoxine (Be) increases the peripheral breakdown of levodopa and diminishes its  effectiveness (Figure 8.9). Concomitant administration of levodopa and monoamine oxidase (MAO) inhibitors,  such as phenelzine, can produce a hypertensive crisis caused by enhanced catecholamine production;  therefore, caution is required when they are used simultaneously. In many psychotic patients, levodopa  exacerbates symptoms, possibly through the buildup of central catecholamines. In patients with glaucoma, the  drug can cause an increase in intraocular pressure. Cardiac patients should be carefully monitored because of   generally contraindicated in parkinsonian patients, because these potently block dopamine receptors and  produce a parkinsonian syndrome themselves. However low doses of certain a€oeatypicala€§ antipsychotic  agents are sometimes employed to treat levodopa-induced psychiatric symptoms.   Selegiline [seh-LEDGE-ah-leen], also called deprenyl [DE-pre-nill], selectively inhibits MAO Type B (which  metabolizes dopamine) at low to moderate doses but does not inhibit MAO Type A (which metabolizes  norepinephrine and serotonin) unless given at above recommended doses, where it loses its selectivity. By thus  decreasing the metabolism of dopamine, selegiline has been found to increase dopamine levels in the brain (Figure  8. 10). Therefore, it enhances the actions of levodopa when these drugs are administered together. Selegiline  substantially reduces the required dose of levodopa. Unlike nonselective MAO inhibitors, selegiline at  recommended doses has little potential for causing hypertensive crises. However, if selegiline is administered at  high doses, the selectivity of the drug is lost, and the patient is at risk for severe hypertension. [Note: Early reports  of possible neuroprotective effects of selegiline have not been supported by long-term studies. ] Selegiline is  metabolized to methamphetamine and amphetamine, whose stimulating properties may produce insomnia if the  drug is administered later than midafternoon. (See p. 148 for the use of selegiline in treating depression).  Rasagiline [ra-SA-gi-leen], an irreversible and selective inhibitor of brain (MAO) Type B, has five times the potency  of selegiline. Unlike selegiline, it is not metabolized to an amphetamine-like substance.   Normally, the methylation of levodopa by catechol-O- methyltransferase (COMT) to 3-O-methyldopa is a minor  pathway for levodopa metabolism. However, when peripheral dopamine decarboxylase activity is inhibited by  carbidopa, a significant concentration of 3-O-methyldopa is formed that competes with levodopa for active  transport into the CNS (Figure 8.11). Inhibition of COMT by entacapone [en-TA-ka-pone] or tolcapone [TOLE-  ka-pone] leads to decreased plasma concentrations of 3-O-methyldopa, increased central uptake of levodopa, and  greater concentrations of brain dopamine. Both of these agents have been demonstrated to reduce the symptoms of  a€oewearing-offa€§ phenomena seen in patients on I evodopaa€" carbidopa. Entacapone and tolcapone are    nitrocatechol derivatives that selectively and reversibly inhibit COMT. The two drugs differ primarily in their  pharmacokinetics and in some adverse effects.   Figure 8.10 Action of selegiline (deprenyl) in dopamine metabolism. MAO =monoamine oxidase Type B.    1. Pharmacokinetics: Oral absorption of both drugs occurs readily and is not influenced by food. They are   extensively bound to plasma albumin ( >98 percent), with limited volumes of distribution. Tolcapone differs from  entacapone in that the former penetrates the blood-brain barrier and inhibits COMT in the CNS. However, the  inhibition of COMT in the periphery appears to be the primary therapeutic action. Tolcapone has a relatively  long duration of action (probably due to its affinity for the enzyme) compared to entacapone, which requires  more frequent dosing. Both drugs are extensively metabolized and eliminated in the feces and urine. Dosage  may need to be adj usted in patients with moderate or severe cirrhosis.    Inhibition of COMT by eaiaccpoo* leads to decreased  plasma concentrations of 3-O-methyldopa.   Increased central uptake of levodopa, and  greater concentrations of brain dopamine.    Figure 8.11 Effect of entacapone on dopa concentration in the central nervous system (CNS). COMT =  catechol-O-methyltransferase.    2. Adverse effects: Both drugs exhibit adverse effects that are observed in patients taking levodopaa€" carbidopa,  including diarrhea, postural hypotension, nausea, anorexia, dyskinesias, hallucinations, and sleep disorders.    Most seriously, fulminating hepatic necrosis is associated with tolcapone use. Therefore, it should be  useda€"along with appropriate hepatic function monitoringa€"only in patients in whom other modalities have  failed. Entacapone does not exhibit this toxicity and has largely replaced tolcapone.   This group of anti-Parkinson compounds includes bromocriptine, an ergot derivative, and two newer, nonergot  drugs, ropinirole, pramipexole and rotigotine. These agents have durations of action longer than that of levodopa  and, thus, have been effective in patients exhibiting fluctuations in their response to levodopa. Initial therapy with  the newer drugs is associated particularly with less risk of developing dyskinesias and motor fluctuations when  compared to patients started with levodopa therapy. Bromocriptine, pramipexole, and ropinirole are all effective  in patients with advanced Parkinson's disease complicated by motor fluctuations and dyskinesias. However, these  drugs are ineffective in patients who have shown no therapeutic response to levodopa. Apomorphine is also used in  severe and advanced stages of the disease as an inj ectable dopamine agonist to supplement the oral medications  commonly prescribed.   1. Bromocriptine: Bromocriptine [broe-moe-KRIP-teen], a derivative of the vasoconstrictive alkaloid, ergotamine,  is a dopamine-receptor agonist. The dose is increased gradually during a period of 2 to 3 months. Side effects  severely limit the utility of the dopamine agonists (Figure 8. 12). The actions of bromocriptine are similar to  those of levodopa, except that hallucinations, confusion, delirium, nausea, and orthostatic hypotension are  more common, whereas dyskinesia is less prominent. In psychiatric illness, bromocriptine and levodopa may  cause the mental condition to worsen. Serious cardiac problems may develop, particularly in patients with a  history of myocardial infarction. In patients with peripheral vascular disease, a worsening of the vasospasm  occurs, and in patients with peptic ulcer, there is a   worsening of the ulcer. Because bromocriptine is an ergot derivative, it has the potential to cause pulmonary  and retroperitoneal fibrosis.   2. Apomorphine, pramipexole, ropinirole, and rotigotine: These are nonergot dopamine agonists that have been  approved for the treatment of Parkinson's disease. Pramipexole [pra-mi-PEX-ole] and ropinirole [roe-PIN-  i-role] are agonists at dopamine receptors. Apomorphine [A-po-mor-feen] and rotigotine [ro-TI-go-teen] are  newer dopamine agonists available in inj ectable and transdermal delivery systems, respectively. Apomorphine is  meant to be used for the acute management of the hypomobility a€oeoffa€§ phenomenon. These agents  alleviate the motor deficits in both levodopa-nak've patients (patients who have never been treated with  levodopa ) and patients with advanced Parkinson's disease who are taking levodopa. Dopamine agonists may  delay the need to employ levodopa therapy in early Parkinson's disease and may decrease the dose of levodopa  in advanced Parkinson's disease. Unlike the ergotamine derivatives, pramipexole and ropinirole do not  exacerbate peripheral vasospasm, nor do they cause fibrosis. Nausea, hallucinations, insomnia, dizziness,  constipation, and orthostatic hypotension are among the more distressing side effects of these drugs;  dyskinesias are less frequent than with levodopa. The dependence of pramipexole on renal function for its  elimination cannot be overly stressed. For example, cimetidine, which inhibits renal tubular secretion of  organic bases, increases the half-life of pramipexole by 40 percent. The fluoroquinolone antibiotics (see p. 387)  and other inhibitors of the CYP450-1A2 hepatic enzyme have been shown to inhibit the metabolism of ropinirole  and to enhance the AUC (area under the concentration vs. time curve) by some 80 percent. Rotigotine is a  dopamine agonist used in the treatment of the signs and symptoms of early stage Parkinson's disease. It is  administered as a once-daily transdermal patch that provides even pharmacokinetics over 24 hours. Figures 8. 13  summarizes some properties of these dopamine agonists.   It was accidentally discovered that the antiviral drug amantadine [a-MAN-ta-deen], which is effective in the  treatment of influenza (see p. 437), has an antiparkinsonism action. Amantadine has several effects on a number of  neurotransmitters implicated in causing parkinsonism, including increasing the release of dopamine, blockading  cholinergic receptors, and inhibiting the N-methyl-D-aspartate (NMDA) type of glutamate receptors. Current  evidence supports an action at NMDA receptors as the primary action at therapeutic concentrations. [Note: If   dopamine release is already at a maximum, amantadine has no effect. ] The drug may cause restlessness, agitation,  confusion, and hallucinations, and at high doses, it may induce acute toxic psychosis. Orthostatic hypotension,  urinary retention, peripheral edema, and dry mouth also may occur. Amantadine is less efficacious than levodopa,  and tolerance develops more readily. However, amantadine has fewer side effects. The drug has little effect on  tremor, but it is more effective than the anticholinergics against rigidity and bradykinesia.    Figure 8.13 Pharmacokinetic properties of dopamine agonists of pramipexole, ropinirole and rotigotine. Vd  =volume of distribution, increases to 12 hours in patients older than 65 years; 2 Less than 10 percent  excreted unchanged; Administered as a once-daily transdermal patch.   The antimuscarinic agents are much less efficacious than levodopa and play only an adj uvant role in  antiparkinsonism therapy. The actions of benztropine [BENZ-tro-peen], trihexyphenidyl [tri-hex-ee FEN-i-dill],  procyclidine [pro-CY-cli-deen], and biperiden [bi-PER-i den] are similar, although individual patients may respond  more favorably to one drug. All of these drugs can induce mood changes and produce xerostomia (dryness of the  mouth) and visual problems, as do all muscarinic blockers. They interfere with gastrointestinal peristalsis and are  contraindicated in patients with glaucoma, prostatic hyperplasia, or pyloric stenosis. Blockage of cholinergic  transmission produces effects similar to augmentation of dopaminergic transmission (again, because of the creation  of an imbalance in the dopamine/ acetylcholine ratio, see Figure 8.6). Adverse effects are similar to those caused by  high doses of atropinea€"for example, pupillary dilation, confusion, hallucination, sinus tachycardia, urinary  retention, constipation, and dry mouth.   Pharmacologic intervention for Alzheimer's disease is only palliative and provides modest short-term benefit. None  of the currently available therapeutic agents have been shown to alter the underlying neurodegenerative process.  Dementia of the Alzheimer's type (versus the other forms of dementia that will not be addressed in this discussion,  such as multi-infarct dementia or Lewy body dementia) has three distinguishing features: 1) accumulation of senile  plaques (f 2 -amyloid accumulations), 2) formation of numerous neurofibrillary tangles, and 3) loss of cortical  neuronsaC" particularly cholinergic neurons. Current therapies are aimed at either improving cholinergic  transmission within the CNS or preventing excitotoxic actions resulting from overstimulation of N-methyl-D-aspartic  acid (NMDA)-glutamate receptors in selected brain areas.   Numerous studies have linked the progressive loss of cholinergic neurons and, presumably, cholinergic transmission  within the cortex to the memory loss that is a hallmark symptom of Alzheimer's disease. It is postulated that  inhibition of acetylcholinesterase (AChE) within the CNS will improve cholinergic transmission, at least at those  neurons that are still functioning. Currently, four reversible AChE inhibitors are approved for the treatment of mild  to moderate Alzheimer's disease. They are donepezil [dah-NE-peh-zeel], galantamine [ga-LAN-ta-meen],  rivastigmine [ri-va-STIG-meen], and tacrine [TAK-reen], Except for galantamine, which is competitive, all are   uncompetitive inhibitors of AChE and appear to have some selectivity for AChE in the CNS as compared to the  periphery. Galantamine may also be acting as an allosteric modulator of the nicotinic receptor in the CNS and,  therefore, secondarily increase cholinergic neurotransmission through a separate mechanism. At best, these  compounds   provide a modest reduction in the rate of loss of cognitive functioning in Alzheimer's patients. Rivastigmine is  hydrolyzed by AChE to a carbamylate metabolite and has no interactions with drugs that alter the activity of  P450-dependent enzymes. The other agents are substrates for P450 and have a potential for such interactions.   Common adverse effects include nausea, diarrhea, vomiting, anorexia, tremors, bradycardia, and muscle  crampsa€"all of which are predicted by the actions of the drugs to enhance cholinergic neurotransmission (Figure  8. 14). Unlike the others, tacrine is associated with hepatotoxicity.   Stimulation of glutamate receptors in the CNS appears to be critical for the formation of certain memories;  however, overstimulation of glutamate receptors, particularly of the NMDA type, has been shown to result in  excitotoxic effects on neurons and is suggested as a mechanism for neurodegenerative or apoptotic (programmed  cell death) processes. Binding of glutamate to the NMDA receptor assists in the opening of an associated ion channel  that allows Na + and, particularly, Ca 2+ to enter the neuron. Unfortunately, excess intracellular Ca 2+ can activate a  number of processes that ultimately damage neurons and lead to apoptosis. Antagonists of the NMDA-glutamate  receptor are often neuroprotective, preventing the loss of neurons following ischemic and other inj uries.   Memantine [MEM-an-teen] is a dimethyl adamantane derivative. Memantine acts by physically blocking the NMDA  receptora€"associated ion channel, but at therapeutic doses, only a fraction of these channels are actually blocked.   This partial blockade may allow memantine to limit Ca 2+ influx into the neuron such that toxic intracellular levels  are not achieved during NMDA receptor overstimulation, while still permitting sufficient Ca 2+ flow through  unblocked channels to preserve other vital processes that depend on Ca 2+ (or Na 4 ) influx through these channels.   This is in contrast to psychotoxic agents such as phencyclidine, which occupy and block nearly all of these channels.   In short term studies, memantine has been shown to slow the rate of memory loss in both vascular-associated and  Alzheimer's dementia in patients with moderate to severe cognitive losses. However, there is no evidence that  memantine prevents or slows the neurodegeneration in patients with Alzheimer's disease or is more effective than  the AChE inhibitors. Memantine is well tolerated, with few dose-dependent adverse events. Expected side effects,  such as confusion, agitation, and restlessness, are indistinguishable from the symptoms of Alzheimer's disease. Given  it's different mechanism of action and possible neuroprotective effects, memantine is often given in combination  with an AChE inhibitor. Long-term data showing a significant effect of this combination is not available.   Though not indicated for the treatment of Alzheimer's disease, another NMDA- receptor antagonist is indicated for  the management of amyotrophic lateral sclerosis (ALS). Riluzole [Rl-lu-zole] blocks glutamate, sodium channels and  calcium channels. It may improve the survival time and delay the need for ventilator support in patients suffering  from ALS.   8.1 Which one of the following combinations of antiparkinson drugs is an appropriate therapy?   8.2 Peripheral adverse effects of levodopa, including nausea, hypotension, and cardiac arrhythmias, can be  diminished by including which of the following drugs in the therapy?   8.3 Which of the following antiparkinson drugs may cause peripheral vasospasm?   8.4 Modest improvement in the memory of patients with Alzheimer's disease may occur with drugs that  increase transmission at which of the following receptors?   >Table of Contents > Unit III - Drugs Affecting the Central Nervous System >Chapter 9 - Anxiolytic and Hypnotic Drugs   Anxiety is an unpleasant state of tension, apprehension, or uneasinessa€"a fear that seems to arise from a  sometimes unknown source. Disorders involving anxiety are the most common mental disturbances. The physical  symptoms of severe anxiety are similar to those of fear (such as tachycardia, sweating, trembling, and palpitations)  and involve sympathetic activation. Episodes of mild anxiety are common life experiences and do not warrant  treatment. However, the symptoms of severe, chronic, debilitating anxiety may be treated with antianxiety drugs  (sometimes called anxiolytic or minor tranquilizers) and/or some form of behavioral or psychotherapy. Because  many of the antianxiety drugs also cause some sedation, the same drugs often function clinically as both anxiolytic  and hypnotic (sleep-inducing) agents. In addition, some have anticonvulsant activity. Figure 9.1 summarizes the  anxiolytic and hypnotic agents. Though also indicated for certain anxiety disorders, the selective serotonin  reuptake inhibitors (SSRIs) will be presented in the chapter discussing antidepressants.   Benzodiazepines are the most widely used anxiolytic drugs. They have largely replaced barbiturates and    meprobamate in the treatment of anxiety, because the benzodiazepines are safer and more effective (Figure 9.2).   The targets for benzodiazepine actions are the i 3 -aminobutyric acid (GABAa) receptors. [Note: GABA is the maj or  inhibitory neurotransmitter in the central nervous system (CNS) . ] These receptors are primarily composed of 1+ I 2  and I 3 subunit families of which a combination of five or more span the postsynaptic membrane (Figure 9.3).   Depending on the types, number of subunits, and brain region localization, the activation of the receptors results in  different pharmacologic effects. Benzodiazepines modulate the GABA effects by binding to a specific, high-affinity  site located at the interface of the ilsubunit and the i 3 2 subunit (see Figure 9.3). [Note: These binding sites are  sometimes labeled benzodiazepine receptors. Two benzodiazepine receptor subtypes commonly found in the CNS  have been designated as BZi and BZ 2 receptor depending on whether their composition includes the T±i subunit or  the T +2 subunit, respectively. The benzodiazepine receptor locations in the CNS parallel those of the GABA neurons.   Binding of GABA to its receptor triggers an opening of a chloride channel, which leads to an increase in chloride  conductance (see Figure 9. 3). Benzodiazepines increase the frequency of channel openings produced by GABA. The  influx of chloride ions causes a small hyperpolarization that moves the postsynaptic potential away from its firing  threshold and, thus, inhibits the formation of action potentials. [Note: Binding of a benzodiazepine to its receptor  site will increase the affinity of GABA for the GABA-binding site (and vice versa) without actually changing the total  number of sites.] The clinical effects of the various benzodiazepines correlate well with each drug's binding affinity  for the GABA receptora€"chloride ion channel complex.   The benzodiazepines have neither antipsychotic activity nor analgesic action, and they do not affect the autonomic  nervous system. All benzodiazepines exhibit the following actions to a greater or lesser extent:   1. Reduction of anxiety: At low doses, the benzodiazepines are anxiolytic. They are thought to reduce anxiety by  selectively enhancing GABAergic transmission in neurons having the i ±2 subunit in their GABA a receptors,  thereby inhibiting neuronal circuits in the limbic system of the brain.   2. Sedative and hypnotic actions: All of the benzodiazepines used to treat anxiety have some sedative properties,  and some can produce hypnosis (artificially produced sleep) at higher doses. Their effects have been shown to  be mediated by the I±l-GABAa receptors.   3. Anterograde amnesia: The temporary impairment of memory with use of the benzodiazepines is also mediated  by the I±l-GABAa receptors. This also impairs a person's ability to learn and form new memories.   4. Anticonvulsant: Several of the benzodiazepines have anticonvulsant activity and some are used to treat  epilepsy (status epilepticus) and other seizure disorders. This effect is partially, although not completely,  mediated by I±i-GABAa receptors.   5. Muscle relaxant: At high doses, the benzodiazepines relax the spasticity of skeletal muscle, probably by  increasing presynaptic inhibition in the spinal cord, where the 1+2 -GABAa receptors are largely located. Baclofen  is a muscle relaxant that is believed to affect GABAb receptors at the level of the spinal cord.   The individual benzodiazepines show small differences in their relative anxiolytic, anticonvulsant, and sedative  properties. Flowever, the duration of action varies widely among this group, and pharmacokinetic considerations are  often important in choosing one benzodiazepine over another.    Benzodiazepines are relatively  safe, because the lethal dose is  over 1000-fold greater than  the typical therapeutic dose.    Figure 9.2 Ratio of lethal dose to effective dose for morphine (an opioid, see Chapter 14), chlorpromazine  (a neuroleptic, see Chapter 13), and the anxiolytic, hypnotic drugs, phenobarbital and diazepam.   1. Anxiety disorders: Benzodiazepines are effective for the treatment of the anxiety symptoms secondary to panic  disorder, generalized anxiety disorder, social anxiety disorder, performance anxiety, posttraumatic stress  disorder, obsessive-compulsive disorder, and the extreme anxiety sometimes encountered with specific phobias,  such as fear of flying. The benzodiazepines are also useful in treating   the anxiety that accompanies some forms of depression and schizophrenia. These drugs should not be used to  alleviate the normal stress of everyday life. They should be reserved for continued severe anxiety, and then  should only be used for short periods of time because of their addiction potential. The longer-acting agents,  such as clonazepam [kloe-NAZ-e-pam], lorazepam [lor-AZ-e-pam], and diazepam [dye-AZ-e-pam], are often  preferred in those patients with anxiety that may require treatment for prolonged periods of time. The  antianxiety effects of the benzodiazepines are less subj ect to tolerance than the sedative and hypnotic effects.   [Note: Tolerancea€"that is, decreased responsiveness to repeated doses of the druga€"occurs when used for  more than one to two weeks. Cross-tolerance exists among this group of agents with ethanol. It has been shown  that tolerance is associated with a decrease in GABA receptor density. ] For panic disorders, alprazolam  [al-PRAY-zoe-lam] is effective for short- and long-term treatment, although it may cause withdrawal reactions in  about 30 percent of sufferers.    [ Entry of Cl hyperpolartzes the cell, making  it more difficult to depolarize, and therefore  reduces neural excitability.    Binding of OABA is  enhanced by benzo  diazepme, resulting in a  greater entry of chloride  Ion.    ion channel  to open, leading to hyper-  polarization of the cell.    Figure 9.3 Schematic diagram of benzodiazepine-GABA-chloride ion channel complex. GABA =l»-aminobutyric  acid.    2. Muscular disorders: Diazepam is useful in the treatment of skeletal muscle spasms, such as occur in muscle  strain, and in treating spasticity from degenerative disorders, such as multiple sclerosis and cerebral palsy.    Figure 9.4 Comparison of the durations of action of the benzodiazepines.    3. Amnesia: The shorter-acting agents are often employed as premedication for anxiety-provoking and unpleasant  procedures, such as endoscopic, bronchoscopic, and certain dental procedures as well as angioplasty. They also  cause a form of conscious sedation, allowing the person to be receptive to instructions during these procedures.  Midazolam [mi-DAY-zoe-lam] is an injectable-only benzodiazepine also used for the induction of anesthesia.   4. Seizures: Clonazepam is occasionally used in the treatment of certain types of epilepsy, whereas diazepam and  lorazepam are the drugs of choice in terminating grand mal epileptic seizures and status epilepticus (see p.    174), Due to cross-tolerance, chlordiazepoxide [klor-di-az-e-POX-ide], clorazepate [klor-AZ-e-pate],  diazepam, and oxazepam [ox-AZ-e-pam] are useful in the acute treatment of alcohol withdrawal and reducing  the risk of withdrawal-related seizures.   5. Sleep disorders: Not all benzodiazepines are useful as hypnotic agents, although all have sedative or calming  effects. They tend to decrease the latency to sleep onset and increase Stage II of non-rapid eye movement  (REM) sleep. Both REM sleep and slow-wave sleep are decreased. In the treatment of insomnia, it is important to  balance the sedative effect needed at bedtime with the residual sedation (a€oehangovera€^) upon awakening.  Commonly prescribed benzodiazepines for sleep disorders include long-acting flurazepam [flure-AZ-e-pam],  intermediate-acting temazepam [te-MAZ-e-pam], and short-acting triazolam [trye-AY-zoe-lam], Unlike the  benzodiazepines, at usual hypnotic doses, the nonbenzodiazepine drugs, zolpidem, zaleplon, and eszopiclone,  do not significantly alter the various sleep stages and, hence, are often the preferred hypnotics (see p. 113).  This may be due to their relative selectivity for the receptor.   a. Flurazepam: This long-acting benzodiazepine significantly reduces both sleep-induction time and the  number of awakenings, and it increases the duration of sleep. Flurazepam has a long-acting effect (Figure  9.4) and causes little rebound insomnia. With continued use, the drug has been shown to maintain its  effectiveness for up to 4 weeks. Flurazepam and its active metabolites have a half-life of approximately 85  hours, which may result in daytime sedation and accumulation of the drug.   b. Temazepam: This drug is useful in patients who experience frequent wakening. However, the peak sedative  effect occurs 1 to 3 hours after an oral dose; therefore, it should be given 1 to 2 hours before the desired  bedtime.   c. Triazolam: This benzodiazepine has a relatively short duration of action and, therefore, is used to induce  sleep in patients with recurring insomnia. Whereas temazepam is useful for insomnia caused by the inability  to stay asleep, triazolam is effective in treating individuals who have difficulty in going to sleep. Tolerance  frequently develops within a few days, and withdrawal of the drug often results in rebound insomnia,  leading the patient to demand another prescription or higher dose. Therefore, this drug is best used  intermittently rather than daily. In general, hypnotics should be given for only a limited time, usually less  than 2 to 4 weeks.    The drugs that are more  potent and rapidly eliminated  (for example, triazolam)  have more frequent and  severe withdrawal problems.    The less potent and more  slowly eliminated drugs  (for example, flurazepam )  continue to improve sleep  even after discontinuation.    Figure 9.5 Frequency of rebound insomnia resulting from discontinuation of benzodiazepine therapy.    1. Absorption and distribution: The benzodiazepines are lipophilic, and they are rapidly and completely absorbed  after oral administration and distribute throughout the body.   2. Duration of actions: The half-lives of the benzodiazepines are very important clinically, because the duration  of action may determine the therapeutic usefulness. The benzodiazepines can be roughly divided into short-,  intermediate-, and long-acting groups (see Figure 9.4). The longer-acting agents form active metabolites with  long half-lives. Flowever, with some benzodiazepines, the clinical durations of action do not always correlate  with actual half-lives (otherwise we would, conceivably, give a dose of diazepam every other day or even less  often given its active metabolites). This may be due to receptor dissociation rates in the CNS and subsequent  redistribution elsewhere.   3. Fate: Most benzodiazepines, including chlordiazepoxide and diazepam, are metabolized by the hepatic  microsomal system to compounds that are also active. For these benzodiazepines, the apparent half-life of the  drug represents the combined actions of the parent drug and its metabolites. The drugs' effects are terminated  not only by excretion but also by redistribution. The benzodiazepines are excreted in the urine as glucuronides  or oxidized metabolites. All the benzodiazepines cross the placental barrier and may depress the CNS of the  newborn if given before birth. Nursing infants may also become exposed to the drugs in breast milk.   Psychological and physical dependence on benzodiazepines can develop if high doses of the drugs are given over a  prolonged period. Abrupt discontinuation of the benzodiazepines results in withdrawal symptoms, including  confusion, anxiety, agitation, restlessness, insomnia, tension, and rarely, seizures. Because of the long half-lives of  some benzodiazepines, withdrawal symptoms may occur slowly and last a number of days after discontinuation of  therapy. Benzodiazepines with a short elimination half-life, such as triazolam, induce more abrupt and severe  withdrawal reactions than those seen with drugs that are slowly eliminated, such as flurazepam (Figure 9.5).    1. Drowsiness and confusion: These effects are the two most common side effects of the benzodiazepines. Ataxia  occurs at high doses and precludes activities that require fine motor coordination, such as driving an  automobile. Cognitive impairment (decreased long-term recall and acquisition of new knowledge) can occur  with use of benzodiazepines. Triazolam, one of the most potent oral benzodiazepines with the most rapid  elimination, often shows a rapid development of tolerance, early morning insomnia, and daytime anxiety, along  with amnesia and confusion.   2. Precautions: Benzodiazepines should be used cautiously in treating patients with liver disease. They should be  avoided in patients with acute narrow-angle glaucoma. Alcohol and other CNS depressants enhance the  sedative-hypnotic effects of the benzodiazepines. Benzodiazepines are, however, considerably less dangerous  than the   older anxiolytic and hypnotic drugs. As a result, a drug overdose is seldom lethal unless other central  depressants, such as alcohol, are taken concurrently.   Flumazenil [floo-MAZ-eh-nill] is a GABA-receptor antagonist that can rapidly reverse the effects of  benzodiazepines. The drug is available for intravenous administration only. Onset is rapid but duration is short, with  a half-life of about 1 hour. Frequent administration may be necessary to maintain reversal of a long-acting  benzodiazepine. Administration of flumazenil may precipitate withdrawal in dependent patients or cause seizures if  a benzodiazepine is used to control seizure activity. Seizures may also result if the patient ingests tricyclic  antidepressants. Dizziness, nausea, vomiting, and agitation are the most common side effects.   Buspirone [byoo-SPYE-rone] is useful in the treatment of generalized anxiety disorder and has an efficacy  comparable to that of the benzodiazepines. The actions of buspirone appear to be mediated by serotonin (5-HTia)  receptors, although other receptors could be involved, because buspirone displays some affinity for DA 2 dopamine  receptors and 5 -HT 2 A serotonin receptors. Thus, its mode of action differs from that of the benzodiazepines. [Note:  a€oe5-HTa€i and not a€oeSa€^l is the accepted abbreviation for serotonin (5-hydroxytryptamine) receptors.] In  addition, buspirone lacks the anticonvulsant and muscle-relaxant properties of the benzodiazepines and causes only  minimal sedation. However, it causes hypothermia and can increase prolactin and growth hormone. Buspirone  undergoes metabolism by CYP3A4; thus, its half-life is shortened if taken with rifampin and lengthened if taken  with erythromycina€"an inducer and an inhibitor of the enzyme, respectively. The frequency of adverse effects is  low, with the most common effects being headaches, dizziness, nervousness, and light-headedness. Sedation and  psychomotor and cognitive dysfunction are minimal, and dependence is unlikely. Buspirone has the disadvantage of  a slow onset of action. Figure 9. 6 compares some of the common adverse effects of buspirone and the  benzodiazepine alprazolam.    Figure 9.6 Comparison of common adverse effects of buspirone and alprazolam. Results are expressed as  the percentage of patients showing each symptom.   Hydroxyzine [hye-DROX-i-zeen] is an antihistamine with antiemetic activity. It has a low tendency for habituation  and, thus, is useful for patients with anxiety who have a history of drug abuse. It is also often used for sedation  prior to dental procedures or surgery. Drowsiness is a possible adverse effect (see p. 552).   Many antidepressants have proven efficacy in managing the long-term symptoms of chronic anxiety disorders and  should be seriously considered as first-line agents, especially in patients with concerns for addiction or dependence  or a history of addiction or dependence to other substances. The SSRIs, TCAs, venlafaxlne, duloxetlne and MAOIs  all have potential usefulness in treating anxiety. Please refer to Chapter 12 for a discussion of the antidepressant  agents.   The barbiturates were formerly the mainstay of treatment to sedate the patient or to induce and maintain sleep.  Today, they have been largely replaced by the benzodiazepines, primarily because barbiturates induce tolerance,   drug-metabolizing enzymes, physical dependence, and are associated with very severe withdrawal symptoms.  Foremost is their ability to cause coma in toxic doses. Certain barbiturates, such as the very short-acting  thiopental, are still used to induce anesthesia (see p. 135).   The sedative-hypnotic action of the barbiturates is due to their interaction with GABA* receptors, which enhances  GABAergic transmission. The binding site is distinct from that of the benzodiazepines. Barbiturates potentiate GABA  action on chloride entry into the neuron by prolonging the duration of the chloride channel openings. In addition,  barbiturates can block excitatory glutamate receptors. Anesthetic concentrations of pentobarbital also block  high-frequency sodium channels. All of these molecular actions lead to decreased neuronal activity.   Barbiturates are classified according to their duration of action (Figure 9.7). For example, thiopental [thye-  oh-PEN-tal], which acts within seconds and has a duration of action of about 30 minutes, is used in the intravenous  induction of anesthesia. By contrast, phenobarbital [fee-noe-BAR-bi-tal], which has a duration of action greater  than a day, is useful in the treatment of seizures (see p. 178). Pentobarbital [pen-toe-BAR-bi-tal], secobarbital  [see-koe-BAR-bi-tal], and amobarbital [am-oh-BAR-bi-tal] are short-acting barbiturates, which are effective as  sedative and hypnotic (but not antianxiety) agents.    1. Depression of CNS: At low doses, the barbiturates produce sedation (calming effect, reducing excitement). At  higher doses, the drugs cause hypnosis, followed by anesthesia (loss of feeling or sensation), and finally, coma  and death. Thus, any degree of depression of the CNS is possible, depending on the dose. Barbiturates do not  raise the pain threshold and have no analgesic properties. They may even exacerbate pain. Chronic use leads to  tolerance.   2. Respiratory depression: Barbiturates suppress the hypoxic and chemoreceptor response to CO 2 , and overdosage  is followed by respiratory depression and death.   3. Enzyme induction: Barbiturates induce P450 microsomal enzymes in the liver. Therefore, chronic barbiturate  administration diminishes the action of many drugs that are dependent on P450 metabolism to reduce their   1. Anesthesia: Selection of a barbiturate is strongly influenced by the desired duration of action. The ultrashort-  acting barbiturates, such as thiopental, are used intravenously to induce anesthesia.   2. Anticonvulsant: Phenobarbital is used in long-term management of tonic-clonic seizures, status epilepticus,  and eclampsia. Phenobarbital has been regarded as the drug of choice for treatment of young children   with recurrent febrile seizures. However, phenobarbital can depress cognitive performance in children, and  the drug should be used cautiously. Phenobarbital has specific anticonvulsant activity that is distinguished from  the nonspecific CNS depression.   3. Anxiety: Barbiturates have been used as mild sedatives to relieve anxiety, nervous tension, and insomnia. When  used as hypnotics, they suppress REM sleep more than other stages. However, most have been replaced by the  benzodiazepines.   Barbiturates are absorbed orally and distributed widely throughout the body. All barbiturates redistribute in the  body from the brain to the splanchnic areas, to skeletal muscle, and finally, to adipose tissue. This movement is  important in causing the short duration of action of thiopental and similar short-acting derivatives. They readily  cross the placenta and can depress the fetus. Barbiturates are metabolized in the liver, and inactive metabolites are  excreted in the urine.   1. CNS: Barbiturates cause drowsiness, impaired concentration, and mental and physical sluggishness (Figure 9.8).  The CNS depressant effects of barbiturates synergize with those of ethanol.   2. Drug hangover: Hypnotic doses of barbiturates produce a feeling of tiredness well after the patient wakes. This  drug hangover may lead to impaired ability to function normally for many hours after waking. Occasionally,  nausea and dizziness occur.   3. Precautions: As noted previously, barbiturates induce the P450 system and, therefore, may decrease the  duration of action of drugs that are metabolized by these hepatic enzymes. Barbiturates increase porphyrin   4. Physical dependence: Abrupt withdrawal from barbiturates may cause tremors, anxiety, weakness, restlessness,  nausea and vomiting, seizures, delirium, and cardiac arrest. Withdrawal is much more severe than that  associated with opiates and can result in death.   5. Poisoning: Barbiturate poisoning has been a leading cause of death resulting from drug overdoses for many  decades. Severe depression of respiration is coupled with central cardiovascular depression, and results in a  shock-like condition with shallow, infrequent breathing. Treatment includes artificial respiration and purging  the stomach of its contents if the drug has been recently taken. [Note: No specific barbiturate antagonist is  available.] Hemodialysis may be necessary if large quantities have been taken. Alkalinization of the urine often  aids in the elimination of phenobarbital .   The hypnotic zolpidem [ZOL-pi-dem] is not a benzodiazepine in structure, but it acts on a subset of the  benzodiazepine receptor family, BZi. Zolpidem has no anticonvulsant or muscle-relaxing properties. It   shows few withdrawal effects, and exhibits minimal rebound insomnia, and little or no tolerance occurs with  prolonged use. Zolpidem is rapidly absorbed from the gastrointestinal tract, and it has a rapid onset of action and  short elimination half-life (about 2 to 3 hours). [Note: An extended-release formulation is now available.] Zolpidem  undergoes hepatic oxidation by the cytochrome P450 system to inactive products. Thus, drugs such as rifampin,  which induce this enzyme system, shorten the half-life of zolpidem, and drugs that inhibit the CYP3A4 isoenzyme  may increase the half-life this drug. Adverse effects of zolpidem include nightmares, agitation, headache,  gastrointestinal upset, dizziness, and daytime drowsiness.   Zaleplon (ZAL-e-plon) is very similar to zolpidem in its hypnotic actions, but it causes fewer residual effects on  psychomotor and cognitive functions compared to zolpidem or the benzodiazepines. This may be due to its rapid  elimination, with a half-life that approximately 1 hour. The drug is metabolized by CYP3A4 (see p. 15).   Eszopiclone [es-ZOE-pi-clone] is an oral nonbenzodiazepine hypnotic (also utilizing the BZi receptor similar to  zolpidem and zaleplon ) and is also used for treating insomnia. Eszopiclone been shown to be effective for up to 6  months compared to a placebo. Eszopiclone is rapidly absorbed (time to peak, 1 hour), extensively metabolized by  oxidation and demethylation via the cytochrome enzyme system and mainly excreted in the urine. Elimination  half-life is approximately 6 hours. Adverse events reported with eszopiclone include anxiety, dry mouth, headache,  peripheral edema, somnolence, and unpleasant taste.   Ramelteon [ram-EL-tee-on] is a selective agonist at the MTi and MT 2 subtypes of melatonin receptors. Normally,  light stimulating the retina transmits a signal to the suprachiasmatic nucleus (SCN) of the hypothalamus, that in turn  relays a signal via a lengthy nerve pathway to the pineal gland that inhibits the release of melatonin from the gland.   As darkness falls and light ceases to strike the retina, melatonin release from the pineal gland is no longer inhibited,  and the gland begins to secrete melatonin. Stimulation of MTi and MT 2 receptors by melatonin in the SCN is able to  induce and promote sleep and is thought to maintain the circadian rhythm underlying the normal sleep-wake cycle.  Ramelteon is indicated for the treatment of insomnia in which falling asleep (increased sleep latency) is the primary  complaint. The potential for abuse of ramelteon is believed to be minimal, and no evidence of dependence or  withdrawal effects has been observed. Therefore, ramelteon can be administered long-term. Common adverse    effects of ramelteon include dizziness, fatigue, and somnolence. Ramelteon may also increase prolactin levels.   Chloral hydrate [KLOR-al-HYE-drate] is a trichlorinated derivative of acetaldehyde that is converted to the active  metabolite, trichloroethanol, in the body. The drug is an effective sedative and hypnotic that induces sleep in  about 30 minutes and the duration of sleep is about 6 hours. Chloral hydrate is irritating to the gastrointestinal  tract and causes epigastric    distress. It also produces an unusual, unpleasant taste sensation. It synergizes with ethanol.   Nonprescription antihistamines with sedating properties, such as diphenhydramine and doxylamine, are effective in  treating mild types of insomnia. However, these drugs are usually ineffective for all but the milder forms of  situational insomnia. Furthermore, they have numerous undesirable side effects (such as anticholinergic effects)  that make them less useful than the benzodiazepines. These sedative antihistamines are marketed in numerous  over-the-counter products.   Ethanol ( ethyl alcohol ) has anxiolytic and sedative effects, but its toxic potential outweighs its benefits.   Alcoholism is a serious medical and social problem. Ethanol [ETH-an-ol] is a CNS depressant, producing sedation  and, ultimately, hypnosis with increasing dosage. Ethanol has a shallow dosea€" response curve; therefore, sedation  occurs over a wide dosage range. It is readily absorbed orally and has a volume of distribution close to that of total  body water. Ethanol is metabolized primarily in the liver, first to acetaldehyde by alcohol dehydrogenase and then  to acetate by aldehyde dehydrogenase (Figure 9.9), Elimination is mostly through the kidney, but a fraction is  excreted through the lungs. Ethanol synergizes with many other sedative agents and can produce severe CNS  depression with benzodiazepines, antihistamines, or barbiturates. Chronic consumption can lead to severe liver  disease, gastritis, and nutritional deficiencies. Cardiomyopathy is also a consequence of heavy drinking. The  treatment of choice for alcohol withdrawal are the benzodiazepines. Carbamazepine is effective in treating  convulsive episodes during withdrawal.   Disulfiram causes  accumulation of  acetaldehyde, resulting  In flushing, tachycardia,  hyperventilation, and  nausea.    Figure 9.9 Metabolism of ethanol, and the effect of disulfiram. NAD+=oxidized form of nicotinamide-  adenine dinucleotide; NADH =reduced form of nicotinamide-adenine dinucleotide.    1. Disulfiram: Disulfiram [dye-SUL-fi-ram] blocks the oxidation of acetaldehyde to acetic acid by inhibiting    aldehyde dehydrogenase (see Figure 9.9). This results in the accumulation of acetaldehyde in the blood, causing  flushing, tachycardia, hyperventilation, and nausea. Disulfiram has found some use in the patient seriously  desiring to stop alcohol ingestion. A conditioned avoidance response is induced so that the patient abstains from  alcohol to prevent the unpleasant effects of d/'su/f/ram-induced acetaldehyde accumulation.   2. Naltrexone: Naltrexone [nal-TREX-own] is a long-acting opiate antagonist (available orally or as a long-acting  injectable) that is U.S. Food and Drug AdministrationaC" approved for the treatment of alcohol dependence and  should be utilized in conj unction with supportive psychotherapy. It is better tolerated than disulfiram and does  not produce the aversive reaction that disulfiram does.   3. Acamprosate: An agent utilized in alcohol dependence treatment programs with an as yet poorly understood  mechanism of action that should also be utilized in conj unction with supportive psychotherapy.   Figure 9. 10 summarizes the therapeutic disadvantages and advantages of some of the anxiolytic and hypnotic drugs.   • The benzodiazepines  have the potential for  dependence, and with-  drawal seizures may  occur.    • Has only marginal effects  on objective measures of  sleep efficacy.    The barbiturates induce  tolerance, drug-metab-  ollzing enzymes, and  physical dependence, and  they show severe with-  drawal symptoms.   • These less potent and more  slowly eliminated drugs  show no rebound insomnia  on discontinuation of  treatment.    Does not roguire Phase I  metabolism, therefore, shows  fewer drug interactions and Is  safer in patients with hepatic  impairment.    • Useful in long-term  therapy for chronic anxiety  with symptoms of  irritability and hostility.    • The potential for abuse is  minimal with minim nal  dependence or withdrawal  effects.    Figure 9.10 Therapeutic disadvantages and advantages of some anxiolytic and hypnotic agents. CNS =central  nervous system.   C. Clinical improvement of anxiety requires 2 to 4 weeks of treatment with benzodiazepines.   C. Phenobarbital is useful in the treatment of acute intermittent porphyria.   D. Phenobarbital induces respiratory depression, which is enhanced by the consumption of ethanol.   9.4 A 45-year-old man who has been injured in a car accident is brought into the emergency room. His blood  alcohol level on admission is 275 mg/dL. Hospital records show a prior hospitalization for alcohol-related  seizures. His wife confirms that he has been drinking heavily for 3 weeks. What treatment should be provided  to the patient if he goes into withdrawal?   >Table of Contents > Unit III - Drugs Affecting the Central Nervous System >Chapter 10 - CNS Stimulants   This chapter describes two groups of drugs that act primarily to stimulate the central nervous system (CNS). The  first group, the psychomotor stimulants, cause excitement and euphoria, decrease feelings of fatigue, and increase  motor activity. The second group, the hallucinogens, or psychotomimetic drugs, produce profound changes in  thought patterns and mood, with little effect on the brainstem and spinal cord. Figure 10. 1 summarizes the CNS  stimulants. As a group, the CNS stimulants have diverse clinical uses and are important as drugs of abuse, as are the  CNS depressants described in Chapter 9 and the narcotics described in Chapter 14 (Figure 10.2).   The methylxanthines include theophylline [thee-OFF-i-lin] which is found in tea; theobromine [thee-o-BRO-min],  found in cocoa; and caffeine [ kaf-EEN] . Caffeine, the most widely consumed stimulant in the world, is found in  highest concentration in coffee, but it is also present in tea, cola drinks, chocolate candy, and cocoa.   1. Mechanism of action: Several mechanisms have been proposed for the actions of methylxanthines, including  translocation of extracellular calcium, increase in cyclic adenosine monophosphate and cyclic guanosine  monophosphate caused by inhibition of phosphodiesterase, and blockade of adenosine receptors. The latter  most likely accounts for the actions achieved by the usual consumption of caffe/ne-containing beverages.   a. CNS: The caffeine contained in one to two cups of coffee (100a€"200 mg) causes a decrease in fatigue and  increased mental alertness as a result of stimulating the cortex and other areas of the brain. Consumption of  1. 5 g of caffeine (12 to 15 cups of coffee) produces anxiety and tremors. The spinal cord is stimulated only  by very high doses (2a€"5 g) of caffeine. Tolerance can rapidly develop to the stimulating properties of  caffeine ; withdrawal consists of feelings of fatigue and sedation.   b. Cardiovascular system: A high dose of caffeine has positive inotropic and chronotropic effects on the  heart. [Note:   Increased contractility can be harmful to patients with angina pectoris. In others, an accelerated heart rate  can trigger premature ventricular contractions.]   c. Diuretic action: Caffeine has a mild diuretic action that increases urinary output of sodium, chloride, and  potassium.   d. Gastric mucosa: Because all methylxanthines stimulate secretion of hydrochloric acid from the gastric  mucosa, individuals with peptic ulcers should avoid beverages containing methylxanthines.    3. Therapeutic uses: Caffeine and its derivatives relax the smooth muscles of the bronchioles. [Note: Previously  the mainstay of asthma therapy, theophylline has been largely replaced by other agents, such as T 2 2 agonists and  corticosteroids.]    4. Pharmacokinetics: The methylxanthines are well absorbed orally. Caffeine distributes throughout the body,  including the brain. The drugs cross the placenta to the fetus and is secreted into the mother's milk. All the  methylxanthines are metabolized in the liver, generally by the CYP1A2 pathway, and the metabolites are then  excreted in the urine.    5. Adverse effects: Moderate doses of caffeine cause insomnia, anxiety, and agitation. A high dosage is required  for toxicity, which is manifested by emesis and convulsions. The lethal dose is about 10 g of caffeine (about 100  cups of coffee), which induces cardiac arrhythmias; death from caffeine is thus highly unlikely. Lethargy,  irritability, and headache occur in users who have routinely consumed more than 600 mg of caffeine per day  (roughly six cups of coffee per day) and then suddenly stop.   Nicotine [NIC-o-teen] is the active ingredient in tobacco. Although this drug is not currently used therapeutically  (except in smoking cessation therapy, see p. 118), nicotine remains important, because it is second only to caffeine  as the most widely used CNS stimulant and second only to alcohol as the most abused drug. In combination with the  tars and carbon monoxide found in cigarette smoke, nicotine represents a serious risk factor for lung and    cardiovascular disease, various cancers, as well as other illnesses. Dependency on the drug is not easily overcome.    1. Mechanism of action: In low doses, nicotine causes ganglionic stimulation by depolarization. At high doses,  nicotine causes ganglionic blockade. Nicotine receptors exist at a number of sites in the CNS, which participate  in the stimulant attributes of the drug.    a. CNS: Nicotine is highly lipid soluble and readily crosses the blood-brain barrier. Cigarette smoking or   administration of low doses of nicotine produces some degree of euphoria and arousal as well as relaxation.  It improves attention, learning, problem solving, and reaction time. High doses of nicotine result in central  respiratory paralysis and severe hypotension caused by medullary paralysis (Figure 10.3). Nicotine is an  appetite suppressant.    b. Peripheral effects: The peripheral effects of nicotine are complex. Stimulation of sympathetic ganglia as  well as the adrenal medulla increases blood pressure and heart rate. Thus, use of tobacco is particularly  harmful in hypertensive patients. Many patients with peripheral vascular disease experience an exacerbation  of symptoms with smoking. For example, n/cot/ne-induced vasoconstriction can decrease coronary blood  flow, adversely affecting a patient with angina. Stimulation of parasympathetic ganglia also increases motor  activity of the bowel. At higher doses, blood pressure falls, and activity ceases in both the gastrointestinal  tract and bladder musculature as a result of a n/cot/ne-induced block of parasympathetic ganglia.    3. Pharmacokinetics: Because nicotine is highly lipid soluble, absorption readily occurs via the oral mucosa, lungs,  gastrointestinal mucosa, and skin. Nicotine crosses the placental membrane and is secreted in the milk of  lactating women. By inhaling tobacco smoke, the average smoker takes in 1 to 2 mg of nicotine per cigarette  (most cigarettes contain 6 to 8 mg of nicotine ). The acute lethal dose is 60 mg. More than 90 percent of the  nicotine inhaled in smoke is absorbed. Clearance of nicotine involves metabolism in the lung and the liver and  urinary excretion. Tolerance to the toxic effects of nicotine develops rapidly, often within days after beginning  usage.   4. Adverse effects: The CNS effects of nicotine include irritability and tremors. Nicotine may also cause intestinal  cramps, diarrhea, and increased heart rate and blood pressure. In addition, cigarette smoking increases the rate  of metabolism for a number of drugs.   5. Withdrawal syndrome: As with the other drugs in this class, nicotine is an addictive substance, and physical  dependence on nicotine develops rapidly and can be severe (Figure 10.4). Withdrawal is characterized by  irritability, anxiety, restlessness, difficulty concentrating, headaches, and insomnia. Appetite is affected, and  gastrointestinal pain often occurs. [Note: Smoking cessation programs that combine pharmacologic and  behavioral therapy are the most successful in helping individuals to stop smoking.] The transdermal patch and  chewing gum containing nicotine have been shown to reduce nicotine withdrawal symptoms and to help smokers  stop smoking. For example, the blood concentration of nicotine obtained from nicotine chewing gum is typically  about one-half the peak level observed with smoking (Figure 10.5). Bupropion, an antidepressant (see p. 145),  can reduce the craving for cigarettes.   Varenicline [ver-EN-e-kleen] is a partial agonist at a 4 b 2 neuronal nicotinic acetylcholine receptors in the CNS.  Because it is only a partial agonist at these receptors, it produces less euphoric effects than those produced by  nicotine itself (nicotine is a full agonist at these receptors). Thus, it is useful as an adj unct in the management of  smoking cessation in patients with nicotine withdrawal symptoms. Additionally, varenicline tends to attenuate the  rewarding effects of nicotine if a person relapses and uses tobacco. Patients should be monitored for suicidal  thoughts, vivid nightmares and mood changes.   Figure 10.5 Blood concentrations of nicotine in individuals who smoked cigarettes, chewed nicotine gum, or  received nicotine by transdermal patch.   Cocaine [KOE-kane] is a widely available and highly addictive drug that is currently abused daily by more than 3  million people in the United States. Because of its abuse potential, cocaine is classified as a Schedule II drug by the  U.S. Drug Enforcement Agency (see p. 541).    1. Mechanism of action: The primary mechanism of action underlying the central and peripheral effects of cocaine  is blockade of reuptake of the monoamines (norepinephrine, serotonin, and dopamine ) into the presynaptic  terminals from which these neurotransmitters are released (Figure 10.6). This blockade is caused by cocaine  binding to the monoaminergic reuptake transporters and, thus, potentiates and prolongs the CNS and peripheral  actions of these monoamines. In particular, the prolongation of dopaminergic effects in the brain's pleasure  system (limbic system) produces the intense euphoria that cocaine initially causes. Chronic intake of cocaine  depletes dopamine. This depletion triggers the vicious cycle of craving for cocaine that temporarily relieves  severe depression (Figure 10.7).    a. CNS: The behavioral effects of cocaine result from powerful stimulation of the cortex and brainstem.  Cocaine acutely increases mental awareness and produces a feeling of well-being and euphoria similar to  that caused by amphetamine. Like amphetamine, cocaine can produce hallucinations and delusions of  paranoia or grandiosity. Cocaine increases motor activity, and at high doses, it causes tremors and  convulsions, followed by respiratory and vasomotor depression.    b. Sympathetic nervous system: Peripherally, cocaine potentiates the action of norepinephrine, and it  produces the a€oef ight or flighta€^ syndrome characteristic of adrenergic stimulation. This is associated with  tachycardia, hypertension, pupillary dilation, and peripheral vasoconstriction. Recent evidence suggests  that the ability of baroreceptor reflexes to buffer the hypertensive effect may be impaired.   c. Hyperthermia: Cocaine is unique among illicit drugs in that death can result not only as a function of dose  but also from the drug's propensity to cause hyperthermia. [Note: Mortality rates for cocaine overdose rise  in hot weather. ] Even a small dose of intranasal cocaine impairs sweating and cutaneous vasodilatation.   3. Therapeutic uses: Cocaine has a local anesthetic action that represents the only current rationale for the  therapeutic use of cocaine. For example, cocaine is applied topically as a local anesthetic during eye, ear, nose,  and throat surgery. Whereas the local anesthetic action of cocaine is due to a block of voltage-activated sodium  channels, an interaction with potassium channels may contribute to the ability of cocaine to cause cardiac  arrhythmias. [Note: Cocaine is the only local anesthetic that causes vasoconstriction. This effect is responsible  for the necrosis and perforation of the nasal septum seen in association with chronic inhalation of cocaine  powder.]   4. Pharmacokinetics: Cocaine is often self-administered by chewing, intranasal snorting, smoking, or intravenous  (IV) inj ection. The peak effect occurs at 15 to 20 minutes after intranasal intake of cocaine powder, and the  a€oehigha€§ disappears in 1 to 1. 5 hours. Rapid but short-lived effects are achieved following IV injection of  cocaine or by smoking the freebase form of the drug (a€oecracka€§). Because the onset of action is most rapid,  the potential for overdosage and dependence is greatest with IV inj ection and crack smoking. Cocaine is rapidly  de-esterified and demethylated to benzoylecgonine, which is excreted in the urine. Detection of this substance  in the urine identifies a user.   a. Anxiety: The toxic response to acute cocaine ingestion can precipitate an anxiety reaction that includes  hypertension, tachycardia, sweating, and paranoia. Because of the irritability, many users take cocaine with  alcohol. A product of cocaine metabolites and ethanol is cocaethylene, which is also psychoactive and  believed to contribute to cardiotoxicity.   b. Depression: Like all stimulant drugs, cocaine stimulation of the CNS is followed by a period of mental  depression. Addicts withdrawing from cocaine exhibit physical and emotional depression as well as agitation.   c. Toxic effects: Cocaine can induce seizures as well as fatal cardiac arrhythmias (Figure 10.8). Use of IV  diazepam and propranolol may be required to control coca/ne-induced seizures and cardiac arrhythmias,  respectively. The incidence of myocardial infarction in cocaine users is unrelated to dose, to duration of  use, or to route of administration. There is no marker to identify those individuals who may have  life-threatening cardiac effects after taking cocaine.   Amphetamine [am-FE-ta-meen] is a noncatecholaminergic sympathetic amine that shows neurologic and clinical  effects quite similar to those of cocaine. Dextroamphetamine [dex-troe-am-FE-ta-meen] is the maj or member of  this class of compounds. Methamphetamine [meth-am-FET-ah-mine] (also known as a€oespeeda€§) is a derivative    of amphetamine that can be smoked, and it is preferred by many abusers.   1. Mechanism of action: As with cocaine, the effects of amphetamine on the CNS and peripheral nervous system  are indirect; that is, both depend upon an elevation of the level of catecholamine neurotransmitters in synaptic  spaces. Amphetamine, however, achieves this effect by releasing intracellular stores of catecholamines (Figure  10.9). Because amphetamine also inhibits monoamine oxidase (MAO), high levels of catecholamines are readily  released into synaptic spaces. Despite different mechanisms of action, the behavioral effects of amphetamine  and its derivatives are similar to those of cocaine.    a. CNS: The major behavioral effects of amphetamine result from a combination of its dopamine and  norepinephrine release-enhancing properties. Amphetamine stimulates the entire cerebrospinal axis,  cortex, brainstem, and medulla. This leads to increased alertness, decreased fatigue, depressed appetite,  and insomnia. These CNS stimulant effects of amphetamine and its derivatives have led to their use in  therapy for hyperactivity in children, narcolepsy, and for appetite control. At high doses, psychosis and  convulsions can ensue.    b. Sympathetic nervous system: In addition to its marked action on the CNS, amphetamine acts on the  adrenergic system, indirectly stimulating the receptors through norepinephrine release.   3. Therapeutic uses: Factors that limit the therapeutic usefulness of amphetamine include psychological and  physiological dependence similar to those with cocaine and the development of tolerance to the euphoric and  anorectic effects with chronic use. [Note: Less tolerance to the toxic CNS effects (for example, convulsions)  develops.]   a. Attention deficit hyperactivity disorder (ADHD): Some young children are hyperkinetic and lack the ability  to be involved in any one activity for longer than a few minutes. Dextroamphetamine and the  amphetamine derivative methylphenidate [meth-i ll-FEN-i-date] are able to improve attention and to  alleviate many of the behavioral problems associated with this syndrome, and to reduce the hyperkinesia  that such children demonstrate. Lisdexamfetamine [lis-dex-am-FE-ta-meen] is a prodrug that is converted  to the active component dextroamphetamine after gastrointestinal absorption and metabolism. The drug  prolongs the patient's span of attention allowing better function in a school atmosphere. Atomoxetine  [AT-oh-mox-e-teen] is a nonstimulant drug approved for ADFID in children and adults. [Note: It should not be  taken by individuals on MAO inhibitors, and it is not recommended for patients with narrow-angle glaucoma. ]   Unlike methylphenidate which blocks dopamine reuptake, atomoxetine is a norepinephrine reuptake  inhibitor. It is not habit forming and is not a controlled substance.   b. Narcolepsy: Narcolepsy is a relatively rare sleep disorder that is characterized by uncontrollable bouts of  sleepiness during the day. It is sometimes accompanied by catalepsy, a loss in muscle control, or even  paralysis brought on by strong emotions, such as laughter. Flowever, it is the sleepiness for which the patient  is usually treated with drugs such as amphetamine or methylphenidate. Recently, a newer drug, modafinil  (moe-DA-fi-nil), and its R-enantiomer derivative, armodafinil , have become available to treat narcolepsy.  Modafinil produces fewer psychoactive and euphoric effects as well as, alterations in mood, perception,  thinking, and feelings typical of other CNS stimulants. It does promote wakefulness. The mechanism of  action remains unclear but may involve the adrenergic and dopaminergic systems, although it has been  shown to differ from that of amphetamine. Modafinil is effective orally. It is well   distributed throughout the body and undergoes extensive hepatic metabolism. The metabolites are excreted  in the urine. Fleadaches, nausea, and rhinitis are the primary adverse effects. There is some evidence to  indicate the potential for abuse and physical dependence with modafinil.   4. Pharmacokinetics: Amphetamine is completely absorbed from the gastrointestinal tract, metabolized by the  liver, and excreted in the urine. [Note: Administration of urinary alkalinizing agents will increase the  non-ionized species of the drug and decrease its excretion.] Amphetamine abusers often administer the drugs  by IV injection and by smoking. The euphoria caused by amphetamine lasts 4 to 6 hours, or four- to eight-fold  longer than the effects of cocaine.    5. Adverse effects: The amphetamines may cause addiction, leading to dependence, tolerance, and drug-seeking  behavior. In addition, they have the following undesirable effects.    a. Central effects: Undesirable side effects of amphetamine usage include insomnia, irritability, weakness,  dizziness, tremor, and hyperactive reflexes (Figure 10.10). Amphetamine can also cause confusion,  delirium, panic states, and suicidal tendencies, especially in mentally ill patients. Chronic amphetamine use  produces a state of a€o eamphetamine psychosisa€^ : that resembles the psychotic episodes associated with   schizophrenia. Whereas long-term amphetamine use is associated with psychic and physical dependence,  tolerance to its effects may occur within a few weeks. Overdoses of amphetamine are treated with  chlorpromazine or haloperidol, which relieve the CNS symptoms as well as the hypertension because of  their T±- blocki ng effects. The anorectic effect of amphetamine is due to its action in the lateral  hypothalamic feeding center. 3,4-Methylenedioxymethamphetamine (also known as MDMA, or Ecstasy) is a  synthetic derivative of methamphetamine with both stimulant and hallucinogenic properties (see p. 537).   b. Cardiovascular effects: In addition to its CNS effects, amphetamine causes palpitations, cardiac  arrhythmias, hypertension, anginal pain, and circulatory collapse. Headache, chills, and excessive sweating  may also occur. Because of its cardiovascular effects, amphetamine should not be given to patients with  cardiovascular disease or those receiving MAO inhibitors.   c. Gastrointestinal system effects: Amphetamine acts on the gastrointestinal system, causing anorexia,  nausea, vomiting, abdominal cramps, and diarrhea. Administration of sodium bicarbonate will increase the  reabsorption of dextroamphetamine from the renal tubules into the bloodstream.   d. Contraindications: Patients with hypertension, cardiovascular disease, hyperthyroidism, or glaucoma should  not be treated with this drug, nor should patients with a history of drug abuse.   Methylphenidate has CNS stimulant properties similar to those of amphetamine and may also lead to abuse,  although its addictive potential   is controversial. It is a Schedule II drug (see p. 541). It is presently one of the most prescribed medications in  children. It is estimated that methylphenidate is taken daily by 4 to 6 million children in the United States for  ADHD. The pharmacologically active isomer, dexmethylphenidate, has been approved in the United States for the  treatment of ADHD.   1. Mechanism of action: Children with ADHD may produce weak dopamine signals, which suggests that usually  interesting activities provide fewer rewards to these children. At present, the basis for the stimulant effect of  methylphenidate is not understood. However, a recent study using positron-emission tomography has opened  up some interesting possibilities. It showed that methylphenidate is a more potent dopamine transport inhibitor  than cocaine, thus making more dopamine available. [Note: Methylphenidate may have less potential for abuse  than cocaine, because it enters the brain much more slowly than cocaine and, thus, does not increase dopamine  levels as rapidly.]   2. Therapeutic uses: Methylphenidate has been used for several decades in the treatment of ADHD in children  aged 6 to 16. It is also effective in the treatment of narcolepsy. Unlike methylphenidate, dexmethylphenidate  is not indicated in the treatment of narcolepsy.   3. Pharmacokinetics: Both methylphenidate and dexmethylphenidate are readily absorbed on oral  administration. Concentrations in the brain exceed those in the plasma. The de-esterified product, ritalinic  acid, is excreted in the urine.   4. Adverse reactions: Gastrointestinal effects are the most common. These include abdominal pain and nausea.   Other reactions include anorexia, insomnia, nervousness, and fever. In seizure patients, methylphenidate  seems to increase the seizure frequency, especially if the patient is taking antidepressants. Methylphenidate is  contraindicated in patients with glaucoma.   5. Drug interactions: Studies have shown that methylphenidate can interfere in the metabolism of warfarin,  diphenylhydantoin, phenobarbital, primidone, and the tricyclic antidepressants.   A few drugs have, as their primary action, the ability to induce altered perceptual states reminiscent of dreams.    Many of these altered states are accompanied by bright, colorful changes in the environment and by a plasticity of  constantly changing shapes and color. The individual under the influence of these drugs is incapable of normal  decision making, because the drug interferes with rational thought. These compounds are known as hallucinogens or  psychotomimetic drugs.   Multiple sites in the CNS are affected by lysergic acid diethylamide (LSD). The drug shows serotonin (5-HT) agonist  activity at presynaptic 5-HTi receptors in the midbrain, and also stimulates 5 -HT 2 receptors. Activation of the  sympathetic nervous system occurs, which causes pupillary dilation, increased blood pressure, piloerection, and  increased body temperature. Taken orally, low doses of LSD can induce hallucinations with brilliant colors. Mood  alteration also occurs. Tolerance   and physical dependence have occurred, but true dependence is rare. Adverse effects include hyperreflexia,  nausea, and muscular weakness. High doses may produce long-lasting psychotic changes in susceptible individuals.  Haloperidol and other neuroleptics can block the hallucinatory action of LSD and quickly abort the syndrome.   The main psychoactive alkaloid contained in marijuana is T' 9 -tetrahydrocannabinol [tet-ra-hi-dro-can-NAB-i-nol]   (' THC ), which is available as dronabinol [droe-NAB-i-nol], Depending on the social situation, THC can produce  euphoria, followed by drowsiness and relaxation. In addition to affecting short-term memory and mental activity,  THC decreases muscle strength and impairs highly skilled motor activity, such as that required to drive a car. Its  wide range of effects include appetite stimulation, xerostomia, visual hallucinations, delusions, and enhancement  of sensory activity. THC receptors, designated CB1 receptors, have been found on inhibitory presynaptic nerve  terminals that interact synaptically with pyramidal neurons. CB1 is coupled to a G protein. Interestingly, like the  endogenous ligands of the opioid system, endocannabinoids have been identified in the CNS. These compounds,  which bind to the CB1 receptors, are membrane-derived and are synthesized on demand, and they may act as local  neuromodulators (Figure 10.11). The action of THC is believed to be mediated through the CB1 receptors but is still  under investigation. The effects of THC appear immediately after the drug is smoked, but maximum effects take   about 20 minutes. By 3 hours, the effects largely disappear. Dronabinol is administered orally and has a peak effect  in 2 to 4 hours. Its psychoactive effects can last up to 6 hours, but its appetite-stimulant effects may persist for 24  hours. It is highly lipid soluble and has a large volume of distribution. THC itself is extensively metabolized by the  mixed-function oxidases. Elimination   is largely through the biliary route. Adverse effects include increased heart rate, decreased blood pressure, and  reddening of the conj unctiva. At high doses, a toxic psychosis develops (Figure 10. 12). Tolerance and mild physical  dependence occur with continued, frequent use of the drug. Dronabinol is indicated as an appetite stimulant for  patients with acquired immunodeficiency syndrome who are losing weight. It is also sometimes given for the severe  emesis caused by some cancer chemotherapeutic agents (see p. 337). The CBl-receptor antagonist, rimonabant  [ri-MOH-nah-bant], is effective in the treatment of obesity and has been found to decrease appetite and body  weight in humans. Rimonabant has also been found to induce psychiatric disturbances, such as anxiety and  depression, during clinical trials.   Phencyclidine [fen-SYE-kli-deen] (also known as PCP, or a€oeangel dusta€§) inhibits the reuptake of dopamine,  5-HT, and norepinephrine. The major action of phencyclidine is to block the ion channel regulated by the NMDA  subtype of glutamate receptor. This action prevents the passage of critical ions (particularly Ca 2+ ) through the  channel. Phencyclidine also has anticholinergic activity but, surprisingly, produces hypersalivation. Phencyclidine,  an analog of ketamine, causes dissociative anesthesia (insensitivity to pain, without loss of consciousness) and  analgesia. In this state, it produces numbness of extremities, staggered gait, slurred speech, and muscular rigidity.  Sometimes, hostile and bizarre behavior occurs. At increased dosages, anesthesia, stupor, or coma result, but  strangely, the eyes may remain open. Increased sensitivity to external stimuli exists, and the CNS actions may  persist for a week. Tolerance often develops with continued use.   10. 1 A very agitated young male was brought to the emergency room by the police. Psychiatric examination   revealed that he had snorted cocaine several times in the past few days, the last time being 10 hours  previously. He was given a drug that sedated him, and he fell asleep. The drug that was used to counter this  patient's apparent cocaine wihdrawal was very likely:   >Table of Contents > Unit III - Drugs Affecting the Central Nervous System >Chapter 11 - Anesthetics   General anesthesia is essential to surgical practice, because it renders patients analgesic, amnesic, and unconscious,  and provides muscle relaxation and suppression of undesirable reflexes. No single drug is capable of achieving these  effects both rapidly and safely. Rather, several different categories of drugs are utilized to produce optimal  anesthesia (Figure 11. 1). Preanesthetic medication serves to calm the patient, relieve pain, and protect against  undesirable effects of the subsequently administered anesthetic or the surgical procedure. Skeletal muscle  relaxants facilitate intubation and suppress muscle tone to the degree required for surgery. Potent general  anesthetics are delivered via inhalation or intravenous inj ection. With the exception of nitrous oxide, modern  inhaled anesthetics are all volatile, halogenated hydrocarbons that derive from early research and clinical  experience with diethyl ether and chloroform. On the other hand, intravenous general anesthetics consist of a  number of chemically unrelated drug types that are commonly used for the rapid induction of anesthesia.   During the preoperative phase, the anesthesiologist selects drugs that provide a safe and efficient anesthetic  regimen based on the nature of the surgical or diagnostic procedure as well as on the patient's physiologic,  pathologic, and pharmacologic state.   1. Liver and kidney: Because the liver and kidney not only influence the long-term distribution and clearance of  anesthetic agents but can also be the target organs for toxic effects, the physiologic status of these organs must  be considered. Of particular concern is that the release of fluoride, bromide, and other metabolic products of  the halogenated hydrocarbons can affect these organs, especially if the metabolites accumulate with repeated  anesthetic administration over a short period of time.    2. Respiratory system: The condition of the respiratory system must be considered if inhalation anesthetics are  indicated. For example, asthma and ventilation or perfusion abnormalities complicate control of an inhalation  anesthetic. All inhaled anesthetics depress the respiratory system. Additionally, they also are bronchodilators.   3. Cardiovascular system: Whereas the hypotensive effect of most anesthetics is sometimes desirable, ischemic  inj ury of tissues could follow reduced perfusion pressure. If a hypotensive episode during a surgical procedure  necessitates treatment, a vasoactive substance is administered. This is done after consideration of the  possibility that some anesthetics, such as halothane, may sensitize the heart to the arrhythmogenic effects of  sympathomimetic agents.    4. Nervous system: The existence of neurologic disorders (for example, epilepsy or myasthenia gravis) influences  the selection of an anesthetic. So, too, would a patient history suggestive of a genetically determined  sensitivity to halogenated hydrocarbona€"induced malignant hyperthermia.   5. Pregnancy: Some precautions should be kept in mind when anesthetics and adj unct drugs are administered to a  pregnant woman. There has been at least one report that transient use of nitrous oxide can cause aplastic  anemia in the unborn child. Oral clefts have occurred in the fetuses of women who have received  benzodiazepines. Diazepam should not be used routinely during labor, because it results in temporary  hypotonia and altered thermoregulation in the newborn.   1. Multiple adjunct agents: Commonly, surgical patients receive one or more of the following preanesthetic  medications: benzodiazepines, such as midazolam or diazepam, to allay anxiety and facilitate amnesia;  barbiturates, such as pentobarbital , for sedation; antihistamines, such as diphenhydramine, for prevention of  allergic reactions, or ranitidine, to reduce gastric acidity; antiemetics, such as ondansetron, to prevent the  possible aspiration of stomach contents; opioids, such as fentanyl, for analgesia; and/or anticholinergics, such  as scopolamine, for their amnesic effect and to prevent bradycardia and secretion of fluids into the respiratory  tract (Figure 11.2). These agents facilitate smooth induction of anesthesia, and when administered  continuously, they also lower the dose of anesthetic required to maintain the desired level of surgical (Stage III)  anesthesia. However, such coadministration can also enhance undesirable anesthetic effects (for example,  hypoventilation), and it may produce negative effects that are not observed when each drug is given  individually.   2. Concomitant use of additional nonanesthetic drugs: Surgical patients may be chronically exposed to agents for  the treatment of the underlying disease as well as to drugs of abuse that alter the response to anesthetics. For  example, alcoholics have elevated levels of hepatic microsomal enzymes involved in the metabolism of  barbiturates, and drug abusers may be overly tolerant of opioids.   Anesthesia can be divided into three stages: induction, maintenance, and recovery. Induction is defined as the  period of time from the onset of administration of the anesthetic to the development of effective surgical  anesthesia in the patient. Maintenance provides a sustained surgical anesthesia.   Recovery is the time from discontinuation of administration of the anesthesia until consciousness and protective  physiologic reflexes are regained. Induction of anesthesia depends on how fast effective concentrations of the  anesthetic drug reach the brain; recovery is the reverse of induction and depends on how fast the anesthetic drug  diffuses from the brain.   During induction, it is essential to avoid the dangerous excitatory phase (Stage II delirium) that was observed with  the slow onset of action of some earlier anesthetics (see below). Thus, general anesthesia is normally induced with  an intravenous anesthetic like thiopental, which produces unconsciousness within 25 seconds after inj ection. At  that time, additional inhalation or intravenous drugs comprising the selected anesthetic combination may be given  to produce the desired depth of surgical (Stage III) anesthesia. [Note: This often includes coadministration of an  intravenous skeletal muscle relaxant to facilitate intubation and relaxation. Currently used muscle relaxants include  pancuronium, doxacurium, rocuronium, vecuronium, cisatri curium, atracurium, mevacuri um and    succinylcholine.] For children, without intravenous access, nonpungent agents, such as halothane or sevoflurane,  are used to induce general anesthesia. This is termed inhalation induction.   Maintenance is the period during which the patient is surgically anesthetized. After administering the selected  anesthetic mixture, the anesthesiologist monitors the patient's vital signs and response to various stimuli throughout  the surgical procedure to carefully balance the amount of drug inhaled and/or infused with the depth of anesthesia.  Anesthesia is usually maintained by the administration of volatile anesthetics, because these agents offer good  minute-to-minute control over the depth of anesthesia. Opioids, such as fentanyl, are often used for pain along  with inhalation agents, because the latter are not good analgesics.   Postoperatively, the anesthesiologist withdraws the anesthetic mixture and monitors the return of the patient to  consciousness. For most anesthetic agents, recovery is the reverse of induction; that is, redistribution from the site  of action (rather than metabolism of the anesthetic) underlies recovery. The anesthesiologist continues to monitor  the patient to be sure that he or she is fully recovered with normal physiologic functions (for example, is able to  breathe on his / her own). Patients are observed for delayed toxic reactions, such as hepatotoxicity caused by  halogenated hydrocarbons.   The depth of anesthesia has been divided into four sequential stages. Each stage is characterized by increased  central nervous system (CNS) depression, which is caused by accumulation of the anesthetic drug in the brain  (Figure 11.3). These stages were discerned and defined with ether, which produces a slow onset of anesthesia.   Flowever, with halothane and other commonly used anesthetics, the stages are difficult to characterize clearly  because of the rapid onset of anesthesia.   1. Stage la€” Analgesia: Loss of pain sensation results from interference with sensory transmission in the  spinothalamic tract. The patient is   conscious and conversational. Amnesia and a reduced awareness of pain occur as Stage II is approached.    2. Stage I la€” Excitement: The patient experiences delirium and possibly violent, combative behavior. There is a  rise and irregularity in blood pressure. The respiratory rate may increase. To avoid this stage of anesthesia, a  short-acting barbiturate, such asthiopental , is given intravenously before inhalation anesthesia is administered.   3. Stage IllaC" Su rgical anesthesia: Regular respiration and relaxation of the skeletal muscles occur in this stage.  Eye reflexes decrease progressively, until the eye movements cease and the pupil is fixed. Surgery may proceed  during this stage.   4. Stage IVa€” Medullary paralysis: Severe depression of the respiratory and vasomotor centers occur during this  stage. Death can rapidly ensue unless measures are taken to maintain circulation and respiration.   Inhaled gases are the mainstay of anesthesia and are used primarily for the maintenance of anesthesia after  administration of an intravenous agent. No one anesthetic is superior to another under all circumstances. Inhalation  anesthetics have a benefit that is not available with intravenous agents, because the depth of anesthesia can be  rapidly altered by changing the concentration of the drug. Inhalation anesthetics are also reversible, because most  are rapidly eliminated from the body by exhalation.   Modern inhalation anesthetics are nonflammable, nonexplosive agents that include the gas nitrous oxide as well as a  number of volatile, halogenated hydrocarbons. As a group, these agents decrease cerebrovascular resistance,  resulting in increased perfusion of the brain. They also cause bronchodilation and decrease both minute ventilation   (volume of air per unit time moved into or out of the lungs) and hypoxic pulmonary vasoconstriction (increased  pulmonary vascular resistance in poorly aerated regions of the lungs, which allows redirection of pulmonary blood  flow to regions that are richer in oxygen content). The movement of these agents from the lungs to the different  body compartments depends upon their solubility in blood and tissues as well as on blood flow. These factors play a  role not only in induction but also in recovery.   The potency of inhaled anesthetics is defined quantitatively as the median alveolar concentration (MAC). This is the  end-tidal concentration of anesthetic gas needed to eliminate movement among 50 percent of patients challenged  by a standardized skin incision. [Note: MAC is the median effective dose (ED50) of the anesthetic. ] MAC is usually  expressed as the percentage of gas in a mixture required to achieve the effect. Numerically, MAC is small for potent  anesthetics, such as halothane, and large for less potent agents, such as nitrous oxide. Therefore, the inverse of  MAC is an index of the potency of the anesthetic. MAC values are useful in comparing pharmacologic effects of  different anesthetics (Figure 11.4). The more lipid soluble an anesthetic, the lower the concentration of anesthetic  needed to produce anesthesia and, thus, the higher the potency of the anesthetic.   The partial pressure of an anesthetic gas at the origin of the respiratory pathway is the driving force that moves the  anesthetic into the alveolar space and, thence, into the blood, which delivers the drug to the brain and various  other body compartments. Because gases move from one compartment to another within the body according to  partial pressure gradients, a steady state is achieved when the partial pressure in each of these compartments is  equivalent to that in the inspired mixture. The time course for attaining this steady state is determined by the  following factors:    1. Alveolar wash-in: This term refers to the replacement of the normal lung gases with the inspired anesthetic  mixture. The time required for this process is directly proportional to the functional residual capacity of the  lung and inversely proportional to the ventilatory rate; it is independent of the physical properties of the gas.   As the partial pressure builds within the lung, anesthetic transfer from the lung begins.   2. Anesthetic uptake: Anesthetic uptake is the product of gas solubility in the blood, cardiac output, and the  anesthetic gradient between alveolar and venous partial pressure gradients.   a. Solubility in the blood: This is determined by a physical property of the anesthetic molecule called the  blood/ gas partition coefficient, which is the ratio of the total amount of gas in the blood relative to the gas  equilibrium phase (Figure 11. 5). Drugs with low versus high solubility in blood differ in their speed of  induction of anesthesia. For example, when an anesthetic gas with low blood solubility, such as nitrous  oxide, diffuses from the alveoli into the circulation, little of the anesthetic dissolves in the blood.  Therefore, the equilibrium between the inhaled anesthetic and arterial blood occurs rapidly, and relatively  few additional molecules of anesthetic are required to raise arterial anesthetic partial pressurea€"that is,  steady state is rapidly achieved. In contrast, an anesthetic gas with high blood solubility, such as haiothane,  dissolves more completely in the blood, and greater amounts of the anesthetic and longer periods of time  are required to raise arterial partial pressure. This results in increased times of induction as well as recovery  and slower changes in the depth of anesthesia in response to alterations in the concentration of the inhaled  drug. Figure 11.6 illustrates the uptake curves for some inhalation anesthetics. The solubility in blood is  ranked in the following order: haiothane >enflurane >isoflurane >sevoflurane >desfiurane >nitrous  oxide.   b. Cardiac output: It is obvious that cardiac output affects the delivery of anesthetic to tissues. Low cardiac  output will result in slow delivery of the anesthetic.   c. Alveolar to venous partial pressure gradient of the anesthetic: This is the driving force of anesthetic  delivery. For all practical purposes, the pulmonary end-capillary anesthetic partial pressure may be  considered as the anesthetic alveolar partial pressure if the patient does not have severe lung diffusion    disease. The arterial circulation distributes the anesthetic to various tissues, and the pressure gradient  drives free anesthetic   gas into tissues. As the venous circulation returns blood depleted of anesthetic to the lung, more gas moves  into the blood from the lung according to the partial pressure difference. Over time, the partial pressure in  the venous blood closely approximates the partial pressure in the inspired mixture; that is, no further net  anesthetic uptake from the lung occurs.   3. Effect of different tissue types on anesthetic uptake; The time required for a particular tissue to achieve a  steady state with the partial pressure of an anesthetic gas in the inspired mixture is inversely proportional to the  blood flow to that tissue; that is, faster flow results in a more rapidly achieved steady state. It is also directly  proportional to the capacity of that tissue to store anesthetic; that is, a larger capacity results in a longer time  required to achieve steady state. Capacity, in turn, is directly proportional to the tissue's volume and the  tissue/ blood solubility coefficient of the anesthetic molecules. Four major tissue compartments determine the  time course of anesthetic uptake.    a. Brain, heart, liver, kidney, and endocrine glands: These highly perfused tissues rapidly attain a steady  state with the partial pressure of anesthetic in the blood.   b. Skeletal muscles: These are poorly perfused during anesthesia. This, and the fact that they have a large  volume, prolong the time required to achieve steady state.   c. Fat: This tissue is also poorly perfused. However, potent general anesthetics are very lipid soluble.  Therefore, fat has a large capacity to store anesthetic. This combination of slow delivery to a high-capacity  compartment prolongs the time required to achieve steady state.   d. Bone, ligaments, and cartilage: These are poorly perfused and have a relatively low capacity to store  anesthetic. Therefore, these tissues have only a slight impact on the time course of anesthetic distribution  in the body.   4. Washout: When the administration of an inhalation anesthetic is discontinued, the body becomes the   a€oesourcea€i that drives the anesthetic into the alveolar space. The same factors that influence attainment of  steady state with an inspired anesthetic determine the time course of clearance of the drug from the body.  Thus, nitrous oxide exits the body faster than halothane (see Figure 11.6).   No specific receptor has been identified as the locus of general anesthetic action. Indeed, the fact that chemically  unrelated compounds produce the anesthetic state argues against the existence of such a receptor. The focus is  now on interactions of the inhaled anesthetics with proteins comprising ion channels. For example, the general  anesthetics increase the sensitivity of the P-aminobutyric acid (GABAa) receptors to the neurotransmitter, GABA, at  clinically effective concentrations of the drug. This causes a prolongation of the inhibitory chloride ion current  after a pulse of GABA release. Postsynaptic neuronal excitability is thus diminished (Figure 11. 7). Other receptors  are also affected   by volatile anesthetics; for example, the activity of the inhibitory glycine receptors in the spinal motor neurons is  increased. In addition, the inhalation anesthetics block the excitatory postsynaptic current of the nicotinic  receptors. The mechanism by which the anesthetics perform these modulatory roles is not understood.   This agent is the prototype to which newer inhalation anesthetics have been compared. When halothane (HAL-oh-  thane) was introduced, its ability to induce the anesthetic state rapidly and to allow quick recoverya€"and the fact  that it was nonexplosivea€"made it an anesthetic of choice. However, with the recognition of the adverse effects  discussed below and the availability of other anesthetics that cause fewer complications, halothane is largely being  replaced in the United States.    Binding of GABA causes  the chloride Ion channel  to open, leading to hyper'  polarization of the cell.    Binding of GABA is enhanced  by inhaled anesthetics,  resulting In a greater entry of  chloride ion.    making it more difficult to  depolarize, and therefore  reduces neural excitability.    1. Therapeutic uses: Whereas halothane is a potent anesthetic, it is a relatively weak analgesic. Thus, halothane  is usually coadministered with nitrous oxide, opioids, or local anesthetics. Halothane relaxes both skeletal and  uterine muscle, and it can be used in obstetrics when uterine relaxation is indicated. Halothane is not  hepatotoxic in pediatric patients (unlike its potential effect on adults, see below), and combined with its  pleasant odor, this makes it suitable in children for inhalation induction.   2. Pharmacokinetics: Halothane is oxidatively metabolized in the body to tissue-toxic hydrocarbons (for example,  trifluoroethanol) and bromide ion. These substances may be responsible for the toxic reaction that some  patients (especially females) develop after halothane anesthesia. This reaction begins as a fever, followed by  anorexia, nausea, and vomiting, and patients may exhibit signs of hepatitis. [Note: Although the incidence of    this reaction is lowa€"approximately 1 in 10,000 i ndi vidualsa€"50 percent of affected patients will die of hepatic  necrosis. To avoid this condition, halothane anesthesia is not repeated at intervals of less than 2 to 3 weeks.]   a. Cardiac effects: Like other halogenated hydrocarbons, halothane is vagomimetic and causes atropine-  sensitive bradycardia. In addition, halothane has the undesirable property of causing cardiac arrhythmias.   [Note: These are especially serious if hypercapnia (increased arterial carbon dioxide partial pressure)  develops due to reduced alveolar ventilation or an increase in the plasma concentration of catecholamines.]  Halothane, like the other halogenated anesthetics, produces concentration-dependent hypotension. Should  it become necessary to counter excessive hypotension during halothane anesthesia, it is recommended that  a direct-acting vasoconstrictor, such as phenylephrine, be given.   b. Malignant hyperthermia: In a very small percentage of patients, all of the halogenated hydrocarbon  anestheticsa€"as well as the muscle relaxant succinylcholinea€"ha\/e the potential to induce malignant  hyperthermia. Whereas the etiology of this condition is poorly understood, recent investigations have  identified a dramatic increase in the myoplasmic calcium ion concentration. Strong evidence indicates that  malignant hyperthermia is due   to an excitationa€"contraction coupling defect. Burn victims and individuals with Duchenne dystrophy,  myotonia, osteogenesis imperfecta, and central-core disease are susceptible to malignant hyperthermia.   Should a patient exhibit the characteristic symptoms of malignant hyperthermia, dantrolene is given as the  anesthetic mixture is withdrawn. Therefore, dantrolene should be available for emergency use when  needed. The patient must be carefully monitored and supported for respiratory, circulatory, and renal  problems.   This gas is less potent than halothane, but it produces rapid induction and recovery. About 2 percent of the  anesthetic is metabolized to fluoride ion, which is excreted by the kidney. Therefore, enflurane [EN-floo-rane] is  contraindicated in patients with kidney failure. Enflurane anesthesia exhibits the following differences from  halothane anesthesia: fewer arrhythmias, less sensitization of the heart to catecholamines, and greater  potentiation of muscle relaxants due to a more potent a€oe curare- 1 ikea€S effect. A disadvantage of enflurane is  that it causes CNS excitation at twice the MAC and also at lower doses if hyperventilation reduces the partial  pressure of carbon dioxide. For this reason, it is not used in patients with seizure disorders.   This halogenated anesthetic is widely used in the United States. It is a very stable molecule that undergoes little  metabolism; as a result, little fluoride is produced. Isoflurane [eye-soe-FLURE-ane] is not tissue toxic. Unlike the  other halogenated anesthetic gases, isoflurane does not induce cardiac arrhythmias and does not sensitize the  heart to the action of catecholamines. Flowever, it produces concentration-dependent hypotension due to  peripheral vasodilation. It also dilates the coronary vasculature, increasing coronary blood flow and oxygen  consumption by the myocardium. This property may make it beneficial in patients with ischemic heart disease.  [Note: All halogenated inhalation anesthetics have been reported to cause hepatitis, but at a much lower incidence  than with halothane. For example, isoflurane does so in 1 in 500,000 individuals.]   The rapidity with which desflurane causes anesthesia and emergence has made it a popular anesthetic for  outpatient surgery. Flowever, desflurane [DES-flure-ane] has a low volatility and, thus, must be delivered using a  special vaporizer. Like isoflurane, it decreases vascular resistance and perfuses all major tissues very well. Because  it is irritating to the airway and can cause laryngospasm, coughing, and excessive secretions, desflurane is not used  to induce extended anesthesia. Its degradation is minimal; thus, tissue toxicity is rare.   Sevoflurane [see-voe-FLOO-rane] has low pungency, allowing rapid uptake without irritating the airway during  induction, thus making it suitable for induction in children. It is replacing halothane for this purpose. The drug has  low solubility in blood and is rapidly taken up and excreted. Recovery is faster than with other anesthetics. It is  metabolized by the liver, releasing fluoride ions; thus, like enflurane, it may prove to be nephrotoxic.   Nitrous oxide [NYE-truss-OX-ide] (a€oelaughing gasa€§) is a potent analgesic but a weak general anesthetic. For  example, nitrous oxide is frequently employed at concentrations of 30 percent in combination with oxygen for  analgesia, particularly in dental surgery. Flowever, nitrous oxide at 80 percent (without adj unct agents) cannot  produce surgical anesthesia. It is therefore frequently combined with other, more potent agents to attain pain-free  anesthesia. Nitrous oxide is poorly soluble in blood and other tissues, allowing it to move very rapidly in and out of  the body. [Note: Nitrous oxide can concentrate the halogenated anesthetics in the alveoli when they are  concomitantly administered because of its fast uptake from the alveolar gas. This phenomenon is known as the  a€oesecond gas effect. a€§] Within closed body compartments, nitrous oxide can increase the volume (for example,  causing a pneumothorax) or increase the pressure (for example, in the sinuses), because it replaces nitrogen in the  various air spaces faster than the nitrogen leaves. Furthermore, its speed of movement allows nitrous oxide to  retard oxygen uptake during recovery, thus causing diffusion hypoxia. This anesthetic does not depress respiration,  nor does it produce muscle relaxation. Under the usual circumstances of coadministration with other anesthetics, it  also has moderate to no effect on the cardiovascular system or on increasing cerebral blood flow, and it is the least  hepatotoxic of the inhalation anesthetics. It is therefore probably the safest of these anesthetics, provided that at  least 20 percent oxygen is always administered simultaneously.   Some characteristics of the inhalation anesthetics are summarized in Figure 11.8   Intravenous anesthetics are often used for the rapid induction of anesthesia, which is then maintained with an  appropriate inhalation agent. They rapidly induce anesthesia and must therefore be injected slowly. Recovery from  intravenous anesthetics is due to redistribution from sites in the CNS.   Thiopental is a potent anesthetic but a weak analgesic. It is an ultrashort-acting barbiturate and has a high lipid  solubility. When agents such as thiopental and methohexital [ meth-oh- HEX- i-tal ] are administered intravenously,  they quickly enter the CNS and depress function, often in less than 1 minute. Flowever, diffusion out of the brain  can occur very rapidly as well because of redistribution of the drug to other body tissues, including skeletal muscle  and, ultimately, adipose tissue (Figure 11.9). [Note: This latter site serves as a reservoir of drugs from which the  agent slowly leaks out and is metabolized and excreted. ] The short duration of anesthetic action is due to the  decrease of its concentration in the brain to a level below that necessary to produce anesthesia. These drugs may  remain in the body for relatively long periods of time after their administration, because only about 15 percent of  the dose of barbiturates entering the circulation is metabolized by the liver per hour. Thus, metabolism of  thiopental is much slower than its tissue redistribution. The barbiturates are not significantly analgesic and,  therefore, require some type of supplementary analgesic administration during anesthesia to avoid objectionable  changes in blood pressure and autonomic function. Thiopental has minor effects on the cardiovascular system, but   it may contribute to severe hypotension in patients with hypovolemia or shock. All barbiturates can cause apnea,  coughing, chest wall spasm, laryngospasm, and bronchospasm. [Note: The latter is of particular concern for  asthmatic patients. ] Barbiturates are contraindicated in patients with acute intermittent or variegate porphyria.   The benzodiazepines are used in conj unction with anesthetics to sedate the patient. The most commonly employed  is midazolam, which is available in many formulations, including oral. Diazepam and lorazepam are alternatives.  All three facilitate amnesia while causing sedation.   Figure 11.9 Redistribution of thiopental from brain to muscle and adipose tissue.   Because of their analgesic property, opioids are frequently used together with anesthetics; for example, the  combination of morphine and nitrous oxide provides good anesthesia for cardiac surgery. The choice of opioid used  perioperatively is based primarily on the duration of action needed. The most frequently employed opioids are  fentanyl and its congeners, sufentanil or remifentanil , because they induce analgesia more rapidly than morphine  does. They are administered either intravenously, epidural ly, or intrathecally. Opioids are not good amnesics, and  they can all cause hypotension, respiratory depression, and muscle rigidity as well as postanesthetic nausea and  vomiting. Opioid effects can be antagonized by naloxone (see p. 168).   Etomidate (eh-TOE-mid-ate) is used to induce anesthesia. It is a hypnotic agent but lacks analgesic activity. Its  water solubility is poor, so etomidate is formulated in a propylene glycol solution. Induction is rapid, and the drug  is short-acting. It is only used for patients with coronary artery disease or cardiovascular dysfunction, such as shock.  Etomidate is hydrolyzed in the liver. Among its benefits are little to no effect on the heart and circulation. Its  adverse effects include a decrease in plasma cortisol and aldosterone levels, which can persist for up to 8 hours.   This is apparently due to inhibition of ll-F-hydroxylase. 1 [Note: Etomidate should not be infused for an extended  time, because prolonged suppression of these hormones can be hazardous.] Venous pain can occur, and skeletal  muscle movements are not uncommon. The latter are managed by administration of benzodiazepines and opioids.   Ketamine [KET-a-meen], a short-acting, nonbarbiturate anesthetic, induces a dissociated state in which the patient  is unconscious but appears to be awake and does not feel pain. This dissociative anesthesia provides sedation,  amnesia, and immobility. Ketamine interacts with the N-methyl-D-aspartate receptor. It also stimulates the central  sympathetic outflow, which, in turn, causes stimulation of the heart and increased blood pressure and cardiac  output. This property is especially beneficial in patients with either hypovolemic or cardiogenic shock as well as in  patients with asthma. Ketamine is therefore used when circulatory depression is undesirable. On the other hand,  these effects mitigate   against the use of ketamine in hypertensive or stroke patients. The drug is lipophilic and enters the brain  circulation very quickly, but like the barbiturates, it redistributes to other organs and tissues. It is metabolized in    the liver, but small amounts can be excreted unchanged. Ketamine is employed mainly in children and young adults  for short procedures. However, it is not widely used, because it increases cerebral blood flow and induces  postoperative hallucinations (a€oenightmaresa€§), particularly in adults.   Propofol [pro-POF-ol] is an intravenous sedative/ hypnotic used in the induction or maintenance of anesthesia.   Onset is smooth and occurs within about 40 seconds of administration. Supplementation with narcotics for analgesia  is required. Whereas propofol facilitates depression in the CNS, it is occasionally accompanied by excitatory  phenomena, such as muscle twitching, spontaneous movement, or hiccups. Propofol   decreases blood pressure without depressing the myocardium. It also reduces intracranial pressure. Propofol is  widely used and has replaced thiopental as the first choice for anesthesia induction and sedation, because it  produces a euphoric feeling in the patient and does not cause postanesthetic nausea and vomiting. It has much less  of a depressant effect than the volatile anesthetics on CNS-evoked potentials, such as somatosensory evoked  potentials. This makes propofol very useful for such surgeries as resection of spinal tumors, in which somatosensory  evoked potentials are monitored to assess spinal cord functions.   Some therapeutic advantages and disadvantages of the anesthetic agents are summarized in Figure 11. 10.   Local anesthetics are generally applied locally and block nerve conduction of sensory impulsesfrom the periphery to  the CNS. [Note: Some of these agents do have additional usesa€"for example, the antiarrhythmic effect of  lidocaine a€"and they are then administered by other routes. ] Local anesthetics abolish sensation (and, in higher  concentrations, motor activity) in a limited area of the body without producing unconsciousness (for example,  during spinal anesthesia). The small, unmyelinated nerve fibers that conduct impulses for pain, temperature, and  autonomic activity are most sensitive to actions of local anesthetics. The most widely used of these compounds are  bupivacaine [byoo-PIV-ah-kane], lidocaine [LYE-doe-kane], mepivacaine [me-PIV-a-kane], procaine [PRO-kane],  ropivacaine [roe-PIV-a-kane], and tetracaine [TET-ra-kane], Of these, lidocaine is the most frequently employed.  At physiologic pH, these compounds are charged; it is this ionized form that interacts with the protein receptor of  the Na + channel to inhibit its function and, thereby, achieve local anesthesia. [Note: The natural product, cocaine,  was recognized years ago as a local anesthetic. However, its toxicity and abuse have limited its use to topical  application in anesthesia of the upper respiratory tract. ] The local anesthetics differ pharmacokinetically as to  onset and duration of action (Figure 11. 11). By adding the vasoconstrictor epinephrine to the local anesthetic, the  rate of anesthetic absorption is decreased. This both minimizes systemic toxicity and increases the duration of  action. Adverse effects result from systemic absorption of toxic amounts of the locally applied anesthetic. Seizures  and cardiovascular collapse are the most significant of these systemic effects. Bupivacaine is noted for its   cardiotoxicity. Mepivacaine should not be used in obstetric anesthesia due to its increased toxicity to the neonate.   Allergic reactions may be encountered with procaine, which is metabolized to p-aminobenzoic acid.   11.2 Children with asthma undergoing a surgical procedure are frequently anesthetized with sevoflurane,  because it:   11.3 Which one of the following is most likely to require administration of a muscle relaxant?   11.4 Which one of the following is a potent intravenous anesthetic but a weak analgesic?    11.5 Which one of the following is a potent analgesic but a weak anesthetic?   >Table of Contents > Unit III - Drugs Affecting the Central Nervous System >Chapter 12 - Antidepressants   Depression is a serious disorder that afflicts approximately 14 million adults in the United States each year. The  lifetime prevalence rate of depression in the United States has been estimated to include 16 percent of adults (21  percent of women, 13 percent of men), or more than 32 million people. The symptoms of depression are intense  feelings of sadness, hopelessness, and despair, as well as the inability to experience pleasure in usual activities,  changes in sleep patterns and appetite, loss of energy, and suicidal thoughts. Mania is characterized by the opposite  behaviora€"that is, enthusiasm, rapid thought and speech patterns, extreme self-confidence, and impaired  j udgment. [Note: Depression and mania are different from schizophrenia (see p. 151), which produces disturbances  in thought. ]   Most clinically useful antidepressant drugs potentiate, either directly or indirectly, the actions of norepinephrine  and/or serotonin in the brain. (See Figure 12. 1 for a summary of the antidepressant agents.) This, along with other  evidence, led to the biogenic amine theory, which proposes that depression is due to a deficiency of monoamines,  such as norepinephrine and serotonin, at certain key sites in the brain. Conversely, the theory envisions that mania  is caused by an overproduction of these neurotransmitters. However, the amine theory of depression and mania is  overly simplistic. It fails to explain why the pharmacologic effects of any of the antidepressant and antimania drugs  on neurotransmission occur immediately, whereas the time course for a therapeutic response occurs over several  weeks. Furthermore, the potency of the antidepressant drugs in blocking neurotransmitter uptake often does not  correlate with clinically observed antidepressant effects. This suggests that decreased uptake of neurotransmitter is  only an initial effect of the drugs, which may not be directly responsible for the antidepressant effects. It has been  proposed that presynaptic inhibitory receptor densities in the brain decrease over a 2- to 4-week period with  antidepressant drug use. This down-regulation of inhibitory receptors permits greater synthesis and release of    neurotransmitters into the synaptic cleft and enhanced signaling in the postsynaptic neurons, presumably leading to  a therapeutic response (Figure 12.2).   The selective serotonin reuptake inhibitors (SSRIs) are a group of chemically diverse antidepressant drugs that  specifically inhibit serotonin reuptake, having 300- to 3000-fold greater selectivity for the serotonin transporter as  compared to the norepinephrine transporter. This contrasts with the tricyclic antidepressants (see p. 145) that  nonselectively inhibit the uptake of norepinephrine and serotonin (Figure 12.3). Both of these antidepressant drug  classes exhibit little ability to block the dopamine transporter. Moreover, the SSRIs have little blocking activity at  muscarinic, i±-adrenergic, and histaminic Hi receptors. Therefore, common side effects associated with tricyclic  antidepressants, such as orthostatic hypotension, sedation, dry mouth, and blurred vision, are not commonly seen  with the SSRIs. Because they have fewer adverse effects and are relatively safe even in overdose, the SSRIs have  largely replaced tricyclic antidepressants and monoamine oxidase inhibitors as the drugs of choice in treating  depression. SSRIs include fluoxetine [floo-OX-e-teen] (the prototypic drug), citalopram [sye-TAL-oh-pram],  escitalopram [es-sye-TAL-oh-pram], fluvoxamine [floo-VOX-e-meen], paroxetine [pa-ROX-e-teen], and sertraline  [SER-tra-leen] . Both citalopram and fluoxetine are racemic mixtures, of which the respective S-enantiomers are  the more potent inhibitors of the serotonin reuptake pump. Escitalopram is the pure S-enatiomer of citalopram.   The SSRIs block the reuptake of serotonin, leading to increased concentrations of the neurotransmitter in the  synaptic cleft and, ultimately, to greater postsynaptic neuronal activity. Antidepressants, including SSRIs, typically  take at least 2 weeks to produce significant improvement in mood, and maximum benefit may require up to 12  weeks or more (Figure 12. 4). However, none of the antidepressants are uniformly effective. Approximately 40  percent of depressed patients treated with adequate doses for 4 to 8 weeks do not respond to the antidepressant  agent. Patients that do not respond to one antidepressant may respond to another, and approximately 80 percent or  more will respond to at least one antidepressant drug. [Note: These drugs do not usually produce central nervous  system (CNS) stimulation or mood elevation in normal individuals.]   The primary indication for SSRIs is depression, for which they are as effective as the tricyclic antidepressants. A  number of other psychiatric disorders also respond favorably to SSRIs, including obsessive-compulsive disorder (the  only approved indication for fluvoxamine), panic disorder, generalized anxiety disorder, posttraumatic stress  disorder, social anxiety disorder, premenstrual dysphoric disorder, and bulimia nervosa (only fluoxetine is approved  for this last indication).    Down-regulation of presynaptic  inhibitory receptors leads to increased  release of neurotransmitter.   Figure 12.2 Proposed mechanism of action of selective serotonin re-uptake inhibitors (SSRI) and tricyclic  antidepressant (TCA) drugs.   All of the SSRIs are well absorbed after oral administration. Peak levels are seen in approximately 2 to 8 hours on   average. Food has little effect on absorption (except with sertraline, for which food increases its absorption). Only  sertraline undergoes significant first-pass metabolism. All of these agents are well distributed, having volumes of  distribution far in excess of body weight ( 15a€" 30 L/kg). The maj ority of SSRIs have plasma half-lives that range  between 16 and 36 hours. Metabolism by P450-dependent enzymes and glucuronide or sulfate conj ugation occur   extensively. [Note: These metabolites do not generally contribute to the pharmacologic activity. ] Fluoxetine differs  from the other members of the class in two respects. First, it has a much longer half-life (50 hours) and is available  as a sustained-release preparation allowing once-weekly dosing. Second, the metabolite of the S-enantiomer,  S-norfluoxetine, is as potent as the parent compound. The half-life of the metabolite is quite long, averaging 10  days. Fluoxetine and paroxetine are potent inhibitors of a hepatic cytochrome P450 isoenzyme (CYP2D6)  responsible for the elimination of tricyclic antidepressant drugs, neuroleptic drugs, and some antiarrhythmic and  l 2 -adrenergica€"antagonist drugs. [Note: About seven percent of the Caucasian population lack this P450 enzyme  and, therefore, metabolize fluoxetine, and other substrates of this enzyme, very slowly. These individuals may be  referred to in the literature as poor metabolizers. ] Other cytochrome enzymes (CYP2C9/ 19, CYP3A4, CYP1A2) are  involved with SSRI metabolism and may also be inhibited to various degrees by the SSRIs and, thus, may affect the  metabolism of multiple medications. Excretion of the SSRIs is primarily through the kidneys, except for paroxetine  and sertraline, which also undergo fecal excretion (35 and 50 percent, respectively). Dosages of all of these drugs  should be adjusted downward in patients with hepatic impairment.    Figure 12.3 Relative receptor specificity of some antidepressant drugs. *Venlafaxine inhibits norepinephrine  re-uptake only at high doses. ++++= very strong affnity; +++ = strong affinity; ++ = moderate affinity; + =  weak affinity; 0 = little or no affinity.   Although the SSRIs are considered to have fewer and less severe adverse effects than the tricyclic antidepressants  and monoamine oxidase inhibitors, the SSRIs are not without troublesome adverse effects, such as, headache,  sweating, anxiety and agitation, gastrointestinal effects (nausea, vomiting, diarrhea), weakness and fatigue, sexual  dysfunction, changes in weight, sleep disturbances (insomnia and somnolence), and the above-mentioned potential  for drug-drug interactions (Figure 12.5).    Figure 12.4 Onset of therapeutic effects of the major antidepressant drugs (tricyclic antidepressants,  selective serotonin re-uptake inhibitors, and monoamine oxidase inhibitors) requires several weeks.    1. Sleep disturbances: Paroxetine and fluvoxamine are generally more sedating than activating, and they may be  useful in patients who have difficulty sleeping. Conversely, patients who are fatigued or complaining of  excessive somnolence may benefit from one of the more activating antidepressants, such as fluoxetine or  sertraline.   2. Sexual dysfunction: Loss of libido, delayed ej aculation, and anorgasmia are underreported side effects often  noted by clinicians but not prominently featured in the list of standard side effects. One option for managing  SSRI-induced sexual dysfunction is to replace the offending antidepressant with an antidepressant having fewer  sexual side effects, such as bupropion or mirtazapine. Alternatively, the dose of the drug may be reduced. In  men with erectile dysfunction and depression, treatment with sildenafil, vardenafil, or tadalafil (see p. 341)  may improve sexual function.   3. Use in children and teenagers: Antidepressants should be used cautiously in children and teenagers, because  about 1 out of 50 children becomes more suicidal as a result of SSRI treatment. Pediatric patients should be  observed for worsening depression and suicidal thinking whenever any antidepressant is started or its dose is  increased or decreased.   4. Overdoses: Large intakes of SSRIs do not usually cause cardiac arrhythmias (compared to the arrhythmia risk for  the tricyclic antidepressants), but seizures are a possibility because all antidepressants   may lower the seizure threshold. All SSRIs have the potential to cause a serotonin syndrome that may include  the symptoms of hyperthermia, muscle rigidity, sweating, myoclonus (clonic muscle twitching), and changes in  mental status and vital signs when used in the presence of a monoamine oxidase inhibitor or another highly  serotonergic drug. Therefore, extended periods of washout for each drug class should occur prior to the  administration of the other class of drugs.   5. Discontinuation syndrome: Whereas all of the SSRIs have the potential for causing a discontinuation syndrome   after their abrupt withdrawal, the agents with the shorter half-lives and having inactive metabolites have a  higher risk for such an adverse reaction. Fluoxetine has the lowest risk of causing an SSRI discontinuation  syndrome. Possible signs and symptoms of such a serotonin-related discontinuation syndrome include headache,  malaise and flu-like symptoms, agitation and irritability, nervousness, and changes in sleep pattern.   Venlafaxine [VEN-la-fax-een] and duloxetine (doo-LOX-e-teen) selectively inhibit the re-uptake of both serotonin  and norepinephrine (Figure 12.6). These agents, termed selective serotonin-norepinephrine reuptake inhibitors  (SNRIs), may be effective in treating depression in patients in whom SSRIs are ineffective. Furthermore, depression  is often accompanied by chronic painful symptoms, such as backache and muscle aches, against which SSRIs are also  relatively ineffective. This pain is, in part, modulated by serotonin and norepinephrine pathways in the CNS. Both  SNRIs and tricyclic antidepressants, with their dual actions of inhibiting both serotonin and norepinephrine reuptake  are sometimes effective in relieving physical symptoms of neuropathic pain, such as diabetic peripheral neuropathy.  However, the SNRIs, unlike the tricyclic antidepressants, have little activity at adrenergic, muscarinic, or histamine  receptors and, thus, have fewer of these receptor-mediated adverse effects than the tricyclic antidepressants (see  Figure 12. 3). Both venlafaxine and duloxetine may precipitate a discontinuation syndrome if treatment is abruptly  stopped.   Venlafaxine is a potent inhibitor of serotonin reuptake and, at medium to higher doses, is an inhibitor of  norepinephrine re-uptake. It is also a mild inhibitor of dopamine reuptake at high doses. Venlafaxine has minimal  inhibition of the cytochrome P450 isoenzymes and is a substrate of the CYP2D6 isoenzyme. The half-life of the  parent compound plus its active metabolite is approximately 11 hours. Venlafaxine is only 27 percent bound to  plasma protein and is not expected to be involved in protein displacement interactions. The most common side  effects of venlafaxine are nausea, headache, sexual dysfunction, dizziness, insomnia, sedation, and constipation.  At high doses, there may be an increase in blood pressure and heart rate.   Duloxetine inhibits serotonin and norepinephrine reuptake at all doses. It is extensively metabolized in the liver to  numerous metabolites. Duloxetine should not be administered to patients with hepatic insufficiency. Metabolites  are excreted in the urine, and the use of duloxetine is not recommended in patients with end-stage renal disease.   Food delays the absorption of the drug. The half-life is approximately 12 hours. Duloxetine is highly bound to  plasma protein. Gastrointestinal side effects are common with duloxetine, including nausea, dry mouth, and  constipation. Diarrhea and vomiting are seen less often. Insomnia, dizziness, somnolence, and sweating are also  seen. Sexual dysfunction also occurs along with the possible risk for an increase in either blood pressure or heart  rate.   The atypical antidepressants are a mixed group of agents that have actions at several different sites. This group  includes bupropion [byoo-PROE-pee-on], mirtazapine [mir-TAZ-a-peen], nefazodone [nef-AY-zoe-done], and  trazodone [TRAZ-oh-done], They are not any more efficacious than the tricyclic antidepressants or SSRIs, but their  side effect profiles are different.   Figure 12.6 Proposed mechanism of action of selective serotonin/ norepinephrine re-uptake inhibitor  antidepressant drugs.   This drug acts as a weak dopamine and norepinephrine reuptake inhibitor to alleviate the symptoms of depression.  Its short half-life may require more than once-a-day dosing or the administration of an extended-release  formulation. Bupropion is unique in that it assists in decreasing the craving and attenuating the withdrawal  symptoms for nicotine in tobacco users trying to quit smoking. Side effects may include dry mouth, sweating,  nervousness, tremor, a very low incidence of sexual dysfunction, and an increased risk for seizures at high doses.  Bupropion is metabolized by the CYP2D6 pathway and is considered to have a relatively low risk for drug-drug  interactions.   This drug enhances serotonin and norepinephrine neurotransmission via mechanisms related to its ability to block  presynaptic i ±2 receptors. Additionally, it may owe at least some of its antidepressant activity to its ability to block  5 -HT 2 receptors. It is a sedative because of its potent antihistaminic activity, but it does not cause the  antimuscarinic side effects of the tricyclic antidepressants, or interfere with sexual functioning, as do the SSRIs.   Increased appetite and weight gain frequently occur. Mirtazapine is markedly sedating, which may be used to  advantage in depressed patients having difficulty sleeping.   These drugs are weak inhibitors of serotonin reuptake. Their therapeutic benefit appears to be related to their  ability to block postsynaptic 5-HT2A receptors. With chronic use, these agents may desensitize 5 -HTia presynaptic  autoreceptors and, thereby, increase serotonin release. Both agents are sedating, probably because of their potent  Hi-blocking activity. Trazodone has been associated with causing priapism, and nefazodone has been associated  with the risk for hepatotoxicity.   The tricyclic antidepressants (TCAs) block norepinephrine and serotonin reuptake into the neuron and, thus, if  discovered today, may be referred to as SNRIs except for their differences in adverse effects relative to this newer  class of antidepressants. The TCAs include the tertiary amines imipramine [ee-MIP-ra-meen] (the prototype drug),  amitriptyline [aye-mee-TRIP-ti-leen], clomipramine [kloe-MIP-ra-meen], doxepin [DOX-e-pin] and trimipramine   [trye-MIP-ra-meen], The TCAs also include the secondary amines desipramine [dess-IP-ra-meen] and nortriptyline  [nor-TRIP-ti-leen] (the respective N-demethylated metabolites of imipramine and amitriptyline ) and protriptyline  [proe-TRIP-ti-leen], Maprotiline [ma-PROE-ti-leen] and amoxapine [a-MOX-a-peen] are related a€oetetracyclica€^  antidepressant agents and are commonly included in the general class of TCAs. All have similar therapeutic efficacy,  and the choice of drug may depend on such issues as patient tolerance to side effects, prior response, preexisting  medical conditions, and duration of action. Patients who do not respond to one TCA may benefit from a different  drug in this group. These drugs are a valuable alternative for patients who do not respond to SSRIs.    1. Inhibition of neurotransmitter reuptake: TCAs and amoxapine are potent inhibitors of the neuronal reuptake    of norepinephrine and serotonin into presynaptic nerve terminals (see Figure 12.2), At therapeutic  concentrations, they do not block dopamine transporters. By blocking the maj or route of neurotransmitter  removal, the TCAs cause increased concentrations of monoamines in the synaptic cleft, ultimately resulting in  antidepressant effects. Maprotiline and desipramine are selective inhibitors of norepinephrine reuptake.   2. Blocking of receptors: TCAs also block serotonergic, l±-adrenergic, histaminic, and muscarinic receptors (see  Figure 12.3). It is not known if any of these actions produce their therapeutic benefit. Flowever, actions at  these receptors are probably responsible for many of the untoward effects of the TCAs. Amoxapine also blocks  the D 2 receptor.   The TCAs elevate mood, improve mental alertness, increase physical activity, and reduce morbid preoccupation in  50 to 70 percent of individuals with maj or depression. The onset of the mood elevation is slow, requiring 2 weeks or  longer (see Figure 12.4). These drugs do not commonly produce CNS stimulation or mood elevation in normal  individuals. Physical and psychological dependence has been rarely reported, however, this necessitates slow  withdrawal to minimize discontinuation syndromes and cholinergic rebound effects. These drugs, like all of the  antidepressants, can be used for prolonged treatment of depression.   The TCAs are effective in treating moderate to severe maj or depression. Some patients with panic disorder also  respond to TCAs. Imipramine has been used to control bed-wetting in children (older than 6 years) by causing  contraction of the internal sphincter of the bladder. At present, it is used cautiously because of the inducement of  cardiac arrhythmias and other serious cardiovascular problems. The TCAs, particularly amitriptyline, have been  used to treat migraine headache and chronic pain syndromes (for example, a€oeneuropathica€§ pain) in a number  of conditions for which the cause of the pain is unclear.   Tricyclic antidepressants are well absorbed upon oral administration. Because of their lipophilic nature, they are  widely distributed and readily penetrate into the CNS. This lipid solubility also causes these drugs to have variable  half- 1 i vesa€"for example, 4 to 17 hours for imipramine.   As a result of their variable first-pass metabolism in the liver, TCAs have low and inconsistent bioavailability.   Therefore, the patient's response and plasma levels can be used to adjust dosage. The initial treatment period is  typically 4 to 8 weeks. The dosage can be gradually reduced to improve tolerability unless relapse occurs. These  drugs are metabolized by the hepatic microsomal system (and, thus, may be sensitive to agents that induce or  inhibit the CYP450 isoenzymes) and conj ugated with glucuronic acid. Ultimately, the TCAs are excreted as inactive  metabolites via the kidney.   Potentiate effects  of biogenic amine  drugs by preventing  their removal from the  synaptic cleft   Block effects of  indirect-acting  sympathomimetic  drugs by preventing  the drugs from  reaching their intra-  celluar sites of action    Figure 12.8 Drugs interacting with tricyclic antidepressants. CNS =central nervous system; MAO =  monoamine oxidase.   Blockade of muscarinic receptors leads to blurred vision, xerostomia (dry mouth), urinary retention, constipation,  and aggravation of narrow-angle glaucoma (Figure 12.7). These agents slow cardiac conduction similarly to  quinidine, which may precipitate life-threatening arrhythmias should an overdose of one of these drugs be taken.  The TCAs also block i±-adrenergic receptors, causing orthostatic hypotension, dizziness, and reflex tachycardia. In  clinical practice, this is the most serious problem in the elderly. Imipramine is the most likely and nortriptyline the  least likely to cause orthostatic hypotension. Sedation may be prominent, especially during the first several weeks  of treatment, and is related to the ability of these drugs to block histamine Hi receptors. Weight gain is a common  adverse effect of the TCAs. Sexual dysfunction, as evidenced by erectile dysfunction in men and anorgasmia in  women, occurs in a significant minority of patients, but the incidence is still considered to be lower than the  incidence of sexual dysfunction associated with the SSRIs.   1. Precautions: TCAs (like all antidepressants) should be used with caution in known manic-depressive patients,  even during their depressed state, because antidepressants may cause a switch to manic behavior. The TCAs  have a narrow therapeutic index; for example, five- to six-fold the maximal daily dose of imipramine can be  lethal. Depressed patients who are suicidal should be given only limited quantities of these drugs and be  monitored closely. Drug interactions with the TCAs are shown in Figure 12.8. The TCAs may exacerbate certain  medical conditions, such as unstable angina, benign prostatic hyperplasia, epilepsy, and patients with  preexisting arrhythmias. Caution should be exercised with their use in very young or very old patients as well.   Monoamine oxidase (MAO) is a mitochondrial enzyme found in nerve and other tissues, such as the gut and liver. In  the neuron, MAO functions as a a€oesafety valvea€§ to oxidatively deaminate and inactivate any excess  neurotransmitter molecules (norepinephrine, dopamine, and serotonin) that may leak out of synaptic vesicles when  the neuron is at rest. The MAO inhibitors may irreversibly or reversibly inactivate the enzyme, permitting  neurotransmitter molecules to escape degradation and, therefore, to both accumulate within the presynaptic  neuron and leak into the synaptic space. This is believed to cause activation of norepinephrine and serotonin  receptors, and it may be responsible for the indirect antidepressant action of these drugs. Three MAO inhibitors are  currently available for treatment of depression: phenelzine [FEN-el-zeen], tranylcypromine [ tran- il-SI P- roe- meen]  and the agent that was prior-approved for Parkinson's disease, but is now also   approved for depression, selegiline, which is the first antidepressant available in a transdermal delivery system. Use  of MAO inhibitors is now limited due to the complicated dietary restrictions required of patients taking MAO  inhibitors.    MAO inactivates mono-  amines (norepinephrine,  serotonin, and dopamine)  that leak from a synaptic  vesicle.    MAO inhibitors prevent  inactivation of monoamines  within a neuron, causing  excess neurotransmitter  to diffuse into the synaptic  space.   Most MAO inhibitors, such as phenelzine, form stable complexes with the enzyme, causing irreversible inactivation.  This results in increased stores of norepinephrine, serotonin, and dopamine within the neuron and subsequent    diffusion of excess neurotransmitter into the synaptic space (Figure 12.9). These drugs inhibit not only MAO in the  brain but also MAO in the liver and gut that catalyze oxidative deamination of drugs and potentially toxic  substances, such astyramine, which is found in certain foods. The MAO inhibitors therefore show a high incidence  of drug-drug and drug-food interactions. Selegiline administered as the transdermal a€oepatcha€- : may produce less  inhibition of hepatic MAO at low doses, because it avoids first-pass metabolism.   Although MAO is fully inhibited after several days of treatment, the antidepressant action of the MAO inhibitors, like  that of the SSRIsand TCAs, is delayed several weeks. Selegiline and tranylcypromine have an amphetamine-like  stimulant effect that may produce agitation or insomnia.   The MAO inhibitors are indicated for depressed patients who are unresponsive or allergic to TCAs or who experience  strong anxiety. Patients with low psychomotor activity may benefit from the stimulant properties of the MAO  inhibitors. These drugs are also useful in the treatment of phobic states. A special subcategory of depression, called  atypical depression, may respond to MAO inhibitors. Atypical depression is characterized by labile mood, rejection  sensitivity, and appetite disorders. Despite their efficacy in treating depression, because of their risk for drug-drug  and drug-food interactions, the MAO inhibitors are considered to be last-line agents in many treatment venues.   These drugs are well absorbed after oral administration, but antidepressant effects require at least 2 to 4 weeks of  treatment. Enzyme regeneration, when irreversibly inactivated, varies, but it usually occurs several weeks after  termination of the drug. Thus, when switching antidepressant agents, a minimum of 2 weeks of delay must be  allowed after termination of MAO inhibitor therapy and the initiation of another antidepressant from any other  class. MAO inhibitors are metabolized and excreted rapidly in the urine.   Severe and often unpredictable side effects due to drug-food and drug-drug interactions limit the widespread use  of MAO inhibitors. For example, tyramine, which is contained in certain foods, such as aged cheeses and meats,  chicken liver, pickled or smoked fish such as anchovies or herring, and red wines, is normally inactivated by MAO in  the gut. Individuals receiving an MAO inhibitor are unable to degrade tyramine obtained from the diet. Tyramine  causes the release of large amounts of stored catecholamines from nerve terminals, resulting in occipital   headache, stiff neck, tachycardia, nausea, hypertension, cardiac arrhythmias, seizures, and possibly, stroke.   Patients must therefore be educated to avoid tyramine-containing foods. Phentolamine or prazosin are helpful in  the management of tyramine-induced hypertension. [Note: Treatment with MAO inhibitors may be dangerous in  severely depressed patients with suicidal tendencies. Purposeful consumption of tyramine-containing foods is a  possibility. ] Other possible side effects of treatment with MAO inhibitors include drowsiness, orthostatic  hypotension, blurred vision, dry mouth, dysuria, and constipation. The MAO inhibitors and SSRIs should not be  coadministered due to the risk of the life-threatening a€oeserotonin syndrome. a€^ Both types of drugs require  washout periods of at least 2 weeks before the other type is administered, with the exception of fluoxetine, which  should be discontinued at least 6 weeks before a MAO inhibitor is initiated. Combination of MAO inhibitors and  bupropion can produce seizures. Figure 12. 10 summarizes the side effects of the antidepressant drugs.   The treatment of bipolar disorder has increased in recent years, partly due to the increased recognition of the  disorder and also due to the increase in the number of medications U.S. Food and Drug Administration  (FDA)a€"approved for the treatment of mania. Lithium salts are used prophylactically for treating manic-depressive  patients and in the treatment of manic episodes and, thus, is considered a a€oemood stabilizer. a€§ Lithium is    effective in treating 60 to 80 percent of patients exhibiting mania and hypomania. Although many cellular processes  are altered by treatment with lithium salts, the mode of action is unknown. [Note: Lithium is believed to attenuate  signaling via receptors coupled to the phosphatidylinositol bisphosphate (PIP 2 ) second-messenger system. Lithium  interferes with the resynthesis (recycling) of PIP 2 , leading to its relative depletion in neuronal membranes of the  CNS. PIP 2 levels in peripheral membranes are unaffected by lithium.] Lithium is given orally, and the ion is  excreted by the kidney. Lithium salts can be toxic. Their safety factor and therapeutic index are extremely  lowa€"comparable to those of digitalis. Common adverse effects may include headache, dry mouth, polydipsia,  polyuria, polyphagia, gastrointestinal distress (give lithium with food), fine hand tremor, dizziness, fatigue,  dermatologic reactions, and sedation. Adverse effects due to higher plasma levels may include ataxia, slurred  speech, coarse tremors, confusion, and convulsions. [Note: The diabetes insipidus that results from taking lithium  can be treated with amiloride. ] Thyroid function may be decreased and should be monitored. Lithium causes no  noticeable effect on normal individuals. It is not a sedative, euphoriant, or depressant.    Figure 12.10 Side effects of some drugs used to treat depression.    Several antiepileptic drugs, including most notably carbamazepine, valproic acid, and lamotrigine, have been  identified and FDA-approved as a€oemood stabilizersa€§ and have been successfully utilized in the treatment of  bipolar disorder. Other agents that may improve manic symptoms include the older and newer antipsychotics. The  atypical antipsychotics (risperidone, olanzapine, ziprasidone, aripiprazole, and quetiapine ) have also received  FDA approval for the management of mania. Benzodiazepines are also frequently used as adj unctive treatments for    the acute stabilization of patients with mania. (See the respective chapters on these psychotropics for a more  detailed description).   12.1 A 55-year-old teacher began to experience changes in mood. He was losing interest in his work and lacked  the desire to play his daily tennis match. He was preoccupied with feelings of guilt, worthlessness, and  hopelessness. In addition to the psychiatric symptoms, the patient complained of muscle aches throughout his  body. Physical and laboratory tests were unremarkable. After 6 weeks of therapy with fluoxetine, the patient's  symptoms resolved. However, the patient complains of sexual dysfunction. Which of the following drugs might  be useful in this patient?    12. 2 A 25-year-old woman has a long history of depressive symptoms accompanied by body aches. Physical and  laboratory tests are unremarkable. Which of the following drugs might be useful in this patient?    12.3 A 51-year-old woman with symptoms of major depression also has narrow-angle glaucoma. Which of the  following antidepressants should be avoided in this patient?    12.4 A 36-year-old man presents with symptoms of compulsive behavior. If anything is out of order, he feels  that aCoework will not be accomplished effectively or efficiently. a€- He realizes that his behavior is  interfering with his ability to accomplish his daily tasks but cannot seem to stop himself. Which of the following  drugs would be most helpful to this patient?   >Table of Contents > Unit III - Drugs Affecting the Central Nervous System >Chapter 13 - Neuroleptics   The neuroleptic drugs (also called antipsychotic drugs, or major tranquilizers) are used primarily to treat  schizophrenia, but they are also effective in other psychotic states, such as manic states with psychotic symptoms  such as grandiosity or paranoia and hallucinations, and delirium. All currently available antipsychotic drugs that  alleviate symptoms of schizophrenia decrease dopaminergic and/or serotonergic neurotransmission. The traditional  or a€oetypicala€§ neuroleptic drugs (also called conventional or first-generation antipsychotics) are competitive  inhibitors at a variety of receptors, but their antipsychotic effects reflect competitive blocking of dopamine  receptors. These drugs vary in potency. For example, chlorpromazine is a low-potency drug, and fluphenazine is a  high-potency agent (Figure 13. 1). No one drug is clinically more effective than another. In contrast, the newer  antipsychotic drugs are referred to as a€oeatypicala€§ (or second-generation antipsychotics), because they have  fewer extrapyramidal adverse effects than the older, traditional agents. These drugs appear to owe their unique  activity to blockade of both serotonin and dopamine (and, perhaps, other) receptors. Current antipsychotic therapy  commonly employs the use of the atypical agents to minimize the risk of debilitating movement disorders associated  with the typical drugs that act primarily at the D 2 dopamine receptor. All of the atypical antipsychotics exhibit an  efficacy that is equivalent to, or occasionally exceeds, that of the typical neuroleptic agents. Flowever, consistent  differences in therapeutic efficacy among the individual atypical neuroleptics have not been established, and  individual patient response and comorbid conditions must often be used as a guide in drug selection. Neuroleptic  drugs are not curative and do not eliminate the fundamental and chronic thought disorder, but they often decrease  the intensity of hallucinations and delusions and permit the person with schizophrenia to function in a supportive  environment.   Schizophrenia is a particular type of psychosisa€"that is, a mental disorder caused by some inherent dysfunction of  the brain. It is characterized by delusions, hallucinations (often in the form of voices), and thinking or speech  disturbances. This mental disorder is a common affliction, occurring among about one percent of the population.  The illness often initially affects people during late adolescence or early adulthood and is a chronic and disabling  disorder. Schizophrenia has a strong genetic component and probably reflects some fundamental biochemical    abnormality, possibly a dysfunction of the mesolimbic or mesocortical dopaminergic neurons.   The neuroleptic drugs represent several diverse, heterocyclic structures with markedly different potencies. The  tricyclic phenothiazine derivative, chlorpromazine [klor-PROE-ma-zeen], was the first neuroleptic drug used to  treat schizophrenia. Antipsychotic drugs developed subsequently, such as haloperidol [hal-oh-PER-i-dole], are  more than 100-fold as potent as chlorpromazine but have an increased ability to induce parkinson-like and other  extrapyramidal effects. Furthermore, these more potent traditional drugs are no more effective than  chlorpromazine.   1. Dopamine receptoraC" blocking activity in the brain: All of the older and most of the newer neuroleptic drugs  block dopamine receptors in the brain and the periphery (Figure 13.2). Five types of dopamine receptors have  been identified. Di and D 5 receptors activate adenylyl cyclase, often exciting neurons, whereas D2, D3 and D 4  receptors inhibit adenylyl cyclase, or mediate membrane K + channel opening leading to neuronal  hyperpolarization. The neuroleptic drugs bind to these receptors to varying degrees. Flowever, the clinical  efficacy of the typical neuroleptic drugs correlates closely with their relative ability to block D2 receptors in the  mesolimbic system of the brain. On the other hand, the atypical drug clozapine [KLOE-za-peen] has higher  affinity for the D 4 receptor and lower affinity for the D2 receptor, which may partially explain its minimal ability  to cause extrapyramidal side effects (EPS). (Figure 13.3 summarizes the receptor-binding properties of  clozapine, chi or promazine, and haloperidol . ) The actions of the neuroleptic drugs are antagonized by agents  that raise synaptic dopamine concentrationsa€"for example, levodopa and amphetaminesa€"or mimic dopamine  at post-synaptic binding sitesa€"for example, bromocriptine.   2. Serotonin receptora€"blocking activity in the brain: Most of the newer atypical agents appear to exert part of  their unique action through inhibition of serotonin receptors (5-FIT), particularly 5- HT 2 a receptors. Thus,  clozapine has high affinity for Di, D 4 , 5-HT2, muscarinic, and i±-adrenergic receptors, but it is also a dopamine  D2-receptor antagonist. Risperidone [ris-PEER-i-dohn] blocks 5-FIT2A receptors to a greater extent than it does  D2 receptors, as does olanzapine. The atypical neuroleptic aripiprazole [ a- ri h- PI P- ra-zol e] is a partial agonist at  D2 and 5 -HTia receptors as well as a blocker of 5-PIT2A receptors. Quetiapine blocks D2 receptors more potently  than 5FIT2A receptors but is relatively weak at blocking either receptor, and its low risk for EPS may also be  related to the relatively short period of time it binds to the D2 receptor.   The antipsychotic actions of neuroleptic drugs appear to reflect a blockade at dopamine and/or serotonin  receptors. Flowever, many of these agents also block cholinergic, adrenergic, and histaminergic receptors (Figure  13.4). It is unknown what role, if any, these actions have in alleviating the symptoms of psychosis. The undesirable  side effects of these agents, however, are often a result of actions at these other receptors.   1. Antipsychotic actions: All of the neuroleptic drugs can reduce the hallucinations and delusions associated with  schizophrenia (the so-called   a€oepositivea€S symptoms) by blocking dopamine receptors in the mesolimbic system of the brain. The  a€oenegativea€§ symptoms, such as blunted affect, anhedonia (not getting pleasure from normally pleasurable  stimuli), apathy, and impaired attention, as well as cognitive impairment are not as responsive to therapy,  particularly with the typical neuroleptics. Many atypical agents, such as clozapine, ameliorate the negative  symptoms to some extent. All of the drugs also have a calming effect and reduce spontaneous physical  movement. In contrast to the central nervous system (CNS) depressants, such as barbiturates, the neuroleptics  do not depress the intellectual functioning of the patient as much, and motor incoordination is minimal. The  antipsychotic effects usually take several days to weeks to occur, suggesting that the therapeutic effects are  related to secondary changes in the corticostriatal pathways.   2. Extrapyramidal effects: Dystonias (sustained contraction of muscles leading to twisting distorted postures),  parkinson-like symptoms, akathisia (motor restlessness), and tardive dyskinesia (involuntary movements of the  tongue, lips, neck, trunk, and limbs) occur with chronic treatment. Blocking of dopamine receptors in the  nigrostriatal pathway probably causes these unwanted movement symptoms. The atypical neuroleptics exhibit a  lower incidence of these symptoms.    Most neuroleptic drugs have  affinities at D 2 -dopaminergic  receptors that parallel clinical  potency.    Clozapine differs from typical  neuroleptic drugs in having a  similar affinity for both D,- and  0 2 -dopaminergic receptors.    Figure 13.3 Relative affinity of clozapine, chlorpromazine, and haloperidol at Di- and D 2 -dopaminergic  receptors.    3. Antiemetic effects: With the exceptions of aripiprazole and thioridazine [thye-oh-RID-a-zeen], most of the  neuroleptic drugs have antiemetic effects that are mediated by blocking D 2 -dopaminergic receptors of the  chemoreceptor trigger zone of the medulla. (See p. 335 for a discussion of emesis. ) Figure 13. 5 summarizes the  antiemetic uses of neuroleptic agents, along with the therapeutic applications of other drugs that combat  nausea. [Note: The atypical antipsychotic drugs are not used as antiemetics. ]   4. Antimuscarinic effects: Some of the neuroleptics, particularly thioridazine, chlorpromazine, clozapine, and  olanzapine [oh-LAN-za-peen], produce anticholinergic effects, including blurred vision, dry   mouth (exception: clozapine increase salivation), confusion, and inhibition of gastrointestinal and urinary tract  smooth muscle, leading to constipation and urinary retention. This anticholinergic property may actually assist in  reducing the risk of EPS with these agents.    Figure 13.4 Neuroleptic drugs block at dopaminergic and serotonergic receptors as well as at adrenergic,  cholinergic, and histamine-binding receptors. GABA =i»-aminobutyric acid.    5. Other effects: Blockade of i±-adrenergic receptors causes orthostatic hypotension and light-headedness. The  neuroleptics also alter temperature-regulating mechanisms and can produce poikilothermia (body temperature  varies with the environment). In the pituitary, neuroleptics block D 2 receptors, leading to an increase in  prolactin release. Atypical neuroleptics are less likely to produce prolactin elevations. Sedation occurs with  those drugs that are potent antagonists of the Hi-histamine receptor, including chlorpromazine, olanzapine,  quetiapine, and clozapine. Sexual dysfunction may also occur with the antipsychotics due to various receptor-  binding characteristics.    1. Treatment of schizophrenia: The neuroleptics are considered to be the only efficacious treatment for  schizophrenia. Not all patients respond, and complete normalization of behavior is seldom achieved. The  traditional neuroleptics are most effective in treating positive symptoms of schizophrenia (delusions,  hallucinations, thought processing, and agitation). The newer agents with 5-HT2A receptora€"blocking activity  may be effective in many patients who are resistant to the traditional agents, especially in treating the negative  symptoms of schizophrenia (social withdrawal, blunted emotions, ambivalence, and reduced ability to relate to  people). However, even the atypical antipsychotics do not consistently improve the negative symptoms of  schizophrenia more than the older agents. [Note: Clozapine is reserved for the treatment of individuals who are  unresponsive to other neuroleptics, because its use is associated with blood dyscrasias and other severe adverse  effects],   2. Prevention of severe nausea and vomiting: The older neuroleptics (most commonly prochlorperazine ) are  useful in the treatment of drug-induced nausea (see p. 336). Nausea arising from motion should be treated with  sedatives, antihistamines, and anticholinergics, however, rather than with the powerful neuroleptic drugs.   [Note: Transdermal scopolamine is a drug of choice for treatment of motion sickness.]   3. Other uses: The neuroleptic drugs can be used as tranquilizers to manage agitated and disruptive behavior  secondary to other disorders. Neuroleptics are used in combination with narcotic analgesics for treatment of  chronic pain with severe anxiety. Chlorpromazine is used to treat intractable hiccups. Promethazine [proe-  METH-a-zeen] is not a good antipsychotic drug; however, this agent is used in treating pruritus because of its  antihistaminic properties. Pimozide [Pl-moe-zide] is primarily indicated for treatment of the motor and phonic  tics of Tourette's disorder. However, risperidone and haloperidol are also commonly prescribed for this tic  disorder. Also, risperidone is now approved for the management of disruptive behavior and irritability  secondary to autism.   After oral administration, the neuroleptics show variable absorption that is unaffected by food (except for  ziprasidone and paliperidone, the absorption of which is increased with food). These agents readily pass into the  brain, have a large volume of distribution, bind well to plasma proteins, and are metabolized to many different  substances, usually by the cytochrome P450 system in the liver, particularly the CYP2D6, CYP1A2, and CYP3A4  isoenzymes. Some metabolites are active. Fluphenazine decanoate, haloperidol decanoate, and risperidone  microspheres are slow-release (up to 2 to 4 weeks) inj ectable formulations of neuroleptics that are administered via  deep gluteal intramuscular injection. These drugs are often used to treat outpatients and individuals who are  noncompliant with oral medications. However, patients may still develop extrapyramidal symptoms (EPS), but the  risk of EPS is lower with these long-acting, injectable formulations compared to their respective oral formulations.  The neuroleptic drugs produce some tolerance but little physical dependence.    Adverse effects of the neuroleptic drugs can occur in practically all patients and are significant in about 80 percent   (Figure 13.6). Although antipsychotic drugs have an array of adverse effects, their therapeutic index is high.   1. Extrapyramidal side effects: The inhibitory effects of dopaminergic neurons are normally balanced by the  excitatory actions of cholinergic neurons in the striatum. Blocking dopamine receptors alters this balance,  causing a relative excess of cholinergic influence, which results in extrapyramidal motor effects. The maximal  risk of appearance of the movement disorders is time and dose dependent, with dystonias occurring within a few  hours to days of treatment, followed by akathisias (the inability to remain seated due to motor restlessness)  occurring within days to weeks. Parkinson-like symptoms of bradykinesia, rigidity, and tremor usually occur  within weeks to months of initiating treatment. Tardive dyskinesia, which can be irreversible, may occur after  months or years of treatment.   a. Effect of anticholinergic drugs: If cholinergic activity is also blocked, a new, more nearly normal balance is  restored, and extrapyramidal effects are minimized. This can be achieved by administration of an  anticholinergic drug, such as benztropine. The therapeutic trade-off will be fewer extrapyramidal effects in  exchange for the side effects of muscarinic receptor blockade. [Note: Sometimes, the parkinson-like actions  persist despite the anticholinergic drugs.] Those drugs that exhibit strong anticholinergic activity, such as  thioridazine, show fewer extrapyramidal disturbances, because the cholinergic activity is strongly  dampened. This contrasts with haloperidol and fluphenazine, which have low anticholinergic activity and  produce extrapyramidal effects more frequently because of the preferential blocking of dopaminergic  transmission without the blocking of cholinergic activity.   b. Atypical antipsychotics (clozapine and risperidone): These drugs exhibit a lower potential for causing  extrapyramidal symptoms and lower risk of tardive dyskinesia, which has been   attributed to their blockade of 5-HT2A receptors. These two drugs appear to be superior to haloperidol and  chlorpromazine in treating some of the symptoms of schizophrenia, especially the negative symptoms.   Risperidone should be included among the first-line antipsychotic drugs, whereas clozapine should be  reserved for severely schizophrenic patients who are refractory to traditional therapy. Clozapine can  produce bone marrow suppression, seizures, and cardiovascular side effects. The risk of severe  agranulocytosis necessitates frequent monitoring of white-blood-cell counts. Paliperidone, the major active  metabolite of risperidone, exhibits neuroleptic activity similar to that of the parent drug. The other atypical  antipsychotics ( olanzapine , quetiapine, ziprasidone, and aripiprazole ) have proven efficacy in treating  psychotic symptoms, but their efficacy is not considered to be consistently superior to that of the older  neurolepitcs. However, their lower incidence of EPS commonly places these newer agents ahead of the  older neuroleptics when treating patients with schizophrenia.   2. Tardive dyskinesia: Long-term treatment with neuroleptics can cause this motor disorder. Patients display  involuntary movements, including lateral j aw movements and a€oef ly-catchinga€§l motions of the tongue. A  prolonged holiday from neuroleptics may cause the symptoms to diminish or disappear within a few months.   However, in many individuals, tardive dyskinesia is irreversible and persists after discontinuation of therapy.   Tardive dyskinesia is postulated to result from an increased number of dopamine receptors that are synthesized  as a compensatory response to long-term dopamine-receptor blockade. This makes the neuron supersensitive to  the actions of dopamine, and it allows the dopaminergic input to this structure to overpower the cholinergic  input, causing excess movement in the patient.   3. Neuroleptic malignant syndrome: This potentially fatal reaction to neuroleptic drugs is characterized by muscle  rigidity, fever, altered mental status and stupor, unstable blood pressure, and myoglobinemia. Treatment  necessitates discontinuation of the neuroleptic and supportive therapy. Administration of dantrolene or  bromocriptine may be helpful.   4. Other effects: Drowsiness occurs due to CNS depression and antihistaminic effects, usually during the first few  weeks of treatment. Confusion is sometimes encountered. Those neuroleptics with potent antimuscarinic  activity often produce dry mouth, urinary retention, constipation, and loss of accommodation. Others may block    l±-adrenergic receptors, resulting in lowered blood pressure and orthostatic hypotension. The neuroleptics  depress the hypothalamus, affecting thermoregulation, and causing amenorrhea, galactorrhea, gynecomastia,  infertility, and impotence. Significant weight gain is often a reason for noncompliance. It is also recommended  that glucose and lipid profiles be monitored in patients taking antipsychotics due to the potential for the  atypical agents to increase these laboratory parameters and the possible exacerbation of preexisting diabetes  mellitusor hyperlipidemia.   5. Cautions and contraindications: Acute agitation accompanying withdrawal from alcohol or other drugs may be  aggravated by the   neuroleptics. Stabilization with a simple sedative, such as a benzodiazepine, is the preferred treatment. All  antipsychotics may lower the seizure threshold, and chi or promazine and clozapine are contraindicated in  patients with seizure disorders. Therefore, the neuroleptics can also aggravate preexisting epilepsy, and they  should be used with caution in patients with epilepsy. The high incidence of agranulocytosis with clozapine may  limit its use to patients who are resistant to other drugs. All of the atypical antipsychotics also carry the warning  of increased risk for mortality when used in elderly patients with dementia-related behavioral disturbances and  psychosis.   Patients who have had two or more psychotic episodes secondary to schizophrenia should receive maintenance  therapy for at least 5 years, and some experts prefer indefinite therapy. There has been a greater emphasis in  research and practice on identifying and aggressively managing first-episode psychosis to determine the benefits of  antipsychotic agents in this population. Low doses of antipsychotic drugs are not as effective as higher-dose  maintenance therapy in preventing relapse (Figure 13.7).    Patients receiving the atypical  neuroleptic risperidone show  fewer relapses than those  treated with haloperidol, a high-  potency, typical neuroleptic.    Figure 13.7 Rates of relapse among patients with schizophrenia after maintenance therapy with either  risperidone or haloperidol.    Figure 13. 8 summarizes the therapeutic uses of some of the neuroleptic drugs.   Little adrenergic or muscarinic activity; available  as slow release depot form;   Low potential for extrapyramidal effects; weight gain;  Used In treatment of bipolar depression    Low potential for extrapyramidal effects; contraindicated  In patients with history of cardiac arrhythmias; weight  gain minimal;   13. 1 An adolescent male is newly diagnosed with schizophrenia. Which of the following neuroleptic agents may  improve his apathy and blunted affect?    13. 2 Which one of the following neuroleptics has been shown to be a partial agonist at the D 2 receptor?   13.3 A 21-year-old male has recently begun pimozide therapy for Tourette's disorder. He is brought to the  emergency department by his parents. They describe that he has been having a€oedifferent-appearingticsa€'  than before, such as prolonged contraction of the facial muscles. While being examined, he experiences  opisthotonus (spasm of the body where the head and heels are bent backward and the body is bowed forward.   A type of extrapyramidal effect). Which of the following drugs would be beneficial in reducing these symptoms?   13.4 A 28-year-old woman with schizoid affective disorder and difficulty sleeping would be most benefited by  which of the following drugs?   >Table of Contents > Unit III - Drugs Affecting the Central Nervous System >Chapter 14 - Opioids   Management of pain is one of clinical medicine's greatest challenges. Pain is defined as an unpleasant sensation that  can be either acute or chronic and that is a consequence of complex neurochemical processes in the peripheral and  central nervous system (CNS). It is subj ective, and the physician must rely on the patient's perception and  description of his or her pain. Alleviation of pain depends on its type. In many casesa€"for example, with headaches  or mild to moderate arthritic paina€"nonsteroidal anti-inflammatory agents (NSAIDs, see Chapter 42) are effective.  Neurogenic pain responds best to anticonvulsants (for example pregabalin, see p. 179), tricyclic antidepressants (for  example, amitriptyline, seep. 145), or serotonin/ norepinephrine reuptake inhibitors (for example, duloxetine,  see p. 144) rather than NSAIDs or opioids. However, for severe or chronic malignant pain, opioids are usually the  drugs of choice. Opioids are natural or synthetic compounds that produce morphine-Wke effects. [Note: The term  a€oeopiatea€§ is reserved for drugs, such as morphine and codeine, obtained from the j uice of the opium poppy. ]  All drugs in this category act by binding to specific opioid receptors in the CNS to produce effects that mimic the  action of endogenous peptide neurotransmitters (for example, endorphins, enkephalins, and dynorphins). Although  the opioids have a broad range of effects, their primary use is to relieve intense pain and the anxiety that  accompanies it, whether that pain is from surgery or a result of inj ury or disease, such as cancer. However, their  widespread availability has led to abuse of those opioids with euphoric properties. [Note: Dependence is seldom a  problem in patients being treated for severe pain with these agents, as in cancer or acute pain in terminally ill  patients.] Antagonists that can reverse the actions of opioids are also very important clinically for use in cases of  overdose. Figure 14.1 lists the opioid agonists and antagonists discussed in this chapter.   Opioids interact stereospecif ical ly with protein receptors on the membranes of certain cells in the CNS, on nerve  terminals in the periphery, and on cells of the gastrointestinal tract and other anatomic regions. The major effects  of the opioids are mediated by three maj or receptor families. These are designated by the Greek letters Ap (mu), i Q  (kappa), and 1' (delta). Each receptor family exhibits a different specificity for the drug(s) it binds. The analgesic  properties of the opioids are primarily mediated by the Ap receptors; however, the i Q receptors in the dorsal horn  also contribute. For example, butorphanol and nalbuphine primarily owe their analgesic effect    to K-receptor activation. The enkephalins interact more selectively with the \' receptors in the periphery. All three  opioid receptors are members of the G proteinaC" coupled receptor family and inhibit adenylyl cyclase. 1 They are  also associated with ion channels, increasing postsynaptic K + efflux (hyperpolarization) or reducing presynaptic Ca 2+  influx, thus impeding neuronal firing and transmitter release (Figure 14.2).   Activation of the opioid  receptor decreases Ca 2+  influx in response to incoming  action potential. This decreases  release of excitatory neuro-  transmitters, such as  glutamate.    Activation of the  opioid receptor  increases K + efflux  and decreases the  response of the post-  synaptic neuron to  excitatory neuro-  transmitters.    Figure 14.2 Mechanism of action of A|i-opioid receptor agonists in the spinal cord.   High densities of opioid receptors known to be involved in integrating information about pain are present in five   general areas of the CNS. They have also been identified on the peripheral sensory nerve fibers and their terminals   and on immune cells. [Note: There is considerable overlap of receptor types in these various areas. ]   1. Brainstem: Opioid receptors influence respiration, cough, nausea and vomiting, blood pressure, pupillary  diameter, and control of stomach secretions.   2. Medial thalamus: This area mediates deep pain that is poorly localized and emotionally influenced.   3. Spinal cord: Receptors in the substantia gelatinosa are involved with the receipt and integration of incoming  sensory information, leading to the attenuation of painful afferent stimuli.   5. Limbic system: The greatest concentration of opiate receptors in the limbic system is located in the amygdala.  These receptors probably do not exert analgesic action, but they may influence emotional behavior.   6. Periphery: Opioids also bind to peripheral sensory nerve fibers and their terminals. As in the CNS, they inhibit  Ca 2+ -dependent release of excitatory, proinflammatory substances (for example, substance P) from these nerve  endings.   7. Immune cells: Opioid-binding sites have also been found on immune cells. The role of these receptors in  nociception (response or sensitivity to painful stimuli) has not been determined.   Morphine [MOR-feen] is the major analgesic drug contained in crude opium and is the prototype strong agonist.   Codeine is present in crude opium in lower concentrations and is inherently less potent. These drugs show a high   1. Mechanism of action: Opioids exert their major effects by interacting with opioid receptors in the CNS and in  other anatomic structures, such as the gastrointestinal tract and the urinary bladder. Opioids cause  hyperpolarization of nerve   cells, inhibition of nerve firing, and presynaptic inhibition of transmitter release. Morphine acts at i 2 receptors  in Lamina I and II of the dorsal horn of the spinal cord, and it decreases the release of substance P, which  modulates pain perception in the spinal cord. Morphine also appears to inhibit the release of many excitatory  transmitters from nerve terminals carrying nociceptive (painful) stimuli.   a. Analgesia: Morphine causes analgesia (relief of pain without the loss of consciousness). Opioids relieve pain  both by raising the pain threshold at the spinal cord level and, more importantly, by altering the brain's  perception of pain. Patients treated with morphine are still aware of the presence of pain, but the sensation  is not unpleasant. However, when given to an individual free of pain, its effects may be unpleasant and may  cause nausea and vomiting. The maximum analgesic efficacy and the addiction potential for representative   b. Euphoria: Morphine produces a powerful sense of contentment and well-being. Euphoria may be caused by  disinhibition of the ventral tegmentum.    Figure 14.3 A comparison of the maximum efficacy and addiction/ abuse liability of commonly used  narcotic analgesics.    c. Respiration: Morphine causes respiratory depression by reduction of the sensitivity of respiratory center  neurons to carbon dioxide. This occurs with ordinary doses of morphine and is accentuated as the dose  increases until, ultimately, respiration ceases. Respiratory depression is the most common cause of death in  acute opioid overdose.   d. Depression of cough reflex: Both morphine and codeine have antitussive properties. In general, cough  suppression does not correlate closely with analgesic and respiratory depressant properties of opioid drugs.  The receptors involved in the antitussive action appear to be different from those involved in analgesia.   e. Miosis: The pinpoint pupil, characteristic of morphine use, results from stimulation of Ap and i 2 receptors.  Morphine excites the Edinger-Westphal nucleus of the oculomotor nerve, which causes enhanced  parasympathetic stimulation to the eye (Figure 14.4). There is little tolerance to the effect, and all  morphine abusers demonstrate pinpoint pupils. [Note: This is important diagnostically, because many other  causes of coma and respiratory depression produce dilation of the pupil. ]   f. Emesis: Morphine directly stimulates the chemoreceptor trigger zone in the area postrema that causes  vomiting.    g. Gastrointestinal tract: Morphine relieves diarrhea and dysentery by decreasing the motility and increasing  the tone of the intestinal circular smooth muscle. Morphine also increases the tone of the anal sphincter.  Overall, morphine produces constipation, with little tolerance developing. It can also increase biliary tract  pressure due to contraction of the gallbladder and constriction of the biliary sphincter.   Figure 14.4 Morphine causes enhanced parasympathetic stimulation to the eye, resulting in pinpoint  pupils.   h. Cardiovascular: Morphine has no maj or effects on the blood pressure or heart rate except at large doses,  when hypotension and bradycardia may occur. Because of respiratory depression and carbon dioxide  retention, cerebral vessels dilate and increase the cerebrospinal fluid (CSF) pressure. Therefore, morphine  is usually contraindicated in individuals with severe brain inj ury.   i. Histamine release: Morphine releases histamine from mast cells, causing urticaria, sweating, and  vasodilation. Because it can cause bronchoconstriction, asthmatics should not receive the drug.   j . Hormonal actions: Morphine inhibits release of gonadotropin-releasing hormone and corticotropin-releasing  hormone, and it decreases the concentration of luteinizing hormone, follicle-stimulating hormone,  adrenocorticotropic hormone, and P-endorphin. Testosterone and cortisol levels decrease. Morphine  increases growth hormone release and enhances prolactin secretion. It increases antidiuretic hormone and,  thus, leads to urinary retention. [Note: It also can inhibit the urinary bladder voiding reflex; thus,  catheterization may be required.]   k. Labor: Morphine may prolong the second stage of labor by transiently decreasing the strength, duration,  and frequency of uterine contractions.   a. Analgesia: Despite intensive research, few other drugs have been developed that are as effective as  morphine in the relief of pain. Opioids induce sleep, and in clinical situations when pain is present and sleep  is necessary, opiates may be used to supplement the sleep-inducing properties of benzodiazepines, such as  temazepam. [Note: The sedative-hypnotic drugs are not usually analgesic, and they may have diminished  sedative effect in the presence of pain.]   b. Treatment of diarrhea: Morphine decreases the motility and increases the tone of intestinal circular   c. Relief of cough: Morphine suppresses the cough reflex; however, codeine or dextromethorphan are more  widely used for this purpose. Codeine has greater antitussive action than morphine.   d. Treatment of acute pulmonary edema: Intravenous (IV) morphine dramatically relieves dyspnea caused by  pulmonary edema associated with left ventricular failurea€"possibly by its vasodilatory effect.   a. Administration: Absorption of morphine from the gastrointestinal tract is slow and erratic. Codeine, by  contrast, is well absorbed when given by mouth. Significant first-pass metabolism of morphine occurs in the  liver; therefore, intramuscular, subcutaneous, or IV injections produce the most reliable responses. When  used orally, morphine is commonly administered in an extended-release form to provide more consistent  plasma levels. [Note: In   cases of chronic pain associated with neoplastic disease, it has become common practice to use either the  extended-release tablets orally or pumps that allow the patient to control the pain through  self-administration, as show in Figure 14. 5. ] Opiates have been taken for nonmedical purposes by inhaling  powders or smoke from burning crude opium, which provide a rapid onset of drug action.   b. Distribution: Morphine rapidly enters all body tissues, including the fetuses of pregnant women, and should  not be used for analgesia during labor. Infants born of addicted mothers show physical dependence on  opiates and exhibit withdrawal symptoms if opioids are not administered. Only a small percentage of  morphine crosses the blood-brain barrier, because morphine is the least lipophilic of the common opioids.   This contrasts with the more fat-soluble opioids, such as fentanyl, methadone, and heroin, which readily  penetrate into the brain.   c. Fate: Morphine is conj ligated in the liver to glucuronic acid, Morphine-6-glucuronide is a very potent  analgesic, whereas the conj ugate at position 3 is much less active. The conj ugates are excreted primarily in  the urine, with small quantities appearing in the bile. The duration of action of morphine is 4 to 6 hours  when administered systemically to morphine-naA've individuals but considerably longer when injected  epidurally, because its low lipophilicity prevents redistribution from the epidural space. [Note: A patient's  age can influence the response to morphine. Elderly patients are more sensitive to the analgesic effects of  the drug, possibly due to decreased metabolism or other factors, such as decreased lean body mass, renal  function, etc. They should be treated with lower doses. Neonates should not receive morphine because of  their low conj ugating capacity. ]    5. Adverse effects: Severe respiratory depression occurs and can result in death from acute opioid poisoning. A  serious effect of the drug is stoppage of respiratory exchange in patients with emphysema or cor pulmonale.  [Note: If employed in such individuals, respiration must be carefully monitored.] Other effects include vomiting,  dysphoria, and allergy-enhanced hypotensive effects (Figure 14.6). The elevation of intracranial pressure,  particularly in head inj ury, can be serious. Morphine enhances cerebral and spinal ischemia. In benign prostatic  hyperplasia, morphine may cause acute urinary retention. Patients with adrenal insufficiency or myxedema may  experience extended and increased effects from the opioids. Morphine should be used with cautiously in  patients with bronchial asthma or liver failure.   6. Tolerance and physical dependence: Repeated use produces tolerance to the respiratory depressant,    analgesic, euphoric, and sedative effects of morphine. However, tolerance usually does not develop to the  pupil-constricting and constipating effects of the drug. Physical and psychological dependence readily occur  with morphine and with some of the other agonists to be described (see Figure 14.3). Withdrawal produces a  series of autonomic, motor, and psychological responses that incapacitate the individual and cause  seriousa€"almost unbearablea€" symptoms. However, it is very rare that the   effects are so profound as to cause death. [Note: Detoxification of heroin- or morpfi/'ne-dependent individuals  is usually accomplished through the oral administration of methadone, buprenorphine (see below), or  clonidine. ]   7. Drug interactions: The depressant actions of morphine are enhanced by phenothiazines, monoamine oxidase  inhibitors, and tricyclic antidepressants (Figure 14. 7). Low doses of amphetamine inexplicably enhance  analgesia, as does hydroxyzine.   Meperidine [me-PER-i-deen] is a synthetic opioid structurally unrelated to morphine. It is used for acute pain.   Figure 14.6 Adverse effects commonly observed in individuals treated with opioids.    1. Mechanism of action: Meperidine binds to opioid receptors, particularly Ap receptors. However, it also binds   2. Actions: Meperidine causes a depression of respiration similar to that of morphine, but it has no significant  cardiovascular action when given orally. On IV administration, meperidine produces a decrease in peripheral  resistance and an increase in peripheral blood flow, and it may cause an increase in cardiac rate. As with  morphine, meperidine dilates cerebral vessels, increases CSF pressure, and contracts smooth muscle (the latter  to a lesser extent than does morphine). Meperidine does not cause pinpoint pupils but, rather, causes the  pupils to dilate because of an atropine- 1 ike action.   3. Therapeutic uses: Meperidine provides analgesia for any type of severe pain. Unlike morphine, meperidine is  not clinically useful in the treatment of diarrhea or cough. Meperidine produces less of an increase in urinary  retention than does morphine. It has significantly less effects on uterine smooth muscle than morphine and is  the opioid commonly employed in obstetrics (see below).   4. Pharmacokinetics: Meperidine is well absorbed from the gastrointestinal tract, and is useful when an orally  administered, potent analgesic is needed. However, meperidine is most often administered parenteral ly. The  drug has a duration of action of 2 to 4 hours, which is shorter than that of morphine (Figure 14.8). Meperidine is  N-demethylated to normeperidine in the liver and is excreted in the urine. [Note: Because of its shorter action  and different route of metabolism, meperidine is preferred over morphine for analgesia during labor.]   5. Adverse effects: Large or repetitive doses of meperidine can cause anxiety, tremors, muscle twitches, and  rarely, convulsions due to the accumulation of a toxic metabolite, normeperidine. The drug differs from opioids  in that when given in large doses, it dilates the pupil and causes hyperactive reflexes. Severe hypotension can  occur when the drug is administered postoperatively. Due to its antimuscarinic action, patients may experience  dry mouth and blurred vision. When used with maj or neuroleptics, depression is greatly enhanced.   Administration to patients taking monoamine oxidase inhibitors can provoke severe reactions, such as  convulsions and hyperthermia. Meperidine can cause dependence, and can substitute for morphine or heroin in  opiate-dependent persons. Partial cross-tolerance with the other opioids occurs.   Methadone [METH-a-done] is a synthetic, orally effective opioid that is approximately equal in potency to  morphine but induces less euphoria and has a somewhat longer duration of action.    Absolute contra-  indication to meperidine  and relative contra-  indication to other  narcotic analgesics  because of high  incidence of hyper-  pyrexic coma    Figure 14.7 Drugs interacting with narcotic analgesics. CNS=central nervous system; MAO =monoamine  oxidase.    1. Mechanism of action: The actions of methadone are mediated by the Ap receptors.   2. Actions: The analgesic activity of methadone is equivalent to that of morphine (see Figure 14.3). Methadone is  well-absorbed when administered orally, in contrast to morphine, which is only partially absorbed from the  gastrointestinal tract. The miotic and respiratory-depressant actions of methadone have average half-lives of 24  hours. Like morphine, methadone increases biliary pressure and is also constipating.   3. Therapeutic uses: Methadone is used as an analgesic as well as in the controlled withdrawal of dependent  abusers from heroin and morphine. Orally administered, methadone is substituted for the injected opioid. The  patient is then slowly weaned from methadone. Methadone causes a withdrawal syndrome that is milder but  more protracted (days to weeks) than that of other opioids.   4. Pharmacokinetics: Methadone is readily absorbed following oral administration. It accumulates in tissues,  where it remains bound to protein, from which it is slowly released. The drug is biotransformed in the liver and    5. Adverse effects: Methadone can produce physical dependence like that of morphine.   Fentanyl [FEN-ta-nil], which is chemically related to meperidine, has 100-fold the analgesic potency of morphine  and is used in anesthesia. The drug is highly lipophilic and has a rapid onset and short duration of action (15 to 30  minutes). It is usually inj ected IV, epidural ly, or intrathecally. Epidural fentanyl is used for analgesia  postoperatively and during labor. An oral transmucosal preparation and a transdermal patch are also available. The  transmucosal preparation is used in the treatment of cancer patients with breakthrough pain who are tolerant to  opioids. The transdermal patch must be used with caution, because death resulting from hypoventilation has been  known to occur. [Note: The transdermal patch creates a reservoir of the drug in the skin. Hence, the onset is  delayed 12 hours, and the offset is prolonged. ] Fentanyl is often used during cardiac surgery because of its  negligible effects on myocardial contractility. Muscular rigidity, primarily of the abdomen and chest wall, is often  observed with fentanyl use in anesthesia. Fentanyl is metabolized to inactive metabolites by the cytochrome  P4503A4 system, and drugs that inhibit this isozyme can potentiate the effect of fentanyl. Most of the drug and  metabolites are eliminated through the urine. Adverse effects of fentanyl are similar to those of other Ap-receptor  agonists. Because of life-threatening hypoventilation, the fentanyl patch is contraindicated in the management of  acute and postoperative pain or pain that can be ameliorated with other analgesics. Unlike meperidine, it causes  pupillary constriction.    Figure 14.8 Time to peak effect and duration of action of several opioids administered intravenously.   Three drugs related to fentanylai" sufentanil [soo-FEN-ta-nil], alfentanil [al-FEN-ta-nil], and remifentanil [rem-i  FEN-ta-ni l]a€"differ in their potency and metabolic disposition. Sufentanil is even more potent than fentanyl,  whereas the other two are less potent but much shorter-acting.   Heroin [HAIR-o-in] does not occur naturally. It is produced by diacetylation of morphine, which leads to a  three-fold increase in its potency. Its greater lipid solubility allows it to cross the blood-brain barrier more rapidly  than morphine, causing a more exaggerated euphoria when the drug is taken by inj ection. Heroin is converted to  morphine in the body, but its effects last about half as long. It has no accepted medical use in the United States.   Oxycodone [ok-see-KOE-done] is a semisynthetic derivative of morphine. It is orally active and is sometimes  formulated with aspirin or acetaminophen. It is used to treat moderate to severe pain and has many properties in  common with morphine. Oxycodone is metabolized to products with lower analgesic activity. Excretion is via the  kidney. Abuse of the sustained-release preparation (ingestion of crushed tablets) has been implicated in many  deaths. It is important that the higher-dosage forms of the latter preparation be used only by patients who are  tolerant to opioids.   The analgesic actions of codeine [KOE-deen] are due to its conversion to morphine, whereas the drug's antitussive  effects are due to codeine itself. Thus, codeine is a much less potent analgesic than morphine, but it has a higher  oral effectiveness. Codeine shows good antitussive activity at doses that do not cause analgesia. At commonly used  doses, the drug has a lower potential for abuse than morphine, and it rarely produces dependence. Codeine  produces less euphoria than morphine. Codeine is often used in combination with aspirin or acetaminophen.  [Note: In most nonprescription cough preparations, codeine has been replaced by drugs such as  dextromethorphana€"a synthetic cough depressant that has relatively no analgesic action and a relatively low  potential for abuse in usual antitussive doses. ] Figure 14.9 shows some of the actions of codeine.   Propoxyphene [proe-POX-i-feen] is a derivative of methadone. The dextro isomer is used as an analgesic to relieve  mild to moderate pain. The levo isomer is not analgesic, but it has antitussive action. Propoxyphene is a weaker  analgesic than codeine, requiring approximately twice the dose to achieve an effect equivalent to that of codeine.  Propoxyphene is often used in combination with acetaminophen for an analgesia greater than that obtained with  either drug alone. It is well absorbed orally, with peak plasma levels occurring in 1 hour, and it is metabolized in the  liver. Propoxyphene can produce nausea, anorexia, and constipation. In toxic doses, it can cause respiratory  depression, convulsions, hallucinations, and confusion. When toxic doses are taken, a very serious problem   can arise in some individuals, with resultant cardiotoxicity and pulmonary edema. [Note: When used with alcohol  and sedatives, severe CNS depression is produced, and death by respiratory depression and cardiotoxicity can   result. Respiratory depression and sedation can be antagonized by naloxone, but the cardiotoxicity cannot. ]   Drugs that stimulate one receptor but block another are termed mixed agonist-antagonists. The effects of these  drugs depend on previous exposure to opioids. In individuals who have not recently received opioids (naA've  patients), mixed agonist-antagonists show agonist activity and are used to relieve pain. In the patient with opioid  dependence, the agonist-antagonist drugs may show primarily blocking effectsa€"that is, produce withdrawal  symptoms.   Pentazocine [pen-TAZ-oh-seen] acts as an agonist on I s receptors and is a weak antagonist at Ap and T' receptors.  Pentazocine promotes analgesia by activating receptors in the spinal cord, and it is used to relieve moderate pain.   It may be administered either orally or parenteral ly. Pentazocine produces less euphoria compared to morphine. In  higher doses, the drug causes respiratory depression and decreases the activity of the gastrointestinal tract. High  doses increase blood pressure and can cause hallucinations, nightmares, dysphoria, tachycardia, and dizziness. The  latter properties have led to its decreased use. In angina, pentazocine increases the mean aortic pressure and  pulmonary arterial pressure and, thus, increases the work of the heart. The drug decreases renal plasma flow.  Despite its antagonist action, pentazocine does not antagonize the respiratory depression of morphine, but it can  precipitate a withdrawal syndrome in a morphine abuser. Tolerance and dependence develop on repeated use.    Figure 14.10 Scores for opiate craving and overall status in opioid-addicted patients assigned to office-based  treatment with buprenorphine or placebo.   Buprenorphine [byoo-pre-NOR-feen] is classified as a partial agonist, acting at the Ap receptor. It acts like  morphine in naA've patients, but it can also precipitate withdrawal in morphine users. A major use is in opiate  detoxification, because it has a less severe and shorter duration of withdrawal symptoms compared to methadone  (Figure 14. 10). It causes little sedation, respiratory depression, and hypotension, even at high doses. In contrast to  methadone, which is available only at specialized clinics, buprenorphine is approved for office-based  detoxification or maintenance. Buprenorphine is administered sublingually or parenteral ly and has a long duration  of action because of its tight binding to the Ap receptor. The tablets are indicated for the treatment of opioid  dependence. The injectable form is indicated for the relief of moderate to severe pain. It is metabolized by the  liver and excreted in the bile and urine. Adverse effects include respiratory depression that cannot easily be  reversed by naloxone, decreased (or, rarely, increased) blood pressure, nausea, and dizziness.   Nalbuphine [NAL byoo feen] and butorphanol [byoo-TOR-fa-nole], like pentazocine, play a limited role in the  treatment of chronic pain. Neither is available for oral use. Their propensity to cause psychotomimetic   (actions mimics the symptoms of psychosis) effects is less than that of pentazocine. Nalbuphine does not affect the  heart or increase blood pressure, in contrast to pentazocine and butorphanol . A benefit of all three medications is  that they exhibit a ceiling effect for respiratory depression.   Tramadol (TRA-ma-dole) is a centrally acting analgesic that binds to the Ap-opioid receptor. In addition, it weakly  inhibits reuptake of norepinephrine and serotonin. It is used to manage moderate to moderately severe pain. Its  respiratory-depressant activity is less than that of morphine. Naloxone (see below) can only partially reverse the  analgesia produced by tramadol or its active metabolite. The drug undergoes extensive metabolism, and one  metabolite is active. Concurrent use with carbamazepine results in increased metabolism, presumably by induction  of the cytochrome P450 2D6 system. [Note: Quinidine, which inhibits this isozyme, increases levels of tramadol  when taken concurrently. ] Anaphylactoid reactions have been reported. Of concern are the seizures that can  occur, especially in patients taking selective serotonin reuptake inhibitors, tricyclic antidepressants, or in overdose.  Tramadol should also be avoided in patients taking monoamine oxidase inhibitors.   The opioid antagonists bind with high affinity to opioid receptors but fail to activate the receptor-mediated  response. Administration of opioid antagonists produces no profound effects in normal individuals. However, in  patients dependent on opioids, antagonists rapidly reverse the effect of agonists, such as heroin, and precipitate  the symptoms of opiate withdrawal.   Naloxone [nal-OX-own] is used to reverse the coma and respiratory depression of opioid overdose. It rapidly  displaces all receptor-bound opioid molecules and, therefore, is able to reverse the effect of a heroin overdose  (Figure 14. 11). Within 30 seconds of IV injection of naloxone, the respiratory depression and coma characteristic of  high doses of heroin are reversed, causing the patient to be revived and alert. Naloxone has a half-life of 60 to 100  minutes. [Note: Because of its relatively short duration of action, a depressed patient who has been treated and  recovered may lapse back into respiratory depression. ] Naloxone is a competitive antagonist at Ap, i e , and i',  receptors, with a 10-fold higher affinity for Ap than for i e receptors. This may explain why naloxone readily reverses  respiratory depression with only minimal reversal of the analgesia that results from agonist stimulation of i 2  receptors in the spinal cord. Naloxone produces no pharmacologic effects in normal individuals, but it precipitates  withdrawal symptoms in opioid abusers. Figure 14. 12 summarizes some of the signs and symptoms of opiate  withdrawal.   Naltrexone [nal-TREX-own] has actions similar to those of naloxone. It has a longer duration of action than  naloxone, and a single oral dose of naltrexone blocks the effect of injected heroin for up to 48 hours. Naltrexone  in combination with clonidine a€"and, sometimes, with buprenorphinea€"\s   employed for rapid opioid detoxification. It may also be beneficial in treating chronic alcoholism by an unknown  mechanism; however, benzodiazepines and clonidine are preferred. Naltrexone is hepatotoxic.   Nalmefene [NAL-meh-freen] is a parenteral opioid antagonist with actions similar to that of naloxone and  naltrexone. It can be administered IV, intramuscularly, or subcutaneously. Its half-life of 8 tolO hours is  significantly longer than that of naloxone and several opioid agonists.   14. 1 A young man is brought into the emergency room. He is unconscious, and he has pupillary constriction  and depressed respiration. You note needle marks on his legs. You administer naltrexone, and he awakens.  This agent was effective because:   A. The patient was suffering from an overdose of a benzodiazepine.    14. 2 A heroin addict has entered a rehabilitation program that requires that she take methadone. Methadone  is effective in this situation because it:   C. Is longer acting than heroin; hence, the withdrawal is milder than with the latter drug.   A. It is used therapeutically to relieve pain caused by severe head inj ury.   14.4 The pain of a patient with bone cancer has been managed with a morphine pump. However, he has  become tolerant to morphine. Which of the following might be indicated to ameliorate his pain?   >Table of Contents > Unit III - Drugs Affecting the Central Nervous System >Chapter 15 - Epilepsy   Epilepsy affects approximately 3 percent of individuals by the time they are 80 years old. About 10 percent of the  population will have at least one seizure in their lifetime. Globally epilepsy is the third most common neurologic  disorder after cerebrovascular and Alzheimer's disease. Epilepsy is not a single entity but, instead, an assortment of  different seizure types and syndromes originating from several mechanisms that have in common the sudden,  excessive, and synchronous discharge of cerebral neurons. This abnormal electrical activity may result in a variety  of events, including loss of consciousness, abnormal movements, atypical or odd behavior, or distorted perceptions  that are of limited duration but recur if untreated. The site of origin of the abnormal neuronal firing determines the  symptoms that are produced. For example, if the motor cortex is involved, the patient may experience abnormal  movements or a generalized convulsion. Seizures originating in the parietal or occipital lobe may include visual,  auditory, or olfactory hallucinations. Drug or vagal nerve stimulator therapy is the most widely effective mode for  the treatment of patients with epilepsy. It is expected that seizures can be controlled completely in approximately  70 to 80 percent of patients with one medication. It is estimated that approximately 10 to 15 percent of patients will  require more than one drug and perhaps 10 percent may not achieve complete seizure control. A summary of  antiseizure drugs is shown in Figure 15. 1.    Figure 15.1 Summary of agents used in the treatment of epilepsy.   In most cases, epilepsy has no identifiable cause. Focal areas that are functionally abnormal may be triggered into  activity by changes in any of a variety of environmental factors, including alteration in blood gases, pH,  electrolytes, blood glucose level, sleep deprivation, alcohol intake, and stress. The neuronal discharge in epilepsy  results from the firing of a small population of neurons in some specific area of the brain that is referred to as the  primary focus. Anatomically, this focal area may appear to be normal. However, advances in technology have  improved ability to detect abnormalities, and in some patients, neuroimaging techniques, such as magnetic  resonance imaging (MRI), positron-emission tomography (PET) scans and single-photon-emission coherence  tomography (SPECT) can identify areas of concern (Figure 15.2). Epilepsy can be labeled idiopathic or symptomatic  depending if the etiology is unknown, or is secondary to an identifiable condition. There are also multiple specific  epilepsy syndromes that have been classified and include symptoms other than seizures.    When no specific anatomic cause for the seizure, such as trauma or neoplasm, is evident, a patient may be  diagnosed with idiopathic or cryptogenic (primary) epilepsy. These seizures may result from an inherited  abnormality in the central nervous system (CNS). Patients are treated chronically with antiseizure drugs or vagal  nerve stimulation. Most cases of epilepsy are idiopathic.   Single-photon-emission-coherence  tomography (SPECT) can be used to  measure regional blood flow in the  brain. The image shows an increased  blood flow in the left temporal lobe  associated with the onset of a seizure  in the same area.    Figure 15.2 Region of the brain in an epileptic individual showing increased blood flow during a seizure.   A number of causes, such as illicit drug use, tumors, head inj ury, hypoglycemia, meningeal infection, or rapid  withdrawal of alcohol from an alcoholic, can precipitate seizures. When two or more seizures occur, then the  patient may be diagnosed with symptomatic (secondary) epilepsy. Chronic treatment with antiseizure medications,  vagal nerve stimulation and surgery are all appropriate treatments and may be used alone or in combination. In some  cases when the cause of a single seizure can be determined and corrected, therapy may not necessary. For  example, a seizure that is caused by transient hypotension or is due to a drug reaction does not require chronic  prophylactic therapy. In other situations, antiseizure drugs may be given until the primary cause of the seizures can  be corrected.   It is important to correctly classify seizures to determine appropriate treatment. Seizures have been categorized by  site of origin, etiology, electrophysiologic correlation, and clinical presentation. The International League Against  Epilepsy developed a nomenclature for describing seizures, and it is considered to be the standard way to document  seizures and epilepsy syndromes (Figure 15.3). Seizures have been classified into two broad groups: partial (or  focal), and generalized. A diagnosis may classify the seizure as partial or primary generalized epilepsy depending on  the onset.   Partial seizures involve only a portion of the brain, typically part of one lobe of one hemisphere. The symptoms of  each seizure type depend on the site of neuronal discharge and on the extent to which the electrical activity  spreads to other neurons in the brain. Consciousness is usually preserved. Partial seizures may progress, becoming  generalized tonic-clonic seizures.   1. Simple partial: These seizures are caused by a group of hyperactive neurons exhibiting abnormal electrical  activity, which are confined to a single locus in the brain. The electrical discharge does not spread, and the  patient does not lose consciousness. The patient often exhibits abnormal activity of a single limb or muscle  group that is controlled by the region of the brain experiencing the disturbance. The patient may also show  sensory distortions. This activity may spread. Simple partial seizures may occur at any age.   2. Complex partial: These seizures exhibit complex sensory hallucinations, mental distortion, and loss of    consciousness. Motor dysfunction may involve chewing movements, diarrhea, and/or urination. Consciousness is  altered. Simple partial seizure activity may spread and become complex and then spread to a secondarily  generalized convulsion. Partial seizures may occur at any age.   Generalized seizures may begin locally, producing abnormal electrical discharges throughout both hemispheres of  the brain. Primary generalized seizures may be convulsive or nonconvulsive, and the patient usually has an  immediate loss of consciousness   1. Tonic-clonic: Seizures result in loss of consciousness, followed by tonic (continuous contraction) and clonic  (rapid contraction and relaxation) phases. The seizure may be followed by a period of confusion and exhaustion  due to the depletion of glucose and energy stores.   2. Absence: These seizures involve a brief, abrupt, and self-limiting loss of consciousness. The onset generally  occurs in patients at 3 to 5 years of age and lasts until puberty or beyond. The patient stares and exhibits rapid  eye-blinking, which lasts for 3 to 5 seconds. This seizure has a very distinct three-per-second spike and wave  discharge seen on electroencephalogram.    3. Myoclonic: These seizures consist of short episodes of muscle contractions that may reoccur for several   minutes. They generally occur after wakening and exhibit as brief j erks of the limbs. Myoclonic seizures occur at  any age but usually begin around puberty or early adulthood.    4. Febrile seizures: Young children may develop seizures with illness accompanied by high fever. This may occur  in siblings. The febrile seizures consist of generalized tonic-clonic convulsions of short duration and do not  necessarily lead to a diagnosis of epilepsy.   5. Status epilepticus: In status epilepticus, two or more seizures recur without recovery of full consciousness  between them. These may be partial or primary generalized, convulsive or nonconvulsive. Status epilepticus is  life-threatening and requires emergency treatment.   Drugs that are effective in seizure reduction accomplish this by a variety of mechanisms, including blockade of  voltage-gated channels (Na + or Ca 2 ' t ), enhancement of inhibitory GABAergic impulses, or interference with  excitatory glutamate transmission. Some antiepileptic drugs appear to have multiple targets within the CNS,  whereas the mechanism of action for some agents is poorly defined. The antiepilepsy drugs suppress seizures but do  not a€oecurea€i or a€oepreventa€i epilepsy.   Choice of drug treatment is based on the classification of the seizures being treated, patient specific variables (for  example, age, comorbid medical conditions, lifestyle, and other preferences), and characteristics of the drug,  including cost and interactions with other medications. For example, partial onset tonic-clonic seizures are treated  differently than primary generalized seizures. Several drugs may be equally effective, and the toxicities of the  agent and characteristics of the patient are major considerations in drug selection. In newly diagnosed patients,  monotherapy is instituted with a single agent until seizures are controlled or toxicity occurs (Figure 15.4).   monotherapy exhibit better adherence and fewer side effects. If seizures are not controlled with the first drug,  monotherapy with an alternate antiepileptic drug(s), or vagal nerve stimulation should be considered (see Figure  15.5). An awareness of the antiepileptic drugs available, including their mechanisms of action, pharmacokinetics,  potential for drug-drug interactions, and adverse effects, is essential for successful therapy.   During the past 15 years, new antiepileptic drugs have been introduced, some of which have potential advantages in  terms of pharmacokinetics, tolerability, and lesser risk for drug-drug interactions when compared with the   older agents used to treat epilepsy. These new drugs, which include gabapentin, lamotrigine, topiramate,  levetiracetam, oxcarbazepine, zonisamide, are labeled a€oesecond generationa€§ when compared with older  antiepileptics, such as phenobarbital, phenytoin, carbamazepine, ethosuximide, divalproex and valproic acid.   However, clinical studies have not shown that the second-generation drugs as a group are significantly better with  respect to efficacy and in some cases, adverse effects than the older agents. For that reason, the authors have  chosen to present the antiepileptic drugs in alphabetic order, rather than attempting to rank them by efficacy.   Figure 15.6 shows the commonly encountered adverse effect of the antiepileptic drugs. In addition, an increased  risk of suicidal behavior and suicidal ideation has been observed with many of the antiepileptic drugs.   Benzodiazepines bind to GABA inhibitory receptors to reduce firing rate. Diazepam, and lorazepam are most often  used as an adj unctive therapy for myoclonic as well as for partial and generalized tonic-clonic seizures. Lorazepam  (see p. 108) has a shorter pharmacokinetic half-life but stays in the brain longer than diazepam. Diazepam is  available for rectal administration to avoid or interrupt prolonged generalized tonic-clonic seizures or clusters.  Other benzodiazepines may be used in the treatment of various epilepsies but should be considered for use only  after trials with monotherapy or combinations of most other medications for treatment of seizures fail.   Carbamazepine [kar-ba-MAZ-a peen] reduces the propagation of abnormal impulses in the brain by blocking sodium  channels, thereby inhibiting the generation of repetitive action potentials in the epileptic focus and preventing  their spread. Carbamazepine is effective for treatment of partial seizures and secondarily generalized tonic-clonic  seizures. It is also used to treat trigeminal neuralgia and in bipolar disease. Carbamazepine is absorbed slowly and  erratically following oral administration and may vary from generic to generic, resulting in large variations in serum  concentrations of the drug. It induces its own drug metabolism and has an active metabolite. It is a substrate for  CYP3A4 with minor metabolism by CYP1A2 and CYC2C8. The epoxide metabolite accounts for 25 percent of the  dose, is active, and can be inhibited by drugs that inhibit UDP glucouronosyltransferase (UGT), leading to toxicity  (Figure 15.7). Carbamazepine is an inducer of the isozyme families CYP1A2, CYP2C, and CYP3A and UGT enzymes  which may increase the clearance and reduce the efficacy of drugs that are metabolized by these enzymes. It is not  as well tolerated by the elderly as other available antiseizure medications. Hyponatremia may be noted in some  patients, especially the elderly, and could indicate a need for change of therapy. The 10, 11-epoxide metabolite of  the drug has been implicated in causing blood dyscrasias. A characteristic rash may develop early in therapy but may  not require a change in treatment. Carbamazepine should not be prescribed for patients with absence seizures  because it may cause an increase in seizures.   Divalproex sodium is a combination of sodium valproate and valproic acid and is reduced to valproate when it  reaches the gastrointestinal tract. It was developed to improve gastrointestinal tolerance of valproic acid. All of the  available salt forms are equivalent in efficacy (valproic acid and valproate sodium). Commercial products are  available in multiple-salt, dosage forms and extended-release formulations. Therefore the risk for medication errors  is high, and it is essential to be familiar with all preparations. Proposed mechanisms of action include sodium  channel blockade, blockade of GABA transaminase, and action at the T-type calcium channels. These many  mechanisms provide a broad spectrum of activity against seizures. It is effective for the treatment of partial and  primary generalized epilepsies. Valproate inhibits metabolism of the CYP2C9, UGT and epoxide hydrolase systems.  Valproate is bound to albumin (greater than 90 percent), which can cause significant interactions with other highly  protein bound drugs. Rare hepatic toxicity may cause a rise in hepatic enzymes in plasma, which should be  monitored   frequently. Teratogenicity is of great concern. Therefore all women of child-bearing age should be placed on other  therapies and counseled about the potential for birth defects, including neural tube defects.   Ethosuximide [eth-oh-SUX-i-mide] reduces propagation of abnormal electrical activity in the brain, most likely by  inhibiting T-type calcium channels. It is effective in treating only primary generalized absence seizures (see Figure  15.5). Use of ethosuximide is limited because of this very narrow spectrum.   Felbamate [FEL-ba-mate] has a broad spectrum of anticonvulsant action. The drug has multiple proposed  mechanisms including 1) blocking voltage-dependent sodium channels, 2) competing with the glycine-coagonist  binding site on the N-methyl-D-aspartate (NMDA) glutamate receptor, 3) blocking calcium channels, and 5)  potentiation of GABA actions. It is an inhibitor of drugs metabolized by CYP2C19 and b-oxidation. It induces drugs  metabolized by CYP3A4. It is reserved for use in refractory epilepsies (particularly Lennox-Gastaut syndrome)  because of the risk of aplastic anemia (about 1:4000) and hepatic failure.   Gabapentin [GA-ba-pen-tin] is an analog of GABA. However, it does not act at GABA receptors nor enhance GABA  actions, nor is it converted to GABA. Its precise mechanism of action is not known. It is approved as adj unct therapy  for partial seizures and for treatment of postherpetic neuralgia. Gabapentin exhibits nonlinear pharmacokinetics    due to its uptake by a saturable transport system from the gut. Gabapentin does not bind to plasma proteins and is  excreted unchanged through the kidneys. Reduced dosing is required in renal disease. Gabapentin has been shown  to be well tolerated by the elderly population with partial seizures due to the relatively mild adverse effects and a  good choice due to limited or no reported pharmacokinetic drug interactions.   Lamotrigine [la-MOE-tri-j een] blocks sodium channels as well as high voltagea€"dependent calcium channels.   Lamotrigine is effective in a wide variety of seizure disorders, including partial seizures, generalized seizures,  typical absence seizures, and the Lennox-Gastaut syndrome. It is approved for use in bipolar disorder as well.   Lamotrigine is metabolized primarily to the N-2 glucuronide through the UGT pathway. The half-life of lamotrigine  (24a€"35 hours) is decreased by enzyme-inducing drugs (for example, carbamazepine and phenytoin) and increased  by greater than 50 percent with addition of valproate. Lamotrigine dosages should be reduced when adding  valproate to therapy unless the valproate is being added in a small dose to provide a boost to the lamotrigine  serum concentration. Rapid titration to high serum concentrations of lamotrigine have been reported to cause a  rash, which in some patients may progress to a serious, life-threatening reaction. Lamotrigine has also been shown  to be well tolerated by the elderly population with partial seizures due to the relatively minor adverse effects when  titrated slowly.   Levetiracetam [lee-ve-tye-RA-se-tam] is approved for adj unct therapy of partial onset seizures, myoclonic  seizures, and primary generalized tonic-clonic seizures in adults and children. The exact mechanism of  anticonvulsant action is unknown. It demonstrates high affinity for a synaptic vesicle protein (SV2A). In mice, this  was associated with potent antiseizure action. The drug is well absorbed orally, and excretion is urinary, with most  of the drug (66 percent) being unchanged. The drug does not interact with CYP or UGT metabolism systems. Side  effects most often reported include dizziness, sleep disturbances, headache, and weakness.   Oxcarbazepine [ox-kar-BAY-zeh-peen] is a prodrug that is rapidly reduced to the 10- monohydroxy (MHD) metabolite  which is responsible for its anticonvulsant activity. MHD blocks sodium channels preventing the spread of the  abnormal discharge. Modulation of calcium channels is also a hypothesis. It is approved for use in adults and children  with partial onset seizures. Oxcarbazepine is a less potent inducer of CYP3A4 and UGT than carbamazepine. The  adverse effects profile is similar to that of other antiepileptic drugs with respect to nausea, vomiting, headache,  and visual disturbance.   Phenobarbital [fee-noe-BAR-bih-tal] was synthesized in 1902 and brought to the market in 1912 by Bayer. The  primary mechanism of action is the enhancement of inhibitory effects of GABA-mediated neurons (see p. 111). The  primary use for phenobarbital in epilepsy is in treatment of status epilepticus. Due to interaction with the  cytochrome P450 enzymes as an inducer, and adverse effects of sedation, cognitive impairment, and potential for  osteoporosis, this drug should only be considered for chronic therapy once a patient is found to be refractory to  many other drugs, and the benefits of therapy outweigh the multiple risks.   Phenytoin [FEN-i-toin] blocks voltage-gated sodium channels by selectively binding to the channel in the inactive  state and slowing its rate of recovery. At very high concentrations, phenytoin can block voltage-dependent calcium  channels and interfere with the release of monoaminergic neurotransmitters. Phenytoin is effective for treatment  of partial seizures and generalized tonic-clonic seizures and in the treatment of status epilepticus (see Figure 15.5).  The drug is 90 percent bound to plasma albumin. Phenytoin is an inducer of drugs metabolized by the CYP2C, and    CYP3A families and the UGT enzyme system. Phenytoin exhibits saturable enzyme metabolism at a low serum  concentration; thus knowledge of zero- order pharmacokinetics and population parameters is important for dosing  adj ustment. Small increases in a daily dose can produce large increases in the plasma concentration, resulting in  drug-induced toxicity (Figure 15.8). Depression of the CNS occurs particularly in the cerebellum and vestibular  system, causing nystagmus and ataxia. The elderly are highly susceptible to this effect. Gingival hyperplasia may  cause the gums to grow over the teeth. Long-term use may lead to development of peripheral neuropathies and  osteoporosis.   Fosphenytoin [FOS-phen-i-toin] is a prodrug and is rapidly converted to phenytoin in the blood, providing high  levels of phenytoin within minutes. Fosphenytoin may also be administered intramuscularly (IM). Phenytoin sodium  should never be given IM because it can cause tissue damage and necrosis. Fosphenytoin is the drug of choice and  standard of care for IV and IM administration. Due to sound-alike and look-alike names, there is a risk for medication  error to occur. The trade name of fosphenytoin is CerebyxA®, which is easily confused with CelebrexA®, the  cyclooxygenase-2 inhibitor, and CelexaA®, the antidepressant.    When the hepatic hydroxylation  system becomes saturated, small  increases in the dose of phenytoin  cause a large increase in the    Figure 15.8 Nonlinear effect of phenytoin dosage on the plasma concentration of the drug.   Pregabalin [pree-GABA-lin] binds to the a 2 -d site, an auxiliary subunit of voltage-gated calcium channels in the  CNS, inhibiting excitatory neurotransmitter release. The exact role this plays in treatment is not known, but the  drug has proven effects on partial onset seizures, neuropathic pain associated with diabetic peripheral neuropathy,  postherpetic neuralgia, and fibromyalgia. Pregabalin is greater than 90 percent eliminated renal ly, with no  indication of CYP involvement. Drowsiness, blurred vision, weight gain, and peripheral edema have been reported.   Primidone [PRIM-i-done] has two active metabolites, phenobarbital and phenylethylmalonamide, which have  longer half-lives than the parent drug. Due to the nature of the long term adverse effects associated with  phenobarbital , this drug should be considered for use only in those patients with refractory epilepsy.   Tiagabine [ty-AG-a-been] blocks GABA uptake into presynaptic neurons, permitting more GABA to be available for  receptor binding, thus, there is thought to be enhanced inhibitory activity. Tiagabine is effective in decreasing the  number of seizures in patients with partial onset epilepsy. Binding to albumin and ai-acid glycoprotein is greater  than 95 percent, and metabolism is mainly completed by the CYP3A family of enzymes. Adverse effects include  tiredness, dizziness, and gastrointestinal upset. There is some indication in postmarketing surveillance that seizures  have occurred in patients who did not have epilepsy when the drug was used. Tiagabine has not been approved for  use for any other indication.   Topiramate [toe-PEER-a-mate] possesses several actions that are believed to contribute to its broad spectrum of  antiseizure activity. Topiramate blocks voltage-dependent sodium channels; it has been shown to increase the  frequency of chloride channel opening by binding to the GABA a receptor. High-voltage calcium currents (L type)  are reduced by topiramate. It is a carbonic anhydrase inhibitor and may act at glutamate (NMDA) sites. Topiramate  is effective and approved for use in partial and primary generalized epilepsies. It is also approved for treatment of  migraine. Topiramate is renal ly eliminated to a high degree, but it also has inactive metabolites. It inhibits CYP2C19  and is induced by phenytoin, and carbamazepine. Lamotrigine is reported to cause an increase in topiramate  concentration. Coadministration of topiramate reduces ethinyl estradiol. Adverse effects include somnolence,  weight loss, and paresthesias; renal stones are reported to occur at a higher   incidence than in a nontreated population. Glaucoma, oligohidrosis, and hyperthermia have also been reported. The  latter are specifically related to the carbonic anhydrase activity.    Zonisamide [zoe-NIS-a-mide] is a sulfonamide derivative that has a broad spectrum of action. The compound has  multiple effects on neuronal systems thought to be involved in seizure generation. These include blockade of both  voltage-gated sodium channels and T-type calcium currents. It has a limited amount of carbonic anhydrase activity.  Cross reactivity with other sulfonamides should be reviewed and its use monitored in patients with reported  allergies. Zonisamide is approved for use in patients with partial epilepsy. It is metabolized by the CYP3A4 isozyme  and may, to a lesser extent, be affected by CYP3A5 and CYP2C19. In addition to the typical CNS adverse effects,  zonisamide may cause kidney stones. Oligohidrosis has been reported, and patients should be monitored for  increased body temperature and decreased sweating.   Vagal nerve stimulation requires surgical implant of a small pulse generator with a battery and a lead wire for  stimulus (Figure 15.9). The device is implanted and lead wires wrapped around the patient's vagal nerve. This device  and treatment were approved in 1997. The device is also approved for treatment of depression. The mechanism of  action is unknown. Because it has diffuse involvement with the neuronal circuits, there are a variety of mechanisms  by which it may exert its affect on seizure control. Vagal nerve stimulation has been effective in treatment of  partial onset seizures and has enabled reduction of drug therapy in some cases. It is an alternative for patients who  have been refractory to multiple drugs, who are sensitive to the many adverse effects of antiseizure drugs, and who  have difficulty adhering to medication schedules. Vagal nerve stimulation requires invasive procedure and is  expensive.   Women with epilepsy are often very concerned about pregnancy and what the medications will do to the  development of the baby. Planning is the most important component. All women should be on high doses of folic  acid prior to conception. Divalproex and barbiturates should be avoided. Switching women to other drugs before  pregnancy should be accomplished when possible. When seizures are controlled, maintenance medication should be  reduced, if possible, to the lowest dose that provides control. If seizures are not controlled, medications and  dosages should be adj usted. The frequency and severity of seizures may change during pregnancy. Women should  be monitored regularly by the obstetrician as well as the neurologist. All women with epilepsy should register with  the AED (Antiepileptic drug) Pregnancy Registry.   Hyponatremia, drowsiness, fatigue, dizziness, and blurred vision. Orug use has as  been associated with Stevens- Johnson Syndrome. Blood dyscraslas: neutropenia,  leukopenia, thrombocytopenia, pancytopenia, and anemias.   Weight gain, easy bruising, nausea, tremor, hair loss, weight gain, Gl upset, liver  damage, alopecia, and sedation. Hepatic failure, pancreatitis, and teratogenic  effects such have been observed. Broad spectrum of antiseizure activity.   Drowsiness, hyperactivity, nausea, sedation, Gl upset, weight gain, lethargy, SLE.  and rash. Blood dyscrasias can occur: periodic CBCs should be done. Abrupt  discontinuance of drug may causes seizures.   Insomnia, dizziness, headache, ataxia, weight gain, and irritability. Aplastic anemia;  hepatic failure. Broad spectrum of antiseizure activity. Requires patient to sign  informed consent at dispensing.   Mild drowsiness, dizziness, ataxia, weight gain, and diarrhea. Few drug Interactions.  One-hundred percent renal elimination.   Nausea, drowsiness, dizziness, headache, and diplopia. Rash (Stevens- Johnson  syndrome— potentially llfe-threatenlngl.   Sedation, dizziness, headache, anorexia, fatigue, infections, and behavioral  symptoms. Few drug Interactions.   Gingival hyperplasia, confusion, slurred speech, double vision, ataxia, sedation,  dizziness, and hirsutism. Stevens- Johnson syndrome — potentially life-threatening Not  recommended for chronic use. Primary treatment for status epilepticus.   Sedation, lethargy, behavioral changes, ataxia, hyperactivity, and nausea. Not  recommended for chronic use.   Sedation, weight gain, fatigue, headache, tremor, dizziness, and anorexia. Multiple  drug interactions.   Paresthesia, weight loss, nervousness, depression, anorexia, anxiety, tremor,  cognitive complaints, headache, and oligohidrosls. Few drug interactions.    Figure 15.10 Summary of antiepileptic drugs. CBC =complete blood count; GABA =l 3 -aminobutyrc acid; Gl =  gastrointestinal; SLE =systemic lupus erythematosus    15.1 A nine-year-old boy is sent for neurologic evaluation because of episodes of confusion. Over the past    year, the child has experienced episodes during which he develops a blank look on his face and fails to respond  to questions. However, it appears to take several minutes before the boy recovers from the episodes. Which  one the following best describes this patient's seizures?   15. 2 Which one of the following therapies would be appropriate for the patient described in the above  question?    15.3 The patient described in Question 15.1 was treated for six months with carbamazepine but, recently, has  been experiencing breakthrough seizures on a more frequent basis. You are considering adding a second drug  to this patient's antiseizure regimen. Which of the following drugs is least likely to have a pharmacokinetic  interaction with carbamazepine?   >Table of Contents > Unit IV - Drugs Affecting the Cardiovascular System >Chapter 16 - Heart Failure   Heart failure (HF) is a complex, progressive disorder in which the heart is unable to pump sufficient blood to meet  the needs of the body. Its cardinal symptoms are dyspnea, fatigue, and fluid retention. HF is due to an impaired  ability of the heart to adequately fill with and/or ej ect blood. It is often accompanied by abnormal increases in  blood volume and interstitial fluid, hence the term a€oecongestivea€' : HF because symptoms include dyspnea from  pulmonary congestion in left HF, and peripheral edema in right HF. Underlying causes of HF include arteriosclerotic  heart disease, myocardial infarction, hypertensive heart disease, valvular heart disease, dilated cardiomyopathy,  and congenital heart disease. Left systolic dysfunction secondary to coronary artery disease is the most common  cause of HF, accounting for nearly 70 percent of all cases. The number of newly diagnosed patients with HF is  increasing, because more individuals now survive acute myocardial infarction.    Figure 16.1 Summary of drugs used to treat heart failure. ACE =angiotensinconverting enzyme.    A. Role of physiologic compensatory mechanisms in the progression of HF   Chronic activation of the sympathetic nervous system and the renin-angiotensin-aldosterone axis is associated with  remodeling of cardiac tissue, characterized by loss of myocytes, hypertrophy, and fibrosis. The geometry of the  heart becomes less elliptical and more spherical, interfering with its ability to efficiently function as a pump. This  prompts additional neurohumoral activation, creating a vicious cycle that, if left untreated, leads to death.   The goals are to alleviate symptoms, slow disease progression, and improve survival. Accordingly, six classes of drugs  have been shown to be effective: 1) inhibitors of the renin-angiotensin system, 2) i 2 -adrenoreceptor blockers, 3)  diuretics, 4) inotropic agents, 5) direct vasodilators, and 6) aldosterone antagonists (Figure 16.1). Depending on the  severity of cardiac failure and individual patient factors, one or more of these classes of drugs are administered.   on the myocardium, decreased extracellular fluid volume, improved cardiac contractility, and slowing of the rate of  cardiac remodeling. Knowledge of the physiology of cardiac muscle contraction is essential to understanding the  compensatory responses evoked by the failing heart as well as the actions of drugs used to treat HF.   The myocardium, like smooth and skeletal muscle, responds to stimulation by depolarization of the membrane,  which is followed by shortening of the contractile proteins and ends with relaxation and return to the resting state.  However, unlike skeletal muscle, which shows graded contractions depending on the number of muscle cells that  are stimulated, the cardiac muscle cells are interconnected in groups that respond to stimuli as a unit, contracting  together whenever a single cell is stimulated.   Cardiac muscle cells are electrically excitable. However, unlike the cells of other muscles and nerves, the cells of  cardiac muscle show a spontaneous, intrinsic rhythm generated by specialized aCoepacemakerad cells located in  the sinoatrial and atrioventricular nodes. The cardiac cells also have an unusually long action potential, which can  be divided into five phases (0a€"4), Figure 16.2 illustrates the major ions contributing to depolarization and  polarization of cardiac cells. These ions pass through channels in the sarcolemmal membrane and, thus, create a  current. The channels open and close at different times during the action potential. Some respond primarily to  changes in ion concentration, whereas others are sensitive to adenosine triphosphate, or to membrane voltage.   The contractile machinery of the myocardial cell is essentially the same as that in striated muscle. The force of  contraction of the cardiac muscle is directly related to the concentration of free (unbound) cytosolic calcium.  Therefore, agents that increase these calcium levels (or that increase the sensitivity of the contractile machinery to  calcium) result in an increased force of contraction (inotropic effect). [Note: The inotropic agents increase the  contractility of the heart by directly or indirectly altering the mechanisms that control the concentration of  intracellular calcium. ]   1. Sources of free intracellular calcium: Calcium comes from several sources. The first is from outside the cell,  where opening of voltage-sensitive calcium channels causes an immediate rise in free cytosolic calcium. Calcium  may aslo enter by exchange with sodium. Calcium is also released from the sarcoplasmic reticulum and  mitochondria, which further increases the cytosolic level of calcium (Figure 16.3).   2. Removal of free cytosolic calcium: If free cytosolic calcium levels were to remain high, the cardiac muscle  would be in a constant state of contraction rather than showing a periodic contraction. Mechanisms of removal  include two alternatives.    a. Sodium/calcium exchange: Calcium is removed by a sodium/ calcium exchange reaction that reversibly  exchanges calcium ions for sodium ions across the cell membrane (see Figure 16. 3).   This interaction between the movement of calcium and sodium ions is significant, because changes in  intracellular sodium can affect cellular levels of calcium.   • The spontaneous depolarization  automatically brings the cell to  the threshold of the next action  potential   Ca 7 * is removed by re-uptake into the sarco-  plasmic reticulum and by extrusion from the  cell by a Ca a */Na* exchange.    O Ca 7 * entry from outside the cell  triggers the release of a much  larger quantity of Ca 7 *from the  sarcoplasmic reticulum.    b. Uptake of calcium by the sarcoplasmic reticulum and mitochondria: Calcium is also recaptured by the  sarcoplasmic reticulum and the mitochondria. More than 99 percent of the intracellular calcium is located in  these organelles, and even a modest shift between these stores and free calcium can lead to large changes  in the concentration of free cytosolic calcium.   The failing heart evokes three major compensatory mechanisms to enhance cardiac output (Figure 16.4). Although   initially beneficial, these alterations ultimately result in further deterioration of cardiac function.   1. Increased sympathetic activity: Baroreceptors sense a decrease in blood pressure and activate the sympathetic  nervous system, which stimulates i 2 -adrenergic receptors in the heart. This results in an increased heart rate  and a greater force of contraction of the heart muscle (see Figure 16.4). In addition, vasoconstriction  (Ill-mediated) enhances venous return and increases cardiac preload. These compensatory responses increase  the work of the heart and, therefore, can contribute to further decline in cardiac function.   2. Activation of the renin-angiotensin system: A fall in cardiac output decreases blood flow to the kidney,  prompting the release of renin, with a resulting increase in the formation of angiotensin II and release of  aldosterone. This results in increased peripheral resistance and retention of sodium and water. Blood volume  increases, and more blood is returned to the heart. If the heart is unable to pump this extra volume, venous  pressure increases and peripheral edema and pulmonary edema occur (see Figure 16.4). These compensatory  responses increase the work of the heart and, therefore, can contribute to further decline in cardiac function.   3. Myocardial hypertrophy: The heart increases in size, and the chambers dilate and become more globular.   Initially, stretching of the heart muscle leads to a stronger contraction of the heart. However, excessive   elongation of the fibers results in weaker contractions, and the geometry diminishes the ability to ej ect blood.  This type of failure is termed systolic failure and is the result of a ventricle being unable to pump effectively.  Less commonly, patients with HF may have diastolic dysfunctiona€"a term applied when the ability of the  ventricles to relax and accept blood is impaired by structural changes, such as hypertrophy. The thickening of  the ventricular wall and subsequent decrease in ventricular volume decrease the ability of heart muscle to  relax. In this case, the ventricle does not fill adequately, and the inadequacy of cardiac output is termed  diastolic HFa€”a particularly common feature of HF in elderly women. Diastolic dysfunction in its pure form is  characterized by signs and symptoms of H F in the presence of a normal function of the left ventricle. Flowever,  both systolic and diastolic dysfunction commonly coexist in HF.   If the mechanisms listed above adequately restore cardiac output, the HF is said to be compensated. Flowever,  these compensations increase the work of the heart and contribute to further decline in cardiac performance. If the  adaptive mechanisms fail to maintain cardiac output, the H F is termed decompensated.   Chronic HF is typically managed by a reduction in physical activity, low dietary intake of sodium (<1500 mg/day),  treatment of comorbid conditions, and j udicious use of diuretics, inhibitors of the renin-angiotensin system, and  inotropic agents. Drugs that may precipitate or exacerbate HF, such as nonsteroidal anti-inflammatory drugs,  alcohol, calcium-channel blockers, and some antiarrhythmic drugs, should be avoided if possible. Patients with HF  complain of dyspnea on exertion, orthopnea, paroxysmal nocturnal dyspnea, fatigue, and dependent edema.   HF leads to activation of the renin-angiotensin system via two mechanisms: 1) Increased renin release by  j uxtaglomerular cells in renal afferent arterioles occurs in response to the diminished renal perfusion pressure  produced by the failing heart, and 2) renin release by the j uxtaglomerular cells is promoted by sympathetic  stimulation. The production of angiotensin lla€"a potent vasoconstrictora€"and the subsequent stimulation of  aldosterone release that causes salt and water retention lead to the increases in    both preload and afterload that are characteristic of the failing heart. In addition, high levels of angiotensin II and  of aldosterone have direct detrimental effects on the cardiac muscle, favoring remodeling, fibrosis, and  inflammatory changes.   Angiotensin-converting enzyme (ACE) inhibitors are the agents of choice in HF. These drugs block the enzyme that  cleaves angiotensin I to form the potent vasoconstrictor angiotensin II (Figure 16. 5). These agents also diminish the  rate of bradykinin inactivation. [Note: Vasodilation occurs as a result of the combined effects of lower  vasoconstriction caused by diminished levels of angiotensin II and the potent vasodilating effect of increased  bradykinin. ] By reducing circulating angiotensin II levels, ACE inhibitors also decrease the secretion of aldosterone,  resulting in decreased sodium and water retention.   1. Actions on the heart: ACE inhibitors decrease vascular resistance, venous tone, and blood pressure, resulting in  an increased cardiac output (see Figure 16. 5). ACE inhibitors also blunt the usual angiotensin lla€" mediated  increase in epinephrine and aldosterone seen in HF. ACE inhibitors improve clinical signs and symptoms in  patients also receiving thiazide or loop diuretics and/or digoxin. The use of ACE inhibitors in the treatment of   H F has significantly decreased both morbidity and mortality. For example, Figure 16.6 shows that the ACE  inhibitor enalapril [e-NAL-a-pril] decreases the cumulative mortality in patients with congestive HF. [Note:   Reduction in mortality is due primarily to a decrease in deaths caused by progressive HF. ] Treatment with  enalapril also reduces arrhythmic death, myocardial infarction, and strokes. Similar data have been obtained  with other ACE inhibitors.   2. Indications: ACE inhibitors may be considered for single-agent therapy in patients who present with mild  dyspnea on exertion and do not show signs or symptoms of volume overload. ACE inhibitors are useful in  decreasing HF in asymptomatic patients with an ejection fraction of less than 35 percent (left ventricular  dysfunction). Patients who have had a recent myocardial infarction also benefit from long-term ACE inhibitor  therapy. Patients with the lowest ej ection   fraction show the greatest benefit. Early use of ACE inhibitors is indicated in patients with all stages of left  ventricular failure, with and without symptoms, and therapy should be initiated immediately after myocardial  infarction. (See p. 221 for the use of ACE inhibitors in the treatment of hypertension. )    3. Pharmacokinetics: All ACE inhibitors are adequately but incompletely absorbed following oral administration.   The presence of food may decrease absorption, so they should be taken on an empty stomach. Except for  captopril [CAP-toe-pril], ACE inhibitors are prodrugs that require activation by hydrolysis via hepatic enzymes.  Renal elimination of the active moiety is important for most ACE inhibitors, an exception being fosinopril  [f oe-SIH- no- pri I ] . Plasma half-lives of active compounds vary from 2 to 12 hours, although the inhibition of ACE  may be much longer. The newer compounds such as ramipril [RA-mi-pril] and fosinopril require only once-a-day  dosing.   Figure 16.6 Effect of enalapril on the mortality of patients with congestive heart failure.    4. Adverse effects: These include postural hypotension, renal insufficiency, hyperkalemia, angioedema, and a  persistent dry cough. The potential for symptomatic hypotension with ACE inhibitor therapy requires careful  monitoring. ACE inhibitors should not be used in pregnant women, because they are fetotoxic.   Angiotensin-receptor blockers (ARBs) are nonpeptide, orally active compounds that are extremely potent  competitive antagonists of the angiotensin type 1 receptor. Losartan [loe-SAR-tan] is the prototype drug. ARBs  have the advantage of more complete blockade of angiotensin action, because ACE inhibitors inhibit only one  enzyme responsible for the production of angiotensin II. Further, the ARBs do not affect bradykinin levels. Although  ARBs have actions similar to those of ACE inhibitors, they are not therapeutically identical. Even so, ARBs are a  substitute for ACE inhibitors in those patients who cannot tolerate the latter.   1. Actions on the cardiovascular system: All the ARBs are approved for treatment of hypertension based on their  clinical efficacy in lowering blood pressure and reducing the morbidity and mortality associated with  hypertension. As indicated above, their use in HF is as a substitute for ACE inhibitors in those patients with  severe cough or angioedema.   2. Pharmacokinetics: All the drugs are orally active and require only once-a-day dosing. Losartan, the first  approved member of the class, differs from the others in that it undergoes extensive first-pass hepatic  metabolism, including conversion to its active metabolite. The other drugs have inactive metabolites.   Elimination of metabolites and parent compounds occurs in the urine and feces; the proportion is dependent on  the individual drug. All are highly plasma proteina€"bound (greater than 90 percent) and, except for  candesartan [kan-des-AR-tan], have large volumes of distribution.   3. Adverse effects: ARBs have an adverse effect profile similar to that of ACE inhibitors. Flowever, ARBs do not   Although it may seem counterintuitive to administer drugs with negative inotropic activity to a patient with HF,  several clinical studies have clearly demonstrated improved systolic functioning and reverse cardiac remodeling in  patients receiving i 2 -blockers. These benefits arise in spite of occasional initial exacerbation of symptoms. The  benefit of l 2 -blockers is attributed, in part, to their ability to prevent the changes that occur because of the  chronic activation of the sympathetic nervous system, including decreasing the heart rate and inhibiting the release  of renin. In addition, T 2 - bl ockers also prevent the direct deleterious effects of norepinephrine on the cardiac  muscle fibers, decreasing remodeling, hypertrophy and cell death. Two T 2 - blockers have been approved for use in  HF: carvedilol [KAR-ve-dil-ol], and long-acting metoprolol [me-TOE-proe-lol], Carvedilol is a nonselective  i 2 -adrenoreceptor antagonist that also blocks i±-adrenoreceptors, whereas metoprolol is a T 2 1 - selective antagonist.  [Note: The pharmacology of f 2 -blockers is described in detail in Chapter 7. ] l 2 -Blockade is recommended for all  patients with heart disease except those who are at high risk but have no symptoms or those who are in acute HF.  Carvedilol and metoprolol reduce morbidity and mortality associated with HF. Treatment should be started at low  doses and gradually titrated to effective doses based on patient tolerance. Obviously, the patient who also is  hypertensive will obtain additional benefit from the T 2 - blocker. Figure 16. 7 shows the beneficial effect of  metoprolol treatment in patients with HF.   Figure 16.7 Cumulative mortality in patients with heart failure treated using placebo or metoprolol.   Diuretics relieve pulmonary congestion and peripheral edema. These agents are also useful in reducing the  symptoms of volume overload, including orthopnea and paroxysmal nocturnal dyspnea. Diuretics decrease plasma  volume and, subsequently, decrease venous return to the heart (preload). This decreases the cardiac workload and  the oxygen demand. Diuretics may also decrease afterload by reducing plasma volume, thus decreasing blood  pressure. Thiazide diuretics are relatively mild diuretics and lose efficacy if patient creatinine clearance is less than  50 mL/ min. Loop diuretics are used for patients who require extensive diuresis and those with renal insufficiency.  [Note: Overdoses of loop diuretics can lead to profound hypovolemia.]   Dilation of venous blood vessels leads to a decrease in cardiac preload by increasing the venous capacitance;  arterial dilators reduce systemic arteriolar resistance and decrease afterload. Nitrates are commonly employed  venous dilators for patients with congestive HF. If the patient is intolerant of ACE inhibitors or i 2 -blockers, the  combination of hydralazine and isosorbide dinitrate is most commonly used. [Note: Calcium-channel blockers  should be avoided in patients with HF. ]   Positive inotropic agents enhance cardiac muscle contractility and, thus, increase cardiac output. Although these  drugs act by different mechanisms, in each case the inotropic action is the result of an increased cytoplasmic  calcium concentration that enhances the contractility of cardiac muscle.   The cardiac glycosides are often called digitalis or digitalis glycosides, because most of the drugs come from the  digitalis (foxglove) plant. They are a group of chemically similar compounds that can increase the contractility of  the heart muscle and, therefore, are widely used in treating HF. Like the antiarrhythmic drugs described in Chapter  17, the cardiac glycosides influence the sodium and calcium ion flows in the cardiac muscle, thereby increasing  contraction of the atrial and ventricular myocardium (positive inotropic action). The digitalis glycosides show only a  small difference between a therapeutically effective dose and doses that are toxic or even fatal. Therefore, the  drugs have a low therapeutic index. The most widely used agent is digoxin [di-J OX-in],   a. Regulation of cytosolic calcium concentration: Free cytosolic calcium concentrations at the end of  contraction must be lowered for cardiac muscle to relax. The Na + / Ca 2+ -exchanger plays an important role in  this process by extruding Ca 2+ from the myocyte in exchange for Na + (Figure 16.8). The concentration  gradient for both ions is a major determinant of the net movement of ions. By inhibiting the ability of the  myocyte to actively pump Na + from the cell, cardiac glycosides decrease the Na + concentration gradient and,  consequently, the ability of the Na + / Ca 2+ -exchanger to move calcium out of the cell. Further, the higher  cellular Na + is exchanged by extracellular Ca 2+ by the Na + /Ca 2+ -exchanger increasing intracellular Ca 2+ .   Because more Ca 2+ is retained intracellularly, a small but physiologically important increase occurs in the  free Ca 2+ that is available at the next contraction cycle of the cardiac muscle. It follows that if the  Na + /K + a€" adenosine triphosphatase is extensively inhibited, the ionic gradient becomes so disturbed that  dysrhythmias can occur.   b. Increased contractility of the cardiac muscle; Administration of digitalis glycosides increases the force of  cardiac contraction, causing the cardiac output to more closely resemble that of the   normal heart (Figure 16.9). Increased myocardial contraction leads to a decrease in end-diastolic volume,  thus increasing the efficiency of contraction (increased ejection fraction). The resulting improved  circulation leads to reduced sympathetic activity, which then reduces peripheral resistance. Together, these  effects cause a reduction in heart rate. Vagal tone is also enhanced, so the heart rate decreases and  myocardial oxygen demand diminishes. [Note: In the normal heart, the positive inotropic effect of digitalis  is counteracted by compensatory autonomic reflexes. ]   Figure 16.8 Mechanism of action of cardiac glycosides, or digitalis. ATPase =adenosine triphosphatase.    2. Therapeutic uses: Digoxin therapy is indicated in patients with severe left ventricular systolic dysfunction after  initiation of ACE inhibitor and diuretic therapy. Digoxin is not indicated in patients with diastolic or right-sided  HF. Digoxin's major indication is HF with atrial fibrillation. Dobutamine [doe-BYOO-ta-meen], another inotropic  agent, can be given intravenously in the hospital, but at present, no effective oral inotropic agents exist other  than digoxin. Patients with mild to moderate HF will often respond to treatment with ACE inhibitors and  diuretics, and they do not require digoxin.    • Decreased sympathetic reflexes and  vascular tone cause a decrease in    • Ventricular end-diastollc pressure  increases (Q to Q ) in an effort to    Figure 16.9 Ventricular function curves in the normal heart, in heart failure (HF), and in H F treated with  digitalis.   3. Pharmacokinetics: All digitalis glycosides possess the same pharmacologic actions, but they vary in potency and  pharmacokinetics (Figure 16. 10). Digoxin is the only digitalis available in the United States. Digoxin is very  potent, with a narrow margin of safety and long half-life of around 36 hours. Digoxin is mainly eliminated intact  by the kidney, requiring dose adj ustment based on creatinine clearance. Digoxin has a large volume of  distribution, because it accumulates in muscle. A loading dose regimen is employed when acute digitalization is  needed. Digitoxin [DIJ -i-tox-in] has a much longer half-life and is extensively metabolized by the liver before  excretion in the feces, and patients with hepatic disease may require decreased doses.   4. Adverse effects: Digitalis toxicity is one of the most commonly encountered adverse drug reactions. Side  effects often can be managed by discontinuing cardiac glycoside therapy, determining serum potassium levels  (decreased K + enhances potential for cardiotoxicity), and if indicated, giving potassium supplements. In general,  decreased serum levels of potassium predispose a patient to digoxin toxicity. Digoxin levels must be closely  monitored in the presence of renal insufficiency, and dosage adjustment may be necessary. Severe toxicity  resulting in ventricular tachycardia may require administration of antiarrhythmic drugs and the use of antibodies  to digoxin (digoxin immune Fab), which bind and inactivate the drug. Types of adverse effects include:   a. Cardiac effects: The common cardiac side effect is arrhythmia, characterized by slowing of atrioventricular  conduction associated with atrial arrhythmias. A decrease in intracellular potassium is the primary  predisposing factor in these effects.   b. Gastrointestinal effects: Anorexia, nausea, and vomiting are commonly encountered adverse effects.   c. Central nervous system effects: These include headache, fatigue, confusion, blurred vision, alteration of  color perception, and halos on dark obj ects.   a. Electrolytic disturbances: Hypokalemia can precipitate serious arrhythmia. Reduction of serum potassium  levels is most frequently observed in patients receiving thiazide or loop diuretics, and this usually can be  prevented by use of a potassium-sparing diuretic or supplementation with potassium chloride. Hypercalcemia  and hypomagnesemia also predispose to digitalis toxicity.   b. Drugs: Quinidine, verapamil, and amiodarone, to name a few, can cause digoxin intoxication, both by  displacing digoxin from tissue protein-binding sites and by competing with digoxin for renal excretion. As a  consequence, digoxin plasma levels may increase by 70 to 100 percent, requiring dosage reduction.  Potassium-depleting diuretics, corticosteroids, and a variety of other drugs can also increase digoxin toxicity  (Figure 16.11). Hypothyroidism, hypoxia, renal failure, and myocarditis are also predisposing factors to  digoxin toxicity.   i 2 -Adrenergic stimulation improves cardiac performance by causing positive inotropic effects and vasodilation.  Dobutamine is the most commonly used inotropic agent other than digitalis. Dobutamine leads to an increase in  intracellular cyclic adenosine monophosphate (cAMP), which results in the activation of protein kinase. Slow  calcium channels are one important site of phosphorylation by protein kinase. When phosphorylated, the entry of  calcium ion into the myocardial cells increases, thus enhancing contraction (Figure 16. 12). Dobutamine must be  given by intravenous infusion and is primarily used in the treatment of acute HF in a hospital setting.   Amrinone [AM-ri-none] and milrinone [ Ml L- ri- none] are phosphodiesterase inhibitors that increase the intracellular  concentration of cAMP (see Figure 16. 12). This results in an increase of intracellular calcium and, therefore, cardiac  contractility, as discussed above for the i 2 -adrenergic agonists. Long-term amrinone or milrinone therapy may be  associated with a substantial increase in the risk of mortality. Flowever, short-term use of intravenous milrinone is  not associated with increased mortality, and some symptomatic benefit may be obtained when it is used in patients  with refractory HF.   Patients with advanced heart disease have elevated levels of aldosterone due to angiotensin II stimulation and  reduced hepatic clearance of the hormone.   Spironolactone is a direct antagonist of aldosterone, thereby preventing salt retention, myocardial hypertrophy,  and hypokalemia. Spironolactone therapy should be reserved for the most advanced cases of HF. Because  spironolactone promotes potassium retention, patients should not be taking potassium supplements. Adverse    effects include gastric disturbances, such as gastritis and peptic ulcer; central nervous system effects, such as  lethargy and confusion; and endocrine abnormalities, such as gynecomastia, decreased libido, and menstrual  irregularities.    Phosphorylation of a calcium  channel increases calcium  How into the cell, causing  Increased force of contraction  of heart muscle.   8lnd!ng of a IWadrenerglc agonist,  such as dopamine, or dobutamine.  activates adenylyl cyclase, which  produces cAMP.    cAMP activates protein kinase,  which in turn phosphorylates  a calcium channel.    Phosphodiesterase Inhibitors prevent  hydrolysis of cAMP and, thus, prolong  the action of protein kinase.    Figure 16.12 Sites of action by P-adrenergic agonists on heart muscle. AMP =adenosine monophosphate; ATP  = adenosine triphosphate; cAMP =cyclic adenosine monophosphate; P =phosphate.    ACE inhibitors or ARBs in all patients; >block*r in selected patients    Treat hypertension, diabetes, dyslipldemla; ACE inhibitors or ARBs In some patients   Figure 16.13 Treatment options for various stages of heart failure. ACE =Angiotensin-converting enzyme;  ARB =angiotensinreceptor blockers. Stage D (refractory symptoms requiring special interventions) is not  shown.   Experts have classified HF into four stages, from least severe to most severe. Figure 16. 13 shows a treatment  strategy using this classification and the drugs described in this chapter. Note that as the disease progresses,  polytherapy is initiated.   In patients with overt heart failure, loop diuretics are often introduced first for relief of signs or symptoms of  volume overload, such as dyspnea and peripheral edema. ACE inhibitors, or if not tolerated, ARBs are added after  the optimization of diuretic therapy. Gradually titrate the dosage to that which is maximally tolerated and/or  produces optimal cardiac output, b Blockers are initiated after the patient is stable on ACE inhibitors, again  beginning at low doses with titration to optimal levels. Digoxin is initiated in patients who continue to have  symptoms of heart failure despite the multiple drug therapy. For example, Figure 16. 14 shows that treatment with  digoxin plus a diuretic plus an ACE inhibitor in patients with HF is superior to treatment with diuretics alone or a  diuretic plus either digoxin or an ACE inhibitor.    Patients receiving triple therapy were  least likely to experience worsening  of heart failure compared to any of  the other three treatment groups.    Figure 16.14 Use of multiple drugs in the treatment of heart failure. ACE =angiotensin-converting enzyme.   16. 1 Digitalis has a profound effect on myocyte intracellular concentrations of Na + , K + , and Ca 2+ . These effects  are caused by digitalis inhibiting:   A. Ca 2+ a€" adenosine triphosphatose (ATPase) of the sarcoplasmic reticulum.   B. Na + / K + -ATPase of the myocyte membrane.   16.2 Compensatory increases in heart rate and renin release that occur in heart failure may be alleviated by  which of the following drugs?   16.3 A 58-year-old man is admitted to the hospital with acute heart failure and pulmonary edema. Which one  of the following drugs would be most useful in treating the pulmonary edema?   16.4 A 46-year-old man is admitted to the emergency department. He has taken more than 90 digoxin tablets  (0.25 mg each), ingesting them about 3 hours before admission. His pulse is 50 to 60 beats per minute, and the  electrocardiogram shows third-degree heart block. Which one of the following is the most important therapy to  initiate in this patient?   >Table of Contents > Unit IV - Drugs Affecting the Cardiovascular System >Chapter 17 - Antiarrhythmics   In contrast to skeletal muscle, which contracts only when it receives a stimulus, the heart contains specialized cells  that exhibit automaticity; that is, they can intrinsically generate rhythmic action potentials in the absence of  external stimuli. These a€oepacemakera€§ cells differ from other myocardial cells in showing a slow, spontaneous  depolarization during diastole (Phase 4), caused by an inward positive current carried by sodium- and calcium-ion  flows. This depolarization is fastest in the sinoatrial (SA) node (the normal initiation site of the action potential),  and it decreases throughout the normal conduction pathway through the atrioventricular (AV) node to the bundle of  His and the Purkinje system. Dysfunction of impulse generation or conduction at any of a number of sites in the  heart can cause an abnormality in cardiac rhythm. Figure 17. 1 summarizes the drugs used to treat cardiac  arrhythmias.   The arrhythmias are conceptually simplea€"dysfunctions cause abnormalities in impulse formation and conduction in  the myocardium. However, in the clinic, arrhythmias present as a complex family of disorders that show a variety of  symptoms. For example, cardiac arrhythmias may cause the heart to beat too slowly (bradycardia) or to beat too  rapidly (tachycardia), and to beat regularly (sinus tachycardia or sinus bradycardia) or irregularly (atrial fibrillation).  The heart cavity from which the arrhythmia originates gives the name to the arrhythmiaa€"atrial tachycardia for a  rapid arrhythmia originating in the atria. Impulses originating from sites other than the SA node, or impulses  traveling along accessory (extra) pathways that lead to deviant depolarizations (AV reentry, Wolff-Parkinson-White  syndrome), may also trigger arrhythmias. To make sense of this large group of disorders, it is useful to organize the  arrhythmias into groups according to the anatomic site of the abnormalitya€"the atria, the AV node, or the  ventricles. Figure 17. 2 summarizes several commonly occurring atrial, AV j unction, or ventricular arrhythmias.  Although not shown here, each of these abnormalities can be further divided into subgroups depending on the  electrocardiogram findings.   Most arrhythmias arise either from aberrations in impulse generation (abnormal automaticity) or from a defect  impulse conduction.    This common Arrhythmia involves multiple  ectopic foci of atrial cells, creating a chaotic  movement of impulses through the atria.  The ventricular response is rapid (100-150  beats per minute) and irregular. Cardiac  output is decreased and exercise intolerance  is common.    ij-Blockers are the drugs of choice in  atrial ftbf illation, because they decrease  heart rate and promote conversion to  sinus rhythm. Long-term, low-dose  anticoagulant therapy reduces the risk  of stroke that is associated with atrial  fibrillation.    This arrhythmia is a common cause of death in patients who have had a  myocardial infarction. Cardiac output is impaired, and tachycardia may  deteriorate into ventricular fibrillation. Therefore, ventricular tachycardia  requires prompt management.   1. Abnormal automaticity: The SA node shows the fastest rate of Phase 4 depolarization and, therefore, exhibits a  higher rate of discharge than that occurring in other pacemaker cells exhibiting automaticity. Thus, the SA node  normally sets the pace of contraction for the myocardium, and latent pacemakers are depolarized by impulses  coming from the SA node. However, if cardiac sites other than the SA node show enhanced automaticity, they  may generate competing stimuli, and arrhythmias may arise. Abnormal automaticity may also occur if the    myocardial cells are damaged (for example, by hypoxia or potassium imbalance). These cells may remain  partially depolarized during diastole and, therefore, can reach the firing threshold earlier than normal cells.  Abnormal automatic discharges may thus be induced.   2. Effect of drugs on automaticity: Most of the antiarrhythmic agents suppress automaticity by blocking either Na +  or Ca 2+ channels to reduce the ratio of these ions to K + . This decreases the slope of Phase 4 (diastolic)  depolarization and/ or raises the threshold of discharge to a less negative voltage. Such drugs cause the  frequency of discharge to decreasea€"an effect that is more pronounced in cells with ectopic pacemaker  activity than in normal cells.   3. Abnormalities in impulse conduction: Impulses from higher pacemaker centers are normally conducted down  pathways that bifurcate to activate the entire ventricular surface (Figure 17.3). A phenomenon called reentry  can occur if a unidirectional block caused by myocardial inj ury or a prolonged refractory period results in an  abnormal conduction pathway. Reentry is the most common cause of arrhythmias, and it can occur at any level  of the cardiac conduction system. For example, consider a single Purkinje fiber with two conduction pathways  to ventricular muscle. An impulse normally travels down both limbs of the conduction path. Flowever, if  myocardial inj ury results in a unidirectional block, the impulse may only be conducted down Pathway 1 (see  Figure 17.3). If the block in Pathway 2 is in the forward direction only, the impulse may travel in a retrograde  fashion through Pathway 2 and reenter the point of bifurcation. This short-circuit pathway results in  reexcitation of the ventricular muscle, causing premature contraction or sustained ventricular arrhythmia.   4. Effects of drugs on conduction abnormalities: Antiarrhythmic agents prevent reentry by slowing conduction  and/or increasing the refractory period, thereby converting a unidirectional block into a bidirectional block.   As noted above, the antiarrhythmic drugs can modify impulse generation and conduction. More than a dozen such  drugs that are potentially useful in treating arrhythmias are currently available. Flowever, only a limited number of  these agents are clinically beneficial in the treatment of selected arrhythmias. For example, the acute termination  of ventricular tachycardia by lidocaine or of supraventricular tachycardia by adenosine or verapamil are examples  in which antiarrhythmic therapy results in decreased morbidity. In contrast, many of the antiarrhythmic agents are  now known to have dangerous proarrhythmic actionsa€"that is, to cause   arrhythmias. The efficacy of many antiarrhythmic agents remains unproven in placebo-controlled, random trials.   [Note: Implantable cardioverter defibrillators are becoming more widely used to manage this condition. ]   The antiarrhythmic drugs can be classified according to their predominant effects on the action potential (Figure  17.4). Although this classification is convenient, it is not entirely clear-cut, because many of the drugs have actions  relating to more than one class or may have active metabolites with a different class of action. Class I  antiarrhythmic drugs act by blocking voltage-sensitive sodium channels via the same mechanism as local anesthetics.  The decreased rate of entry of sodium slows the rate of rise of Phase 0 of the action potential. [Note: At  therapeutic doses, these drugs have little effect on the resting, fully polarized membrane because of their higher  affinity for the active and inactive channels rather than for the resting channel. ] Class I antiarrhythmic drugs,  therefore, generally cause a decrease in excitability and conduction velocity. The use of sodium channel blockers  has been declining continuously due to their possible proarrhythmic effects, particularly in patients with reduced  left ventricular function and ischemic heart disease.   Class I drugs bind more rapidly to open or inactivated sodium channels than to channels that are fully repolarized   following recovery from the previous depolarization cycle. Therefore, these drugs show a greater degree of  blockade in tissues that are frequently depolarizing (for example, during tachycardia, when the sodium channels  open often). This property is called use-dependence (or state-dependence), and it enables these drugs to block  cells that are discharging at an abnormally high frequency without interfering with the normal, low-frequency  beating of the heart. The Class I drugs have been subdivided into three groups according to their effect on the  duration of the action potential. Class IA agents slow the rate of rise of the action potential (thus slowing  conduction), prolong the action potential, and increase the ventricular effective refractory period. They have an  intermediate speed of association   with activated/ inactivated sodium-channels and an intermediate rate of dissociation from resting channels.   Prolongation of duration of the action potential and increased ventricular effective period are due to concomitant  Class III activity. Class IB drugs have little effect on the rate of depolarization; rather, they decrease the duration of  the action potential by shortening repolarization. They rapidly interact with sodium channels. Class 1C agents  markedly depress the rate of rise of the membrane action potential. Therefore, they cause marked slowing of  conduction but have little effect on the duration of the membrane action potential or the ventricular effective  refractory period. They bind slowly to sodium channels.   Inhibition of potassium channels (Class III activity) widens the action potential, leading to a prolonged QT interval on  the electrocardiogram. Such an effect is associated with increased risk of developing life-threatening ventricular  tachyarrhythmias (torsades de pointes). The most common cause of QT prolongation is drug-induced, although it  may also be genetic. QT prolongation is not only seen with Class III antiarrhythmics. Drugs such as cisapride,  grepafloxacin, terfenadine, and astemizole were withdrawn from the market because of severe and fatal  arrhythmias. Erythromycin, clarithromycin, pentamidine, moxifloxacin, levofloxacin, imipramine, desipramine,  amitriptyline, doxepin, thioridazine, mesoridazine, haloperidol, risperidone, ziprasidone, and quetiapine are  some of the drugs known to prolong the QT interval. Caution should be exerted when combining several drugs with  effects on the QT interval (for example, quinidine with levofloxacin ) or when giving these drugs combined with  azole antifungals (fluconazole and itraconazole). The latter are known to inhibit drug metabolism, leading to large  increases in plasma drug concentrations.   Quinidine [KWIN-i-deen] is the prototype Class IA drug. Because of its concomitant Class III activity, it can actually   precipitate arrhythmias such as polymorphic ventricular tachycardia (torsades de pointes), which can degenerate  into ventricular fibrillation. Because of the toxic potential of quinidine, calcium antagonists, such as amiodarone  and verapamil, are increasingly replacing this drug in clinical use.   1. Mechanism of action: Quinidine binds to open and inactivated sodium channels and prevents sodium influx,  thus slowing the rapid upstroke during Phase 0 (Figure 17. 5). It also decreases the slope of Phase 4 spontaneous  depolarization and inhibits potassium channels.   2. Therapeutic uses: Quinidine is used in the treatment of a wide variety of arrhythmias, including atrial,   AV-j unctional, and ventricular tachyarrhythmias. Quinidine is used to maintain sinus rhythm after direct-current  cardioversion of atrial flutter or fibrillation and to prevent frequent ventricular tachycardia.    Class IA drugs slow  Phase 0 depolarization,  prolong action potential,  and slow conduction.   Quinidine, procainamide,  and disopyramide block  open or inactivated sodium  channels. These drugs have an  intermediate rate of  association with sodium  channels.   Figure 17.5 Schematic diagram of the effects of Class IA agents. INa and IK are transmembrane currents  due to the movement of Na+and K+, respectively.    3. Pharmacokinetics: Quinidine sulfate is rapidly and almost completely absorbed after oral administration. It  undergoes extensive metabolism by the hepatic cytochrome P450 enzymes, forming active metabolites.   4. Adverse effects: A potential adverse effect of quinidine (or of any antiarrhythmic drug) is development of  arrhythmia (torsades de pointes). Quinidine may cause SA and AV block or asystole. At toxic levels, the drug  may induce ventricular tachycardia. Cardiotoxic effects are exacerbated by hyperkalemia. Nausea, vomiting,  and diarrhea are commonly observed. Large doses of quinidine may induce the symptoms of cinchonism (for  example, blurred vision, tinnitus, headache, disorientation, and psychosis). The drug has a mild i±-adrenergic  blocking action as well as an atrop/ne-like effect. Quinidine can increase the steady-state concentration of  digoxin by displacement of digoxin from tissue-binding sites (minor effect) and by decreasing digoxin renal  clearance (major effect).   1. Actions: This Class IA drug, a derivative of the local anesthetic procaine, shows actions similar to those of  quinidine.   2. Pharmacokinetics: Procainamide [proe-KANE-a-mide] is well-absorbed following oral administration. [Note:  The intravenous route is rarely used, because hypotension occurs if the drug is infused too rapidly. ]  Procainamide has a relatively short half-life of 2 to 3 hours. A portion of the drug is acetylated in the liver to  N-acetylprocainamide (NAPA), which has little effect on the maximum polarization of Purkinj e fibers but  prolongs the duration of the action potential. Thus, NAPA has properties of a Class III drug. NAPA is eliminated  via the kidney, and dosages of procainamide may need to be adj usted in patients with renal failure.   3. Adverse effects: With chronic use, procainamide causes a high incidence of side effects, including a reversible  lupus erythematosusa€"like syndrome that develops in 25 to 30 percent of patients. Toxic concentrations of  procainamide may cause asystole or induction of ventricular arrhythmias. Central nervous system (CNS) side  effects include depression, hallucination, and psychosis. With this drug, gastrointestinal intolerance is less  frequent than with quinidine.   1. Actions: This Class IA drug shows actions similar to those of quinidine. Disopyramide [dye-soe-PEER-a-mide]  produces a negative inotropic effect that is greater than the weak effect exerted by quinidine and  procainamide, and unlike the latter drugs, disopyramide causes peripheral vasoconstriction. The drug may  produce a clinically important decrease in myocardial contractility in patients with preexisting impairment of  left ventricular function. Disopyramide is used in the treatment of ventricular arrhythmias as an alternative to  procainamide or quinidine. Like procainamide and quinidine, it also has Class III activity.   2. Pharmacokinetics: Approximately half of the orally ingested drug is excreted unchanged by the kidneys.   Approximately 30 percent of the drug is converted by the liver to the less active mono-N-dealkylated  metabolite.   3. Adverse effects: Disopyramide shows effects of anticholinergic activity (for example, dry mouth, urinary  retention, blurred vision, and constipation).   Lidocaine [LYE-doe-kane] is a Class IB drug. The Class IB agents rapidly associate and dissociate from sodium   channels. Thus, the actions of Class IB agents are manifested when the cardiac cell is depolarized or firing rapidly.   Class IB drugs are particularly useful in treating ventricular arrhythmias. Lidocaine was the drug of choice for   1. Actions: Lidocaine, a local anesthetic, shortens Phase 3 repolarization and decreases the duration of the action  potential (Figure 17.6).   2. Therapeutic uses: Lidocaine is useful in treating ventricular arrhythmias arising during myocardial ischemia,  such as that experienced during a myocardial infarction. The drug does not markedly slow conduction and, thus,  has little effect on atrial or AV j unction arrhythmias.   3. Pharmacokinetics: Lidocaine is given intravenously because of extensive first-pass transformation by the liver,  which precludes oral administration. The drug is dealkylated and eliminated almost entirely by the liver;  consequently, dosage adj ustment may be necessary in patients with liver dysfunction or those taking drugs that  lower hepatic blood flow, such as propranolol.   4. Adverse effects: Lidocaine has a fairly wide toxic-to-therapeutic ratio. It shows little impairment of left  ventricular function and has no negative inotropic effect. CNS effects include drowsiness, slurred speech,  paresthesia, agitation, confusion, and convulsions. Cardiac arrhythmias may also occur.   These Class IB drugs have actions similar to those of lidocaine, and they can be administered orally. Mexiletine  [MEX-i-le-teen] is used for chronic treatment of ventricular arrhythmias associated with previous myocardial  infarction. Tocainide [toe-KAY-nide] is used for treatment of ventricular tachyarrhythmias. Tocainide has  pulmonary toxicity, which may lead to pulmonary fibrosis.   Flecainide [FLEK-a-nide] is a Class 1C drug. These drugs slowly dissociate from resting sodium channels, and they  show prominent effects even at normal heart rates. They are approved for refractory ventricular arrhythmias and  for the prevention of paroxysmal atrial fibrillation/ flutter associated with disabling symptoms and paroxysmal  supraventricular tachycardia. Flowever, recent data have cast serious doubts on the safety of the Class 1C drugs.    Class IB drugs shorten  Phase 3 repolarization  and decrease the duration  of the action potential.   Lidocaine, mexiletine, and  tocainide block open or  inactivated sodium channels.  These drugs have a rapid rate  of association with sodium   Figure 17.6 Schematic diagram of the effects of Class IB agents. l Na and l K are transmembrane currents due  to the movement of N a +and K+, respectively.    1. Actions: Flecainide suppresses Phase 0 upstroke in Purkinje and myocardial fibers (Figure 17.7). This causes  marked slowing of conduction   in all cardiac tissue, with a minor effect on the duration of the action potential and refractoriness. Automaticity  is reduced by an increase in the threshold potential rather than a decrease in the slope of Phase 4  depolarization.   2. Therapeutic uses: Flecainide is useful in treating refractory ventricular arrhythmias. It is particularly useful in  suppressing premature ventricular contraction. Flecainide has a negative inotropic effect and can aggravate  congestive heart failure.   3. Pharmacokinetics: Flecainide is absorbed orally, undergoes minimal biotransformation, and has a half-life of 16  to 20 hours.   4. Adverse effects: Flecainide can cause dizziness, blurred vision, headache, and nausea. Like other Class 1C  drugs, flecainide can aggravate preexisting arrhythmias or induce life-threatening ventricular tachycardia that is  resistant to treatment.   This Class 1C drug shows actions similar to those of flecainide. Propafenone [proe-pa-FEEN-one], like flecainide,  slows conduction in all cardiac tissues and is considered to be a broad-spectrum antiarrhythmic agent.   Class II agents are i 2 -adrenergic antagonists. These drugs diminish Phase 4 depolarization, thus depressing  automaticity, prolonging AV conduction, and decreasing heart rate and contractility. Class II agents are useful in  treating tachyarrhythmias caused by increased sympathetic activity. They are also used for atrial flutter and  fibrillation and for AV-nodal reentrant tachycardia. [Note: In contrast to the sodium-channel blockers, l 2 -blockers  and Class III compounds, such as sotalol and amiodarone, are increasing in use. ]   Propranolol [pro-PRAN-oh-lol] reduces the incidence of sudden arrhythmic death after myocardial infarction (the  most common cause of death in this group of patients). The mortality rate in the first year after a heart attack is  significantly reduced by propranolol , partly because of its ability to prevent ventricular arrhythmias.   Metoprolol [me-TOE-pro-lol] is the i 2 -adrenergic antagonist most widely used in the treatment of cardiac  arrhythmias. Compared to propranolol, it reduces the risk of bronchospasm.   Esmolol [ESS- moe-lol] is a very short-acting T 2 - bl ocker used for intravenous administration in acute arrhythmias that  occur during surgery or emergency situations.    Figure 17.7 Schematic diagram of the effects of Class 1C agents. l Na and l K are transmembrane currents due  to the movement of Na+and K+, respectively.   Class III agents block potassium channels and, thus, diminish the outward potassium current during repolarization of   cardiac cells. These agents prolong the duration of the action potential without altering Phase 0 of depolarization or   the effective refractory period. All Class III drugs have the potential to induce arrhythmias.   1. Actions: Amiodarone [a-MEE-oh-da-rone] contains iodine and is related structurally to thyroxine. It has complex  effects, showing Class I, II, III, and IV actions. Its dominant effect is prolongation of the action potential  duration and the refractory period. Amiodarone has antianginal as well as antiarrhythmic activity.   2. Therapeutic uses: Amiodarone is effective in the treatment of severe refractory supraventricular and  ventricular tachyarrhythmias. Despite its side-effect profile, amiodarone is the most commonly employed  antiarrhythmic.   3. Pharmacokinetics: Amiodarone is incompletely absorbed after oral administration. The drug is unusual in  having a prolonged half-life of several weeks, and it distributes extensively in adipose issue. Full clinical effects  may not be achieved until 6 weeks after initiation of treatment.   4. Adverse effects: Amiodarone shows a variety of toxic effects. After long-term use, more than half of patients  receiving the drug show side effects that are severe enough to prompt its discontinuation. Flowever, use of low  doses reduces toxicity, while retaining clinical efficacy. Some of the more common effects include interstitial  pulmonary fibrosis, gastrointestinal tract intolerance, tremor, ataxia, dizziness, hyper- or hypothyroidism, liver  toxicity, photosensitivity, neuropathy, muscle weakness, and blue skin discoloration caused by iodine  accumulation in the skin. As noted earlier, recent clinical trials have shown that amiodarone does not reduce  the incidence of sudden death or prolong survival in patients with congestive heart failure.   Sotalol [SOE-ta-lol], although a class III antiarrhythmic agent, also has potent nonselective P-blocker activity. It is   well established that l 2 -blockers reduce mortality associated with acute myocardial infarction.   1. Actions: Sotalol blocks a rapid outward potassium current, known as the delayed rectifier. This blockade  prolongs both repolarization and duration of the action potential, thus lengthening the effective refractory  period.   2. Therapeutic uses: T 2 - Blockers are used for long-term therapy to decrease the rate of sudden death following an  acute myocardial infarction. T 2 - Blockers have a modest ability to suppress ectopic beats and to reduce  myocardial oxygen demand. They have strong antif ibrillatory effects, particularly in the ischemic myocardium.  Sotalol was more effective in preventing recurrence of arrhythmia and in decreasing mortality than  imipramine, mexiletine, procainamide, propafenone, and quinidine in patients with sustained ventricular  tachycardia (Figure 17.9).    Class III drugs prolong  Phase 3 repolarization,  without altering Phase 0.   Figure 17.8 Schematic diagram of the effects of Class III agents. Ipj a and Ik are transmembrane currents  due to the movement of Na+and K+, respectively.    3. Adverse effects: This drug also has the lowest rate of acute or long-term adverse effects. As with all drugs that  prolong the QT interval,   the syndrome of torsade de pointes is a serious potential adverse effect, typically seen in three to four percent  of patients.   Dofetilide [doh-FET-il-ide] can be used as a first-line antiarrhythmic agent in patients with persistent atrial  fibrillation and heart failure or in those with coronary artery disease with impaired left ventricular function.   Because of the risk of proarrhythmia, dofetilide initiation is limited to the inpatient setting and is restricted to  prescribers who have completed a specific manufacturer's training session. Along with amiodarone and i 2 -blockers,  dofetilide is the only antiarrhythmic drug that is recommended by experts for the treatment of atrial fibrillation in  a wide range of patients. The half-life is 10 hours, Excretion is in the urine, with 80 percent as unchanged drug and  20 percent as inactive or minimally active metabolites.   Figure 17.9 Comparison of sotalol with six other drugs with respect to deaths due to cardiac arrhythmias.   Class IV drugs are calcium-channel blockers (see p. 223). They decrease the inward current carried by calcium,  resulting in a decreased rate of Phase 4 spontaneous depolarization. They also slow conduction in tissues that are  dependent on calcium currents, such as the AV node (Figure 17.10). Although voltage-sensitive calcium channels  occur in many different tissues, the maj or effect of calcium-channel blockers is on vascular smooth muscle and the  heart.    Verapamil [ver-AP-a-mil] shows greater action on the heart than on vascular smooth muscle, whereas nifedipine, a  calcium-channel blocker used to treat hypertension (see p. 223), exerts a stronger effect on the vascular smooth  muscle than on the heart. Diltiazem [dil-TYE-a-zem] is intermediate in its actions.   1. Actions: Calcium enters cells by voltage-sensitive channels and by receptor-operated channels that are  controlled by the binding of agonists, such as catecholamines, to membrane receptors. Calcium-channel  blockers, such as verapamil and diltiazem, are more effective against the voltage-sensitive channels, causing a  decrease in the slow inward current that triggers cardiac contraction. Verapamil and diltiazem bind only to  open, depolarized channels, thus preventing repolarization until the drug dissociates from the channel. These  drugs are therefore use-dependent; that is, they block most effectively when the heart is beating rapidly,  because in a normally paced heart, the calcium channels have time to repolarize and the bound drug dissociates  from the channel before the next conduction pulse. By decreasing the inward current carried by calcium,  verapamil and diltiazem slow conduction and prolong the effective refractory period in tissues that are  dependent on calcium currents, such as the AV node. These drugs are therefore effective in treating  arrhythmias that must traverse calcium-dependent cardiac tissues.   2. Therapeutic uses: Verapamil and diltiazem are more effective against atrial than against ventricular  arrhythmias. They are useful in treating reentrant supraventricular tachycardia and in reducing   the ventricular rate in atrial flutter and fibrillation. In addition, these drugs are used to treat hypertension and  angina.   3. Pharmacokinetics: Verapamil and diltiazem are absorbed after oral administration. Verapamil is extensively  metabolized by the liver; thus, care should be taken when administering this drug to patients with hepatic  dysfunction.   4. Adverse effects: Verapamil and diltiazem have negative inotropic properties and, therefore, may be  contraindicated in patients with preexisting depressed cardiac function. Both drugs can also produce a decrease  in blood pressure because of peripheral vasodilationa€"an effect that is actually beneficial in treating  hypertension.   Digoxin [di-J OX-in] shortens the refractory period in atrial and ventricular myocardial cells while prolonging the  effective refractory period and diminishing conduction velocity in the AV node. Digoxin is used to control the  ventricular response rate in atrial fibrillation and flutter. At toxic concentrations, digoxin causes ectopic  ventricular beats that may result in ventricular tachycardia and fibrillation. [Note: This arrhythmia is usually treated  with lidocaine or phenytoin. ]   Adenosine [ah-DEN-oh-zeen] is a naturally occurring nucleoside, but at high doses, the drug decreases conduction  velocity, prolongs the refractory period, and decreases automaticity in the AV node. Intravenous adenosine is the  drug of choice for abolishing acute supraventricular tachycardia. It has low toxicity but causes flushing, chest pain,  and hypotension. Adenosine has an extremely short duration of action (approximately 15 seconds).    Class IV drugs slow Phase 4  spontaneous depolarization  and slow conduction in  tissues dependent on calcium  currents, such as the AV node.    Figure 17.10 Schematic diagram of the effects of Class IV agents, lea and Ik are transmembrane currents due  to the movement of Ca2+and K+, respectively.   17.1 A 66-year-old man had a myocardial infarct. Which one of the following would be appropriate  prophylactic antiarrhythmic therapy?   17.2 Suppression of arrhythmias resulting from a reentry focus is most likely to occur if the drug:   17.3 A 57-year-old man is being treated for an atrial arrhythmia. He complains of headache, dizziness, and  tinnitus. Which one of the following antiarrhythmic drugs is the most likely cause?   17.4 A 58-year-old woman is being treated for chronic suppression of a ventricular arrhythmia. After 2 months  of therapy, she complains about feeling tired all the time. Examination reveals a resting heart rate of 10 beats  per minute lower than her previous rate. Her skin is cool and clammy. Laboratory test results indicate low  thyroxin and elevated thyroid-stimulating hormone levels. Which of the following antiarrhythmic drugs is the  likely cause of these signs and symptoms?   >Table of Contents > Unit IV - Drugs Affecting the Cardiovascular System >Chapter 18 - Antianginal Drugs   Angina pectoris is a characteristic sudden, severe, pressing chest pain radiating to the neck, j aw, back, and arms. It  is caused by coronary blood flow that is insufficient to meet the oxygen demands of the myocardium, leading to  ischemia. The imbalance between oxygen delivery and utilization may result during exertion, from a spasm of the  vascular smooth muscle, or from obstruction of blood vessels caused by atherosclerotic lesions. These transient  episodes (15 seconds to 15 minutes) of myocardial ischemia do not cause cellular death, such as occurs in myocardial  infarction. Three classes of drugs, used either alone or in combination, are effective in treating patients with stable  angina: organic nitrates, P-blockers, and calcium-channel blockers (Figure 18. 1). These agents lower the oxygen  demand of the heart by affecting blood pressure, venous return, heart rate, and contractility. Lifestyle and risk  factor modifications, especially cessation of smoking, are also important in the treatment of angina. [Note: Options  other than medications for treating angina include angioplasty and coronary artery bypass surgery. ]   Angina pectoris has three overlapping patterns: 1) stable or typical angina, 2) unstable angina, and 3) Prinzmetal's or  variant angina. They are caused by varying combinations of increased myocardial demand and decreased myocardial  perfusion.   Stable angina is the most common form of angina and, therefore, is called typical angina pectoris. It is characterized  by a burning, heavy, or squeezing feeling in the chest. It is caused by the reduction of coronary perfusion due to a  fixed obstruction produced by coronary atherosclerosis. The heart becomes vulnerable to ischemia whenever there  is increased demand, such as that produced by physical activity, emotional excitement, or any other cause of  increased cardiac workload. Typical angina pectoris is promptly relieved by rest or nitroglycerin (a vasodilator).   Unstable angina lies between stable angina on the one hand and myocardial infarction on the other. In unstable  angina, chest pains occur with increased frequency and are precipitated by progressively   less effort. The symptoms are not relieved by rest or nitroglycerin. Unstable angina requires hospital admission and  more aggressive therapy to prevent death and progression to myocardial infarction.   Prinzmetal's angina is an uncommon pattern of episodic angina that occurs at rest and is due to coronary artery  spasm. Symptoms are caused by decreased blood flow to the heart muscle due to spasm of the coronary artery.  Although individuals with this form of angina may have significant coronary atherosclerosis, the angina attacks are  unrelated to physical activity, heart rate, or blood pressure. Prinzmetal's angina generally responds promptly to  coronary vasodilators, such as nitroglycerin and calcium-channel blockers.   Patients with advanced coronary artery disease may present with angina episodes during effort as well as at rest,  suggesting the presence of a fixed obstruction associated with endothelial dysfunction.   Organic nitrates (and nitrites) used in the treatment of angina pectoris are simple nitric and nitrous acid esters of  glycerol. They differ in their volatility. For example, isosorbide dinitrate and isosorbide mononitrate are solids at  room temperature, nitroglycerin is only moderately volatile, and amyl nitrite is extremely volatile. These  compounds cause a rapid reduction in myocardial oxygen demand, followed by rapid relief of symptoms. They are  effective in stable and unstable angina as well as in variant angina pectoris.    Figure 18.2 Effects of nitrates and nitrites on smooth muscle. cGMP =cyclic guanosine 3', 5'-monophosphate.   Nitrates decrease coronary vasoconstriction or spasm and increase perfusion of the myocardium by relaxing  coronary arteries. In addition, they relax veins, decreasing preload and myocardial oxygen consumption. Organic  nitrates, such as nitroglycerin [nye-troe-GLIS-er-in], which is also known as glyceryl trinitrate, are thought to  relax vascular smooth muscle by their intracellular conversion to nitrite ions, and then to nitric oxide, which in turn  activates guanylate cyclase and increases the cells' cyclic guanosine monophosphate (GMP). 1 Elevated cGMP  ultimately leads to dephosphorylation of the myosin light chain, resulting in vascular smooth muscle relaxation  (Figure 18.2).   All these agents are effective, but they differ in their onset of action and rate of elimination. For prompt relief of  an ongoing attack of angina precipitated by exercise or emotional stress, sublingual (or spray form) nitroglycerin is    the drug of choice. At therapeutic doses, nitroglycerin has two maj or effects. First, it causes dilation of the large  veins, resulting in pooling of blood in the veins. This diminishes preload (venous return to the heart) and reduces  the work of the heart. Second, nitroglycerin dilates the coronary vasculature, providing an increased blood supply  to the heart muscle. Nitroglycerin decreases myocardial oxygen consumption because of decreased cardiac work.   The time to onset of action varies from 1 minute for nitroglycerin to more than 1 hour for isosorbide mononitrate  (Figure 18.3). Significant first-pass metabolism of nitroglycerin occurs in the liver. Therefore, it is common to take  the drug either sublingually or via a transdermal patch, thereby avoiding this route of elimination. Isosorbide  mononitrate owes its improved bioavailability and long duration of action to its stability against hepatic breakdown.  Oral isosorbide dinitrate undergoes denitration to two mononitrates, both of which possess antianginal activity.   The most common adverse effect of nitroglycerin, as well as of the other nitrates, is headache. From 30 to 60  percent of patients receiving intermittent nitrate therapy with long-acting agents develop headaches. High doses of  organic nitrates can also cause postural hypotension, facial flushing, and tachycardia. Sildenafil potentiates the  action of the nitrates. To preclude the dangerous hypotension that may occur, this combination is contraindicated.   Tolerance to the actions of nitrates develops rapidly. The blood vessels become desensitized to vasodilation.  Tolerance can be overcome by providing a daily a€oenitrate-free intervalaC^ to restore sensitivity to the drug. This  interval is typically 10 to 12 hours, usually at night, because demand on the heart is decreased at that time.  Nitroglycerin patches are worn for 12 hours then removed for 12 hours. Flowever, variant angina worsens early in  the morning, perhaps due to circadian catecholamine surges. Therefore, the nitrate-free interval in these patients  should occur in the late afternoon. Patients who continue to have angina despite nitrate therapy may benefit by  addition of another class of agent.   Figure 18.3 Time to peak effect and duration of action for some common organic nitrate preparations.   The i 2 -adrenergica€"blocking agents decrease the oxygen demands of the myocardium by lowering both the rate  and the force of contraction of the heart (see p. 86). They suppress the activation of the heart by blocking i 2 i  receptors, and they reduce the work of the heart by decreasing heart rate, contractility, cardiac output, and blood  pressure. With T 2 - blockers, the demand for oxygen by the myocardium is reduced both during exertion and at rest.  Propranolol is the prototype for this class of compounds, but it is not cardioselective. Thus, other T 2 - blockers, such  as metoprolol or atenolol, are preferred. [Note: All i 2 -blockers are nonselective at high doses and can inhibit i 2 2  receptors. This is particularly important to remember in the case of asthmatics. ] Agents with intrinsic  sympathomimetic activity (for example, pindolol ) are less effective and should be avoided in angina. The   I 2 - blockers reduce the frequency and severity of angina attacks. These agents are particularly useful in the  treatment of patients with myocardial infarction and have been shown to prolong survival. The i 2 -blockers can be  used with nitrates to increase exercise duration and tolerance. They are, however, contraindicated in patients with  asthma, diabetes, severe bradycardia, peripheral vascular disease, or chronic obstructive pulmonary disease. [Note:   It is important not to discontinue T 2 - blocker therapy abruptly. The dose should be gradually tapered off over 5 to 10  days to avoid rebound angina or hypertension.]   Calcium is essential for muscular contraction. Calcium influx is increased in ischemia because of the membrane  depolarization that hypoxia produces. In turn, this promotes the activity of several adenosine  triphosphatea€"consuming enzymes, thereby depleting energy stores and worsening the ischemia. The calcium-  channel blockers protect the tissue by inhibiting the entrance of calcium into cardiac and smooth muscle cells of the  coronary and systemic arterial beds. All calcium-channel blockers are therefore arteriolar vasodilators that cause a  decrease in smooth muscle tone and vascular resistance. (See p. 206 for a description of the mechanism of action  for this group of drugs. ) At clinical doses, these agents affect primarily the resistance of vascular smooth muscle and  the myocardium. [Note: Verapamil mainly affects the myocardium, whereas nifedipine exerts a greater effect on  smooth muscle in the peripheral vasculature. Diltiazem is intermediate in its actions. ] All calcium-channel blockers  lower blood pressure. They may worsen heart failure due to their negative inotropic effect. [Note: Variant angina  caused by spontaneous coronary spasm (either at work or at rest; Figure 18.4) rather than by increased myocardial  oxygen requirement is controlled by organic nitrates or calcium-channel blockers; l 2 -blockers are contraindicated. ]   Nifedipine [nye-FED-i-peen], a dihydropyridine derivative, functions mainly as an arteriolar vasodilator. This drug  has minimal effect on cardiac conduction or heart rate. Other members of this class, amlodipine, nicardipine, and  felodipine, have similar cardiovascular characteristics except for amlodipine, which does not affect heart rate or  cardiac output. Nifedipine is administered orally, usually as extended-release tablets. It undergoes hepatic  metabolism to products that are eliminated in both urine and the feces. The vasodilation effect of nifedipine is  useful in the treatment of variant angina caused by spontaneous coronary spasm. Nifedipine can cause flushing,  headache, hypotension, and peripheral edema as side effects of its vasodilation activity. As with all calcium-channel  blockers, constipation is a problem. Because it has little to no sympathetic antagonistic action, nifedipine may  cause reflex tachycardia if peripheral vasodilation is marked. [Note: The general consensus is that short-acting  dihydropyridines should be avoided in coronary artery disease.]   The diphenylalkylamine verapamil [ver-AP-a-mil] slows cardiac atrioventricular (AV) conduction directly, and  decreases heart rate, contractility, blood pressure, and oxygen demand. Verapamil causes greater negative  inotropic effects than nifedipine, but it is a weaker vasodilator. The drug is extensively metabolized by the liver;  therefore, care must be taken to adj ust the dose in patients with liver dysfunction. Verapamil is contraindicated in  patients with preexisting depressed cardiac function or AV conduction abnormalities. It also causes constipation.  Verapamil should be used with caution in patients taking digoxin, because verapamil increases digoxin levels.   Diltiazem [dil-TYE-a-zem] has cardiovascular effects that are similar to those of verapamil. Both drugs slow AV  conduction and decrease the rate of firing of the sinus node pacemaker. Diltiazem reduces the heart   rate, although to a lesser extent than verapamil, and also decreases blood pressure. In addition, diltiazem can  relieve coronary artery spasm and, therefore, is particularly useful in patients with variant angina. It is extensively  metabolized by the liver. The incidence of adverse side effects is low (the same as those for other calcium-channel  blockers). Interactions with other drugs are the same as those indicated for verapamil.    Figure 18.5 Treatment of angina in patients with concomitant diseases. COPD =chronic obstructive  pulmonary disease.    Figure 18. 5 summarizes the treatment of angina in patients with concomitant diseases.   18. 1 A 56-year-old patient complains of chest pain following any sustained exercise. He is diagnosed with  atherosclerotic angina. He is prescribed sublingual nitroglycerin for treatment of acute chest pain. Which of  the following adverse effects is likely to be experienced by this patient?    18.2 The patient described in Question 18. 1 is also prescribed propranolol to prevent episodes of angina. The  i 2 -blocker has the added benefit of preventing which of the following side effects of sublingual nitroglycerin?   18.3 A 68-year-old man has been successfully treated for exercise-induced angina for several years. He  recently has been complaining about being awakened at night with chest pain. Which of the following drugs  would be useful in preventing this patient's nocturnal angina?   >Table of Contents > Unit IV - Drugs Affecting the Cardiovascular System >Chapter 19 - Antihypertensives   Hypertension is defined as either a sustained systolic blood pressure (SBP) of greater than 140 mm Hg or a sustained  diastolic blood pressure (DBP) of greater than 90 mm Hg. Hypertension results from increased peripheral vascular  smooth muscle tone, which leads to increased arteriolar resistance and reduced capacitance of the venous system.  In most cases, the cause of the increased vascular tone is unknown. Elevated blood pressure is an extremely  common disorder, affecting approximately 15 percent of the population of the United States (60 million people).  Although many of these individuals have no symptoms, chronic hypertensiona€"either systolic or diastolica€"can  lead to cerebrovascular accidents (strokes), congestive heart failure, myocardial infarction, and renal damage. The  incidence of morbidity and mortality significantly decreases when hypertension is diagnosed early and is properly  treated. In recognition of the progressive nature of hypertension, the Seventh Report of the J oint National  Committee classifies hypertension into four categories for the purpose of treatment management. The categories  are normal (SBP/ DBP, <120/ <80), prehypertension (SBP/ DBP, 120a€"139/80a€"89), stage 1 hypertension (SBP/ DBP,  140a€"159/90 a€" 99) , and stage 2 hypertension (SBP/DBP >a€" 160/ >a€" 100).   Although hypertension may occur secondary to other disease processes, more than 90 percent of patients have  essential hypertension, a disorder of unknown origin affecting the blood pressure regulating mechanism. A family  history of hypertension increases the likelihood that an individual will develop hypertensive disease. The incidence  of essential hypertension is four-fold more frequent among blacks than among whites. It occurs more often among  middle-aged males than among middle-aged females, and its prevalence increases with age and obesity.  Environmental factors, such as a stressful lifestyle, high dietary intake of sodium, and smoking, further predispose  an individual to the occurrence of hypertension. Figure 19. 1 summarizes the drugs used to treat hypertension. ]   Arterial blood pressure is regulated within a narrow range to provide adequate perfusion of the tissues without  causing damage to the vascular system, particularly the arterial intima (endothelium). Arterial blood pressure is  directly proportional to the product of the cardiac output and the peripheral vascular resistance (Figure 19.2).   Cardiac output and peripheral resistance are controlled mainly by two overlapping control mechanisms: the  baroreflexes, which are mediated by the sympathetic nervous system, and the renin-angiotensin-aldosterone system  (Figure 19.3). Most antihypertensive drugs lower blood pressure by reducing cardiac output and/or decreasing  peripheral resistance.   Baroreflexes involving the sympathetic nervous system are responsible for the rapid, moment-to-moment regulation  of blood pressure. A fall in blood pressure causes pressure-sensitive neurons (baroreceptors in the aortic arch and  carotid sinuses) to send fewer impulses to cardiovascular centers in the spinal cord. This prompts a reflex response  of increased sympathetic and decreased parasympathetic output to the heart and vasculature, resulting in  vasoconstriction and increased cardiac output. These changes result in a compensatory rise in blood pressure (see  Figure 19.3).   The kidney provides for the long-term control of blood pressure by altering the blood volume. Baroreceptors in the  kidney respond to reduced arterial pressure (and to sympathetic stimulation of i 2 -adrenoceptors) by releasing the  enzyme renin (see Figure 19.3). Low sodium intake and greater sodium loss also increase renin release. This  peptidase converts angiotensinogen to angiotensin I, which is converted in turn to angiotensin II in the presence of  angiotensin-converting enzyme (ACE). Angiotensin II is the body's most potent circulating vasoconstrictor,  constricting both arterioles and veins, causing an increase in blood pressure. Angiotensin II exerts a preferential  vasoconstrictor action on the efferent arterioles of the renal glomerulus, increasing glomerular filtration.   Furthermore, angiotensin II stimulates aldosterone secretion, leading to increased renal sodium reabsorption and  increased blood volume, which contribute to a further increase in blood pressure. These effects of angiotensin II  are mediated by stimulation of angiotensin lla€"ATl receptors.   The goal of antihypertensive therapy is to reduce cardiovascular and renal morbidity and mortality. The relationship  between blood pressure and the risk of a cardiovascular event is continuous, and thus lowering of even moderately  elevated blood pressure significantly reduces cardiovascular disease. The newly added classification of  a€oeprehypertensiona€§ recognizes this relationship and emphasizes the need for decreasing blood pressure in the  general population by education and adoption of blood pressurea€"lowering behaviors. Mild hypertension can often  be controlled with a single drug; however, most patients require more than one drug to achieve blood pressure  control. Current recommendations are to initiate therapy with a thiazide diuretic unless there are compelling  reasons to employ other drug classes (Figure 19.4). If blood pressure is inadequately controlled, a second   drug is added, with the selection based on minimizing the adverse effects of the combined regimen. A l 2 -blocker is  usually added if the initial drug was a diuretic, or a diuretic is usually added if the first drug was a i 2 -blocker. A  vasodilator can be added as a third step for those patients who still fail to respond. Flowever, angiotensin    lla€"converting enzyme inhibitors, angiotensin lla€" ATI receptor blockers, and calcium-channel blockers can also be  used to initiate therapy.   Certain subsets of the hypertensive population respond better to one class of drug than they do to another. For  example, black patients   respond well to diuretics and calcium-channel blockers, but therapy with T 2 - blockers or ACE inhibitors is often less  effective. Similarly, calcium-channel blockers, ACE inhibitors, and diuretics are favored for treatment of  hypertension in the elderly, whereas T 2 - blockers and i±-antagonists are less well tolerated. Furthermore,  hypertension may coexist with other diseases that can be aggravated by some of the antihypertensive drugs. For  example, Figure 19. 4 shows the preferred therapy in hypertensive patients with various concomitant diseases. In  such cases, it is important to match antihypertensive drugs to the particular patient. Figure 19.5 shows the  frequency of concomitant disease in the hypertensive patient population.    Figure 19.3 Response of the autonomic nervous system and the renin-angiotensin-aldosterone system to a  decrease in blood pressure.   Figure 19.4 Treatment of hypertension in patients with concomitant diseases. Drug classes shown in blue  boxes provide improvement in outcome (for example diabetes or renal disese) independent of blood pressure  . [Note: ARBs are an alternative to ACE inhibitors. ] ACE =angiotensin-converting enzyme; ARB =angiotensin  receptor blocker.   Lack of patient compliance is the most common reason for failure of antihypertensive therapy. The hypertensive  patient is usually asymptomatic and is diagnosed by routine screening before the occurrence of overt end-organ  damage. Thus, therapy is generally directed at preventing future disease sequelae rather than relieving the patient's  present discomfort. The adverse effects associated with the hypertensive therapy may influence the patient more  than the future benefits.   For example, i 2 -blockers can decrease libido and induce impotence in males, particularly middle-aged and elderly  men. This drug-induced sexual dysfunction may prompt the patient to discontinue therapy. Thus, it is important to  enhance compliance by carefully selecting a drug regimen that both reduces adverse effects and minimizes the  number of doses required daily.    Figure 19.5 Frequency of occurrence of concomitant disease among the hypertensive patient population.   Diuretics can be used as first-line drug therapy for hypertension unless there are compelling reasons to choose  another agent. Low-dose diuretic therapy is safe, inexpensive, and effective in preventing stroke, myocardial  infarction, and congestive heart failure, all of which can cause mortality. Recent data suggest that diuretics are  superior to T 2 - blockers for treating hypertesnion in older adults.   All oral diuretic drugs are effective in the treatment of hypertension, but the thiazides have found the most   1. Actions: Thiazide diuretics, such as hydrochlorothiazide [hye-droe-klor-oh-THYE-a-zide], lower blood pressure  initially by increasing sodium and water excretion. This causes a decrease in extracellular volume, resulting in a  decrease in cardiac output and renal blood flow (Figure 19.6). With long-term treatment, plasma volume  approaches a normal value, but peripheral resistance decreases. Potassium-sparing diuretics are often used  combined with thiazides.   2. Therapeutic uses: Thiazide diuretics decrease blood pressure in both the supine and standing positions, and  postural hypotension is rarely observed except in elderly, volume-depleted patients. These agents counteract  the sodium and water retention observed with other agents used in the treatment of hypertension (for example,  hydralazine). Thiazides are therefore useful in combination therapy with a variety of other antihypertensive  agents, including T 2 - bl ockers, ACE inhibitors, angiotensin-receptor blockers, and potassium-sparing diuretics.  Thiazide diuretics are particularly useful in the treatment of black or elderly patients. They are not effective in  patients with inadequate kidney function (creatinine clearance, <50 mL/ min). Loop diuretics may be required in  these patients.    3. Pharmacokinetics: Thiazide diuretics are orally active. Absorption and elimination rates vary considerably,  although no clear advantage is present for one agent over another. All thiazides are ligands for the organic acid  secretory system of the nephron, and as such, they may compete with uric acid for elimination.   4. Adverse effects: Thiazide diuretics induce hypokalemia and hyperuricemia in 70 percent of patients and  hyperglycemia in 10 percent of patients. Hypomagnesemia may also occur. Serum potassium levels should be  monitored closely in patients who are predisposed to cardiac arrhythmias (particularly individuals with left  ventricular hypertrophy, ischemic heart disease, or chronic heart failure) and who are concurrently being  treated with both thiazide diuretics and digoxin.   The loop diuretics act promptly, even in patients with poor renal function or who have not responded to thiazides  or other diuretics. Loop diuretics cause decreased renal vascular resistance and increased renal blood flow. [Note:   Loop diuretics increase the Ca 2+ content of urine, whereas thiazide diuretics decrease it. ]   Amiloride [a-MIL-oh-ride] and triamterene [tri- AM-ter-een] (inhibitors of epithelial sodium transport at the late  distal and collecting ducts) as well as spironolactone [speer-on-oh-LAK-tone] and eplerenone [eh-PLEH-reh-none]  (aldosterone-receptor antagonists) reduce potassium loss in the urine. Spironolactone has the additional benefit of  diminishing the cardiac remodeling that occurs in heart failure. (A complete discussion of diuretics is found in  Chapter 22, p. 257.)   T 2 - Blockers are currently recommended as first-line drug therapy for hypertension when when concomitant disease  is present (see Figure 19.4)a€"for example, with heart failure. These drugs are efficacious but have some  contraindications.   The T 2 - blockers reduce blood pressure primarily by decreasing cardiac output (Figure 19.7). They may also decrease  sympathetic outflow from the central nervous system (CNS) and inhibit the release of renin from the kidneys, thus  decreasing the formation of angiotensin II and the secretion of aldosterone. The prototype l 2 -blocker is propranolol  [proe PRAN-oh- lol] , which acts at both l 2 i and i 2 2 receptors. Selective blockers of i 2 i receptors, such as metoprolol  [met-OH-pro-lol] and atenolol [ ah-TEN-oh- 1 ol ] , are among the most commonly prescribed T 2 - bl ockers. The selective  T 2 - blockers may be administered cautiously to hypertensive patients who also have asthma, for which propranolol is  contraindicated due to its blockade of i 2 2 - mediated bronchodilation. (See p. 220 for a   discussion of the f 2 -blockers). The i 2 -blockers should be employed cautiously in the treatment of patients with  acute heart failure or peripheral vascular disease.   1. Subsets of the hypertensive population: The i 2 -blockers are more effective for treating hypertension in white  than in black patients and in young compared to elderly patients. [Note: Conditions that discourage the use of  T 2 - blockers (for example, severe chronic obstructive lung disease, chronic congestive heart failure, or severe  symptomatic occlusive peripheral vascular disease) are more commonly found in the elderly and in diabetics.]   2. Hypertensive patients with concomitant diseases: The T 2 - blockers are useful in treating conditions that may  coexist with hypertension, such as supraventricular tachyarrhythmia, previous myocardial infarction, angina  pectoris, chronic heart failure, and migraine headache.   The T 2 - blockers are orally active. Propranolol undergoes extensive and highly variable first-pass metabolism. The   T 2 - blockers may take several weeks to develop their full effects.   1. Common effects: The T 2 - blockers may cause bradycardia and CNS side effects such as fatigue, lethargy,  insomnia, and hallucinations; these drugs can also cause hypotension (Figure 19.8). The T 2 - blockers may  decrease libido and cause impotence. [Note: Drug-induced sexual dysfunction can severely reduce patient  compliance.]   2. Alterations in serum lipid patterns: The T 2 -blockers may disturb lipid metabolism, decreasing high-density  lipoprotein cholesterol and increasing plasma triacylglycerol.   3. Drug withdrawal: Abrupt withdrawal may induce angina, myocardial infarction, or even sudden death in  patients with ischemic heart disease. Therefore, the dose of these drugs must be tapered over 2 to 3 weeks in  patients with hypertension and ischemic heart disease.   The ACE inhibitors, such as enalapril [e-NAL-ah-pril] or lisinopril [ lye-SIN-oh- pri I ] , are recommended when the  preferred first-line agents (diuretics or P-blockers) are contraindicated or ineffective. Despite their widespread  use, it is not clear if antihypertensive therapy with ACE inhibitors increases the risk of other maj or diseases.   The ACE inhibitors lower blood pressure by reducing peripheral vascular resistance without reflexively increasing   cardiac output, rate, or contractility. These drugs block the ACE that cleaves angiotensin I to form the potent  vasoconstrictor angiotensin II (Figure 19.9). The converting enzyme is also responsible for the breakdown of  bradykinin. ACE inhibitors decrease angiotensin II and increase bradykinin levels. Vasodilation   occurs as a result of the combined effects of lower vasoconstriction caused by diminished levels of angiotensin II  and the potent vasodilating effect of increased bradykinin. By reducing circulating angiotensin II levels, ACE  inhibitors also decrease the secretion of aldosterone, resulting in decreased sodium and water retention.   Like i 2 -blockers, ACE inhibitors are most effective in hypertensive patients who are white and young. However,  when used in combination with a diuretic, the effectiveness of ACE inhibitors is similar in white and black patients  with hypertension. Along with the angiotensin-receptor blockers, ACE inhibitors slow the progression of diabetic  nephropathy and decrease albuminuria. ACE inhibitors are also effective in the management of patients with  chronic heart failure. ACE inhibitors are a standard in the care of a patient following a myocardial infarction.  Therapy is started 24 hours after the end of the infarction.   Common side effects include dry cough, rash, fever, altered taste, hypotension (in hypovolemic states), and  hyperkalemia (Figure 19. 10). The dry cough, which occurs in about 10 percent of patients, is thought to be due to  increased levels of bradykinin in the pulmonary tree. Potassium levels must be monitored, and potassium  supplements (or a high postasium diets) or potassium-sparing diuretics are contraindicated. Angioedema is a rare but  potentially life-threatening reaction and may also be due to increased levels of bradykinin. Because of the risk of  angioedema and first-dose syncope, ACE inhibitors may be first administered in the physician's office with close  observation. Reversible renal failure can occur in patients with severe bilateral renal artery stenosis. ACE inhibitors  are fetotoxic and should not be used by women who are pregnant.   The angiotensin I la€" receptor blockers (ARBs) are alternatives to the ACE inhibitors. These drugs block the ATI  receptors. Losartan [LOW-sar-tan], is the prototypic ARB; currently, there are six additional ARBs. Their  pharmacologic effects are similar to those of ACE inhibitors in that they produce   arteriolar and venous dilation and block aldosterone secretion, thus lowering blood pressure and decreasing salt and  water retention. ARBs do not increase bradykinin levels. ARBs decrease the nephrotoxicity of diabetes, making them    an attractive therapy in hypertensive diabetics. Their adverse effects are similar to those of ACE inhibitors,  although the risks of cough and angioedema are significantly decreased. ARBs are also fetotoxic. [Note: The ARBs  are discussed more fully in Chapter 16.]   A selective renin inhibitor, aliskiren [a-LIS-ke-rin] has been released for the treatment of hypertension. Aliskiren  directly inhibits renin and, thus, acts earlier in the renin-angiotensin-aldosterone system than ACE inhibitors or  ARBs. It lowers blood pressure about as effectively as ARBs, ACE inhibitors, and thiazides. It can also be combined  other antihypertensives, such diuretics, ACE inhibitors, ARBs, or calcium-channel blockers. Aliskiren can cause  diarrhea, especially at the higher doses. Aliskiren can also cause cough and angioedema but probably less often  than ACE inhibitors. The drug is contraindicated during pregnancy. The combination of maximum doses of aliskiren  and valsartan decreased blood pressure more than maximum doses of either agent alone but not more than would  be expected with dual therapy consisting of agents of different classes. Hyperkalemia was significantly more  common in patients who received both valsartan and aliskiren.   Calcium-channel blockers are recommended when the preferred first-line agents are contraindicated or ineffective.   They are effective in treating hypertension in patients with angina or diabetes. High doses of short-acting calcium-   channel blockers should be avoided because of increased risk of myocardial infarction due to excessive vasodilation   The calcium-channel blockers are divided into three chemical classes, each with different pharmacokinetic   1. Diphenylalkylamines: Verapamil [ver-AP-ah-mil] is the only member of this class that is currently approved in  the United States. Verapamil is the least selective of any calcium-channel blocker and has significant effects on  both cardiac and vascular smooth muscle cells. It is used to treat angina, supraventricular tachyarrhythmias, and  migraine headache.   2. Benzothiazepines: Diltiazem [dil-TYE-ah-zem] is the only member of this class that is currently approved in the  United States. Like verapamil, diltiazem affects both cardiac and vascular smooth muscle cells; however, it has  a less pronounced negative inotropic effect on the heart compared to that of verapamil. Diltiazem has a  favorable side-effect profile.   3. Dihydropyridines: This rapidly expanding class of calcium-channel blockers includes the first-generation  nifedipine [ni-FED-i-peen] and five second-generation agents for treating cardiovascular disease: amlodipine  [am-LOE-di-peen], felodipine [fe-LOE-di-peen], isradipine   [iz-RA-di-peen], nicardipine [nye-KAR-de-peen], and nisoldipine [ ni- SOLD- i- peen ] . These second-generation  calcium-channel blockers differ in pharmacokinetics, approved uses, and drug interactions. All dihydropyridines  have a much greater affinity for vascular calcium channels than for calcium channels in the heart. They are  therefore particularly attractive in treating hypertension. Some of the newer agents, such as amlodipine and  nicardipine, have the advantage that they show little interaction with other cardiovascular drugs, such as  digoxin or warfarin, which are often used concomitantly with calcium-channel blockers.   The intracellular concentration of calcium plays an important role in maintaining the tone of smooth muscle and in  the contraction of the myocardium. Calcium enters muscle cells through special voltage-sensitive calcium channels.   This triggers release of calcium from the sarcoplasmic reticulum and mitochondria, which further increases the  cytosolic level of calcium. Calcium-channel antagonists block the inward movement of calcium by binding to L-type  calcium channels in the heart and in smooth muscle of the coronary and peripheral vasculature. This causes vascular  smooth muscle to relax, dilating mainly arterioles.   Calcium-channel blockers have an intrinsic natriuretic effect and, therefore, do not usually require the addition of  a diuretic. These agents are   useful in the treatment of hypertensive patients who also have asthma, diabetes, angina, and/ or peripheral vascular  disease (Figure 19. 12). Black hypertensives respond well to calcium-channel blockers.   Most of these agents have short half-lives (3a€"8 hours) following an oral dose. Treatment is required three times a  day to maintain good control of hypertension. Sustained-release preparations are available and permit less frequent  dosing. Amlodipine has a very long half-life and does not required a sustained-release formulation.   Constipation occurs in 10 percent of patients treated with verapamil. Dizziness, headache, and a feeling of fatigue  caused by a decrease in blood pressure are more frequent with dihydropyridines (Figure 19. 13). Verapamil should  be avoided in patients with congestive heart failure or with atrioventricular block due to its negative inotropic  (force of cardiac muscle contraction) and dromotropic (velocity of conduction) effects.   Prazosin [PRAY-zo-sin], doxazosin [dox-AH-zoe-sin], and terazosin [ter-AH-zoe-sin] produce a competitive block  of i±L-adrenoceptors. They decrease peripheral vascular resistance and lower arterial blood pressure by causing  relaxation of both arterial and venous smooth muscle. These drugs cause only minimal changes in cardiac output,  renal blood flow, and glomerular filtration rate. Therefore, long-term tachycardia does not occur, but salt and  water retention does. Postural hypotension may occur in some individuals. Prazosin is used to treat mild to  moderate hypertension and is prescribed in combination with propranolol or a diuretic for additive effects. Reflex  tachycardia and first-dose syncope are almost universal adverse effects. Concomitant use of a l 2 -blocker may be  necessary to blunt the short-term effect of reflex tachycardia. An increased rate of congestive heart failure occurs  in patients taking doxazosin alone compared to those taking a thiazide diuretic alone. Because of the side-effect  profile, development of tolerance, and the advent of safer antihypertensives, T±- bl ockers are seldom used in the    treatment of hypertension. Tamsulosin, an aia€"blocker with greater selectivity for prostate muscle, has been used  in the treatment of prostate hyperplasia.   Labetalol [la-BET-ah-lol] and carvedilol [kar-VEH-di-lol] block both ai- and b r and b2- receptors. Carvedilol,  although an effective antihypertensive, is mainly used in the treatment of heart failure. Carvedilol has been shown  to reduce mortality associated with heart failure.   ThisT± 2 -agonist diminishes central adrenergic outflow. Clonidine [KLOE-ni-deen] is used primarily for the treatment  of hypertension that has not responded adequately to treatment with two or more drugs. Clonidine does not  decrease renal blood flow or glomerular filtration and, therefore, is useful in the treatment of hypertension  complicated   by renal disease. Clonidine is absorbed well after oral administration and is excreted by the kidney. Because it may  cause sodium and water retention, clonidine may be administered in combination with a diuretic. Adverse effects  are generally mild, but the drug can produce sedation and drying of the nasal mucosa. Rebound hypertension occurs  following abrupt withdrawal of clonidine. The drug should therefore be withdrawn slowly if the clinician wishes to  change agents.   Thisi+?-agonist is converted to methylnorepinephrine centrally to diminish the adrenergic outflow from the CNS.   This leads to reduced total peripheral resistance and a decreased blood pressure. Cardiac output is not decreased,  and blood flow to vital organs is not diminished. Because blood flow to the kidney is not diminished by its use,  \±-methyldopa [ met h- i 1 1 - DOE- pa] is especially valuable in treating hypertensive patients with renal insufficiency.   The most common side effects of \±-methyldopa are sedation and drowsiness. It has been used in hypertensive  pregnant patients.   The direct-acting smooth muscle relaxants, such as hydralazine and minoxidil, have traditionally not been used as  primary drugs to treat hypertension. Vasodilators act by producing relaxation of vascular smooth muscle, which  decreases resistance and, therefore, blood pressure. These agents produce reflex stimulation of the heart, resulting  in the competing reflexes of increased myocardial contractility, heart rate, and oxygen consumption. These actions  may prompt angina pectoris, myocardial infarction, or cardiac failure in predisposed individuals. Vasodilators also  increase plasma renin concentration, resulting in sodium and water retention. These undesirable side effects can be  blocked by concomitant use of a diuretic and a T 2 - blocker.   This drug causes direct vasodilation, acting primarily on arteries and arterioles. This results in a decreased  peripheral resistance, which in turn prompts a reflex elevation in heart rate and cardiac output. Hydralazine  [hye-DRAL-ah-zeen] is used to treat moderately severe hypertension. It is almost always administered in  combination with a T 2 -blocker, such as propranolol (to balance the reflex tachycardia), and a diuretic (to decrease  sodium retention). Together, the three drugs decrease cardiac output, plasma volume, and peripheral vascular  resistance. Hydralazine monotherapy is an accepted method of controlling blood pressure in pregnancy-induced  hypertension. Adverse effects of hydralazine therapy include headache, tachycardia, nausea, sweating,  arrhythmia, and precipitation of angina. A lupus-like syndrome can occur with high dosage, but it is reversible on  discontinuation of the drug.   This drug causes dilation of resistance vessels (arterioles) but not of capacitance vessels (venules). Minoxidil  [mi-NOX-i-dill] is administered orally for treatment of severe to malignant hypertension that is refractory to other  drugs. Reflex tachycardia and fluid retention may be severe and require the concomitant use of a loop diuretic and  a i 2 -blocker.   Minoxidil causes serious sodium and water retention, leading to volume overload, edema, and congestive heart  failure. [Note: Minoxidil treatment also causes hypertrichosis (the growth of body hair). This drug is now used   Hypertensive emergency is a rare but life-threatening situation in which the DBP is either >150 mm Hg (with SBP  >210 mm Hg) in an otherwise healthy person or >130 mm Hg in an individual with preexisting complications, such as  encephalopathy, cerebral hemorrhage, left ventricular failure, or aortic stenosis. The therapeutic goal is to rapidly  reduce blood pressure.   Nitroprusside [nye-troe-PRUSS-ide] is administered intravenously and causes prompt vasodilation with reflex  tachycardia. It is capable of reducing blood pressure in all patients regardless of the cause of hypertension (Figure  19. 14). The drug has little effect outside the vascular system, acting equally on arterial and venous smooth muscle.  [Note: Because nitroprusside also acts on the veins, it can reduce cardiac preload. ] Nitroprusside is metabolized  rapidly (half-life of minutes) and requires continuous infusion to maintain its hypotensive action. Sodium  nitroprusside exerts few adverse effects except for those of hypotension caused by overdose. Nitroprusside  metabolism results in cyanide ion production. Although cyanide toxicity is rare, it can be effectively treated with an  infusion of sodium thiosulfate to produce thiocyanate, which is less toxic and is eliminated by the kidneys. [Note:  Nitroprusside is poisonous if given orally because of its hydrolysis to cyanide. ] Nitroprusside is light sensitive, and  when in solution, it should be protected from light.    Figure 19.14 Time to peak effect and duration of action for some drugs used in hypertensive emergency.   Labetalol [lah-BET-a-lole] is both an i±- and a T 2 -blocker and is given as an intravenous bolus or infusion in    hypertensive emergencies. Labetalol does not cause reflex tachycardia. Labetalol carries the contraindications of  a nonselective T 2 - blocker. The major limitation is a longer half-life, which precludes rapid titration (see Figure  19. 14)   Fenoldopam [feh-NOL-doh-pam] is a peripheral dopamine-1 receptor agonist that is given as an intravenous  infusion. Unlike other parenteral antihypertensive agents, fenoldopam maintains or increases renal perfusion while  it lowers blood pressure. Fenoldopam can be safely used in all hypertensive emergencies and may be particularly  beneficial in patients with renal insufficiency. The drug is contraindicated in patients with glaucoma.   Nicardipine, a calcium-channel blocker, can be given as an intravenous infusion. The initial dose is 5 mg/ h and can  be increased to a maximum of 15 mg/h. The major limitation of nicardipine in treating hypertensive emergency is  its long half-time (approximately 8 hours), which precludes rapid titration.   19.1 A 45-year-old man has recently been diagnosed with hypertension and started on monotherapy designed  to reduce peripheral resistance and prevent NaCI and water retention. He has developed a persistent cough.  Which of the following drugs would have the same benefits but would not cause cough?    19. 2 Which one of the following drugs may cause a precipitous fall in blood pressure and fainting on initial  administration?    19.3 Which one of the following antihypertensive drugs can precipitate a hypertensive crisis following abrupt  cessation of therapy?    19.4 A 48-year-old hypertensive patient has been successfully treated with a thiazide diuretic for the last 5  years. Over the last 3 months, his diastolic pressure has steadily increased, and he has been started on an  additional antihypertensive medication. He complains of several instances of being unable to achieve an  erection and that he is no longer able to complete three sets of tennis. The second antihypertensive medication  is most likely which one of the following?   >Table of Contents > Unit IV - Drugs Affecting the Cardiovascular System >Chapter 20 - Blood Drugs   This chapter describes drugs that are useful in treating three important dysfunctions of blood: thrombosis, bleeding,  and anemia. Thrombosisa€"the formation of an unwanted clot within a blood vessela€"is the most common  abnormality of hemostasis. Thrombotic disorders include acute myocardial infarction, deep-vein thrombosis,  pulmonary embolism, and acute ischemic stroke. These are treated with drugs such as anticoagulants and  fibrinolytics. Bleeding disorders involving the failure of hemostasis are less common than thromboembolic diseases.   These disorders include hemophilia, which is treated with transfusion of Factor VIII prepared by recombinant DNA  techniques, and vitamin K deficiency, which is treated with dietary supplements of the vitamin. Anemias caused by  nutritional deficiencies, such as the commonly encountered iron-deficiency anemia, can be treated with either  dietary or pharmaceutical supplementation. However, individuals with anemias that have a genetic basis, such as  sickle-cell disease, can benefit from additional treatment. See Figure 20. 1 for a summary of drugs affecting the  blood.   First, a few definitions to clarify the discussion of undesirable blood clots: A clot that adheres to a vessel wall is  called a thrombus, whereas an intravascular clot that floats in the blood is termed an embolus. Thus, a detached  thrombus becomes an embolus. Both thrombi and emboli are dangerous, because they may occlude blood vessels  and deprive tissues of oxygen and nutrients. Arterial thrombosis most often occurs in medium-sized vessels  rendered thrombogenic by surface lesions on endothelial cells caused by atherosclerosis. Arterial thrombosis usually  consists of a platelet-rich clot. In contrast, venous thrombosis is triggered by blood stasis or inappropriate activation  of the coagulation cascade, frequently as a result of a defect in the normal hemostatic defense mechanisms. Venous  thrombosis typically involves a clot that is rich in fibrin, with fewer platelets than are observed with arterial clots.   Physical trauma to the vascular system, such as a puncture or a cut, initiates a complex series of interactions  between platelets, endothelial cells, and the coagulation cascade. This results in the formation of a platelet-fibrin  plug (clot) at the site of the puncture. The creation of an unwanted   thrombus involves many of the same steps as normal clot formation, except that the triggering stimulus is a  pathologic condition in the vascular system rather than an external physical trauma.    Figure 20.1 Summary of drugs used in treating dysfunctions of the blood.   Platelets act as vascular sentries, monitoring the integrity of the endothelium. In the absence of inj ury, resting  platelets circulate freely, because the balance of chemical signals indicates that the vascular system is not damaged  (Figure 20.2).   1. Chemical mediators synthesized by endothelial cells: Chemical mediators, such as prostacyclin and nitric  oxide, are synthesized by intact endothelial cells and act as inhibitors of platelet aggregation. Prostacyclin  (prostaglandin 1 2 ) acts by binding to platelet membrane receptors that are coupled to the synthesis of cyclic  adenosine monophosphate (cAMP; Figure 20. 2)a€"an intracellular messenger. 1 Elevated levels of intracellular  cAMP are associated with a decrease in intracellular Ca 2+ . This leads to inhibition of platelet activation and the  subsequent release of platelet aggregation agents. [Note: The drug dipyridamole inhibits the enzyme  phosphodiesterase, which inactivates cAMP, thus prolonging its active life. ] Damaged endothelial cells  synthesize less prostacyclin, resulting in a localized reduction in prostacyclin levels. The binding of prostacyclin  to platelet receptors is decreased, resulting in lower levels of intracellular cAMP, which leads to platelet  aggregation.   2. Roles of thrombin, thromboxanes, and collagen: The platelet membrane also contains receptors that can bind  thrombin, thromboxanes, 2 and exposed collagen. 3 In the intact, normal vessel, circulating levels of thrombin  and thromboxane are low, and the intact   endothelium covers the collagen in the subendothelial layers. The corresponding platelet receptors are thus  unoccupied and remain inactive; as a result, platelet activation and aggregation are not initiated. Flowever,  when occupied, each of these receptor types triggers a series of reactions leading to the release into the  circulation of intracellular granules by the platelets. This ultimately stimulates platelet aggregation.   When the endothelium is inj ured, platelets adhere to and virtually cover the exposed collagen of the  subendothelium (see Figure 20.2), This triggers a complex series of chemical reactions, resulting in platelet  activation.   Receptors on the surface of the adhering platelets are activated by the collagen of the underlying connective  tissue. This causes morphologic changes in the platelets (Figure 20.3) and the release of platelet granules containing  chemical mediators, such as adenosine diphosphate (ADP), thromboxane A 2 , serotonin, platelet-activation factor,  and thrombin (see Figure 20.2). These signaling molecules bind to receptors in the outer membrane of resting  platelets circulating nearby. These receptors function as sensors that are activated by the signals sent from the  adhering platelets. The previously dormant platelets become activated and start to aggregatea€"actions mediated  by several messenger systems that ultimately result in elevated levels of Ca 2+ and a decreased concentration of  cAMP within the platelet.   The increase in cytosolic Ca 2+ accompanying activation is due to a release of sequestered stores within the platelet  (see Figure 20.2). This leads to 1) the release of platelet granules containing mediators, such   as ADP and serotonin that activate other platelets; 2) activation of thromboxane A 2 synthesis; and 3) activation of  the glycoprotein (GP) lib/ Ilia receptors that bind fibrinogen and, ultimately, regulate platelet-platelet interaction  and thrombus formation (see Figure 20.2). Fibrinogen, a soluble plasma GP, simultaneously binds to GP lib/ Ilia  receptors on two separate platelets, resulting in platelet cross-linking and platelet aggregation. This leads to an  avalanche of platelet aggregation, because each activated platelet can recruit other platelets (Figure 20.4).   Local stimulation of the coagulation cascade by tissue factors released from the inj ured tissue and by mediators on  the surface of platelets results in the formation of thrombin (Factor lla). In turn, thrombina€"a serine  proteasea€"catalyzes the hydrolysis of fibrinogen to fibrin, which is incorporated into the plug. Subsequent cross-  linking of the fibrin strands stabilizes the clot and formsa hemostatic platelet-fibrin plug (see Figure 20.2).   During plug formation, the fibrinolytic pathway is locally activated. Plasminogen is enzymatically processed to  plasmin (fibrinolysin) by plasminogen activators in the tissue (see Figure 20.2). Plasmin limits the growth of the clot  and dissolves the fibrin network as wounds heal. At present, a number of fibrinolytic enzymes are available for  treatment of myocardial infarctions, pulmonary emboli, or ischemic stroke.   Platelet aggregation inhibitors decrease the formation or the action of chemical signals that promote platelet  aggregation. The last step in this response to vascular trauma depends on a family of membrane GP receptors  thata€"after activationa€"can bind adhesive proteins, such as fibrinogen, von Willebrand factor, and fibronectin.  The most important of these is the GP lib/ Ilia receptor that ultimately regulates platelet-platelet interaction and  thrombus formation. Thus, platelet activation agents, such as thromboxane A 2 , ADP, thrombin, serotonin, and  collagen, all promote the conformational change necessary for the GP lib/ Ilia receptor to bind ligands, particularly  fibrinogen. Fibrinogen simultaneously binds to GP Mb/ Ilia receptors on two separate platelets, resulting in platelet  cross-linking and aggregation (see Figure 20.4). The platelet aggregation inhibitors described below inhibit  cyclooxygenase-1 (COX-1) or block GP lib/ Ilia or ADP receptors, thereby interfering in the signals that promote  platelet aggregation. Since these agents have different mechanisms of actions, synergistic or additive effects may  be achieved when agents from different classes are combined. These agents are beneficial in the prevention and  treatment of occlusive cardiovascular diseases, in the maintenance of vascular grafts and arterial patency, and as  adj uncts to thrombin inhibitors or thrombolytic therapy in myocardial infarction.   Stimulation of platelets by thrombin, collagen and ADP results in activation of platelet membrane phospholipases  that liberate arachidonic acid from membrane phospholipids. 4 Arachidonic acid is first converted    to prostaglandin H 2 by COX-1 (Figure 20.5); prostaglandin H 2 isfurther metabolized to thromboxane A 2 , which is  released into plasma. Thromboxane A 2 produced by the aggregating platelets further promotes the clumping process  that is essential to the rapid formation of a hemostatic plug. Aspirin [AS-pir-in] inhibits thromboxane A 2 synthesis  from arachidonic acid in platelets by irreversible acetylation of a serine, resulting in a blockade of arachidonate to  the active site and, thus, inhibition of COX-1 (Figure 20.6). This shifts the balance of chemical mediators to favor  the antiaggregatory effects of prostacyclin, thus impeding platelet aggregation. The inhibitory effect is rapid,  apparently occurring in the portal circulation. The asp/'r/n-induced suppression of thromboxane A 2 synthetase and  the resulting suppression of platelet aggregation last for the life of the anucleate plateleta€"approximately 7 to 10  days. Aspirin is currently employed in the prophylactic treatment of transient cerebral ischemia, to reduce the  incidence of recurrent myocardial infarction, and to decrease mortality in prea€" and posta€" myocardial infarct  patients. The recommended dose of aspirin ranges from 81 to 325 mg, with side effects determining the dose  chosen. Bleeding time is prolonged by aspirin treatment, causing complications that include an increased incidence  of hemorrhagic stroke as well as gastrointestinal bleeding, especially at higher doses of the drug. Aspirin is  frequently used in combination with other drugs having anticlotting propertiesa€"for example, heparin or  dopidogrel. Nonsteroidal anti-inflammatory drugs, such as ibuprofen, inhibit COX-1 by transiently competing at the  catalytic site. Ibuprofen, if taken concomitantly with, or 2 hours prior to aspirin, can obstruct the access of aspirin  to the serine residue and, thereby, antagonize the platelet inhibition by aspirin. Therefore, aspirin should be  taken at least 30 minutes before ibuprofen or at least 8 hours after ibuprofen. Although celecoxib (a selective  COX-2 i nhi bitora€" see Chapter 39) does not interfere in the antiaggregation activity of aspirin, there is some  evidence that it may contribute to cardiovascular events by shifting the balance of chemical mediators in favor of  thromboxane A 2 .   Ticlopidine [ti-KLOE-pi-deen] and clopidogrel (kloh-PID-oh-grel) are closely related thienopyridines that also block   platelet aggregation, but by a mechanism different from that of aspirin.   1. Mechanism of action: These drugs irreversibly inhibit the binding of ADP to its receptors on platelets and, thus,  inhibit the activation of the GP lib/ Ilia receptors required for platelets to bind to fibrinogen and to each other  (Figure 20.7).   2. Therapeutic use: Although ticlopidine and clopidogrel are similar in both structure and mechanism of action,  their therapeutic uses are different. Ticlopidine is approved for the prevention of transient ischemic attacks  and strokes for patients with prior cerebral thrombotic event. It is also used as adj unct therapy with aspirin  following coronary stent implantation to decrease the incidence of stent thrombosis. However, due to its  life-threatening hematologic adverse reactions, including neutropenia/ agranulocytosis, thrombotic  thrombocytopenic purpura (TTP), and aplastic anemia, it is generally reserved for patients who are intolerant to  other therapies. Clopidogrel is approved for prevention of atherosclerotic events following recent myocardial  infarction, stroke, or established peripheral arterial disease. It is also approved for prophylaxis of thrombotic  events in acute coronary syndrome (unstable angina or non-Q-wave   myocardial infarction). Additionally, clopidogrel is used to prevent thrombotic events associated with  percutaneous coronary intervention with or without coronary stent. Compared to ticlopidine, clopidogrel is the    preferred agent in ischemic heart disease events, because there is more data to support use of dopidogrel in  these cardiac patients. Furthermore, dopidogrel has a better overall side-effect profile, although TTP may also  occur with this agent.    3. Pharmacokinetics: Food interferes with the absorption of tidopidine but not with dopidogrel. After oral  ingestion, both drugs are extensively bound to plasma proteins. They undergo hepatic metabolism by the  cytochrome P450 system to active metabolites that are yet to be identified. The maximum effect is achieved in 3  to 5 days; when treatment is suspended, the platelet system requires time to recover. Elimination of the drugs  and metabolites occurs by both the renal and fecal routes. Tidopidine has a black box warning due to the  severe hematologic adverse reactions associated with its use. Both drugs can cause prolonged bleeding for which  there is no antidote. Serious adverse effects of tidopidine include neutropenia, TTP, and aplastic anemia  requiring frequent blood monitoring, especially during the first 3 months of treatment, dopidogrel causes  fewer adverse reactions, and the incidence of neutropenia is lower. Flowever, TTP has been reported as an  adverse effect for both drugs. Because these drugs can inhibit cytochrome P450, they may interfere with the  metabolism of drugs such as phenytoin, tolbutamide, warfarin, fluvastatin, and tamoxifen if taken  concomitantly. Indeed, phenytoin toxicity has been reported when taken with tidopidine.    Abciximab, eptifibatide and  tirofiban block the GP llb/llla  receptor of platelets.   The realization of the key role of the platelet GP llb/llla receptor in stimulating platelet aggregation directed  attempts to block this receptor on activated platelets. This led to the development of a chimeric monoclonal  antibody, abciximab [ab-SIKS-eh-mab], which is composed of the constant regions of human immunoglobulin j oined  to the Fab fragments of a murine monoclonal antibody directed against the GP llb/llla complex. By binding to GP  lib/ Ilia, the antibody blocks the binding of fibrinogen and von Willebrand factor; consequently, aggregation does  not occur (Figure 20.8). Abciximab is given intravenously along with heparin or aspirin as an adj unct to  percutaneous coronary intervention for the prevention of cardiac ischemic complications. After cessation of  infusion, platelet function gradually returns to normal, with the antiplatelet effect persisting for 24 to 48 hours.   The maj or adverse effect of abciximab therapy is the potential for bleeding, especially if the drug is used with  anticoagulants or if the patient has a clinical hemorrhagic condition. Abciximab is expensive, limiting its use in some  settings.   These two antiplatelet drugs act similarly to abc/x/maba€"namely, blocking the GP llb/llla receptor (see Figure  20.8). Eptifibatide [ep-ti-FIB-ih-tide] is a cyclic peptide that binds to GP lib/ Ilia at the site that interacts with the  arginine-glycine-aspartic acid sequence of fibrinogen. Tirofiban [tye-roe-FYE-ban] is not a peptide, but it blocks  the same site as eptifibatide. These compounds, like abciximab, can decrease the incidence of thrombotic  complications associated with acute coronary syndromes. When intravenous infusion is stopped, these agents are  rapidly cleared from the plasma, but their effect can persist for as long as 4 hours. [Note: Only intravenous  formulations are available, because oral preparations   of GP lib/ Ilia blockers are too toxic.] Eptifibatide and its metabolites are excreted by the kidney. Tirofiban is    excreted unchanged by the kidney. The major adverse effect of both drugs is bleeding. Figure 20.9 summarizes the  effects of the GP lib/ II laa€" receptor antagonists on death and myocardial infarction.    Figure 20.9 Effects of glycoprotein (GP) lib/ IllaaC" receptor antagonists on the incidence of death or  nonfatal myocardial infarction following percutaneous transluminal coronary angioplasty. [Note: Data are  from several studies; thus, reported incidence of complications with standard therapy, such as as heparin, is  not the same for each drug.]   Dipyridamole [dye-peer-ID-a-mole], a coronary vasodilator, is employed prophyl act ical ly to treat angina pectoris. It  is usually given in combination with aspirin or warfarin ; it is ineffective when used alone. Dipyridamole increases  intracellular levels of cAMP by inhibiting cyclic nucleotide phosphodiesterase, resulting in decreased thromboxane  A 2 synthesis. It may potentiate the effect of prostacyclin to antagonize platelet stickiness and, therefore, decrease  platelet adhesion to thrombogenic surfaces (see Figure 20.2). The meager data available suggest that dipyridamole  makes only a marginal contribution to the antithrombotic action of aspirin. In combination with warfarin, however,  dipyridamole is effective for inhibiting embolization from prosthetic heart valves.   The coagulation process that generates thrombin consists of two interrelated pathwaysa€"the extrinsic and the  intrinsic systems. The extrinsic system, which is probably the more important system in vivo, is initiated by the  activation of clotting Factor VII by tissue factor, or thromboplastin. Tissue factor is a lipoprotein that is expressed  by activated endothelial cells, activated leukocytes, subendothelial fibroblasts, and subendothelial smooth muscle  cells at the site of vascular inj ury. The intrinsic system is triggered by the activation of clotting Factor XII, following  its contact in vitro with glass or highly charged surfaces. In vivo, this pathway may be initiated by Factor XII contact  with charged cell surfaces containing phospholipids.   Both systems involve a cascade of enzyme reactions that sequentially transform various plasma factors (proenzymes)  to their active (enzymatic) forms. They ultimately produce Factor Xa, which converts prothrombin (Factor II) to  thrombin (Factor lla, Figure 20. 10). Thrombin plays a key role in coagulation, because it is responsible for  generation of fibrin, the GP that forms the mesh-like matrix of the blood clot. If thrombin is not formed or if its  function is impeded (for example, by antithrombin III), coagulation is inhibited. Each step in the activation process  is catalytic; for example, one unit of activated Factor X (Xa) can potentially generate 40 units of thrombin. This will    result in the production of large amounts of fibrin at the site of inj ury.   Each reaction involved with the coagulation cascade takes place at a localized activated cell surface where a  phospholipid-based protein-protein complex has formed. This complex consists of membrane surfaces provided by  phospholipid (primarily phosphatidyl serine) of activated platelets or activated endothelial cells, an enzyme (an  activated coagulation factor), a substrate (the proenzyme form of the downstream coagulation factor), and a  cofactor. Ca 2+ is essential in this process, bridging the anionic phospholipids and i 3 -carboxyglutamic acid residues of  the clotting factors. [Note: Removal of Ca 2+ with calcium chelators such as ethylenediamine tetra-acetic acid or  citrate is used to prevent clotting in a test tube],   It is important that coagulation is restricted to the local site of vascular inj ury. Endogenously, there are several  inhibitors of coagulation factors, including protein C, protein S, antithrombin III, and tissue factor pathway  inhibitor. The mechanism of action of several anticoagulant agents, including heparin and heparin- related  products, involves activation of these endogenous inhibitors (primarily antithrombin III).   The anticoagulant drugs either inhibit the action of the coagulation factors (the thrombin inhibitors, such as  heparin and bepar/'n-related agents) or interfere with the synthesis of the coagulation factors (the vitamin K  antagonists, such as warfarin).   Heparin [HEP-a-rin] is an inj ectable, rapidly acting anticoagulant that is often used acutely to interfere with the  formation of thrombi. Heparin normally occurs as a macromolecule complexed with histamine in mast cells, where  its physiologic role is unknown. It is extracted for commercial use from porcine intestine. Unfractionated heparin is  a mixture of straight-chain, anionic glycosaminoglycans with a wide range of molecular weights (Figure 20.11). It is  strongly acidic because of the presence of sulfate and carboxylic acid groups (Figure 20.12). [Note: In this  discussion, the term heparin will indicate the unfractionated form of the drug.] The realization that low-molecular-  weight forms of heparin (LMWHs) can also act as anticoagulants led to the isolation of enoxaparin [e-NOX-a-par-in],  the first LMWH ( <6000) available in the United States. The LMWHs are heterogeneous compounds (one-third the size  of unfractionated heparin ) produced by the chemical or enzymatic depolymerization of unfractionated heparin.  Because they are free of some of the drawbacks associated with the polymer, they are replacing the use of heparin  in many clinical situations. Heparin is used in the prevention of venous thrombosis and the treatment of a variety of  thrombotic diseases, such as pulmonary embolism and acute myocardial infarction.   Figure 20.11 Typical molecular weight distributions of low-molecular-weight heparins (LMWHs) and  heparin.   Figure 20.12 Disaccharide component of heparin showing negative charges due to carboxyl and sulfate  groups.    1. Mechanism of action: Heparin acts at a number of molecular targets, but its anticoagulant effect is a   consequence of binding to antithrombin III, with the subsequent rapid inactivation of coagulation factors (Figure  20. 13). Antithrombin III is an i±-globulin. It inhibits serine proteases, including several of the clotting  factorsa€"most importantly, thrombin (Factor lla) and Factor Xa (see Figure 20. 10). In the absence of heparin,  antithrombin III interacts very slowly with thrombin and Factor Xa. Heparin molecules bind antithrombin III  inducing a conformational change that accelerates its rate of action about 1000-fold. Heparin also serves as a  catalytic template for the interaction of antithrombin III and the activated coagulation factors. Heparin serves  as a true catalyst, allowing antithrombin III to rapidly combine with and inhibit circulating thrombin and Factor  Xa (Figure 20. 14). In contrast, LMWHs complex with antithrombin III and inactivate Factor Xaa€"including that  located on platelet surf acesa€” but do not bind as avidly to thrombin. Indeed, LMWHs are less likely than heparin  to activate resting platelets. [Note: A unique pentasaccharide sequence contained in heparin and LMWHs  permits their binding to antithrombin III (see Figure 20. 14). ]    2. Therapeutic uses: Heparin and the LMWHs limit the expansion of thrombi by preventing fibrin formation.   Heparin has been the major antithrombotic drug for the treatment of acute deep-vein thrombosis and  pulmonary embolism. The incidence of recurrent thromboembolic episodes is also decreased. Clinically, heparin  is used prophyl act ical ly to prevent postoperative venous thrombosis in patients undergoing elective surgery (for  example, hip replacement) and those in the acute phase of myocardial infarction. Coronary artery rethrombosis  after thrombolytic treatment is reduced with heparin. The drug is also used in extracorporeal devices (for  example, dialysis machines) to prevent thrombosis. Heparin and LMWHs are the anticoagulants of choice for  treating pregnant women with prosthetic heart valves or venous thromboembolism, because these agents do not  cross the placenta (due to their large size and negative charge). Heparin has the advantage of speedy onset of  action, which is rapidly terminated on suspension of therapy. However, it is being supplanted by the LMWHs,  such as enoxaparin and dalteparin, because they can be conveniently injected subcutaneously on a patient  weighta€"adj usted basis, have predictable therapeutic effects, and have a more predictable pharmacokinetic  profile (Figure 20. 15). Specifically, LMWHs do not require the same intense monitoring that heparin needs,  subsequently saving laboratory costs as well as nursing time and costs. Therefore, these advantages make LMWHs  useful for inpatient and outpatient therapy.   a. Absorption: Whereas the anticoagulant effect with heparin occurs within minutes of intravenous   administration (or 1 to 2 hours after subcutaneous injection), the maximum antia€"Factor Xa activity of the  LMWHs occurs about 4 hours after subcutaneous inj ection. (This is in comparison to the vitamin  Ka€"antagonist anticoagulants, such as warfarin, the activity of which requires 8 to 12 hours. ) Heparin must  be given parenteral ly, either in a deep subcutaneous site or intravenously,   because the drug does not readily cross membranes (Figure 20. 16). The LMWHs are administered  subcutaneously. [Note: Intramuscular administration of either agent is contraindicated because of hematoma  formation. ] Heparin is often administered intravenously in a bolus to achieve immediate anticoagulation.   This is followed by lower doses or continuous infusion of heparin for 7 to 10 days, titrating the dose so that  the activated partial thromboplastin time (aPTT) is 1. 5- to 2. 5-fold that of the normal control. It is usually  not necessary to obtain such an index with the LMWHs because the plasma levels and pharmacokinetics of  these drugs are predictable, However, for those patients with renal impairment, the dose should be reduced  to account for decreased renal function.   Figure 20.14 Heparin- and low-molecular-weight heparin (I/WH/aC" mediated inactivation of thrombin or  Factor Xa.    b. Fate: In the blood, heparin binds to many proteins that neutralize its activity, thereby causing resistance to  the drug. Although generally restricted to the circulation, heparin is taken up by the monocyte/ macrophage  system, and it undergoes depolymerization and desulfation to inactive products. [Note: Heparin therefore  has a longer half-life in patients with hepatic cirrhosis. ] The inactive metabolites as well as some of the  parent heparin and LMWHs are excreted into the urine. Therefore, renal insufficiency also prolongs the  half-life. Neither heparin nor the LMWHs cross the placental barrier. The half-life of heparin is  approximately 1. 5 hours, whereas the half-life of the LMWHs is two to four times longer than that of  heparin, ranging from around 3 to 7 hours.   4. Adverse effects: Despite early hopes of fewer side effects with LMWHs, complications have proven to be similar  to those seen with heparin. However, exceptions are thromboembolic problems, which are less common.    a. Bleeding complications: The chief complication of heparin therapy is hemorrhage (Figure 20.17). Careful  monitoring of the bleeding time is required to minimize this problem. Excessive bleeding may be managed by  ceasing administration of the drug or by treating with protamine sulfate. Infused slowly, the latter  combines ionically with heparin to form a stable, 1: 1 inactive complex. It is very important that the dosage  of protamine sulfate is carefully titrated (1 mg for every 100 units of heparin administered) because  heparin sulfate is a weak anticoagulant and excess amounts may trigger bleeding episodes or worsen  bleeding potential.   Figure 20.16 Administration and fate of heparin and low-molecularweight heparins (LMWHs) .    b. Hypersensitivity reactions: Heparin preparations are obtained from porcine sources and, therefore, may be  antigenic. Possible adverse reactions include chills, fever, urticaria, or anaphylactic shock.   c. Thrombosis: Chronic or intermittent administration of heparin can lead to a reduction in antithrombin III  activity, thus decreasing the inactivation of coagulation factors and, thereby, increasing the risk of  thrombosis. To minimize this risk, low-dose heparin therapy is usually employed.    d. Thrombocytopenia: This condition, in which circulating blood contains an abnormally small number of   platelets, is a common abnormality among hospital patients and can be caused by a variety of factors. One of  these is associated with the use of heparin and is called hepar/n-induced thrombocytopenia (HIT). Two  types of this abnormality have been identified. Type I is common and involves a mild decrease in platelet  number due to nonimmunologic mechanisms. Type I usually occurs within the first 5 days of treatment and is  not serious. In Type II, platelets are activated by an immunoglobulin Ga€" mediated reaction with a  heparina€" platelet Factor 4 complex, causing platelet aggregation and release of platelet contents. This can  result in thrombocytopenia and thrombosisa€"dangerous complications of heparin therapy occurring  between the fifth and fourteenth days of treatmenta€"that range from mild to life-threatening. Platelet  counts can drop 50 percent or more, and thromboembolic complications can develop. Although Type II is  relatively rare, the wide use of heparin has resulted in a greater recognition of its role in  thrombocytopenia. It is imperative that heparin therapy be discontinued in such patients. Heparin can be    replaced by another anticoagulant, such as lepirudin or argatroban (see below).   e. Heparin may produce abnormal liver function tests, and osteoporosis has been observed in patients on long  term heparin therapy.   f. Contraindications: Heparin is contraindicated for patients who are hypersensitive to it, have bleeding  disorders, are alcoholics, or are having or have had recent surgery of the brain, eye, or spinal cord.   1. Lepirudin: A highly specific, direct thrombin antagonist, lepirudin [leh-PEE-roo-din] is a polypeptide that is  closely related to hirudina€"a thrombin inhibitor derived from medicinal leech saliva. Lepirudin is produced in  yeast cells by recombinant DNA technology. One molecule of lepirudin binds to one molecule of thrombin,  resulting in blockade of the thrombogenic activity of thrombin. It has little effect on platelet aggregation.  Administered intravenously (Figure 20. 18), lepirudin is effective in the treatment of HIT and other  thromboembolic disorders, and it can prevent further thromboembolic complications. Lepirudin has a half-life  of about 1 hour, and it undergoes hydrolysis. The parent drug and its fragments are eliminated in the urine.  Bleeding is the maj or adverse effect of treatment with lepirudin, and it can be exacerbated by concomitant  thrombolytic therapy, such as treatment with streptokinase or alteplase. About half the patients receiving  lepirudin develop antibodies. However, the drug-antibody complex retains anticoagulant activity. Because renal  elimination of the complex is slower than that of the free drug, the anticoagulant effect may be increased. It is    important to monitor the aPTT and renal function when a patient is receiving lepirudin.   2. Argatroban: Argatroban [ar-GA-troh-ban] is a parenteral anticoagulant that is a small molecule that direct  inhibits thrombin. Argatroban   is used prophyl actical ly for the treatment of thrombosis in patients with HIT, and it is also approved for use  during percutaneous coronary interventions in patients who have or are at risk for developing HIT. Argatroban  is metabolized in the liver and has a half life of about 50 minutes. It is monitored by aPTT. The patient's  hemoglobin and hematocrit must also be monitored. Because argatroban is metabolized in the liver, it may be  used in patients with renal dysfunction but it should be used cautiously in patients with hepatic impairment. As  with other agents in this class, the maj or side effect is bleeding.   3. Fondaparinux: Fondaparinux [fawn-da-PEH-rih-nox] is the first in a new class of pentasaccharide   anticoagulants that is purely synthetically, derived with no variable biologic activity. It has been recently  approved by the U.S. Food and Drug Administration for use in the prophylaxis of deep-vein thrombosis that  could lead to pulmonary embolism in patients undergoing hip fracture surgery, hip replacement surgery, and  knee replacement surgery. This agent selectively inhibits only Factor Xa. By selectively binding to antithrombin  III, fondaparinux potentiates (300- to 1000-fold) the innate neutralization of Factor Xa by antithrombin III. It is  well absorbed from the subcutaneous route with a predictable pharmacokinetic profile. Fondaparinux requires  less monitoring than heparin. Fondaparinux is eliminated in urine mainly as unchanged drug with an elimination  half-life of 17 to 21 hours. It is contraindicated in patients with severe renal impairment ( <30 mL/ min). Bleeding  episodes are the maj or side effect of fondaparinux therapy. Thrombocytopenia, in particular Type II  thrombocytopenia, is not a problem, and this agent may be used in patients with HIT.   ( bishydroxycoumarin ), owe their action to their ability to antagonize the cofactor functions of vitamin K. The only    therapeutically relevant coumarin anticoagulant is warfarin. Initially used as a rodenticide, warfarin is now widely  employed clinically as an oral anticoagulant. With the availability of the LMWHs and platelet aggregate inhibitors,  however, use of the vitamin K antagonists is decreasing. The potential morbidity associated with the use of warfarin  makes it important to identify those patients who are truly at risk for thrombosis. Even careful monitoring to keep  the prothrombin time at 1.5- to 2. 5-fold longer than normal values does not prevent bleeding complications in about  20 percent of the patients.   1. Mechanism of action: Several of the protein coagulation factors (including Factors II, VII, IX, and X; see Figure  20. 10) require vitamin K as a cofactor for their synthesis by the liver. These factors undergo vitamin  Ka€"dependent posttranslational modification, whereby a number of their glutamic acid residues are  carboxylated to form / 3 -carboxyglutamic acid residues (Figure 20. 19). The / 3 -carboxyglutamyl residues bind  calcium ions, which are essential for interaction between the coagulation factors and platelet membranes.   In the carboxylation reactions, the vitamin Ka€"dependent carboxylase fixes CO 2 to form the new COOFI group  on glutamic acid. The reduced vitamin K cofactor is converted to vitamin K epoxide during the reaction. Vitamin  K is regenerated from the epoxide by vitamin K epoxide reductasea€"the enzyme that is inhibited by warfarin.  Warfarin treatment results in the production of clotting factors with diminished activity (10°/ca€"40%of normal),  because they lack sufficient / 3 -carboxyglutamyl side chains. Unlike heparin, the anticoagulant effects of  warfarin are not observed until 8 to 12 hours after drug administration, but peak effects may be delayed for 72  to 96 hoursa€"the time required to deplete the pool of circulating clotting factors. The anticoagulant effects of  warfarin can be overcome by the administration of vitamin K. Flowever, reversal following administration of  vitamin K takes approximately 24 hours (the time necessary for degradation of already synthesized clotting  factors).   Figure 20.19 Mechanism of action of warfarin. NADP+ = oxidized form of nicotinamide-adenine  dinucleotide phosphate; NADPH = reduced form of nicotinamide-adenine dinucleotide phosphate.    2. Therapeutic uses: Warfarin is used to prevent the progression or recurrence of acute deep-vein thrombosis or  pulmonary embolism after initial heparin treatment. It is also used for the prevention of venous  thromboembolism during orthopaedic or gynecologic surgery. Prophylactically, it is used in patients with acute  myocardial infarction, prosthetic heart valves, or chronic atrial fibrillation.   a. Absorption: Warfarin is rapidly absorbed after oral administration ( 100% bi oavai labi I ity with little individual  patient variation). Although food may delay absorption, it does not affect the extent of absorption of the  drug. Warfarin is 99 percent bound to plasma albumin, which prevents its diffusion into the cerebrospinal  fluid, urine, and breast milk. However, drugs that have a greater affinity for the albumin binding site, such  as sulfonamides, can displace the anticoagulant and lead to a transient, elevated activity. Warfarin readily  crosses the placental barrier. The mean half life of warfarin is approximately 40 hours, but this value is  highly variable among individuals. Prothrombin time, a measure of the extrinsic pathway, may be used to  monitor warfarin therapy. In the 1990s, the international normalized ratio (INR) was adopted to monitor  warfarin concentration. The INR corrects for variations that would occur with different thromboplastin  reagents, between different hospitals, or when a single hospital gets a new lot of reagent. The goal of  warfarin therapy is an INR of 2 to 3 for most indications and 2.5 to 3.5 in patients with mechanical heart  valves.   b. Fate: The products of warfarin metabolism, catalyzed by the cytochrome P450 system, are inactive. After  conj ugation to glucuronic acid, they are excreted in the urine and stool.    a. Bleeding disorders: The principal untoward reaction caused by warfarin treatment is hemorrhage.   Therefore, it is important to frequently monitor and adj ust the anticoagulant effect. Minor bleeding may be  treated by withdrawal of the drug and administration of oral vitamin Ki; severe bleeding requires that  greater doses of the vitamin be given intravenously. Whole blood, frozen plasma, or plasma concentrates of  the blood factors may also be employed to arrest hemorrhaging. Skin lesions   and necrosis are rare complications of warfarin therapy and are observed primarily in women. Purple toe  syndrome, a painful, blue-tinged discoloration of the toe caused by cholesterol emboli from plaques, has  also been observed with warfarin therapy.   b. Drug interactions: Warfarin has numerous drug interactions that may potentiate or attenuate its  anticoagulant effect. The list of interacting drugs is extensive. A summary of some of the important  interactions is shown in Figure 20.20.   c. Disease states: Vitamin K deficiency, hepatic disease that impairs synthesis of the clotting factors or affects  warfarin metabolism, and hypermetabolic states that increase catabolism of the vitamin Ka€"dependent  clotting factors can all influence the hypoprothrombinemic state of the patient and augment the response to  the oral anticoagulants.   d. Contraindications: Warfarin should never be used during pregnancy, because it is teratogenic and can  cause abortion as well as birth defects.   Acute thromboembolic disease in selected patients may be treated by the administration of agents that activate the  conversion of plasminogen to plasmina€"a serine protease that hydrolyzes fibrin and, thus, dissolves clots (Figure  20.21). Streptokinase, one of the first such agents to be approved, causes a systemic fibrinolytic state that can lead  to bleeding problems. Aitepiase acts more locally on the thrombotic fibrin to produce fibrinolysis. Figure 20.22  compares these commonly used thrombolytic agents. Clinical experience has shown nearly equal efficacy between  streptokinase and aitepiase. Unfortunately, thrombolytic therapy is unsuccessful in about 20 percent of infarcted  arteries, and about 15 percent of the arteries that are opened will later close again. In the case of acute myocardial  infarction, the thrombolytic drugs are reserved for those instances when angioplasty is not an option or until the  patient can be taken to a facility that performs percutaneous coronary interventions. Fibrinolytic drugs may lyse  both normal and pathologic thrombi.   1. Mechanism of action: The thrombolytic agents share some common features. All act either directly or indirectly  to convert plasminogen to plasmin, which in turn cleaves fibrin, thus lysing thrombi (see Figure 20.21). Clot  dissolution and reperfusion occur with a higher frequency when therapy is initiated early after clot formation,  because clots become more resistant to lysis as they age. Unfortunately, increased local thrombi may occur as  the clot dissolves, leading to enhanced platelet aggregability and thrombosis. Strategies to prevent this include  administration of antiplatelet drugs, such as aspirin, or antithrombotics, such as heparin.    2. Therapeutic uses: Originally used for the treatment of deep-vein thrombosis and serious pulmonary embolism,  thrombolytic drugs are now being used less frequently for these conditions. Their   tendency to cause bleeding has also blunted their used in treating acute myocardial infarction or peripheral  arterial thrombosis. However, thrombolytic agents are helpful in restoring catheter and shunt function, by lysing  clots causing occlusions. Thrombolytic agents are also used to dissolve clots that result in strokes.   3. Pharmacokinetics: For myocardial infarction, intracoronary delivery of the drugs is the most reliable in terms of  achieving recanalization. However, cardiac catheterization may not be possible in the 2- to 6-hour  a€oetherapeutic window, a€^ beyond which significant myocardial salvage becomes less likely. Thus,  thrombolytic agents are usually administered intravenously, because this route is rapid, is inexpensive, and does  not have the risks of catheterization.    4. Adverse effects: The thrombolytic agents do not distinguish between the fibrin of an unwanted thrombus and  the fibrin of a beneficial hemostatic plug. Thus, hemorrhage is a maj or side effect. For example, a previously  unsuspected lesion, such as a peptic ulcer, may hemorrhage following inj ection of a thrombolytic agent (Figure  20.23). These drugs are contraindicated in patients with healing wounds, pregnancy, history of cerebrovascular  accident, or metastatic cancer. Continued presence of thrombogenic stimuli may cause rethrombosis after lysis  of the initial clot.   Alteplase [AL-te-place] (formerly known astlssue plasminogen activator, or tPA) is a serine protease originally  derived from cultured human melanoma cells. It is now obtained as a product of recombinant DNA technology.   1. Mechanism of action: Alteplase has a low affinity for free plasminogen in the plasma, but it rapidly activates  plasminogen that is bound to fibrin in a thrombus or a hemostatic plug. Thus, alteplase is said to be a€oefibrin  selective, a€^ and at low doses, it has the advantage of lysing only fibrin, without unwanted degradation of    other proteinsa€"notably fibrinogen. This contrasts with streptokinase, which acts on free plasminogen and  induces a general fibrinolytic state. [Note: At dose levels of alteplase currently in use clinically, circulating  plasminogen may be activated, resulting in hemorrhage.]   2. Therapeutic uses: Alteplase is approved for the treatment of myocardial infarction, massive pulmonary  embolism, and acute ischemic stroke. Alteplase seems to be superior to streptokinase in dissolving older clots  and, ultimately, may be approved for other applications. Alteplase, administered within 3 hours of the onset of  ischemic stroke, significantly improves clinical outcomea€"that is, the patient's ability to perform activities of  daily living (Figure 20.24). Reteplase (Retavase) is similar to alteplase and can be used as an alternative.   3. Pharmacokinetics: Alteplase has a very short half-life (about 5 minutes) and, therefore, is administered as a  total dose equal to 0.9 mg/ kg. Ten percent of the total dose injected intravenously as a bolus and the remaining  drug is administered over 60 minutes.   4. Adverse effects: Bleeding complications, including gastrointestinal and cerebral hemorrhages, may occur.   Streptokinase [strep-toe-KYE-nase] is an extracellular protein purified from culture broths of Group C l 2 -hemolytic  streptococci. 6    1. Mechanism of action: Streptokinase has no enzymic activity. Instead, it forms an active one-to-one complex  with plasminogen. This enzymatically active complex converts uncomplexed plasminogen to the active enzyme  plasmin (Figure 20.25). In addition to the hydrolysis of fibrin plugs, the complex also catalyzes the degradation  of fibrinogen as well as clotting FactorsV and VII (Figure 20.26).   2. Therapeutic uses: Streptokinase is approved for use in acute pulmonary embolism, deep-vein thrombosis,  acute myocardial infarction, arterial thrombosis, and occluded access shunts.   3. Pharmacokinetics: Streptokinase therapy is instituted within 4 hours of a myocardial infarction and is infused  for 1 hour. Its half-life is less than half an hour. Thromboplastin time is monitored and maintained at two- to  five-fold the control value. On discontinuation of treatment, either heparin or oral anticoagulants may be  administered.   a. Bleeding disorders: Activation of circulating plasminogen by streptokinase leads to elevated levels of  plasmin, which may precipitate bleeding by dissolving hemostatic plugs (see Figure 20.23). In the rare  instance of life-threatening hemorrhage, aminocaproic acid may be administered.    b. Hypersensitivity: Streptokinase is a foreign protein and is antigenic. Rashes, fever, and rarely, anaphylaxis  occur. Because most individuals have had a streptococcal infection sometime in their lives, circulating  antibodies against streptokinase are likely to be present in most patients. These antibodies can combine  with streptokinase and neutralize its fibrinolytic properties. Therefore, sufficient quantities of  streptokinase must be administered to overwhelm the antibodies and provide a therapeutic concentration  of plasmin. Fever, allergic reactions, and therapeutic failure may be associated with the presence of  antistreptococcal antibodies in the patient. The incidence of allergic reactions is approximately 3 percent.   Anistreplase is a preformed complex of streptokinase and plasminogen and it is considered to be a prodrug.  Streptokinase must be released, and only plasminogen to which it was associated will get converted to plasmin.    Figure 20.24 Outcome at 12 months of stroke patients treated with alteplase within 3 hours of the onset of  symptoms compared to those treated with placebo.   Bleeding problems may have their origin in naturally occurring pathologic conditions, such as hemophilia, or as a  result of fibrinolytic states that may arise after gastrointestinal surgery or prostatectomy. The use of anticoagulants  may also give rise to hemorrhage. Certain natural proteins and vitamin K, as well as synthetic antagonists, are  effective in controlling this bleeding. For example, hemophilia is a consequence of a deficiency in plasma  coagulation factors, most frequently Factors VIII and IX. Concentrated preparations of these factors are available  from human donors. Flowever, these preparations carry the risk of transferring viral infections. Blood transfusion is  also an option for treating severe hemorrhage.   Fibrinolytic states can be controlled by the administration of aminocaproic [a-mee-noe-ka-PROE-ic] acid or  tranexamic [tran-ex-AM-ic] acid. Both agents are synthetic, inhibit plasminogen activation, are orally active, and  are excreted in the urine. A potential side effect of treatment is intravascular thrombosis.   Protamine [PROE-ta-meen] sulfate antagonizes the anticoagulant effects of heparin. This protein is derived from  fish sperm or testes and is high in arginine content, which explains its basicity. The positively charged protamine  interacts with the negatively charged heparin, forming a stable complex without anticoagulant activity. Adverse  effects of drug administration include hypersensitivity as well as dyspnea, flushing, bradycardia, and hypotension  when rapidly injected.   That vitamin Ki (phytonadione) administration can stem bleeding problems due to the oral anticoagulants is not  surprising, because those substances act by interfering with the action of the vitamin (see Figure 20. 19). The  response to vitamin K is slow, requiring about 24 hours (time to synthesize new coagulation factors). Thus, if  immediate hemostasis is required, fresh-frozen plasma should be infused.   Aprotinin [ah-PRO-ti-nin] is a serine protease inhibitor that stops bleeding by blocking plasmin. It can inhibit  streptokinase. It is approved for prophylactic use to reduce perioperative blood loss and the need for blood    transfusion in patients undergoing cardiopulmonary bypass surgery. Aprotinin may cause renal dysfunction and  hypersensitivity (anaphylactic) reactions. In addition, aprotinin should not be administered to patients who have  already been exposed to the drug within the previous 12 months due to the possibility of anaphylactic reactions.   Anemia is defined as a below-normal plasma hemoglobin concentration resulting from a decreased number of  circulating red blood cells or an abnormally low total hemoglobin content per unit of blood volume. Anemia can be  caused by chronic blood loss, bone marrow abnormalities, increased hemolysis, infections, malignancy, endocrine  deficiencies, renal failure, and   a number of other disease states. Anemia can be at least temporarily corrected by transfusion of whole blood. A  large number of drugs cause toxic effects on blood cells, hemoglobin production, or erythropoietic organs, which in  turn may cause anemia. In addition, nutritional anemias are caused by dietary deficiencies of substances such as  iron, folic acid, or vitamin B12 (cyanocobalamin) that are necessary for normal erythropoiesis.   Iron is stored in intestinal mucosal cells as ferritin (an iron-protein complex) until needed by the body. Iron  deficiency results from acute or chronic blood loss, from insufficient intake during periods of accelerated growth in  children, or in heavily menstruating or pregnant women. Thus, iron deficiency results from a negative iron balance  due to depletion of iron stores and/or inadequate intake, culminating in hypochromic microcytic anemia (due to low  iron and small-sized red blood cells). Supplementation with ferrous sulfate is required to correct the deficiency.  Gastrointestinal disturbances caused by local irritation are the most common adverse effects of iron supplements.   The primary use of folic acid is in treating deficiency states that arise from inadequate levels of the vitamin. Folate  deficiency may be caused by 1 ) increased demand (for example, pregnancy and lactation), 2 ) poor absorption  caused by pathology of the small intestine, 3 ) alcoholism, or 4 ) treatment with drugs that are dihydrofolate  reductase inhibitors (for example, methotrexate or trimethoprim). A primary result of folic acid deficiency is  megaloblastic anemia (large-sized red blood cells), which is caused by diminished synthesis of purines and  pyrimidines. This leads to an inability of erythropoietic tissue to make DNA and, thereby, proliferate 7 (Figure  20 . 27 ). [Note: To avoid neurological complications of vitamin B12 deficiency, it is important to evaluate the basis of  the megaloblastic anemia prior to instituting therapy. Vitamin B12 and folate deficiency causes similar symptoms (see  below). ] Folic acid is well absorbed in the jej unum unless pathology is present. If excessive amounts of the vitamin  are ingested, they are excreted in the urine and feces. Oral folic acid administered has no known toxicity.   Deficiencies of vitamin B12 can result from either low dietary levels or, more commonly, poor absorption of the  vitamin due to the failure of gastric parietal cells to produce intrinsic factor (as in pernicious anemia) or a loss of  activity of the receptor needed for intestinal uptake of the vitamin . 8 Intrinsic factor is a GP produced by the  parietal cells of the stomach and it is required for vitamin B12 absorption. In patients with bariatric surgery (surgical  gastrointestinal treatment for obesity), vitamin B12 supplementation is required in large oral doses, sublingually or  once a month by the parenteral route. Nonspecific malabsorption syndromes or gastric resection can also cause  vitamin B12 deficiency. The vitamin may be administered orally (for dietary deficiencies), intramuscularly,   or deep subcutaneously (for pernicious anemia). [Note: Folic acid administration alone reverses the hematologic  abnormality and, thus, masks the B12 deficiency, which can then proceed to severe neurologic dysfunction and  disease. Therefore, megaloblastic anemia should not be treated with folic acid alone but, rather, with a  combination of folate and vitamin B12. ] Therapy must be continued for the remainder of the life of a patient  suffering from pernicious anemia. There are no known adverse effects of this vitamin.   Erythropoietin [ee-rith-ro-POI-eh-tin] is a GP, normally made by the kidney, that regulates red blood cell  proliferation and differentiation in bone marrow. Human erythropoietin, produced by recombinant DNA  technology, is effective in the treatment of anemia caused by end-stage renal disease, anemia associated with  human immunodeficiency virus infection, and anemia in some cancer patients. Darbepoetin [dar-be-POE-e-tin] is a  long-acting version of erythropoietin that differs from erythropoietin by the addition of two carbohydrate chains,  which improves its biologic activity. Therefore, darbepoetin has decreased clearance and has a half life about three  times that of erythropoietin. Due to its delayed onset of action, darbepoetin has no value in acute treatment of  anemia. Supplementation with iron may be required to assure an adequate response. The protein is usually  administered intravenously in renal dialysis patients, but the subcutaneous route is preferred. Side effects are  generally well tolerated but may include elevation in blood pressure and arthralgia in some cases. [Note: The former  may be due to increases in peripheral vascular resistance and/ or blood viscosity. ] When erythropoietin is used to  target hemoglobin concentration >12 g / dL, serious and life-threatening cardiovascular events, increased risk of  death, shortened time to tumor progression and/or decreased survival have been observed. The recommendations  for all patients receiving erythropoietin include a minimum effective dose that does not exceed a hemoglobin level  of 12 g / dL, and this should not rise more than 1 g/ dL over a 2- week period.   Figure 20.28 Effect of treatment with hydroxyurea on the percentage of sickle-cell patients experiencing  first painful episode.   Clinical trials have shown that hydroxyurea can relieve the painful clinical course of sickle-cell disease (Figure  20.28). Hydroxyurea is currently also being used to treat chronic myelogenous leukemia and polycythemia vera. In  sickle-cell disease, the drug apparently increases fetal hemoglobin levels, thus diluting the abnormal hemoglobin S  (HbS). 9 This process takes several months. Polymerization of HbS is delayed in the treated patients so that painful    crises are not caused by sickled cells blocking capillaries and causing tissue anoxia. Important side effects of  hydroxyurea include bone marrow suppression and cutaneous vasculitis. It is important that hydroxyurea is  administered under the supervision of a physician experienced in the treatment of sickle-cell disease.   20. 1 A 22-year-old woman who experienced pain and swelling in her right leg presented at the emergency  room. An ultrasound study showed thrombosis in the popliteal vein. The patient, who was in her second  trimester of pregnancy, was treated for 7 days with intravenous unfractionated heparin. The pain resolved  during the course of therapy, and the patient was discharged on Day 8. Which one of the following drugs would  be most appropriate out-patient follow-up therapy for this patient, who lives 100 miles from the nearest  hospital?    20. 2 A 60-year-old man is diagnosed with deep-vein thrombosis. The patient was treated with a bolus of  heparin, and a heparin drip was started. One hour later, he was bleeding profusely from the intravenous site.  The heparin therapy was suspended, but the bleeding continued. Protamine was administered intravenously,  and the bleeding resolved. The protamine:    20.3 A 54-year-old male with a prosthetic aortic valve replacement complained to his family physician of black  and tarry stools. Physical examination and vital signs were unremarkable except for subconjunctival  hemorrhages and bleeding gums. Stools tested positive for heme, and hematuria was observed. The patient has  been receiving oral warfarin since his valve replacement 1 year earlier. Prothrombin time was found to be  significantly elevated. Which one of the following therapies would provide the most rapid recovery from the  observed bleeding secondary to warfarin treatment?   >Table of Contents > Unit IV - Drugs Affecting the Cardiovascular System >Chapter 21 - Hyperlipidemias   Coronary heart disease (CHD) is the cause of about half of all deaths in the United States. The incidence of CHD is  correlated with elevated levels of low-density lipoprotein (LDL) cholesterol and triacylglycerols and with low levels  of high-density lipoprotein (HDL) cholesterol. Other risk factors for CHD include cigarette smoking, hypertension,  obesity, and diabetes. Cholesterol levels may be elevated as a result of an individual's lifestyle (for example, by lack  of exercise and consumption of a diet containing excess saturated fatty acids). Hyperlipidemias can also result from  a single inherited gene defect in lipoprotein metabolism or, more commonly, from a combination of genetic and  lifestyle factors. Appropriate lifestyle changes in combination with drug therapy can lead to a decline in the  progression of coronary plaque, regression of preexisting lesions, and reduction in mortality due to CHD by 30 to 40  percent. Antihyperlipidemic drugs must be taken indefinitely; when therapy is terminated, plasma lipid levels return  to pretreatment levels. The lipid-lowering drugs are listed in Figure 21.1. Figure 21.2 illustrates the normal  metabolism of serum lipoproteins and the characteristics of the major genetic hyperlipidemias.   Plasma lipids consist mostly of lipoproteinsaC" spherical macromolecular complexes of lipids and specific proteins  (apolipoproteins). The clinically important lipoproteins, listed in decreasing order of atherogenicity, are LDL,  very-low-density lipoprotein (VLDL) and chylomicrons, and HDL. The occurrence of CHD is positively associated with  high total cholesterol, and even more strongly with elevated LDL cholesterol in the blood. In contrast to LDL  cholesterol, high levels of HDL cholesterol have been associated with a decreased risk for heart disease (Figure  21.3). Reduction of the LDL level is the primary goal of cholesterol-lowering therapy. Figure 21.4 shows the current  goals in the treatment of hyperlipidemia. Recommendations for the reduction of LDL cholesterol to specific target  levels are influenced by the coexistence of CHD and the number of other cardiac risk factors. The higher the overall  risk of heart disease, the more aggressive the recommended LDL-lowering therapy.   In patients with moderate hyperlipidemia, lifestyle changes, such as diet, exercise, and weight reduction, can lead  to modest decreases in LDL levels and increases in HDL levels. However, most patients are   unwilling to modify their lifestyle sufficiently to achieve LDL treatment goals, and drug therapy may be required.   Patients with LDL levels higher than 160 mg/ dL and with one other maj or risk factor, such as hypertension,  diabetes, smoking, or a family history of early CHD, are candidates for drug therapy. Patients with two or more  additional risk factors should be treated aggressively, with the aim of reducing their LDL level to less than 100  mg/ dL and, in some patients, to as low as 70 mg/ dL.    Figure 21.1 Summary of antihyperlipidemic drugs. HMG CoA =3-hydroxy-3- methylglutaryl coenzyme A.    Figure 21.2 Metabolism of plasma lipoproteins and related genetic diseases. Roman numerals in the white  circles refer to specific genetic types of hyperlipidemias summarized on the facing page. CM =chylomicron,  TG =triacylglycerol; VLDL =very-low density lipoprotein, LDL =low-density lipoprotein, IDL intermediate-  density lipoprotein, apo Cll = apol i poprotei n Cll found in chylomicrons and VLDL.   Elevated triacylglycerol (triglyceride) levels are independently associated with increased risk of CHD. Diet and  exercise are the primary modes of treating hypertriacylglycerolemia. If indicated, niacin and fibric acid derivatives  are the most efficacious in lowering triacylglycerol levels. Triacylglycerol reduction is a secondary benefit of the  statin drugs (the primary benefit being LDL cholesterol reduction). [Note: The major lipid component of VLDL is  composed of triacylglycerol.]    Figure 21.3 Effect of circulating LDL and HDL on the risk of coronary heart disease (CHD).   Antihyperlipidemic drugs target the problem of elevated serum lipids with complementary strategies. Some of these  agents decrease production of the lipoprotein carriers of cholesterol and triglyceride, whereas others increase the  degradation of lipoprotein. Still others decrease cholesterol absorption or directly increase cholesterol removal  from the body. These drugs may be used singly or in combination. However, they are always accompanied by the  requirement that dietary saturated and transfats 1 be low, and the caloric content of the diet must be closely  monitored.   3-Hydroxy- 3- met hyl gl utaryl (HMG) coenzyme A (COA) reductase inhibitors (commonly known as statins) lower  elevated LDL cholesterol levels, resulting in a substantial reduction in coronary events and death from CHD. This  group of antihyperlipidemic agents inhibits the first committed enzymatic step of cholesterol synthesis, and they  are the first-line and more effective treatment for patients with elevated LDL cholesterol. Therapeutic benefits  include plaque stabilization, improvement of coronary endothelial function, inhibition of platelet thrombus  formation, and anti-inflammatory activity. The value of lowering the level of cholesterol with statin drugs has now  been demonstrated in 1) patients with CHD with or without hyperlipidemia, 2) men with hyperlipidemia but no  known CHD, and 3) men and women with average total and LDL cholesterol levels and no known CHD.   a. Inhibition of HMG CoA reductase: Lovastatin [LOE-vah-stat-in] simvastatin [sim-vah-STAT-in], pravastatin  [PRAH-vah-stat-in], atorvastatin (a-TOR-vah-stat-in), fiuvastatin [FLOO-vah-stat-in], and rosuvastatin  [roe-SOO-va-sta-tin] are analogs of HMG, the precursor of cholesterol. Lovastatin and simvastatin are  lactones that are hydrolyzed to the active drug. Pravastatin and fiuvastatin are active as such. Because of  their strong affinity for the enzyme, all compete effectively to inhibit HMG CoA reductase, the rate-limiting  step in cholesterol synthesis. By inhibiting de novo cholesterol synthesis, they deplete the intracellular  supply of cholesterol (Figure 21.5). Rosuvastatin and atorvastatin are the most potent LDL  cholesterola€"lowering statin drugs, followed by simvastatin, pravastatin and then lovastatin and  fiuvastatin.   b. Increase in LDL receptors: Depletion of intracellular cholesterol causes the cell to increase the number of  specific cell-surface LDL receptors that can bind and internalize circulating LDLs. Thus, the end result is a  reduction in plasma cholesterol, both by lowered cholesterol synthesis and by increased catabolism of LDL.  [Note: Because these agents undergo a marked first-pass extraction by the liver, their dominant effect is on  that organ. ] The HMG CoA reductase inhibitors, like the bile acid sequestrant cholestyramine, can increase  plasma HDL levels in some patients, resulting in an additional lowering of risk for CHD. Decreases in    2. Therapeutic uses: These drugs are effective in lowering plasma cholesterol levels in all types of hyperlipidemias  (Figure 21.6). However, patients who are homozygous for familial hypercholesterolemia lack LDL receptors and,  therefore, benefit much less from treatment with these drugs. [Note: These drugs are often given in  combination with other antihyperlipidemic drugs; see below.] It should be noted that in spite of the protection  afforded by cholesterol lowering, about one-fourth of the patients treated with these drugs still present with  coronary events. Thus, additional strategies, such as diet, exercise, or additional agents, may be warranted.   3. Pharmacokinetics: Pravastatin and fluvastatin are almost completely absorbed after oral administration; oral  doses of lovastatin and simvastatin are from 30 to 50 percent absorbed. Similarly, pravastatin   and fluvastatin are active as such, whereas lovastatin and simvastatin must be hydrolyzed to their acid forms.   Due to first-pass extraction, the primary action of these drugs is on the liver. All are biotransformed, with some  of the products retaining activity. Excretion takes place principally through the bile and feces, but some urinary  elimination also occurs. Their half-lives range from 1. 5 to 2 hours. Some characteristics of the statins are  summarized in Figure 21.7.    Increased number  of LDL receptors  promotes uptake  of LDL from blood.    Statins Inhibit HMG CoA reductase,  leading to a decreased concentration  of cholesterol within the cell.    Figure 21.5 Inhibition of HMG CoA reductase by the statin drugs.    4. Adverse effects: It is noteworthy that during the 5-year trials of simvastatin and lovastatin, only a few adverse  effects, related to liver and muscle function, were reported (Figure 21.8).    a. Liver: Biochemical abnormalities in liver function have occurred with the HMG CoA reductase inhibitors.  Therefore, it is prudent to evaluate liver function and measure serum transaminase levels periodically.  These return to normal on suspension of the drug. [Note: Hepatic insufficiency can cause drug  accumulation.]   b. Muscle: Myopathy and rhabdomyolysis (disintegration or dissolution of muscle) have been reported only    rarely. In most of these cases, patients usually suffered from renal insufficiency or were taking drugs such as  cyclosporine, itraconazole, erythromycin, gemfibrozil, or niacin. Plasma creatine kinase levels should be  determined regularly.    Figure 21.6 Effect of simvastatin on serum lipids of 130 patients with Type 2 diabetes treated for 6  weeks. HDL = high-density lipoprotein; LDL =low-density lipoprotein; TG =triacyglycerol.    Figure 21.7 Summary of 3-hydroxy- 3- methylglutaryl coenzyme (HMG CoA) reductase inhibitors.    c. Drug interactions: The HMG CoA reductase inhibitors may also increase warfarin levels. Thus, it is  important to evaluate INR times frequently.    d. Contraindications: These drugs are contraindicated during pregnancy and in nursing mothers. They should  not be used in children or teenagers.   Niacin * 2 3 [NYE-a-sin] can reduce LDL (the a€oebada€'- : cholesterol carrier) levels by 10 to 20 percent and is the most  effective agent for increasing HDL (the a€oegooda€^ cholesterol carrier) levels. Niacin can be used in combination  with statins, and a fixed-dose combination of lovastatin and long-acting niacin is available.   1. Mechanism of action: At gram doses, niacin strongly inhibits lipolysis in adipose tissuea€"the primary producer  of circulating free fatty acids. The liver normally utilizes these circulating fatty acids as a maj or precursor for  triacylglycerol synthesis. Thus, niacin causes a decrease in liver triacylglycerol synthesis, which is required for  VLDL production (Figure 21.9). LDL (the cholesterol-rich lipoprotein) is derived from VLDL in the plasma.  Therefore, a reduction in the VLDL concentration also results in a decreased plasma LDL concentration. Thus,  both plasma triacylglycerol (in VLDL) and cholesterol (in VLDL and LDL) are lowered (Figure 21.10).  Furthermore, niacin treatment increases HDL cholesterol levels. Moreover, by boosting secretion of tissue  plasminogen activator and lowering the level of plasma fibrinogen, niacin can reverse some of the endothelial  cell dysfunction contributing to thrombosis associated with hypercholesterolemia and atherosclerosis.    Figure 21.8 Some adverse effects and precautions associated with 3-hydroxy- 3- methylglutaryl coenzyme  (HMG CoA) reductase inhibitors.   2. Therapeutic uses: Niacin lowers plasma levels of both cholesterol and triacylglycerol. Therefore, it is  particularly useful in the treatment of familial hyperlipidemias. Niacin is also used to treat other severe  hypercholesterolemias, often in combination with other antihyperlipidemic agents. In addition, it is the most  potent antihyperlipidemic agent for raising plasma H DL levels, which is the most common indication for its  clinical use.    3. Pharmacokinetics: Niacin is administered orally. It is converted in the body to nicotinamide, which is   incorporated into the cofactor nicotinamide-adenine dinucleotide (NAD 4 ). Niacin, its nicotinamide derivative,  and other metabolites are excreted in the urine. [Note: Nicotinamide alone does not decrease plasma lipid  levels. ]   4. Adverse effects: The most common side effects of niacin therapy are an intense cutaneous flush (accompanied  by an uncomfortable feeling of warmth) and pruritus. Administration of aspirin prior to taking niacin decreases  the flush, which is prostaglandin mediated. The sustained-release formulation of niacin, which is taken once  daily at bedtime, reduces bothersome initial adverse effects. Some patients also experience nausea and  abdominal pain. Niacin inhibits tubular secretion of uric acid and, thus, predisposes to hyperuricemia and gout.  Impaired glucose tolerance and hepatotoxicity have also been reported.   Figure 21.9 Niacin inhibits lipolysis in adipose tissue, resulting in decreased hepatic VLDL synthesis and  production of LDLs in the plasma.   Fenofibrate [fen-oh-FIH-brate] and gemfibrozil [ j em- FI- broh-zi 1 1 ] are derivatives of fibric acid that lower serum  triacylglycerols and increase H DL levels. Both have the same mechanism of action. Flowever, fenofibrate is more  effective than gemfibrozil in lowering plasma LDL cholesterol and triglyceride levels.   1. Mechanism of action: The peroxisome proliferatora€" activated receptors (PPARs) are members of the nuclear  receptor supergene family that regulates lipid metabolism. PPARs functions as a ligand-activated transcription  factor. Upon binding to its natural ligand (fatty acids or eicosanoids) or hypolipidemic drugs, PPARs are  activated. They then bind to peroxisome proliferator response elements, which are localized in numerous gene  promoters. In particular, PPARs regulates the expression of genes encoding for proteins involved in lipoprotein  structure and function. Fibrate- mediated gene expression ultimately leads to decreased triacylglycerol  concentrations by increasing the expression of lipoprotein lipase (Figure 22. 11) and decreasing apo CM    concentration. Fibrates also increase the level of HDL cholesterol by increasing the expression of apo Al and apo  All. Fenofibrate is a prodrug, producing an active metabolite, fenofibric acid, which is responsible for the  primary effects of the drug.   Figure 21.10 Plasma levels of cholesterol in hyperlipidemic patients during treatment with niacin.    2. Therapeutic uses: The fibrates are used in the treatment of hypertriacyl glycerolemias, causing a significant  decrease in plasma triacylglycerol levels. Fenofibrate and gemfibrozil are particularly useful in treating Type III  hyperlipidemia (dysbetalipoproteinemia), in which   intermediate-density lipoprotein particles accumulate. Patients with hypertriacylglycerolemia [Type IV  (elevated VLDL) or Type V (elevated VLDL plus chylomicron) disease] who do not respond to diet or other drugs  may also benefit from treatment with these agents.   3. Pharmacokinetics: Both drugs are completely absorbed after an oral dose. Gemfibrozil and fenofibrate  distribute widely, bound to albumin. Both drugs undergo extensive biotransformation and are excreted in the  urine as their glucuronide conj ugates.   a. Gastrointestinal effects: The most common adverse effects are mild gastrointestinal disturbances. These  lessen as the therapy progresses.   b. Lithiasis: Because these drugs increase biliary cholesterol excretion, there is a predisposition to the  formation of gallstones.   c. Muscle: Myositis (inflammation of a voluntary muscle) can occur with both drugs; thus, muscle weakness or  tenderness should be evaluated. Patients with renal insufficiency may be at risk. Myopathy and  rhabdomyolysis have been reported in a few patients taking gemfibrozil and lovastatln together.   d. Drug interactions: Both fibrates compete with the coumarin anticoagulants for binding sites on plasma  proteins, thus transiently potentiating anticoagulant activity. INR times should therefore be monitored when  a patient is taking both drugs. Similarly, these drugs may transiently elevate the levels of sulfonylureas.   e. Contraindications: The safety of these agents in pregnant or lactating women has not been established.   They should not be used in patients with severe hepatic and renal dysfunction or in patients with preexisting  gallbladder disease.   Bile acid sequestrants (resins) have significant LDL cholesterola€"lowering effects, although the benefits are less  than those observed with statins.   1. Mechanism of action: Cholestyramine [koe-LES-tir-a-meen], colestipol [koe-LES-tih-pole], and colesevelam  [koh-le-SEV-e-lam] are anion-exchange resins that bind negatively charged bile acids and bile salts in the small  intestine (Figure 21.12). The resin/ bile acid complex is excreted in the feces, thus preventing the bile acids  from returning to the liver by the enterohepatic circulation. Lowering the bile acid concentration causes  hepatocytes to increase conversion of cholesterol to bile acids, resulting in a replenished supply of these  compounds, which are essential components of the bile. Consequently, the intracellular cholesterol  concentration decreases, which activates an increased hepatic uptake of cholesterol-containing LDL particles,   increased uptake is mediated by an up-regulation of cell-surface LDL receptors. ] In some patients, a modest rise  in plasma HDL levels is also observed. The final outcome of this sequence of events is a decreased total plasma  cholesterol concentration.   2. Therapeutic uses: The bile aci da€" binding resins are the drugs of choice (often in combination with diet or  niacin ) in treating Type lla and Type lib hyperlipidemias. [Note: In those rare individuals who are homozygous  for Type llaa€"that is, for whom functional LDL receptors are totally lackinga€"these drugs have little effect on  plasma LDL levels. ] Cholestyramine can also relieve pruritus caused by accumulation of bile acids in patients  with biliary obstruction.   3. Pharmacokinetics: Cholestyramine, colestipol, and colesevelam are taken orally. Because they are insoluble  in water and are very large (molecular weights are greater than 10 6 ), they are neither absorbed nor  metabol ical ly altered by the intestine. Instead, they are totally excreted in the feces.   a. Gastrointestinal effects: The most common side effects are gastrointestinal disturbances, such as  constipation, nausea, and flatulence. Colesevelam has fewer gastrointestinal side effects than other bile  acid sequestrants.   b. Impaired absorptions: At high doses, cholestyramine and colestipol (but not colesevelam ) impair the  absorption of the fat-soluble vitamins (A, D, E, and K).   c. Drug interactions: Cholestyramine and colestipol interfere with the intestinal absorption of many  drugsa€"for example, tetracycline, phenobarbital, digoxin, warfarin, pravastatin, fluvastatin, aspirin,  and thiazide diuretics. Therefore, drugs should be taken at least 1 to 2 hours before, or 4 to 6 hours after,  the bile acida€" binding resins.   Ezetimibe [eh-ZEH-teh-mib] selectively inhibits intestinal absorption of dietary and biliary cholesterol in the small  intestine, leading to a decrease in the delivery of intestinal cholesterol to the liver. This causes a reduction of  hepatic cholesterol stores and an increase in clearance of cholesterol from the blood. Ezetimibe lowers LDL  cholesterol by 17 percent and triacylglycerols by 6 percent, and it increases HDL cholesterol by 1.3 percent.  Ezetimibe is primarily metabolized in the small intestine and liver via glucuronide conj ugation (a Phase II reaction),  with subsequent biliary and renal excretion. Both ezetimibe and ezef/m/be-glucuronide are slowly eliminated from  plasma, with a half-life of approximately 22 hours. Ezetimibe has no clinically meaningful effect on the plasma  concentrations of the fat-soluble vitamins A, D, and E. Patients with moderate to severe hepatic insufficiency  should not be treated with ezetimibe. [Note: A formulation of ezetimibe and simvastatin has been shown to lower  LDL levels more effectively than the statin alone.]    Cholestyramine, colestipol, or  colesevelam form an insoluble  complex with the bile acids and  salts, preventing their reabsorption  from the intestine.    Most of the bile acids and salts  that are secreted into the  intestine are reabsorbed.   It is often necessary to employ two antihyperlipidemic drugs to achieve treatment goals in plasma lipid levels. For   example, in Type II hyperl ipidemias, patients are commonly treated with a combination of niacin plus a bile  acida€"binding agent, such as cholestyramine. [Note: Remember that cholestyramine causes an increase in LDL  receptors that clears the plasma of circulating LDL, whereas niacin decreases synthesis of VLDL and, therefore, also  the synthesis of LDL.] The combination of an HMG CoA reductase inhibitor with a bile acida€"binding agent has also  been shown to be very useful in lowering LDL cholesterol levels (Figure 21.13). A low dose statin in combination  with ezetimibe achieves comparable or even greater LDL cholesterol reduction than a very-high-dose statin.  Simvastatin and ezetimibe are currently available combined in one pill to treat elevated LDL cholesterol.   Flowever, the clinical value of ezetimibe either alone or in combination with statins is uncertain. For example, in  the ENFIANCE study, patients with familial hypercholesterolemia were randomized to simvastatin plus either  ezetimibe or placebo. At 2 years, patients who received ezetimibe had significantly greater reductions in LDL  cholesterol, triglycerides, and C-reactive protein than did those on placebo. Flowever, there were no significant  differences between groups in H DL cholesterol, cardiovascular events, adverse events, or the primary  endpointa€"change in carotid-artery intimaa€" media thickness    Figure 21.13 Response of total plasma cholesterol in patients with heterozygous familial  hypercholesterolemia to a diet (low in cholesterol, low in saturated fat) and antihyperlipidemic drugs.    This study contradicts previous results in which clinical benefits correlated with the concurrent reduction in LDL  cholesterol. Until this discrepancy is resolved, many experts recommend clinicians maximize statin dosages and use  niacin, fibrates, and resins before considering ezetimibe,    Figure 21.14 Characteristics of antihyperlipidemic drug families. HDL = high-density lipoprotein; HMG-CoA =  3-hydroxy- 3- methylglutaryl coenzyme A; LDL =low-density lipoprotein.   21.1 Which one of the following is the most common side effect of antihyperlipidemic drugtherapy?   21.2 Which one of the following hyperlipidemias is characterized by elevated plasma levels of chylomicrons  and has no drugtherapy available to lower the plasma lipoprotein levels?   21.3 Which one of the following drugs decreases de novo cholesterol synthesis by inhibiting the enzyme  3-hydroxy-3-methylglutaryl coenzyme A reductase?   21.4 Which one of the following drugs causes a decrease in liver triacylglycerol synthesis by limiting available  free fatty acids needed as building blocks for this pathway?   21.5 Which one of the following drugs binds bile acids in the intestine, thus preventing their return to the liver  via the enterohepatic circulation?   >Table of Contents > Unit IV - Drugs Affecting the Cardiovascular System >Chapter 22 - Diuretics   Drugs inducing a state of increased urine flow are called diuretics. These agents are inhibitors of renal ion  transporters that decrease the reabsorption of Na + at different sites in the nephron. As a result, Na + and other ions,  such as Cl", enter the urine in greater than normal amounts along with water, which is carried passively to maintain  osmotic equilibrium. Diuretics thus increase the volume of urine and often change its pH as well as the ionic  composition of the urine and blood. The efficacy of the different classes of diuretics varies considerably, with the  increase in Na + secretion varying from less than two percent for the weak, potassium-sparing diuretics to over 20  percent for the potent loop diuretics. In addition to these ion-transport inhibitors, there are osmotic diuretics that  prevent water reabsorption, as well as aldosterone antagonists and a carbonic anhydrase inhibitor. The maj or  clinical uses of diuretics are in managing disorders involving abnormal fluid retention (edema) or treating  hypertension in which their diuretic action causes a decreased blood volume, leading to reduced blood pressure. In  this chapter, the diuretic drugs (Figure 22. 1) are discussed according to the frequency of their use.   Approximately 16 to 20 percent of the blood plasma entering the kidneys is filtered from the glomerular capillaries  into the Bowman's capsule. The filtrate, although normally free of proteins and blood cells, does contain most  low-molecular-weight plasma components in approximately the same concentrations as are found in the plasma.  These include glucose, sodium bicarbonate, amino acids, and other organic solutes as well as electrolytes, such as  Na + , K + , and Cl". The kidney regulates the ionic composition and volume of urine by the active reabsorption or  secretion of ions and/ or the passive reabsorption of water at five functional zones along the nephrona€"namely,  the proximal convoluted tubule, the descending loop of Henle, the ascending loop of Henle, the distal convoluted  tubule, and the collecting tubule and duct (Figure 22.2).   In the extensively convoluted proximal tubule located in the cortex of the kidney, almost all the glucose,  bicarbonate, amino acids, and other metabolites are reabsorbed. Approximately two-thirds of the Na + is also  reabsorbed. Chloride enters the lumen of the tubule in   exchange for a base anion, such as formate or oxalate, as well as paracellularly through the lumen. Water follows  passively from the lumen to the blood to maintain osmolar equality. If not for the extensive reabsorption of solutes  and water in the proximal tubule, the mammalian organism would rapidly become dehydrated and lose its normal  osmolarity. The Na + that is reabsorbed is pumped into the interstitium by Na + / K + a€" adenosine triphosphatase  (ATPase), thereby maintaining normal levels of Na + and K + in the cell. Carbonic anhydrase in the luminal membrane  and cell of the proximal tubule modulates the reabsorption of bicarbonate (see acetazolamide below). Water  follows salt reabsorption; thus, the presence of substances like mannitol and glucose would tend to become  concentrated. This condition results in a higher osmolarity of the tubular fluid and prevents further water  reabsorption, resulting in osmotic diuresis.   • A carbonic anhydrase inhibitor that inhibits the reabsorption  of HCO] in the proximal convoluted tubule.   • Inhibit reabsorption of Na* and Cl' In the distal convol-  uted tubule, resulting In retention of water In the tubule.   • The loop diuretics inhibit the  Na’/K V2CI cotransport In the  ascending loop of Henle, resulting  In retention of Na*. Cl', and water  in the tubule.    SPIRONOLACTONE,  AMILORIDE,  TRIAMTERENE  I Spironolactone , an  aldosterone antagonist  inhibits tho aldosterone-  mediated reabsorption of  Na* and secretion of K*.   I These agents can prevent  loss of K* that occurs with  thiazide or loop diuretics.    Figure 22.2 Maj or locations of ion and water exchange in the nephron, showing sites of action of the diuretic  drugs.    1. Acid and base secretory systems: The proximal tubule is the site of the organic acid and base secretory systems  (Figure 22.3). The organic acid secretory system, located in the middle-third segment, secretes a variety of  organic acids, such as uric acid, some antibiotics, and diuretics, from the bloodstream into the proximal tubule's  lumen. Most diuretic drugs are delivered to the tubular fluid via this system. The organic acid secretory system is  saturable, and diuretic drugs in the bloodstream compete for transfer with endogenous organic acids, such as  uric acid. This explains the hyperuricemia seen with certain of the diuretic drugs, such as furosemide or  hydrochlorothiazide. A number of other interactions can also occur; for example,   probenecid interferes with penicillin secretion. The organic base secretory system is responsible for the  secretion of creatinine, choline, and so on, and it is found in the upper and middle segments of the proximal  tubule.   The remaining filtrate, which is isotonic, next enters the descending limb of the loop of Henle and passes into the  medulla of the kidney. The osmolarity increases along the descending portion of the loop of Henle because of the  countercurrent mechanism that is responsible for water reabsorption. This results in a tubular fluid with a three-fold  increase in salt concentration. Osmotic diuretics exert part of their action in this region (see Figure 22.2).   The cells of the ascending tubular epithelium are unique in being impermeable to water. Active reabsorption of Na + ,  K + , and Cl" is mediated by a Na + /K + /2CI" cotransporter. Both Mg 2+ and Ca 2+ enter the interstitial fluid via the  paracel lular pathway. The ascending loop is thus a diluting region of the nephron. Approximately 25 to 30 percent of  the tubular sodium chloride returns to the interstitial fluid, thus helping to maintain the fluid's high osmolarity.   Because the ascending loop of Henle is a major site for salt reabsorption, drugs affecting this site, such as loop  diuretics (see Figure 22.2), are the most efficacious of all the diuretic classes.   The cells of the distal convoluted tubule are also impermeable to water. About 10 percent of the filtered sodium  chloride is reabsorbed via a Na + /CI' transporter that is sensitive to thiazide diuretics. Calcium reabsorption is  mediated by passage through a channel and then transported by a Na + / Ca 2+ -exchanger into the interstitial fluid. The  mechanism thus differs from that in the loop of Henle. Additionally, Ca 2+ excretion is regulated by parathyroid  hormone in this portion of the tubule.   Figure 22.3 Sites of transport of solutes and water along the nephron.   The principal cells of the collecting tubule and duct are responsible for Na + , K + , and water transport, whereas the  intercalated cells affect H + secretion, The sodium enters the principal cells through channels but relies on a  Na + / K + -ATPase to be transported into the blood. Aldosterone receptors in the principal cells influence Na +  reabsorption and K + secretion. Antidiuretic hormone (ADH; vasopressin) receptors promote the reabsorption of  water from the collecting tubules and ducts (see Figure 22.3). This action is mediated by cyclic adenosine  monophosphate.   In many diseases, the amount of sodium chloride reabsorbed by the kidney tubules is abnormally high. This leads to  the retention of water, an increase in blood volume, and expansion of the extravascular fluid compartment,  resulting in edema of the tissues. Several commonly encountered causes of edema include the following.   1. Heart failure: The decreased ability of the failing heart to sustain adequate cardiac output causes the kidney to  respond as if there were a decrease in blood volume (hypovolemia). The kidney, as part of the normal  compensatory mechanism, retains more salt and water as a means of raising blood volume and increasing the  amount of blood that is returned to the heart. However, the diseased heart cannot increase its output, and the  increased vascular volume results in edema (see p. 183 for causes and treatment of heart failure). Loop diuretics  are commonly used.   2. Hepatic ascites: Ascites, the accumulation of fluid in the abdominal cavity, is a common complication of  cirrhosis of the liver.   a. Increased portal blood pressure: Blood flow in the portal system is often obstructed in cirrhosis, resulting in  an increased portal blood pressure. Furthermore, the colloidal osmotic pressure of the blood is decreased as  a result of impaired synthesis of plasma proteins by the diseased liver. Increased portal blood pressure and  low osmolarity of the blood cause fluid to escape from the portal vascular system and collect in the  abdomen.   b. Secondary hyperaldosteronism: Fluid retention is also promoted by elevated levels of circulating  aldosterone due to decreased blood volume. This secondary hyperaldosteronism results from the decreased  ability of the liver to inactivate the steroid hormone and leads to increased Na + and water reabsorption,  increased vascular volume, and exacerbation of fluid accumulation (see Figure 22.3). The potassium-sparing  diuretic spironolactone is effective in this condition, but the loop diuretics are usually not.   3. Nephrotic syndrome: When damaged by disease, the glomerular membranes allow plasma proteins to enter the  glomerular ultrafiltrate. The loss of protein from the plasma reduces the colloidal osmotic pressure, resulting in  edema. The low plasma volume stimulates aldosterone secretion through the renin-angiotensin-aldosterone  system. This leads to retention of Na + and fluid, further aggravating the edema.   4. Premenstrual edema: Edema associated with menstruation is the result of imbalances in hormones, such as  estrogen excess, which facilitates the loss of fluid into the extracellular space. Diuretics can reduce the edema.   Diuretics also find wide usage in the treatment of nonedematous diseases.   1. Hypertension: Thiazides have been widely used in the treatment of hypertension, because of their ability not  only to reduce blood volume but also to dilate arterioles (see p. 219).    2. Hypercalcemia: The seriousness of this condition requires a fast response. Usually, loop diuretics are employed,  because they promote calcium excretion. However, it is important to understand that hypovolemia may  counteract the desired effect; therefore, normal saline must also be infused to maintain blood volume.   3. Diabetes insipidus: When patients suffer from polyuria and polydipsia associated with this condition, they  usually respond to thiazide diuretics. This seemingly paradoxic treatment depends on the ability of the thiazide  to reduce plasma volume, thus causing a drop in glomerular filtration rate and promoting the reabsorption of Na +  and water. The volume of urine entering the diluting segment and the subsequent urine flow are both  decreased.   The thiazides are the most widely used of the diuretic drugs. They are sulfonamide derivatives and, as such, are  related in structure to the carbonic anhydrase inhibitors. However, the thiazides have significantly greater diuretic  activity than acetazolamide (see below), and they act on the kidney by different mechanisms. All thiazides affect  the distal tubule, and all have equal maximum diuretic effects, differing only in potency (expressed on a per  milligram basis). [Note: They are sometimes called a€oeceiling diuretics, a€§ because increasing the dose above  normal does not promote a further diuretic response.] Like the actions of the loop diuretics, the thiazides partly  depend on renal prostaglandin synthesis by a mechanism that is not yet understood.   Chlorothiazide [klor-oh-THYE-ah-zide] was the first modern diuretic that was active orally, and was capable of  affecting the severe edema of cirrhosis and heart failure with a minimum of side effects. Its properties are  representative of the thiazide group, although newer derivatives, such as hydrochlorothiazide [ hi-d ro- klor-oh-  THYE-ah-zide] or chlorthalidone, are now used more commonly. Hydrochlorothiazide has far less ability to inhibit  carbonic anhydrase compared to chlorothiazide. It is also more potent, so that the required dose is considerably  lower than that of chlorothiazide. On the other hand, the efficacy is exactly the same as that of the parent drug. In  all other aspects it resembles chlorothiazide. [Note: Chlorthalidone, indapamide, and metolazone are referred to  as thiazide-like diuretics, because they contain the sulfonamide residue in their chemical structures and their  mechanism of action is similar. However, they are not truly thiazides. ]   1. Mechanism of action: The thiazide derivatives act mainly in the distal tubule to decrease the reabsorption of  Na + a€"apparently by inhibition of a Na + /CI" cotransporter on the luminal membrane of the distal convoluted  tubule (see Figure 22.2). They have a lesser effect in the proximal tubule. As a result, these drugs increase the  concentration of Na + and Cl" in the tubular fluid. The acid-base balance is not usually affected. [Note: Because  the site of action of the thiazide derivatives is on the luminal membrane, these drugs must be excreted into the  tubular lumen to be effective. Therefore, with decreased renal function, thiazide diuretics lose efficacy.]   a. Increased excretion of Na + and Cl": Chlorothiazide causes diuresis with increased Na + and Cl" excretion,  which can result in the excretion of a very hyperosmolar urine. This latter effect is unique; the other  diuretic classes are unlikely to produce a hyperosmolar urine. The diuretic action is not affected by the  acid-base status of the body, nor does chlorothiazide change the   acid-base status of the blood. The relative changes in the ionic composition of the urine during therapy with  thiazide diuretics are given in Figure 22.4.   b. Loss of K + : Because thiazides increase the Na + in the filtrate arriving at the distal tubule, more K + is also  exchanged for Na + , resulting in a continual loss of K + from the body with prolonged use of these drugs.   Therefore, it is imperative to measure serum K + often (more frequently at the beginning of therapy) to  assure that hypokalemia does not develop.    c. Loss of Mg 2+ : Magnesium deficiency requiring supplementation can occur with chronic use of thiazide  diuretics, particularly in the elderly. The mechanism for the magnesuria is not understood.   Figure 22.4 Relative changes in the composition of urine induced by thiazide diuretics.    d. Decreased urinary calcium excretion: Thiazide diuretics decrease the Ca 2+ content of urine by promoting  the reabsorption of Ca 2+ . This contrasts with the loop diuretics, which increase the Ca 2+ concentration of  the urine. [Note: There is evidence from epidemiologic studies that use of thiazides preserves bone mineral  density at the hip and spine and that the risk for hip fracture is reduced by a third.]    e. Reduced peripheral vascular resistance: An initial reduction in blood pressure results from a decrease in  blood volume and, therefore, a decrease in cardiac output. With continued therapy, volume recovery  occurs. However, there are continued hypotensive effects, resulting from reduced peripheral vascular  resistance caused by relaxation of arteriolar smooth muscle.    a. Hypertension: Clinically, the thiazides have long been the mainstay of antihypertensive medication,  because they are inexpensive, convenient to administer, and well tolerated. They are effective in reducing  systolic and diastolic blood pressure for extended periods in the majority of patients with mild to moderate  essential hypertension (see p. 215 for details on the treatment of hypertension). After 3 to 7 days of  treatment, the blood pressure stabilizes at a lower level and can be maintained indefinitely by a daily-  dosage level of the drug, which causes lower peripheral resistance without having a maj or diuretic effect.  Many patients can be continued for years on the thiazides alone, although a small percentage of patients  require additional medication, such asP-adrenergic blockers. [Note: The hypotensive actions of  angiotensin-converting enzyme inhibitors are enhanced when given in combination with the thiazides.]   b. Heart failure: Thiazides can be the diuretic of choice in reducing extracellular volume in mild to moderate  heart failure. If the thiazide fails, loop diuretics may be useful.   c. Hypercalciuria: The thiazides can be useful in treating idiopathic hypercalciuria, because they inhibit  urinary Ca 2+ excretion, This is particularly beneficial for patients with calcium oxalate stones in the urinary  tract.    d. Diabetes insipidus: Thiazides have the unique ability to produce a hyperosmolar urine. Thiazides can    substitute for antidiuretic hormone in the treatment of nephrogenic diabetes insipidus. The urine volume of  such individuals may drop from 11 L/day to about 3 L/day when treated with the drug.   4. Pharmacokinetics: The drugs are effective orally. Most thiazides take 1 to 3 weeks to produce a stable  reduction in blood pressure, and they exhibit a prolonged biologic half-life (40 hours). All thiazides are secreted  by the organic acid secretory system of the kidney (see Figure 22.3).   5. Adverse effects: Most of the adverse effects involve problems in fluid and electrolyte balance.   a. Potassium depletion: Hypokalemia is the most frequent problem encountered with the thiazide diuretics,  and it can predispose patients who are taking digitalis to ventricular arrhythmias (Figure 22.5). Often, K + can  be supplemented by diet alone, such as by increasing the intake of citrus fruits, bananas, and prunes. In  some cases, K + salt supplementation may be necessary. Activation of the renin-angiotensin-aldosterone  system by the decrease in intravascular volume contributes significantly to urinary K + losses. Under these  circumstances, the K + deficiency can be overcome by spironolactone, which interferes with aldosterone  action, or by administering triamterene, which acts to retain K + . Low-sodium diets blunt the potassium  depletion caused by thiazide diuretics.   b. Hyponatremia: This serious adverse effect may develop due to elevation of ADH as a result of hypovolemia,  as well as diminished diluting capacity of the kidney and increased thirst. Limiting water intake and lowering  the dose of diuretic can prevent this condition.   c. Hyperuricemia: Thiazides increase serum uric acid by decreasing the amount of acid excreted by the  organic acid secretory system. Being insoluble, the uric acid deposits in the joints, and a full-blown attack of  gout may result in individuals who are predisposed to gouty attacks. It is important, therefore, to perform  periodic blood tests for uric acid levels. [Note: Probenecid, a drug sometimes used in the treatment of gout,  can interfere in the excretion of the thiazides and increase serum uric acid levels. ]    Figure 22.5 Summary of some adverse effects commonly observed with thiazide diuretics.   e. Hypercalcemia: The thiazides inhibit the secretion of Ca 2+ , sometimes leading to elevated levels of Ca 2+ in  the blood.    f. Hyperglycemia: Patients with diabetes mellitus who are taking thiazides for hypertension may become  hyperglycemic and have difficulty in maintaining appropriate blood sugar levels. This is due to impaired  release of insulin and tissue uptake of glucose.   g. Hyperlipidemia: The thiazides can cause a 5- to 15-percent increase in serum cholesterol as well as  increased serum low-density lipoproteins. Lipid levels, however, may return to normal with long-term  therapy.    h. Hypersensitivity: Bone marrow suppression, dermatitis, necrotizing vasculitis, and interstitial nephritis are   very rare. Individuals who are hypersensitive to sulfa drugs may also be allergic to the thiazide diuretics.   These compounds lack the thiazide structure, but like the thiazides, they have the unsubstituted sulfonamide group   1. Chlorthalidone: Chlorthalidone [klor-THAL-i-done] is a nonthiazide derivative that behaves pharmacologically  like hydrochlorothiazide. It has a very long duration of action and, therefore, is often used to treat  hypertension. It is given once per day for this indication.   2. Metolazone: Metolazone [me-TOL-ah-zone] is more potent than the thiazides and, unlike the thiazides, causes  Na + excretion in advanced renal failure.   3. Indapamide: Indapamide [in-DAP-a-mide] is a lipid-soluble, nonthiazide diuretic that has a long duration of  action. At low doses, it shows significant antihypertensive action with minimal diuretic effects. Indapamide is  metabolized and excreted by the gastrointestinal tract and the kidneys. It is therefore less likely to accumulate  in patients with renal failure and may be useful in their treatment.   Bumetanide [byoo-MET-ah-nide], furosemide [fu-RO-se-mide], torsemide [TOR-se-myde], and ethacrynic [eth-a-  KRIN-ik] acid are four diuretics that have their major action on the ascending limb of the loop of Henle (see Figure  22.2). Compared to all other classes of diuretics, these drugs have the highest efficacy in mobilizing Na + and Cl'  from the body. They produce copious amounts of urine. Furosemide is the most commonly used of these drugs.   Ethacrynic acid has a steeper dose-response curve than furosemide, but it shows greater side effects than those  seen with the other loop diuretics and its use is therefore limited. Bumetanide is much more potent than  furosemide, and its use is increasing. Bumetanide and furosemide are sulfonamide derivatives.   1. Mechanism of action: Loop diuretics inhibit the cotransport of Na + /K + / 2CI' in the luminal membrane in the  ascending limb of the loop of Henle. Therefore, reabsorption of these ions is decreased (Figure 22.6). The loop  diuretics are the most efficacious of the diuretic drugs, because the ascending limb accounts for the  reabsorption of 25 to 30 percent of filtered NaCI and downstream sites are not able to compensate for this  increased Na + load.   2. Actions: The loop diuretics act promptly, even among patients who have poor renal function or have not  responded to thiazides or other   diuretics. Changes in the composition of the urine induced by loop diuretics are shown in Figure 22.6. [Note:   Loop diuretics increase the Ca 2+ content of urine, whereas thiazide diuretics decrease the Ca 2+ concentration of  the urine. In patients with normal serum Ca 2+ concentrations, hypocalcemia does not result, because Ca 2+ is  reabsorbed in the distal convoluted tubule. However, hypomagnesemia can occur due to loss of Mg 2+ . ] The loop  diuretics cause decreased renal vascular resistance and increased renal blood flow. In addition, loop diuretics  increase prostaglandin synthesis. The prostaglandins have a role in their diuretic action, and substances such as  indomethacin that interfere in prostaglandin synthesis can reduce the diuretic action of these agents.    Figure 22.6 Relative changes in the composition of urine induced by loop diuretics.    3. Therapeutic uses: The loop diuretics are the drugs of choice for reducing the acute pulmonary edema of heart  failure. Because of their rapid onset of action, particularly when given intravenously, the drugs are useful in  emergency situations, such as acute pulmonary edema, which calls for a rapid, intense diuresis. Loop diuretics  (along with hydration) are also useful in treating hypercalcemia, because they stimulate tubular Ca 2+ excretion.  They also are useful in the treatment of hyperkalemia.   4. Pharmacokinetics: Loop diuretics are administered orally or parenteral ly. Their duration of action is relatively  brief a€"2 to 4 hours. They are secreted into the urine.   5. Adverse effects: The adverse effects of the loop diuretics are summarized in Figure 22.7.    a. Ototoxicity: Hearing can be affected adversely by the loop diuretics, particularly when used in conj unction  with the aminoglycoside antibiotics. Permanent damage may result with continued treatment. Ethacrynic  acid is the most likely to cause deafness. Vestibular function is less likely to be disturbed, but it, too, may  be affected by combined treatment with the antibiotic.   b. Hyperuricemia: Furosemide and ethacrynic acid compete with uric acid for the renal and biliary secretory  systems, thus blocking its secretion and, thereby, causing or exacerbating gouty attacks.   c. Acute hypovolemia: Loop diuretics can cause a severe and rapid reduction in blood volume, with the  possibility of hypotension, shock, and cardiac arrhythmias. Hypercalcemia may occur under these  conditions.   d. Potassium depletion: The heavy load of Na + presented to the collecting tubule results in increased exchange  of tubular Na + for K + , with the possibility of inducing hypokalemia. The loss of K + from cells in exchange for   H + leads to hypokalemic alkalosis. Potassium depletion can be averted by use of potassium-sparing diuretics  or dietary supplementation with K + .   e. Hypomagnesemia: A combination of chronic use of loop diuretics and low dietary intake of Mg 2+ can lead to  hypomagnesemia, particularly in the elderly. This can be corrected by oral supplementation.   Potassium-sparing diuretics act in the collecting tubule to inhibit Na + reabsorption and K + excretion (Figure 22.8).  Potassium-sparing diuretics are used alone primarily when aldosterone is present in excess. The maj or use of  potassium-sparing agents is in the treatment of hypertension, most often in combination with a thiazide. It is   extremely important that patients who are treated with any potassium-sparing diuretic be closely monitored for  potassium levels. Exogenous potassium supplementation is usually discontinued when potassium-sparing diuretic  therapy is instituted.   1. Mechanism of action: Spironolactone [spear-oh-no-LAK-tone] is a synthetic steroid that antagonizes   aldosterone at intracellular cytoplasmic receptor sites. The spironolactone-receptor complex is inactive. That  is, it prevents translocation of the receptor complex into the nucleus of the target cell; thus, it cannot bind to  DNA. This results in a failure to produce proteins that are normally synthesized in response to aldosterone.  These mediator proteins normally stimulate the Na + / K + -exchange sites of the collecting tubule. Thus, a lack of  mediator proteins prevents Na + reabsorption and, therefore, K + and H + secretion.    Figure 22.8 Relative changes in the composition of urine induced by potassiumsparing diuretics.    2. Actions: In most edematous states, blood levels of aldosterone are high, which is instrumental in retaining Na + .  When spironolactone is given to a patient with elevated circulating levels of aldosterone, the drug antagonizes  the activity of the hormone, resulting in retention of K + and excretion of Na + (see Figure 22.8). In patients who  have no significant circulating levels of aldosterone, such as those with Addison's disease (primary adrenal  insufficiency), no diuretic effect of the drug occurs. In common with the thiazides and loop diuretics, the  effect of spironolactone depends on renal prostaglandin synthesis. Eplerenone [eh-PLEH-reh-none] is a new  aldosterone-receptor antagonist, with actions comparable to those of spironolactone. Eplerenone may have  less endocrine effects than spironolactone.    a. Diuretic: Although spironolactone has a low efficacy in mobilizing Na + from the body in comparison with the  other drugs, it has the useful property of causing the retention of K + . Because of this latter action,  spironolactone is often given in conj unction with a thiazide or loop diuretic to prevent the K + excretion that  would otherwise occur with these drugs. It is the diuretic of choice in patients with hepatic cirrhosis.   b. Secondary hyperaldosteronism: Spironolactone is the only potassium-sparing diuretic that is routinely used  alone to induce a net negative salt balance. It is particularly effective in clinical situations associated with  secondary hyperaldosteronism.    c. Heart failure: Spironolactone prevents the remodeling that occurs as compensation for the progressive  failure of the heart.   4. Pharmacokinetics: Spironolactone is completely absorbed orally and is strongly bound to proteins. It is rapidly  converted to an active metabolite, canrenone. The action of spironolactone is largely due   to the effect of canrenone, which has mi neral ocorti coi d- blocki ng activity. Spironolactone induces hepatic  cytochrome P450.   5. Adverse effects: Spironolactone frequently causes gastric upsets and can cause peptic ulcers. Because it  chemically resembles some of the sex steroids, spironolactone may act at receptors in other organs to induce  gynecomastia in males and menstrual irregularities in females; therefore, the drug should not be given at high  doses on a chronic basis. It is most effectively employed in mild edematous states, for which it is given for a few  days at a time. At low doses, spironolactone can be used chronically with few side effects. Hyperkalemia,  nausea, lethargy, and mental confusion can occur.   Triamterene [trye-AM-ter-een] and amiloride [a-MIL-oh-ride] block Na + transport channels, resulting in a decrease  in Na + /K + exchange. Although they have a K + -sparing diuretic action similar to that of spironolactone, their ability  to block the Na + / K + -exchange site in the collecting tubule does not depend on the presence of aldosterone. Thus,  they have diuretic activity even in individuals with Addison's disease. Like spironolactone, they are not very  efficacious diuretics. Both triamterene and amiloride are frequently used in combination with other diuretics,  usually for their potassium-sparing properties. For example, much like spironolactone, they prevent the loss of K +  that occurs with thiazides and furosemide. The side effects of triamterene are leg cramps and the possibility of  increased blood urea nitrogen as well as uric acid and K + retention.   Figure 22.9 Role of carbonic anhydrase in sodium retention by epithelial cells of renal tubule.   Acetazolamide [ah-set-a-ZOLE-a-mide] inhibits the enzyme carbonic anhydrase in the proximal tubular epithelial  cells. Carbonic anhydrase inhibitors are more often used for their other pharmacologic actions rather than for their  diuretic effect, because they are much less efficacious than the thiazides or loop diuretics.   1. Mechanism of action: Acetazolamide inhibits carbonic anhydrase located intracellularly (cytoplasm) and on the  apical membrane of the proximal tubular epithelium (Figure 22.9). [Note: Carbonic anhydrase catalyzes the  reaction of CO 2 and H 2 O, leading to H 2 CO 3 , which spontaneously ionizes to H + and HCO 3 " (bicarbonate)]. The  decreased ability to exchange Na + for H + in the presence of acetazolamide results in a mild diuresis.   Additionally, HCO 3 " is retained in the lumen, with marked elevation in urinary pH. The loss of HCO 3 " causes a  hyperchloremic metabolic acidosis and decreased diuretic efficacy following several days of therapy. Changes in  the composition of urinary electrolytes induced by acetazolamide are summarized in Figure 22. 10. Phosphate  excretion is increased by an unknown mechanism.   a. Treatment of glaucoma: The most common use of acetazolamide is to reduce the elevated intraocular  pressure of open-angle glaucoma. Acetazolamide decreases the production of aqueous humor, probably by  blocking carbonic anhydrase in the ciliary   body of the eye. It is useful in the chronic treatment of glaucoma but should not be used for an acute  attack; pilocarpine is preferred for an acute attack because of its immediate action. Topical carbonic  anhydrase inhibitors, such as dorzolamide and brinzolamide, have the advantage of not causing any  systemic effects.    Figure 22.10 Relative changes in the composition of urine induced by acetazolamide.   b. Mountain sickness: Less commonly, acetazolamide can be used in the prophylaxis of acute mountain  sickness among healthy, physically active individuals who rapidly ascend above 10,000 feet. Acetazolamide  given nightly for 5 days before the ascent prevents the weakness, breathlessness, dizziness, nausea, and  cerebral as well as pulmonary edema characteristic of the syndrome.   3. Pharmacokinetics: Acetazolamide is given orally once to four times daily. It is secreted by the proximal tubule.   4. Adverse effects: Metabolic acidosis (mild), potassium depletion, renal stone formation, drowsiness, and  paresthesia may occur. The drug should be avoided in patients with hepatic cirrhosis, because it could lead to a  decreased excretion of NH 4 + .   A number of simple, hydrophilic chemical substances that are filtered through the glomerulus, such as mannitol  [MAN-i-tol] and urea [yu-REE-ah], result in some degree of diuresis. This is due to their ability to carry water with  them into the tubular fluid. If the substance that is filtered subsequently undergoes little or no reabsorption, then  the filtered substance will cause an increase in urinary output. Only a small amount of additional salt may also be  excreted. Because osmotic diuretics are used to effect increased water excretion rather than Na + excretion, they  are not useful for treating conditions in which Na + retention occurs. They are used to maintain urine flow following  acute toxic ingestion of substances capable of producing acute renal failure. Osmotic diuretics are a mainstay of  treatment for patients with increased intracranial pressure or acute renal failure due to shock, drug toxicities, and  trauma. Maintaining urine flow preserves long-term kidney function and may save the patient from dialysis. [Note:  Mannitol is not absorbed when given orally and should only be given intravenously. ] Adverse effects include  extracellular water expansion and dehydration as well as hypo- or hypernatremia. The expansion of extracellular  water results because the presence of mannitol in the extracellular fluid extracts water from the cells and causes  hyponatremia until diuresis occurs. Dehydration, on the other hand, can occur if water is not replaced adequately.   Figure 22.11 Summary of relative changes in urinary composition induced by diuretic drugs.    Figure 22. 11 summarizes the relative changes in urinary composition induced by diuretic drugs.   22.1 An elderly patient with a history of heart disease and who is having difficulty breathing is brought into the  emergency room. Examination reveals that she has pulmonary edema. Which of the following treatments is  indicated?   22.2 A group of college students is planning a mountain climbing trip to the Andes. Which of the following drugs  would be appropriate for them to take to prevent mountain sickness?   22.3 An alcoholic male has developed hepatic cirrhosis. To control the ascites and edema, he is prescribed  which one of the following?   22.4 A 55-year-old male with kidney stones has been placed on a diuretic to decrease calcium excretion.   However, after a few weeks, he develops an attack of gout. Which diuretic was he taking?   22.5 A 75-year-old woman with hypertension is being treated with a thiazide. Her blood pressure responds and  reads at 120/76 mm Hg. After several months on the medication, she complains of being tired and weak. An  analysis of the blood indicates low values for which of the following ?   22.6 Which of the following drugs is contraindicated in a patient with hyperkalemia?   22.7 Which would be the initial treatment choice to manage the hypertension in an African-American woman  with a past medical history of gout and severe hypokalemia?   >Table of Contents > Unit V - Drugs Affecting the Endocrine System >Chapter 23 - Pituitary and Thyroid   The neuroendocrine system, which is controlled by the pituitary and hypothalamus, coordinates body functions by  transmitting messages between individual cells and tissues. This contrasts with the nervous system which  communicates locally by electrical impulses and neurotransmitters directed through neurons to other neurons or to  specific target organs, such as muscle or glands. Nerve impulses generally act within milliseconds. The endocrine  system releases hormones into the bloodstream, which carries these chemical messengers to target cells throughout  the body. Hormones have a much broader range of response time than do nerve impulses, requiring from seconds to  days, or longer, to cause a response that may last for weeks or months. The two regulatory systems are closely  interrelated. For example, in several instances, the release of hormones is stimulated or inhibited by the nervous  system, and some hormones can stimulate or inhibit nerve impulses. Chapters 24 to 26 focus on drugs that affect the  synthesis and/ or secretion of specific hormones and their actions. In this chapter, the central role of the  hypothalamic and pituitary hormones in regulating body functions is briefly presented (Figure 23. 1). In addition,  drugs affecting thyroid hormone synthesis and/or secretion are discussed.   The hormones secreted by the hypothalamus and the pituitary are all peptides or low-molecular-weight proteins  that act by binding to specific receptor sites on their target tissues. The hormones of the anterior pituitary are  regulated by neuropeptides that are called either a€oereleasinga€' ; or a€ce i nh i b i t i nga€ ' i: factors or hormones. These  are produced in cell bodies in the hypothalamus, and they reach the cells of the pituitary by the hypophysial portal  system (Figure 23.2). The interaction of the releasing hormones with their receptors results in the activation of  genes that promote the synthesis of protein precursors. These are then processed posttranslati onal ly to the  hormones and are released into the circulation. [Note: Unlike those of the posterior pituitary, the hormones of the  anterior pituitary are not stored in granules prior to release. ] Each hypothalamic regulatory hormone controls the  release of a specific hormone   from the anterior pituitary. The hypothalamic-releasing hormones are primarily used for diagnostic purposes (that  is, to determine pituitary insufficiency). [Note: The hypothalamus also synthesizes the precursor proteins of the  hormones vasopressin and oxytocin, which are transported to the posterior pituitary, where they are stored until  released. ] Although a number of pituitary hormone preparations are currently used therapeutically for specific  hormonal deficiencies (examples of which follow), most of these agents have limited therapeutic applications.   Hormones of the anterior and posterior pituitary are administered either intramuscularly (IM), subcutaneously, or  i ntranasal ly, but not orally, because their peptidyl nature makes them susceptible to destruction by the proteolytic  enzymes of the digestive tract.    Figure 23.1 Some of the hormones and drugs affecting the hypothalamus, pituitary, and thyroid.   Figure 23.2 Hypothalamic-releasing hormones and actions of anterior pituitary hormones. GHRH =growth  hormone-releasing hormone; TRH =thyrotropin-releasing hormone; CRH=corticotropin-releasing hormone;  GnRH (LHRH) =gonadotropinreleasing hormone (luteinizing hormone-releasing hormone); PIH = prolacti n-  inhibiting hormone (dopamine); and PRH = prol acti n- rel easi ng hormone; ACTH =adrenocorticotropic hormone;  TSH = thyrot ropi n- sti mu lati ng hormone; FSH =f ollicle-sti mulating hormone; LH = luteinizing hormone   Corticotropin-releasing hormone (CRH) is responsible for the synthesis and release of the peptide  proopiomelanocortin by the hypothalamus (Figure 23.3). Adrenocorticotropic hormone (ACTH), or corticotropin   [kor-ti-koe-TROE-pin] is a product of the posttranslational processing of this precursor polypeptide. [Note: CRH is  used diagnostically to differentiate between Cushing's syndrome and ectopic ACTH-producing cells.] Other products  of proopiomelanocortin are i 3 -melanocyte stimulating hormone and T * 1 2 -l ipotropin, the latter being the precursor of  the endorphins. Normally, ACTH is released from the pituitary in pulses with an overriding diurnal rhythm, with the  highest concentration occurring at approximately 6 AM and the lowest in the evening. Stress stimulates its  secretion, whereas cortisol acting via negative feedback suppresses its release.   1. Mechanism of action: The target organ of ACTH is the adrenal cortex, where it binds to specific receptors on  the cell surfaces. The occupied receptors activate G proteina€"coupled processes to increase cyclic adenosine  monophosphate (cAMP), which in turn stimulates the rate-limiting step in the adrenocorticosteroid synthetic  pathway (cholesterol to pregnenolone). This pathway ends with the synthesis and release of the  adrenocorticosteroids and the adrenal androgens (see Figure 23.3).   2. Therapeutic uses: The availability of synthetic adrenocorticosteroids with specific properties has limited the   use of corticotropin mainly to serving as a diagnostic tool for differentiating between primary adrenal  insufficiency (Addison's disease, associated with adrenal atrophy) and secondary adrenal insufficiency (caused  by the inadequate secretion of ACTH by the pituitary). Therapeutic corticotropin preparations are extracts  from the anterior pituitaries of domestic animals or synthetic human ACTH. The latter, cosyntropin [ko-sin-  TROE-pin], which consists of the amino-terminal 24 amino acids of the hormone, is preferred for the diagnosis of  adrenal insufficiency. ACTH is used in the treatment of infantile spasm (West Syndrome).   3. Adverse effects: Toxicities are similar to those of glucocorticoids. Antibodies can form against ACTH derived  from animal sources.   Somatotropin [soe-mah-toe-TROE pin] is a large polypeptide that is released by the anterior pituitary in response to  growth hormone (GH)a€"releasing hormone produced by the hypothalamus (see Figure 23.2). Secretion of GH is  inhibited by another pituitary hormone, somatostatin (see below). GH is released in a pulsatile manner, with the  highest levels occurring during sleep. With increasing age, GH secretion decreases, being accompanied by a  decrease in lean muscle mass. Human GH is produced synthetically by recombinant DNA technology. GH from animal  sources is ineffective in humans. Somatotropin influences a wide variety of biochemical processes; for example,  through stimulation of protein synthetic processes, cell proliferation and bone growth are promoted. Increased  formation of hydroxyproline from proline boosts cartilage synthesis.   Figure 23.3 Secretion and actions of adrenocorticotropic hormone (ACTH). CRH =corticotropin-releasing    1. Mechanism of action: Although many physiologic effects of GH are exerted directly at its targets, others are  mediated through the somatomedinsa€"insulin-like growth factors I and II (IGF-I and IGF-II). [Note: In  acromegaly, IGF-I levels are consistently high, reflecting elevated GH.]   2. Therapeutic uses: Somatotropin is used in the treatment of GH deficiency in children. It is important to  establish whether the GH deficit is actually due to hypopituitarism, because other factors, such as normal  thyroid status, are essential for successful somatotropin therapy. [Note: After a study published in 1990  indicated that GH administered to men over 60 years of age for 6 months increased their lean body mass, bone  density, and skin thickness, whereas adipose tissue mass decreased, many started to call GH the antiaging  hormone. This has led to abuse by some athletes seeking to enhance their performance. GH is not approved for  this purpose, and some who have taken it have developed diabetes. ] A therapeutically equivalent drug,  somatrem [SOE-ma-trem], contains an extra terminal methionyl residue not found in somatotropin. Although  the half-lives of these drugs are short (approximately 25 minutes), they induce the release from the liver of  IGF-I (formerly somatomedin C), which is responsible for subsequent GH- 1 i ke actions. Somatotropin and  somatrem should not be used in individuals with closed epiphyses or an enlarging intracranial mass.   In the pituitary, somatostatin [soe-ma-toe-STAT in] binds to distinct receptors, SSTR2 and SSTR5, which suppress  GH and thyroid-stimulating hormone release. Originally isolated from the hypothalamus, somatostatin is a small  polypeptide that is also found in neurons throughout the body as well as in the intestine and pancreas.   Somatostatin therefore has a number of actions. For example, it not only inhibits the release of GH but, also, that  of insulin, glucagon, and gastrin. Octreotide [ok-TREE-oh-tide] is a synthetic octapeptide analog of somatostatin.  Its half-life is longer than that of the natural compound, and a depot form is also available. The two forms suppress  GH and IGF-I for 12 hours and 6 weeks, respectively. They have found use in the treatment of acromegaly caused by  hormone-secreting tumors and in secretory diarrhea associated with tumors producing vasoactive intestinal peptide  (VIPomas). Adverse effects of octreotide treatment are flatulence, nausea, and steatorrhea. Gallbladder emptying  is delayed, and asymptomatic cholesterol gallstones can occur with long-term treatment. [Note: An analog of human  GH that has polyethylene glycol polymers attached, pegvisomant [peg-VI-soe-mant], is being employed in the  treatment of acromegaly that is refractory to other modes of surgical, radiologic, or pharmacologic intervention. It  acts as an antagonist at one of the GH receptors and results in the normalization of IGF-I levels.   Gonadotropin-releasing hormone (GnRH), also called gonadorelin [go-nad-oh-RELL-in], is a decapeptide obtained  from the hypothalamus. Pulsatile secretion of GnRFI is essential for the release of follicle-stimulating hormone  ( FSH ) and luteinizing hormone ( LH ) from the pituitary, whereas continuous administration inhibits gonadotropin  release. GnRFI is employed to stimulate gonadal hormone production in hypogonadism. A number of synthetic  analogs, such as leuprolide [loo-PROE-lide], goserelin [GOE-se-rel-in], nafarelin [naf-A-rel-in], and histreiin  [his-TREL-in], act as agonists at GnRFI receptors (Figure 23.4). These are effective in suppressing production of the  gonadal hormones and, thus, are effective in the treatment of prostatic cancer,   endometriosis, and precocious puberty. Adverse effects of gonadorelin include hypersensitivity, dermatitis, and  headache. In women, the analogs may cause hot flushes and sweating as well as diminished libido, depression, and  ovarian cysts. They are contraindicated in pregnancy and breast-feeding. In men, they initially cause a rise in  testosterone that can result in bone pain; hot flushes, edema, gynecomastia, and diminished libido also occur.   Figure 23.4 Secretion of follicle-stimulating hormone (FSH) and lutenizing hormone (LH). GnRH =  gonadotropin-releasing hormone.    E. Gonadotropins: Human menopausal gonadotropin, follicle-stimulating  hormone, and human chorionic gonadotropin   The gonadotropins are glycoproteins that are produced in the anterior pituitary. The regulation of gonadal steroid  hormones depends on these agents. They find use in the treatment of infertility in men and women. Menotropins  [men-oh-TROE-pin] ( human menopausal gonadotropins, or hMG ) are obtained from the urine of menopausal  women and contain FSH and luteinizing hormone LH. Chorionic gonadotropin ( hCG ) is a placental hormone and an  LH agonist, to which it is structurally related. It is also excreted in the urine. Urofoiiitropin [yoor-oh-fol-  li-TROE-pin] is FSH obtained from menopausal women and is devoid of LH. Follitropin beta [fol-ih-TROE-pin] is  human FSH manufactured by recombinant DNA technology. All of these hormones are injected IM. Inj ection of hMG  or FSH over a period of 5 to 12 days causes ovarian follicular growth and maturation, and with subsequent inj ection  of hCG, ovulation occurs. In men who are lacking gonadotropins, treatment with hCG causes external sexual  maturation, and with the subsequent inj ection of hMG, spermatogenesis occurs. Adverse effects include ovarian  enlargement and possible hypovolemia. Multiple births are not uncommon. Men may develop gynecomastia.   Prolactin is a peptide hormone similar in structure to GH, and is also secreted by the anterior pituitary. Its secretion  is inhibited by dopamine acting at D 2 receptors. Its primary function is to stimulate and maintain lactation. In  addition, it decreases sexual drive and reproductive function. The hormone enters a cell, where it activates a  tyrosine kinase to promote tyrosine phosphorylation and gene activation. There is no preparation available for  hypoprolactinemic conditions. On the other hand, hyperprolactinemia, which is associated with galactorrhea and  hypogonadism, is usually treated with D 2 -receptor agonists, such as bromocriptine and cabergoline. Both of these  agents also find use in the treatment of microadenomas and macroprolactinomas. They not only act at the D 2  receptor to inhibit prolactin secretion but also cause increased hypothalamic dopamine by decreasing its turnover.    Among their adverse effects are nausea, headache, and sometimes, psychiatric problems.   In contrast to the hormones of the anterior lobe of the pituitary, those of the posterior lobe, vasopressin and  oxytocin, are not regulated by releasing hormones. Instead, they are synthesized in the hypothalamus, transported  to the posterior pituitary, and released in response to specific physiologic signals, such as high plasma osmolarity or  parturition, Each is a nonapeptide with a circular structure due to a disulfide bridge. Reduction of the disulfide  inactivates these hormones. They are susceptible to proteolytic   cleavage and, thus, are given parenteral ly. Both hormones have very short half-lives. Their actions are summarized  in Figure 23. 5.   Oxytocin [ok-se-TOE-sin], originally extracted from animal posterior pituitaries, is now chemically synthesized. Its  only use is in obstetrics, where it is employed to stimulate uterine contraction to induce or reinforce labor or to  promote ej ection of breast milk. [Note: The sensitivity of the uterus to oxytocin increases with the duration of  pregnancy when it is under estrogenic dominance. ] To induce labor, the drug is administered intravenously.   However, when used to induce a€oemilk let-down, a€^ it is given as a nasal spray. Oxytocin causes milk ejection by  contracting the myoepithelial cells around the mammary alveoli. Although toxicities are uncommon when the drug is  used properly, hypertensive crises, uterine rupture, water retention, and fetal death have been reported. Its  antidiuretic and pressor activities are very much lower than those of vasopressin. [Note: Oxytocin is  contraindicated in abnormal fetal presentation, fetal distress, and premature births.]   Vasopressin [vas-oh-PRESS-in] (antidiuretic hormone), is structurally related to oxytocin. The chemically  synthesized nonapeptide has replaced that extracted from animal posterior pituitaries. Vasopressin has both  antidiuretic and vasopressor effects (see Figure 23.5). In the kidney, it binds to the V 2 receptor to increase water  permeability and resorption in the collecting tubules. Thus, the maj or use of vasopressin is to treat diabetes  insipidus. It also finds use in controlling bleeding due to esophageal varices or colonic diverticula. Other effects of  vasopressin are mediated by the Vi receptor, which is found in liver, vascular smooth muscle (where it causes  constriction), and other tissues. As might be expected, the maj or toxicities are water intoxication and  hyponatremia. Headache, bronchoconstriction, and tremor can also occur. Caution must be used when treating  patients with coronary artery disease, epilepsy, and asthma.   Because of its pressor properties, vasopressin has been modified to desmopressin [des-moe-PRESS-in] (1-desamino-  8-d-arginine vasopressin), which has minimal activity at the Vi receptor, making it largely free of pressor effects.   This analog is now preferred for diabetes insipidus and nocturnal enuresis and is longer-acting than vasopressin.  Desmopressin is conveniently administered intranasally. However, local irritation may occur.   The thyroid gland facilitates normal growth and maturation by maintaining a level of metabolism in the tissues that is  optimal for their normal function. The two maj or thyroid hormones are triiodothyronine ( T3 ; the most active form)  and thyroxine (T4). Although the thyroid gland is not essential for life, inadequate secretion of thyroid hormone  (hypothyroidism) results in bradycardia, poor resistance to cold, and mental and physical slowing (in children, this  can cause mental retardation and dwarfism). If, however, an excess of thyroid hormones is secreted  (hyperthyroidism), then tachycardia and cardiac arrhythmias, body wasting, nervousness, tremor, and excess   heat production can occur. [Note: The thyroid gland also secretes the hormone calcitonina€"a serum calcium-  lowering hormone. ]   The thyroid gland is made up of multiple follicles that consist of a single layer of epithelial cells surrounding a lumen  filled with colloid (thyroglobulin), which is the storage form of thyroid hormone. A summary of the steps in thyroid  hormone synthesis and secretion is shown in Figure 23.6.   1. Regulation of synthesis: Thyroid function is controlled by a tropic hormone, thyroid-stimulating hormone (TSH;  thyrotropin). TSH is a glycoprotein, structurally related to LH and FSH, which is synthesized by the anterior  pituitary (see Figure 23.2). TSH generation is governed by the hypothalamic thyrotropin-releasing hormone  (TRH). TSH action is mediated by cAMP and leads to stimulation of iodide (I") uptake. Oxidation to iodine (I 2 ) by  a peroxidase is followed by iodination of tyrosines on thyroglobulin. [Note: Antibodies to thyroid peroxidase are  diagnostic for Hashimoto's thyroiditis. ] Condensation of two diiodotyrosine residues gives rise to T4, whereas  condensation of a monoiodotyrosine residue with a diiodotyrosine residue generates T3, which is still bound to  the   protein. The hormones are released following proteolytic cleavage of the thyroglobulin.   2. Regulation of secretion: Secretion of TSH by the anterior pituitary is stimulated by the hypothalamic TRH.   Feedback inhibition of TRH occurs with high levels of circulating thyroid hormone. [Note: At pharmacologic  doses, dopamine, somatostatin, or glucocorticoids can also suppress TSH secretion.] Most of the hormone ( T3  and T4) is bound to thyroxine-binding globulin in the plasma.   Both T4 and T3 must dissociate from thyroxine-binding plasma proteins prior to entry into cells, either by diffusion  or by active transport. In the cell, T4 is enzymatically deiodinated to T3, which enters the nucleus and attaches to  specific receptors. The activation of these receptors promotes the formation of RNA and subsequent protein  synthesis, which is responsible for the effects of T 4 .   Both T4 and T3 are absorbed after oral administration. Food, calcium preparations, and aluminum-containing  antacids can decrease the absorption of T4 but not of T3. T4 is converted to T3 by one of two distinct deiodinases,  depending on the tissue. The hormones are metabolized through the microsomal P450 system. Drugs that induce the  P450 enzymes, such as phenytoin, rifampin, and phenobarbital , accelerate metabolism of the thyroid hormones  (Figure 23.7).   Hypothyroidism usually results from autoimmune destruction of the gland or the peroxidase and is diagnosed by  elevated TSH. It is treated with levothyroxine ( T4 ) [leh-vo-thye-ROK-sin], The drug is given once daily because of  its long half-life. Steady state is achieved in 6 to 8 weeks. Toxicity is directly related to T4 levels and manifests  itself as nervousness, heart palpitations and tachycardia, intolerance to heat, and unexplained weight loss.   Excessive amounts of thyroid hormones in the circulation are associated with a number of disease states, including  Graves' disease, toxic adenoma, and goiter. In these situations, TSH levels are reduced. The goal of therapy is to  decrease synthesis and/ or release of additional hormone. This can be accomplished by removing part or all of the  thyroid gland, by inhibiting synthesis of the hormones, or by blocking release of the hormones from the follicle.   1. Removal of part or all of the thyroid: This can be accomplished either surgically or by destruction of the gland  by beta particles emitted by radioactive iodine ( 131 l), which is selectively taken up by the thyroid follicular cells.  Younger patients are treated with the isotope without prior pretreatment with methimazole (see below),   whereas the opposite is the case in elderly patients. Most patients become hypothyroid as a result of this drug  and require treatment with levothyroxine.   ( PTU ) and methimazole [meth-IM-ah-zole], are concentrated in the thyroid, where they inhibit both the  oxidative processes required for iodination of tyrosyl groups and the coupling of iodotyrosines to form T3 and 74  (see Figure 23.6). PTU can also block the conversion of 74 to T3 [Note: These drugs have no effect on the  thyroglobulin already stored in the gland; therefore, observation of any clinical effects of these drugs may be  delayed until thyroglobulin stores are depleted. ] The thioamides are well absorbed from the gastrointestinal  tract, but they have short half-lives. Several doses of PTU are required per day, whereas a single dose of  methimazole suffices due to the duration of its antithyroid effect. The effects of these drugs are slow in onset;  thus, they are not effective in the treatment of thyroid storm (see below). Relapse may occur. Relatively rare  adverse effects include agranulocytosis, rash, and edema.   3. Thyroid storm: I 2 - Bl ockers that lack sympathomimetic activity, such as propranolol , are effective in blunting  the widespread sympathetic stimulation that occurs in hyperthyroidism. Intravenous administration is effective  in treating thyroid storm. An alternative in patients suffering from severe heart failure or asthma is the calcium-  channel blocker, diltiazem. Other agents used in the treatment of thyroid storm include PTU (because it  inhibits the peripheral conversion of T 4 to T3 but methimazole does not), iodides, and glucocorticoids (to  protect against shock).   4. Blockade of hormone release: A pharmacologic dose of iodide inhibits the iodination of tyrosines (the so-called  a€oeacute Wolff-Chaikoff effecta€i), but this effect lasts only a few days. What is more important, iodide  inhibits the release of thyroid hormones from thyroglobulin by mechanisms not yet understood. Today, iodide is  rarely used as the sole therapy. However, it is employed to treat potentially fatal thyrotoxic crisis (thyroid  storm) or prior to surgery, because it decreases the vascularity of the thyroid gland. Iodide is not useful for  long-term therapy, because the thyroid ceases to respond to the drug after a few weeks. Iodide is administered  orally. Adverse effects are relatively minor and include sore mouth and throat, swelling of the tongue or larynx,  rashes, ulcerations of mucous membranes, and a metallic taste in the mouth.    23. 2 Which of the following best describes the effect of propylthiouracil on thyroid hormone production?   D. It blocks iodination and coupling of tyrosines in thyroglobulin to form thyroid hormones.    E. It blocks the release of hormones from the thyroid gland.   23.3 Hyperthyroidism can be treated by all but which one of the following?   23.4 Which one of the following hormones is a non-peptide, allowing oral administration?   23.5 Which one of the following agents is INCORRECTLY paired to a clinical use of the drug?   B. Octreotide: treatment of diarrhea associated with vasoactive intestinal peptide tumors   >Table of Contents > Unit V - Drugs Affecting the Endocrine System >Chapter 24 - Insulin and OralHypoglycemic Drugs   The pancreas is both an endocrine gland that produces the peptide hormones insulin, glucagon, and somatostatin and an exocrine gland that  produces digestive enzymes. The peptide hormones are secreted from cells located in the islets of Langerhans (i 2 cells produce insulin, iicells  produce glucagon, and i' cells produce somatostatin). These hormones play an important role in regulating the metabolic activities of the  body, particularly the homeostasisof blood glucose. 1 Hyperinsulinemia (due, for example, to an insulinoma) can cause severe hypoglycemia.   More commonly, a relative or absolute lack of insulin, such as in diabetes mellitus, can cause serious hyperglycemia, which, if left untreated,  can result in retinopathy, nephropathy, neuropathy, and cardiovascular complications. Administration of insulin preparations or oral  hypoglycemic agents (Figure 24. 1) can prevent morbidity and reduce mortality associated with diabetes.   The incidence of diabetes is growing rapidly both in the United States and worldwide. For example, it is estimated that more than 180 million  people worldwide are afflicted with diabetes, and the prevalence is expected to more than double by the year 2030. In the United States,  approximately 21 million people are estimated to suffer from diabetes, and it is a maj or cause of morbidity and mortality. Diabetes is not a  single disease. Rather, it is a heterogeneous group of syndromes characterized by an elevation of blood glucose caused by a relative or  absolute deficiency of insulin. [Note: Frequently, the inadequate release of insulin is aggravated by an excess of glucagon.] The American  Diabetes Association (ADA) recognizes four clinical classifications of diabetes: Type 1 diabetes (formerly /nsu/in-dependent diabetes mellitus),   Type 2 diabetes (formerly nona €" insulin dependent diabetes mellitus), gestational diabetes, and diabetes due to other causes (e.g., genetic  defects or medication induced). 2 Figure 24.2 summarizes the characteristics of Type landType 2 diabetes. Gestational diabetes is defined as  carbohydrate intolerance with onset or first recognition during pregnancy. It is important to maintain adequate glycemic control during  pregnancy, because uncontrolled gestational diabetes   can lead to fetal macrosomia (overly large body) and shoulder dystocia (difficult delivery), as well as neonatal hypoglycemia. Diet, exercise,  and/or insulin administration are effective in this condition. Glyburide may be a reasonably safe alternative to insulin therapy for gestational  diabetes. However, larger randomized studies are needed to fully assess neonatal outcomes and optimal dosing regimens.   _ Glimepiride  _ Glyburide  _ Metformin  _ Miglitol  _ Nateglinide  _ Pioglitazone  _ Repaglinide  _ Rosiglitazone  _ Sitagliptin    Figure 24.1 Summary of drugs used in the treatment of diabetes.   Inability of {i cells  to produce  appropriate  quantities of  insulin; insulin  resistance; other  defects   Type 1 diabetes most commonly afflicts individuals in puberty or early adulthood, but some latent forms can occur later in life. The disease is  characterized by an absolute deficiency of insulin caused by massive i 1 2 -cell necrosis. Loss of I 2 -cell function is usually ascribed to autoimmune-  mediated processes directed against the l 2 cell, and it may be triggered by an invasion of viruses or the action of chemical toxins. As a result of  the destruction of these cells, the pancreas fails to respond to glucose, and the Type 1 diabetic showsclassic symptoms of insulin deficiency  (polydipsia, polyphagia, polyuria, and weight loss). Type 1 diabetics require exogenous insulin to avoid the catabolic state that results from  and is characterized by hyperglycemia and life-threatening ketoacidosis.   1. Cause of Type 1 diabetes: In the postabsorptive period of a normal individual, low, basal levels of circulating insulin are maintained  through constant i 2 -cell secretion. This suppresses lipolysis, proteolysis, and glycogenolysis. A burst of insulin secretion occurs within 2  minutes after ingesting a meal, in response to transient increases in the levels of circulating glucose and amino acids. This lasts for up to 15  minutes, and, is followed by the postprandial secretion of insulin. However, having virtually no functional l 2 cells, the Type 1 diabetic can  neither maintain a basal secretion level of insulin nor respond to variations in circulating fuels (Figure 24.3). The development and  progression of neuropathy, nephropathy, and retinopathy are directly related to the extent of glycemic control (measured as blood levels  of glucose and/or hemoglobin Ai c [HbAi c ]). 3   2. Treatment: A Type 1 diabetic must rely on exogenous (injected) insulin to control hyperglycemia, avoid ketoacidosis, and maintain  acceptable levels of glycosylated hemoglobin (HbAi c ). [Note: The rate of formation of HbAi c is proportional to the average blood glucose  concentration over the previous 3 months; thus, HbAi c provides a measure of how well treatment has normalized blood glucose in  diabetics. ] The goal in administering insulin to Type 1 diabetics is to maintain blood glucose concentrations as close to normal as possible  and to avoid wide swings in glucose levels that may contribute to long-term complications. The use of home blood glucose monitors  facilitates frequent self-monitoring and treatment with insulin injections. Continuous subcutaneous insulin inf usionaC" also called the  insulin pumpa€"is another method of insulin delivery. This method of administration may be more convenient for some patients,  eliminating the multiple daily inj ections of insulin. The pump is programmed to deliver a basal rate   of insulin secretion, and it also allows the patient to control delivery of a bolus of insulin to compensate for high blood glucose or in  anticipation of postprandial needs. Other methods of insulin delivery, such astransdermal, buccal, and intranasal, are currently under  investigation. Amylin is a hormone that is cosecreted with insulin from pancreatic I 2 cells following food intake. Pramlintide [PRAM-  len-tide], a synthetic analog of amylin, may be used as an adjunct to insulin therapy.    Figure 24.3 Release of insulin that occurs in response to an IV glucose load in normal subjects and diabetic patients.   Most diabetics are Type 2. The disease is influenced by genetic factors, aging, obesity, and peripheral insulin resistance rather than by  autoimmune processes or viruses. The metabolic alterations observed are milder than those described for Type 1 (for example, Type 2 patients  typically are not ketotic), but the long-term clinical consequences can be just as devastating (for example, vascular complications and  subsequent infection can lead to amputation of the lower limbs).   1. Cause: In Type 2 diabetes, the pancreas retains some I 2 -cell function, but variable insulin secretion is insufficient to maintain glucose  homeostasis (see Figure 24.3). The l 2 -cell mass may become gradually reduced in Type 2 diabetes. In contrast to patients with Type 1, those  with Type 2 diabetes are often obese. [Note: Not all obese individuals become diabetic.] Type 2 diabetes is frequently accompanied by the  lack of sensitivity of target organs to either endogenous or exogenous insulin (Figure 24.4). This resistance to insulin is considered to be a  major cause of this type of diabetes .   Figure 24.4 Major factors contributing to hyperglycemia observed in Type 2 diabetes.    2. Treatment: The goal in treating Type 2 diabetes is to maintain blood glucose concentrations within normal limits and to prevent the  development of long-term complications of the disease. Weight reduction, exercise, and dietary modification decrease insulin resistance  and correct the hyperglycemia of Type 2 diabetes in some patients. However, most patients are dependent on pharmacologic intervention  with oral hypoglycemic agents. As the disease progresses, P-cell function declines, and insulin therapy is often required to achieve  satisfactory serum glucose levels (Figure 24.5).   Insulin [IN-su-lin] is a polypeptide hormone consisting of two peptide chains that are connected by disulfide bonds. It is synthesized as a  precursor (pro-insulin) that undergoes proteolytic cleavage to form insulin and C peptide, both of which are secreted by the I 2 cells of the  pancreas. 4 [Note: Type 2 patients secrete high levelsof proinsulin. Because radioimmunoassays do not distinguish between proinsulin and  insulin, Type 2 patients may have lower levels of the active hormone than the assay indicates. Thus, measurement of circulating C peptide  provides a better index of insulin levels.]   Insulin secretion is regulated not only by blood glucose levels but also by certain amino acids, other hormones (see gastrointestinal hormones   below), and autonomic mediators. Secretion is most commonly triggered by high blood glucose, which is taken up by the glucose transporter  into the I 2 cells of the pancreas. There, it is phosphorylated by glucokinase, which acts as a glucose sensor. The products of glucose  metabolism enter the mitochondrial respiratory chain and generate adenosine triphosphate (ATP). The rise in ATP levelscauses a block of K +  channels, leading to membrane depolarization and an influx of Ca 2+ , which results in pulsatile insulin exocytosis. The sulfonylureas and  meglitinidesowe their hypoglycemic effect to the inhibition of the K + channels. [Note: Glucose given by injection has a weaker effect on  insulin secretion than does glucose taken orally, because when given orally, glucose stimulates production of digestive hormones by the gut,  which in turn stimulate insulin secretion by the pancreas.]    Figure 24.5 Duration of Type 2 diabetes mellitus, suffciency of endogenous insulin, and recommended sequence of therapy.   Human insulin is produced by recombinant DNA technology using special strains of Escherichia coli or yeast that have been genetically altered  to contain the gene for human insulin. Modifications of the amino acid sequence of human insulin have produced insulins with different  pharmacokinetic properties. For example, three such insulinsa€"lispro, aspart, and glulisine a€"have a faster onset and shorter duration of  action than regular insulin, because they do not aggregate or form complexes. On the other hand, glargine and detemir are long-acting  insulins and show prolonged, flat levels of the hormone following injection.   Because insulin is a polypeptide, it is degraded in the gastrointestinal tract if taken orally. It therefore is generally administered by  subcutaneous injection. [Note: In a hyperglycemic emergency, regular insulin is injected intravenously.] Continuous subcutaneous insulin  infusion has become popular, because it does not require multiple daily inj ections. Insulin preparations vary primarily in their times of onset of  activity and in their durations of activity. This is due to differences in the amino acid sequences of the polypeptides. Dose, site of injection,  blood supply, temperature, and physical activity can affect the duration of action of the various preparations. Insulin is inactivated by insulin-  degrading enzyme (also called insulin protease), which is found mainly in the liver and kidney.   The symptoms of hypoglycemia are the most serious and common adverse reactions to an overdose of insulin (Figure 24.6). Long-term diabetics  often do not produce adequate amounts of the counter-regulatory hormones (glucagon, epinephrine, cortisol, and growth hormone), which  normally provide an effective defense against hypoglycemia. Other adverse reactions include weight gain, lipodystrophy (less common with  human insulin), allergic reactions, and local inj ection site reactions. Diabetics with renal insufficiency may require adj ustment of the insulin  dose.   It is important that any change in insulin treatment be made cautiously by the clinician, with strict attention paid to the dose. Figure 24. 7  summarizes onset of action, timing of peak level, and duration of action for the various types of insulins that are currently in use.   Four insulin preparations fall into this category: regular insulin, insulin lispro, insulin aspart, and insulin glulisine. Regular insulin is a short-  acting, soluble, crystalline zinc insulin. Regular insulin is usually given subcutaneously (or intravenously in emergencies), and it rapidly lowers  blood glucose (Figure 24. 8). Regular insulin, insulin lispro, and insulin aspart are pregnancy category B. Insulin glulisine has not been studied  in pregnancy. Because of their rapid onset and short duration of action, the lispro [LIS-proe], aspart [AS-part], and glulisine [gloo-LYSE-een]  forms of insulin are classified as rapid- acting insulins. These agents offer more flexible treatment regimens and may lower the risk of  hypoglycemia. Insulin lispro differs from regular insulin in that lysine and proline at positions 28 and 29 in the B chain are reversed. This results  in more rapid absorption after subcutaneous injection than is seen with regular insulin; as a consequence, insulin lispro acts more rapidly.   Peak levels of insulin lispro are seen at 30 to 90 minutes after injection, as compared with 50 to 120 minutes for regular insulin. Insulin lispro  also has a shorter duration of activity. Insulin aspart and insulin glulisine have pharmacokinetic and pharmacodynamic properties similar to  those of insulin lispro. They are administered to mimic the prandial (mealtime) release of insulin, and they are usually not used alone but,  rather, along with a longer-acting insulin to assure proper glucose control. Like regular insulin, they are administered subcutaneously. Insulin  lispro is usually administered 15 minutes prior to a meal or immediately following a meal, whereas glulisine can be taken either 15 minutes  before a meal or within 20 minutes after starting a meal. Insulin aspart must be administered just prior to the meal. All of the rapid- acting  formulations are suitable for intravenous administration, although regular insulin is most commonly used when the intravenous route is  needed. Insulin lispro, insulin aspart, and insulin glulisine may also be used in external insulin pumps.   Neutral protamine Hagedorn ( NPH ) insulin is a suspension of crystalline zinc insulin combined at neutral pH with a positively charged  polypeptide, protamine. [Note: Another name for this preparation is insulin isophane. ] Its duration of action is intermediate. This is due to  delayed absorption of the insulin because of its conj ugation with protamine, forming a less-soluble complex. NPH insulin should only be given  subcutaneously (never intravenously) and is useful in treating all forms of   diabetes except diabetic ketoacidosis or emergency hyperglycemia. It is used for basal control and is usually given along with rapid- or short-   acting insulin for mealtime control. [Note: A similar compound called neutral protamine lispro ( NPL ) insulin, has been prepared that is used  only in combination with insulin lispro (see below).] Figure 24. 8 shows three of many regimens that use combinations of insulins.   Figure 24.7 Onset and duration of action of human insulin and insulin analogs. NPH =Neutral Protamine Hagedorn.   1. Insulin glargine: The isoelectric point of insulin glargine (GLAR-geen) is lower than that of human insulin, leading to precipitation at the  inj ection site, thereby extending its action. It is slower in onset than NPH insulin and has a flat, prolonged hypoglycemic effectaC'that is,  it has no peak (see Figure 24. 7) . Like the other insulins, it must be given subcutaneously.   2. Insulin detemir: Insulin detemir (deh-TEE-meer) has a fatty-acid side chain. The addition of the fatty-acid side chain enhances association  to albumin. Slow dissociation from albumin results in long-acting properties similar to those of insulin glargine.   Various premixed combinations of human insulins, such as 70-percent NPH insulin plus 30-percent regular insulin, 50 percent of each of these,  or 75 percent NPL insulin plus 25 percent insulin lispro, are also available.   Standard treatment of patients with diabetes mellitus involves inj ection of insulin twice daily. In contrast, intensive treatment seeks to  normalize blood glucose through more frequent injections of insulin (three or more times daily in response to monitoring blood glucose  levels). Mean blood glucose levels of 170 mg/dL or less can be achieved with intensive treatment, with an HbAi c content of approximately  seven percent or less of total hemoglobin. [Note: Normal mean blood glucose is approximately 135 mg/dL or less, with an HbAi c content of six  percent or less. ] Thus, the frequency of hypoglycemic episodes, coma, and seizures due to excessive insulin is particularly high with intensive  treatment regimens (Figure 24. 9A). Nonetheless, patients on intensive therapy show a significant reduction in the long-term complications of  diabetesa€"retinopathy, nephropathy, and neuropathya€" compared to patients receiving standard care (Figure 24. 9B). However, the  commonly used treatment algorithm of normalizing blood glucose in diabetics has recently been challenged. The ACCORD trial found that  among adults with Type 2 diabetes who are at especially high risk of cardiovascular disease, a medical treatment strategy to intensively lower  their blood glucose levels below the current guidelines increased the risk of death compared to standard blood glucose-lowering treatment.  The intensive therapy arm of the trial, including those patients treated with intensive insulin therapy, was halted.   Figure 24.8 Examples of three regimens that provide both prandial and basal insulin replacement. B =breakfast; L =lunch; S =supper.   Praml intide [PRAM-lin-tide] is a synthetic amylin analog that is indicated as an adjunct to mealtime insulin therapy in patients with Type 1 or  Type 2 diabetes. By acting as an amylinomimetic, praml intide delays gastric emptying, decreases postprandial glucagon secretion, and  improves satiety.   Praml intide is administered by subcutaneous injection and should be injected immediately prior to meals. When praml intide is initiated, the  dose of rapid- or short-acting insulin should be decreased by 50% prior to meals to avoid a risk of severe hypoglycemia. Pramlintide may not be  mixed in the same syringe with any insulin preparation. Adverse effects are mainly gastrointestinal and consist of nausea, anorexia, and  vomiting. Pramlintide should not be given to patients with diabetic gastroparesis (delayed stomach emptyingjor a history of hypoglycemic   These agents are useful in the treatment of patients who have Type 2 diabetes but who cannot be managed by diet alone. The patient most  likely to respond well to oral hypoglycemic agents is one who develops diabetes after age 40 and has had diabetes less than 5 years. Patients  with long-standing disease may require a combination of hypoglycemic drugs with or without insulin to control their hyperglycemia. Insulin is  added because of the progressive decline in i 2 cells that occurs due to the disease or aging. Oral hypoglycemic agents should not be given to  patients with Type 1 diabetes. Figure 24. 10 summarizes the duration of action of some of the oral hypoglycemic drugs, and Figure 24. 11  illustrates some of the common adverse effects of these agents.   These agents are classified as insulin secretagogues, because they promote insulin release from the I 2 cells of the pancreas. The primary drugs  used today are tolbutamide [tole-BYOO-ta-mide] and the second-generation derivatives, glyburide [GLYE-byoor-ide], glipizide [GLIP-  i-ih-zide], and glimepiride [GLYE-me-pih-ride].   1. Mechanisms of action of the sulfonylureas: These include 1) stimulation of insulin release from the i 2 cells of the pancreas by blocking  the ATP-sensitive K + channels, resulting in depolarization and Ca 2+ influx; 2) reduction in hepatic glucose production; and 3) increase in  peripheral insulin sensitivity.   2. Pharmacokinetics and fate: Given orally, these drugs bind to serum proteins, are metabolized by the liver, and are excreted by the liver  or kidney. Tolbutamide has the shortest duration of action (6a€"12 hours), whereas the second-generation agents last about 24 hours.   3. Adverse effects: Shortcomings of the sulfonylureas are their propensity to cause weight gain, hyperinsulinemia, and hypoglycemia. These  drugs should be used with caution in patientswith hepatic or renal insufficiency, because delayed excretion of the druga€" resulting in its  accumulation^" may cause hypoglycemia. Renal impairment is a particular problem in the case of those agents that are metabolized to  active compounds, such as glyburide. Glyburide has minimal transfer across the placenta and may be a reasonably safe alternative to  insulin therapy for diabetes in pregnancy. Figure 24. 12 summarizes some of the interactions of the sulfonylureas with other drugs.    Intensive therapy results in a  three-fold increase in the  frequency of hypoglycemia.    Many clinicians believe the  increased risk of hypo-  glycemia that accompanies  intensive therapy is justified  by the substantial decrease  in the incidence of long-term  complications, such as diabetic  retinopathy and nephropathy.    Figure 24.9 A. Effect of tight glucose control on hypoglycemic episodes in a population of patients with Type 1 diabetes receiving  intensive or standard therapy.   B. Effect of standard and intensive care on the long-term complications of diabetes.   Thisclassof agents includes repaglinide [re-PAG-lin-ide] and nateglinide [ nuh-TAY-gl i- nide] . Although they are not sulfonylureas, they have  common actions.   1. Mechanism of action: Like the sulfonylureas, their action is dependent on functioning pancreatic I 2 cells. They bind to a distinct site on   the sulfonylurea receptor of ATP-sensitive potassium channels, thereby initiating a series of reactions culminating in the release of insulin.  However, in contrast to the sulfonylureas, the meglitinides have a rapid onset and a short duration of action. They are particularly  effective in the early release of insulin that occurs after a meal and, thus, are categorized as postprandial glucose regulators. Combined  therapy of these agents with metformin or the glitazones has been shown to be better than monotherapy with either agent in improving  glycemic control. Meglitinides should not be used in combination with sulfonylureas due to overlapping mechanisms of action.   2. Pharmacokinetics and fate: These drugs are well absorbed orally after being taken 1 to 30 minutes before meals. Both meglitinides are  metabolized to inactive products by CYP3A4 (see p. 14) in the liver and are excreted through the bile.   3. Adverse effects: Although these drugs can cause hypoglycemia, the incidence of this adverse effect appears to be lower than that with the  sulfonylureas. [Note: Drugs that inhibit CYP3A4, like ketoconazole, itraconazole, fluconazole, erythromycin, and clarithromycin, may  enhance the glucose-lowering effect of repaglinide, whereas drugs that increase levels of this enzyme, such as barbiturates,  carbamazepine, and rifampin, may have the opposite effect. ] Repaglinide has been reported to cause severe hypoglycemia in patients  who are also taking the lipid-lowering drug gemfibrozil. Weight gain is less of a problem with the meglitinides than with the sulfonylureas.  These agents must be used with caution in patients with hepatic impairment.   Two classes of oral agentsaC'the biguanides and thiazolidinedionesaCimprove insulin action. These agents lower blood sugar by improving   Metformin [met-FOR-min], the only currently available biguanide, is classed as an insulin sensitizer; that is, it increases glucose uptake and  utilization by target tissues, thereby decreasing insulin resistance. Like the sulfonylureas, metformin requires insulin for its action, but it  differs from the sulfonylureas in that it does not promote insulin secretion. Hyperinsuiinemia is not a problem. Thus, the risk of hypoglycemia  is far less than that with sulfonylurea agents, and it may only occur if caloric intake is not adequate or exercise is not compensated for  calorically.   1. Mechanism of action: The main mechanism of action of metformin is reduction of hepatic glucose output, largely by inhibiting hepatic  giuconeogenesis. [Note: Excess glucose produced by the liver is the major source of high blood glucose in Type 2 diabetic, accounting for  the high blood glucose on waking in the morning. ] Metformin also slows intestinal absorption of sugars and improves peripheral glucose  uptake and utilization. A very important property of this drug is its ability to modestly reduce hyperlipidemia (low-density lipoprotein [LDL]  and very-low-density lipoprotein [VLDL] cholesterol concentrations fall, and high-density lipoprotein [HDL] cholesterol rises). These  effects may not be apparent until 4 to 6 weeks of use. The patient often loses weight because of loss of appetite. The ADA treatment  algorithm recommends metformin as the drug of choice for newly diagnosed Type 2 diabetics. Metformin may be used alone or in  combination with one of the other agents, as well as with insulin. Hypoglycemia has occurred when metformin was taken in combination.  [Note: If used with insulin, the dose of insulin may require adjustment, because metformin decreases the production of glucose by the  liver.]   2. Pharmacokinetics and fate: Metformin is well absorbed orally, is not bound to serum proteins, and is not metabolized. Excretion is via the  urine.   3. Adverse effects: These are largely gastrointestinal. Metformin iscontraindicated in diabeticswith renal and/or hepatic disease, acute  myocardial infarction, severe infection, or diabetic ketoacidosis. It should be used with caution in patients greater than 80 years of age or  in those with a history of congestive heart failure or alcohol abuse. [Note: Diabetics being treated with heart-failure medications should  not be given metformin because of an increased risk of lactic acidosis.] Metformin should be temporarily discontinued in patients  undergoing diagnosis requiring intravenous radiographic contrast agents. Rarely, potentially fatal lactic acidosis has occurred. Long-term  use may interfere with vitamin B 12 absorption.    4. Other uses: In addition to the treatment of Type 2 diabetes, metformin is effective in the treatment of polycystic ovary disease. Its ability  to lower insulin resistance in these women can result in ovulation and, possibly, pregnancy.   Another group of agents that are insulin sensitizers are the thiazolidinediones (TZDs) or, more familiarly the glitazones. Although insulin is  required for their action, these drugs do not promote its release from the pancreatic i 2 cells; thus, hyperinsulinemia does not result.   Troglitazone [TROE-glit-a-zone] was the first of these to be approved for the treatment of Type 2 diabetic, but was withdrawn after a number  of deaths due to hepatotoxicity were reported. Presently, two members of this class are available, pioglitazone [pye-oh-GLI-ta-zone] and  rosiglitazone [roe-si-GLIH-ta-zone],   1. Mechanism of action: Although the exact mechanism by which the TZDs lower insulin resistance remains to be elucidated, they are known  to target the peroxisome proliferatoraC" activated receptor-P (PPARl 3 )a€"a nuclear hormone receptor. Ligandsfor PPARI 3 regulate  adipocyte production and secretion of fatty acids as well as glucose metabolism, resulting in increased insulin sensitivity in adipose tissue,  liver, and skeletal muscle. Hyperglycemia, hyperinsulinemia, hypertriacylglycerolemia, and elevated HbAi c levels are improved.   Interestingly, LDL levels are not affected by pioglitazone monotherapy or when the drug is used in combination with other agents, whereas  LDL levels have increased with rosiglitazone. HDL levels increase with both drugs. The TZDs lead to a favorable redistribution of fat from  visceral to subcutaneous tissues. [Note: Whether the adipogenic effects can be separated from those of increased insulin sensitivity is the  subject of much research, particularly because of the role of obesity in this disease.] Pioglitazone and rosiglitazone can be used as  monotherapy or in combination with other hypoglycemics or with insulin. The dose of insulin required for adequate glucose control in   these circumstances may have to be lowered. The glitazones are recommended as a second-line alternative for patientswho fail or have  contraindications to metformin therapy.   2. Pharmacokinetics and fate: Both pioglitazone and rosiglitazone are absorbed very well after oral administration and are extensively  bound to serum albumin. Both undergo extensive metabolism by different cytochrome P450 isozymes (see p. 14). Some metabolitesof  pioglitazone have activity. Renal elimination of pioglitazone is negligible, with the majority of the active drug and metabolites excreted in  the bile and eliminated in the feces. The metabolitesof rosiglitazone are primarily excreted in the urine. No dosage adjustment is  required in renal impairment. It is recommended that these agents not be used in nursing mothers.   3. Adverse effects: Because there have been deaths from hepatotoxicity in patients taking troglitazone, it is recommended that liver  enzyme levels of patients on these medications be measured initially and periodically thereafter. Very few cases of liver toxicity have been  reported with rosiglitazone or pioglitazone. Weight increase can occur, possibly through the ability of TZDs to increase subcutaneous fat  or due to fluid retention. [Note: The latter can lead to or worsen heart failure. ] Glitazones have been associated with osteopenia and  increased fracture risk. A recent retrospective meta-analysis found that rosiglitazone was associated with an increased risk of myocardial  infarction and death from cardiovascular causes: however, future prospective studies are needed to better ascertain the cardiovascular  risks associated with rosiglitazone. Other adverse effects include headache and anemia. Women taking oral contraceptives and TZDs may  become pregnant, because the latter have been shown to reduce plasma concentrations of the estrogen-containing contraceptives.   4. Other uses: As with metformin, the relief of insulin resistance with the TZDs can cause ovulation to resume in premenopausal women with  polycystic ovary syndrome.   Acarbose [AY-car-bose] and miglitol [MIG-li-tol] are orally active drugs used for the treatment of patientswith Type 2 diabetes.   These drugs are taken at the beginning of meals. They act by delaying the digestion of carbohydrates, thereby resulting in lower postprandial  glucose levels. Both drugs exert their effects by reversibly inhibiting membrane-bound I±-glucosidase in the intestinal brush border. This  enzyme is responsible for the hydrolysis of oligosaccharides to glucose and other sugars. [Note: Acarbose also inhibits pancreatic I±-amylase,  thus interfering with the breakdown of starch to oligosaccharides.] Consequently, the postprandial rise of blood glucose is blunted. Unlike the  other oral hypoglycemic agents, these drugs do not stimulate insulin release, nor do they increase insulin action in target tissues. Thus, as  monotherapy, they do not cause hypoglycemia. However, when used in combination with the sulfonylureas or with insulin, hypoglycemia may  develop. [Note: It is important that the hypoglycemic patient be treated with glucose rather than sucrose, because sucrase is also inhibited by  these drugs.]   Acarbose is poorly absorbed. It is metabolized primarily by intestinal bacteria, and some of the metabolites are absorbed and excreted into the  urine. On the other hand, miglitol is very well absorbed but has no systemic effects. It is excreted unchanged by the kidney.   The major side effects are flatulence, diarrhea, and abdominal cramping. Patientswith inflammatory bowel disease, colonic ulceration, or  intestinal obstruction should not use these drugs.   Sitagliptin [si-ta-GLIP-tin] is an orally active dipeptidyl peptidase-IV (DPP-IV) inhibitor used for the treatment of patients with Type 2  diabetes. Other agents in this category are currently in development.   Sitagliptin inhibits the enzyme DPP-IV, which is responsible for the inactivation of incretin hormones, such as giucagon-like peptide-1 (GLP-1).  Prolonging the activity of incretin hormones results in increased insulin release in response to meals and a reduction in inappropriate secretion  of glucagon. Sitagliptin may be used as monotherapy or in combination with a sulfonylurea, metformin or a glitazone.   Sitagliptin is well absorbed after oral administration. Food does not affect the extent of absorption. The majority of sitagliptin is excreted  unchanged in the urine. Dosage adj ustments are recommended for    In general, sitagliptin is well tolerated, with the most common adverse effects being nasopharyngitis and headache. Rates of hypoglycemia are  comparable to those with placebo when sitagliptin is used as monotherapy or in combination with metformin or pioglitazone.   Oral glucose results in a higher secretion of insulin than occurs when an equal load of glucose is given intravenously. This effect is referred to  as the a€oeincretin effectad and is apparently reduced in Type 2 diabetes. It demonstrates the important role of the gastrointestinal  hormonesa€"notably GLP-1 and gastric inhibitory polypeptideaC'in the digestion and absorption of nutrients, including glucose. Exenatide  [EX-e-nah-tide] is an incretin mimetic with a polypeptide sequence about 50-percent homologous to GLP-1. Exenatide not only improves  glucose-dependent insulin secretion but also slows gastric emptying time, decreases food intake, decreases postprandial glucagon secretion,  and promotes t 2 -cell proliferation. Consequently, weight gain and postprandial hyperglycemia are reduced, and HbAi c levels decline. Being a  polypeptide, exenatide must be administered subcutaneously. A drawback to its use is its short duration of action, requiring frequent  injections. A once-weekly preparation is under investigation. Exenatide may be used as an adjunct to therapy in patients with Type 2 diabetes  who have failed to achieve adequate glycemic control on a sulfonylurea, metformin, glitazone, or combination thereof. Similar to  pramlintide, the main adverse effects consist of nausea, vomiting, and diarrhea.   A summary of the oral antidiabetic agents is presented in Figure 24. 13.   Short action with less hypoglycemia either  at night or with missed meal. Post-prandial  effect.   Binds to peroxisome  proliferator-activated  receptor- /in muscle,  fat and liver to decrease  insulin resistance.   Once-daily dosing. May be taken with  or without food. Well tolerated.    24.1 A 50-year-old woman has just been diagnosed as a Type 2 diabetic and given a prescription for metformin. Which of the following   24.2 Which of the following statements is true for therapy with insulin glargine?   C. It is now used preferentially in Type 1 diabetics who are pregnant.   D. Pharmacokinetically, there is no peak activity, and the activity lasts about 24 hours.   24.3 The ability to reduce insulin resistance is associated with which one of the following classes of hypoglycemic agents?   24.4 A 64-year-old woman with a history of Type 2 diabetes is diagnosed with heart failure. Which of the following drugs would be a poor  choice in controlling her diabetes?   >Table of Contents > Unit V - Drugs Affecting the Endocrine System >Chapter 25 - Estrogens and Androgens   Sex hormones produced by the gonads are necessary for conception, embryonic maturation, and development of  primary and secondary sexual characteristics at puberty. Their activity in target cells is modulated by receptors. The  gonadal hormones are used therapeutically in replacement therapy, for contraception, and in management of  menopausal symptoms. Several antagonists are effective in cancer chemotherapy. All gonadal hormones are  synthesized from the precursor, cholesterol, in a series of steps that includes shortening of the hydrocarbon side  chain and hydroxylation of the steroid nucleus. Aromatization is the last step in estrogen synthesis. 1 Figure 25. 1 lists  the steroid hormones referred to in this chapter.   Estradiol [ess-tra-DYE-ole], also known as 17 P-estradiol , is the most potent estrogen produced and secreted by  the ovary. It is the principle estrogen in the premenopausal woman. Estrone [ESS-trone] is a metabolite of estradiol  that has approximately one-third the estrogenic potency of estradiol. Estrone is the primary circulating estrogen  after menopause, and it is generated mainly from conversion of androstenedione in peripheral tissues. Estriol  [ess-TRI-ole], another metabolite of estradiol, is significantly less potent than estradiol. It is present in significant  amounts during pregnancy, because it is the principal estrogen produced by the placenta. A preparation of  conj ugated estrogens containing sulfate esters of estrone and egu/7/na€"obtained from pregnant mare's urinea€"is a  widely used oral preparation for hormone replacement therapy. Plant-derived conj ugated estrogen products are  also available. Synthetic estrogens, such as ethinyl estradiol [ETH-ih-ni l-ess-tra- DYE-ole], undergo less first-pass  metabolism than naturally occurring steroids and, thus, are effective when administered orally at lower doses.  Nonsteroidal compounds that bind to estrogen receptors and exert either estrogenic or antiestrogenic effects on  target tissues are called selective estrogen-receptor modulators. These include tamoxifen and raloxifene, among  others.   After dissociation from their binding sites on sex hormonea€"binding globulin or albumin in the plasma, steroid  hormones diffuse across the cell membrane and bind with high affinity to specific nuclear-receptor proteins. [Note:   These receptors belong to a large, nuclear hormonea€"receptor family that includes those for thyroid hormones and  vitamin D. ] Two estrogen-receptor subtypes, i±and i 2 , mediate the effects of the hormone. The ilreceptor may be  considered as the classic estrogen receptor; the T 2 receptor is highly homologous to the lireceptor. However, the  N-terminal portion of the i±receptor contains a region that promotes transcription activation, whereas the i 2  receptor contains a repressor domain. As a result, the transcriptional properties of the l±and I 2 estrogen receptors  are different. Affinity for the receptor type varies with the particular estrogen. These receptor isoforms vary in  structure, chromosomal location, and tissue distribution. The activated steroid-receptor complex interacts with  nuclear chromatin to initiate hormone-specific RNA synthesis. The attachment of two estrogen-linked receptors  (estrogen receptor dimer) to the genome is required for a response. This results in the synthesis of specific proteins  that mediate a number of physiologic functions. [Note: The steroid hormones may elicit the synthesis of different  RNA species in diverse target tissues and, therefore, are both receptor and tissue specific. ] Other pathways that  require these hormones have been identified that lead to more rapid results. For example, activation of an estrogen  receptor in the membranes of hypothalamic cells has been shown to couple to a G protein, thereby initiating a  second-messenger cascade. 2 In addition, estrogen-mediated dilation of coronary arteries occurs by the increased  formation and release of nitric oxide and prostacyclin in endothelial cells.   The most frequent uses of estrogens are for contraception and postmenopausal hormone therapy, also called  estrogen-progestogen therapy (EPT). Due to recent concerns over the risks of EPT, the National American  Menopause Society recommends that EPT be prescribed at the lowest effective dose for the shortest possible time  to relieve vasomotor symptoms and vaginal atrophy. Women that have only urogenital symptoms should be treated  with vaginal rather than systemic estrogen. Estrogens were previously widely used for prevention and treatment of  osteoporosis, but current guidelines recommend use of other therapies over estrogen. Estrogens are also used  extensively for replacement therapy in premenopausal patients who are deficient in this hormone. Such a  deficiency can be due to lack of development of the ovaries, premature menopause, or surgical menopause.   1. Postmenopausal hormone therapy: The primary indication for estrogen therapy is menopausal symptoms such  as vasomotor instability (for example, a€oehot flashesa€i or a€oehot flushesa€§) and vaginal atrophy. (Figure  25.2). For women who have not undergone a hysterectomy, a progestin is always included with the estrogen  therapy, because the combination reduces the risk of endometrial carcinoma associated with unopposed  estrogen. For women whose uterus   has been surgically removed, unopposed estrogen therapy is recommended, because progestins may unfavorably  alter the beneficial effects of estrogen on lipid parameters. [Note: The amount of estrogen used in replacement  therapy is substantially less than the doses used in oral contraception. Thus, the adverse effects of estrogen r  eplacement therapy tend to be less severe than the adverse effects seen in women who are taking estrogen for  contraceptive purposes.] Delivery of estradiol by transdermal patch is also effective in treating postmenopausal  symptoms. Osteoporosis is effectively treated with estrogen; however, other drugs, such as alendronate, should  be considered first-line therapy over estrogen. (See p. 343 for a summary of some of the agents that are useful  in the treatment of osteoporosis.)    2. Primary hypogonadism: Estrogen therapy mimicking the natural cyclic pattern, and usually in combination with  progestins, is instituted to stimulate development of secondary sex characteristics in young women ( lla€" 13  years of age) with hypogonadism. Continued treatment is required after growth is completed.   1. Naturally occurring estrogens: These agents and their esterified or conj ugated derivatives are readily absorbed  through the gastrointestinal tract, skin, and mucous membranes. Taken orally, estradiol is rapidly metabolized  (and partially inactivated) by the microsomal enzymes of the liver. Micronized estradiol is available and has  better bioavailability. Although there is some first-pass metabolism, it is not sufficient to lessen the  effectiveness when taken orally.   2. Synthetic estrogen analogs: These compounds, such as ethinyl estradiol and mestranol [MES-trah-nole]), are  well absorbed after oral administration or through the skin or mucous membranes. Mestranol is quickly  demethylated to ethinyl estradiol, which is metabolized more slowly than the naturally occurring estrogens by  the liver and peripheral tissues. Being fat soluble, they are stored in adipose tissue, from which they are slowly  released. Therefore, the synthetic estrogen analogs have a prolonged action and a higher potency compared to  those of natural estrogens.   3. Metabolism: Estrogens are transported in the blood while bound to serum albumin or sex hormoneaC" binding  globulin. As mentioned above, bioavailability of estrogen taken orally is low due to first-pass metabolism in the  liver. To reduce first-pass metabolism, the drugs may be administered by transdermal patch, topical gel or  emulsion, i ntravagi nal ly, or by inj ection. They are hydroxylated in the liver to derivatives that are subsequently  glucuronidated or sulfated. The parent drugs and their metabolites undergo excretion into the bile and are then  reabsorbed through the enterohepatic circulation. Inactive products are excreted in the urine. [Note: In  individuals with liver damage, serum estrogen levels may increase due to reduced metabolism, causing  feminization in males or signs of estrogen excess in females. ]   • Estrogen decreases the resorption  of bone but has no effect on bone  formation.   • Estrogen decreases the  frequency of hip fracture. [Note:  Dietary calcium (1 200 mg daily)  and weight-bearing exercise  also slow loss of bone.]   • Treatment with estrogens must  begin within 2 or 3 years of  menopause — and earlier if  possible.    • Estrogen treatment reverses  postmenopausal atrophy  of the vulva, vagina, urethra,  and trigone of the bladder.   Nausea and breast tenderness are among the most common adverse effects of estrogen therapy. Postmenopausal  uterine bleeding can occur.   In addition, the risk of thromboembolic events, myocardial infarction, and breast and endometrial cancer is  increased with use of estrogen therapy. [Note: The increased risk of endometrial cancer can be offset by including a  progestin along with the estrogen therapy.] Other effects of estrogen therapy are shown in Figure 25.3. The  synthetic nonsteroidal estrogen diethylstilbestrol has been implicated as the possible cause of a rare, clear-cell  cervical or vaginal adenocarcinoma observed among the daughters of women who took the drug during pregnancy.   3 See p. 360 in Lippincott's Illustrated Reviews: Biochemistry (4th ed.) for a discussion of LDLs, HDLs, and health.  pharm4th.mdb 300 4/ 26/ 08 9: 18:08 AM   Selective estrogen-receptor modulators (SERMs) are a new class of estrogen-related compounds. In the past, a  number of these agents had been categorized as antiestrogens, and consequently, there is some confusion. The  term SERM is now reserved for compounds that interact at estrogen receptors but have different effects on  different tissues; that is, they display selective agonism or antagonism according to the tissue type. For example,  tamoxifen is an estrogen antagonist in breast cancer tissue but can cause endometrial hyperplasia by acting as a  partial agonist in the uterus. Other SERMs are toremifene and raloxifene. Clomiphene is also sometimes designated  as a SERM.   Considered to be the first SERM, tamoxifen [tah-MOKS-ih-fen] competes with estrogen for binding to the estrogen  receptor in breast tissue and is currently used in the palliative treatment of metastatic breast cancer in  postmenopausal women. It may also be used as adj uvant therapy following mastectomy or radiation and to reduce  the risk of breast cancer in high-risk patients. [Note: Normal breast growth is stimulated by estrogens. It is therefore  not surprising that some breast tumors regress following treatment with tamoxifen .] The most frequent adverse  effects of tamoxifen treatment are hot flashes and nausea. Menstrual irregularities and vaginal bleeding can also  occur. Due to its estrogenic activity in the endometrium, hyperplasia and malignancies have been reported in  women who have been maintained on tamoxifen. This has led to recommendations for limiting the length of time on  the drug for some indications.   Raloxifene [rah-LOX-ih-feen] is a second-generation SERM that is related to tamoxifen. Its clinical use is based on  its ability to decrease bone resorption and overall bone turnover. Bone density is increased, and vertebral fractures  are decreased (Figure 25.4). Unlike estrogen and tamoxifen, it apparently has little to no effect on the  endometrium and, therefore, may not predispose to uterine cancer. Raloxifene lowers total cholesterol and  low-density lipoprotein (LDL) in the serum, but it has no effect on high-density lipoprotein (HDL) or triacylglycerol  levels. To date, clinical trials have not shown any significant reduction in coronary events with raloxifene. The drug  is currently approved only for the prevention and treatment of osteoporosis in postmenopausal women. Raloxifene  has been shown to reduce the incidence of invasive breast cancer in postmenopausal women. [Note: At present, an  U.S. Food and Drug Administration advisory panel has recommended that raloxifene be approved for the prevention   Figure 25.4 Hip bone density increases with raloxifene in postmenopausal women.   1. Pharmacokinetics: The drug is readily absorbed orally and is rapidly converted to glucuronide conj ugates  through first-pass metabolism. More than 95 percent of raloxifene is bound to plasma proteins. Both the parent  drug and the conj ugates undergo enterohepatic cycling. The primary route of excretion is through the bile into  the feces.   2. Adverse effects: Hot flashes and leg cramps are common adverse effects with raloxifene. As with the estrogens  and tamoxifen, the use of raloxifene has an increased risk of deep-vein thrombosis, pulmonary embolism, and  retinal-vein thrombosis. Raloxifene should be avoided in women who are or may become pregnant. In addition,  women who have a past or active history of venous thromboembolic events should not take the drug.   Coadministration with cholestyramine can reduce the absorption of raloxifene by 60 percent; therefore, these  drugs should not be taken together. In one study, raloxifene caused a 10 percent drop in prothrombin time in  patients taking warfarin. Thus, it is prudent to monitor prothrombin time in these individuals.   Toremifene [tor-EH-mih-feen] is a SERM with properties and side effects similar to those of tamoxifen. Data on the  risk of endometrial hyperplasia and cancer with toremifene are lacking. The use of toremifene is restricted to  postmenopausal women with metastatic breast cancer.   By acting as a partial estrogen agonist and interfering with the negative feedback of estrogens on the hypothalamus,  clomiphene [KLOE-mi-feen] increases the secretion of gonadotropin-releasing hormone and gonadotropins, leading  to a stimulation of ovulation. The drug has been used successfully to treat infertility associated with anovulatory  cycles, but it is not effective in women with ovulatory dysfunction due to pituitary or ovarian failure. Adverse  effects are dose related and include headache, nausea, vasomotor flushes, visual disturbances, and ovarian  enlargement.   Progesterone, the natural progestin, is produced in response to luteinizing hormone (LH) by both females (secreted  by the corpus luteum, primarily during the second half of the menstrual cycle, and by the placenta) and by males  (secreted by the testes). It is also synthesized by the adrenal cortex in both sexes. In females, progesterone  promotes the development of a secretory endometrium that can accommodate implantation of a newly forming  embryo. The high levels of progesterone that are released during the second half of the menstrual cycle (the luteal  phase) inhibit the production of gonadotropin and, therefore, prevent further ovulation. If conception takes place,  progesterone continues to be secreted, maintaining the endometrium in a favorable state for the continuation of  the pregnancy and reducing uterine contractions. If conception does not take place, the release of progesterone  from the corpus luteum ceases abruptly. This decline stimulates the onset of menstruation. (Figure 25. 5 summarizes  the hormones produced during the menstrual cycle.) Progestins exert their mechanism of action in a manner  analogous to that of the other steroid hormones. They cause: 1) an increase in hepatic glycogena€"probably through  an insulin-mediated mechanism; 2) a decrease in Na + reabsorption in the kidney due to competition   with aldosterone at the mineralocorticoid receptor; 3) an increase in body temperature through an unknown  mechanism; 4) a decrease in some plasma amino acids; and 5) an increase in excretion of urinary nitrogen.   Figure 25.5 The menstrual cycle with plasma levels of pituitary and ovarian hormones and a schematic   representation of changes in the morphology of the uterine lining. FSH =f ollicle-stimulating hormone; LH =  luteinizing hormone.   The maj or clinical uses of progestins are to rectify a hormonal deficiency and for contraception, in which they are  generally used with estrogens, either in combination or in a sequential manner. Progesterone by itself is not used  widely as a therapy because of its rapid metabolism, resulting in low bioavailability. Synthetic progestins used in  contraception are more stable to first-pass metabolism, allowing lower doses when administered orally. These  agents include norethindrone [nor-ETH-in-drone], norethindrone acetate, norgestrel [nor-J ES-trel],  levonorgestrel [lee-voe-nor-J ES-trel], desogestrel [des-oh-J ES-trel], norgestimate [nor-J ES-tih-mate], and  drospirenone [dro-SPY-re-none], Most synthetic progestins used in oral contraceptives (for example,  norethindrone, norethindrone acetate, norgestrel, levonorgestrel ) are derived from 19-nortestosterone and  possess some androgenic activity because of their structural similarity to testosterone. Medroxyprogesterone  [me-DROK-see-proe-J ES-ter-one] acetate is an injectable contraceptive, and the oral form is a common progestin  component of postmenopausal EPT. Other clinical uses of the progestins are in the control of dysfunctional uterine  bleeding, treatment of dysmenorrhea, and management of endometriosis.   A micronized preparation of progesterone is rapidly absorbed after oral administration. It has a short half-life in the  plasma and is almost completely metabolized by the liver. The glucuronidated metabolite (pregnanediol  glucuronide) is excreted primarily by the kidney. Synthetic progestins are less rapidly metabolized.  Medroxyprogesterone acetate is inj ected intramuscularly or subcutaneously and has a duration of action of 3  months. The other progestins last from 1 to 3 days.   The maj or adverse effects associated with the use of progestins are headache, depression, weight gain, and changes  in libido (Figure 25.6). Some progestins, such as the 19-nortestosterone derivatives, have androgenic activity and  can increase the ratio of LDL to H DL cholesterol and cause acne and hirsutism. Less androgenic progestins, such as  norgestimate and drospirenone, may be preferred in women with acne. Injectable medroxyprogesterone acetate  has been associated with an increased risk of osteoporosis, which has led to recommendations for limiting the  duration of use.   Mifepristone [mih-feh-PRIH-stone] (also designated as RU 486) is a progesterone antagonist with partial agonist  activity. [Note: Mifepristone also has potent antiglucocorticoid activity. ] Administration of this drug to females  early in pregnancy results, in most cases (up to 94 percent), in abortion of the fetus due to the interference with    progesterone and the decline in human chorionic gonadotropin. The maj or adverse effects are significant uterine  bleeding and the possibility of an incomplete abortion. However, administration of misoprostol orally or  intravaginally after a single oral dose of mifepristone effectively terminates gestation. Mifepristone is being  investigated as an oral contraceptive and an emergency contraceptive agent.   Drugs are available that decrease fertility by a number of different mechanisms, such as preventing ovulation,  impairing gametogenesis or gamete maturation, or interfering with gestation. Currently, interference with ovulation  is the most common pharmacologic intervention for preventing pregnancy (Figure 25.7).   1. Combination oral contraceptives: Products containing a combination of an estrogen and a progestin are the  most common type of oral contraceptives. Monophasic combination pills contain a constant dose of estrogen and  progestin given over 21 days. Triphasic oral contraceptive products attempt to mimic the natural female cycle  and contain a constant dose of estrogen with increasing doses of progestin given over three successive 7-day  periods. With either type of combination oral contraceptive, active pills are taken for 21 days followed by 7 days  of placebo. Withdrawal bleeding occurs during the hormone-free interval. [Note: Estrogens that are commonly  present in the combination pills are ethinyl estradiol and mestranol. The most common progestins are  norethindrone, norethindrone acetate, norgestrel, levonorgestrel, desogestrel, norgestimate, and  drospirenone. ] These preparations are highly effective in achieving contraception (Figure 25.8). Use of  extended-cycle contraception (84 active pills followed by 7 days of placebo) results in less frequent withdrawal  bleeding. A continuous oral contraceptive product (active pills taken 365 days of the year) is also available.   Figure 25.7 Comparison of contraceptive use among United States women ages 15 to 44 years.    2. Transdermal patch: An alternative to combination oral contraceptive pills is a transdermal contraceptive patch  containing ethinyl estradiol and the progestin norelgestromin. One contraceptive patch is applied each week  for 3 weeks to the abdomen, upper torso, or buttock. Week 4 is patch-free, and withdrawal bleeding occurs.    The transdermal patch has efficacy comparable to that of the oral contraceptives; however, it has been shown  to be less effective in women weighing greater than 90 kilograms. Contraindications and adverse effects for the  patch are similar to those of oral contraceptives. Recent data have indicated that total estrogen exposure with  the transdermal patch is up to 60 percent greater than that seen with a 35 Apg estrogen oral contraceptive.   Increased exposure to estrogen may increase the risk of adverse events such as thromboembolism.   3. Vaginal ring: An additional contraceptive option is a vaginal ring containing ethinyl estradiol and etonogestrel .   The ring is inserted into the vagina and is left in place for 3 weeks. Week 4 is ring-free, and withdrawal bleeding  occurs. The contraceptive vaginal ring has efficacy, contraindications, and adverse effects similar to those of  oral contraceptives. One caveat with the vaginal ring is that it may occasionally slip or be expelled accidentally.   4. Progestin-only pills: Products containing a progestin only, usually norethindrone or norgestrel (called a  a€oemini-pilla€§), are taken daily on a continuous schedule. Progestin-only pills deliver a low, continuous  dosage of drug. These preparations are less effective than the combination pill (see Figure 25.8), and they may  produce irregular menstrual cycles more frequently than the combination product. The progestin-only pill has  limited patient acceptance because of   anxiety over the increased possibility of pregnancy and the frequent occurrence of menstrual irregularities. The  progestin-only pill may be used for patients who are breast-feeding (unlike estrogen, progestins do not have an  effect on milk production), are intolerant to estrogen, or are smokers or have other contraindications to  estrogen-containing products.    5. Progestin implants: A subdermal implant containing etonogestrel offers long-term contraception. One 4-cm  capsule is placed subcutaneously in the upper arm and provides contraception for approximately 3 years. The  implant is nearly as reliable as sterilization, and the effect is totally reversible when surgically removed. Once  the progestin-containing capsule is implanted, this method of contraception does not rely on patient  compliance. This may, in part, explain the low failure rate for this method. Principal side effects of the implants  are irregular menstrual bleeding and headaches.   6. Progestin intrauterine device: A /evonorgestre/-releasing intrauterine system offers a highly effective method  of long-term contraception. This intrauterine device provides contraception for up to 5 years. It is a suitable  method of contraception for women who already have at least one child and do not have a history of pelvic  inflammatory disease or ectopic pregnancy.   7. Postcoital contraception: The overall risk of pregnancy after an episode of coitus without effective  contraception is shown in the Figure 25.9. Postcoital or emergency contraception reduces the probability of  pregnancy to between 0. 2 and 3 percent. Emergency contraception uses high doses of progestin (for example,  0.75 mg of levonorgestrel) or high doses of estrogen (100 Apg of ethinyl estradiol) plus progestin (0.5 mg of  levonorgestrel) administered within 72 hours of unprotected intercourse (the a€oemorning-aftera€^ pill). A  second dose of emergency contraception should be taken 12 hours after the first dose. For maximum  effectiveness, emergency contraception should be taken as soon as possible after unprotected intercourse. The  progestin-only emergency contraceptive regimens are generally better tolerated than the estrogen-progestin  combination regimens. A single dose of mifepristone has also been used for emergency contraception.    Figure 25.9 Risk of pregnancy after unprotected intercourse in young couples in their mid twenties.   The mechanism of action for these contraceptives is not completely understood. It is likely that the combination of  estrogen and progestin administered over an approximately 3-week period inhibits ovulation. [Note: The estrogen  provides a negative feedback on the release of LH and follicle-stimulating hormone (FSH) by the pituitary gland,  thus preventing ovulation. The progestin also inhibits LH release and thickens the cervical mucus, thus hampering  the transport of sperm. Withdrawal of the progestin stimulates menstrual bleeding during the placebo week].    Most adverse effects are believed to be due to the estrogen component, but cardiovascular effects reflect the   action of both estrogen and progestin. The incidence of adverse effects with oral contraceptives is relatively low   1. Major adverse effects: The major adverse effects are breast fullness, depression, fluid retention, headache,  nausea, and vomiting.   2. Cardiovascular: Although rare, the most serious adverse effect of oral contraceptives is cardiovascular disease,  including thromboembolism, thrombophlebitis, hypertension, increased incidence of myocardial infarction, and  cerebral and coronary thrombosis. These adverse effects are most common among women who smoke and who  are older than 35 years, although they may affect women of any age.   3. Carcinogenicity: Oral contraceptives have been shown to decrease the incidence of endometrial and ovarian  cancer. Their ability to induce other neoplasms is controversial. The production of benign tumors of the liver  that may rupture and hemorrhage is rare.   4. Metabolic: Abnormal glucose tolerance (similar to the changes seen in pregnancy) is sometimes associated with  oral contraceptives. Weight gain is common in women who are taking the nortestosterone derivatives.   5. Serum lipids: The combination pill causes a change in the serum lipoprotein profile: Estrogen causes an increase  in HDL and a decrease in LDL (a desirable occurrence), whereas progestins may negate some of the beneficial  effects of estrogen. [Note: The potent progestin norgestrel causes the greatest increase in the LDL: HDL ratio.  Therefore, estrogen-dominant preparations are best for individuals with elevated serum cholesterol.]   6. Contraindications: Oral contraceptives are contraindicated in the presence of cerebrovascular and  thromboembolic disease, estrogen-dependent neoplasms, liver disease, and pregnancy. Combination oral  contraceptives should not be used in patients over the age of 35 who are heavy smokers.   The androgens are a group of steroids that have anabolic and/or masculinizing effects in both males and females.  Testosterone [tess-TOSS-te-rone], the most important androgen in humans, is synthesized by Leydig cells in the    testes and, in smaller amounts, by cells in the ovary of the female and by the adrenal gland in both sexes. Other  androgens secreted by the testes are 5\±di hydrotestosterone ( DHT ), androstenedione, and  dehydroepiandrosterone (DHEA) in small amounts. In adult males, testosterone secretion by Leydig cells is  controlled by gonadotropin-releasing hormone from the hypothalamus, which stimulates the anterior pituitary gland  to secrete FSH and LH. [Note: LH stimulates steroidogenesis in the Leydig cells, whereas FSH is necessary for  spermatogenesis. ] Testosterone or its active metabolite, DHT, inhibits production of these specific trophic  hormones through a negative feedback loop and, thus, regulates testosterone production (Figure 25. 10). The  androgens are required for 1) normal maturation in the male, 2) sperm production, 3) increased synthesis of muscle  proteins and hemoglobin, and 4) decreased bone resorption. Synthetic modifications of the androgen structure are  designed to modify solubility and susceptibility to enzymatic breakdown (thus prolonging the half-life of the  hormone) and to separate anabolic and androgenic effects.   Like the estrogens and progestins, androgens bind to a specific nuclear receptor in a target cell. Although  testosterone itself is the active ligand in muscle and liver, in other tissues it must be metabolized to derivatives,  such as DHT. For example, after diffusing into the cells of the prostate, seminal vesicles, epididymis, and skin,  testosterone is converted by 5i±-reductase to DHT, which binds to the receptor. In the brain, liver, and adipose  tissue, testosterone is biotransformed to estradiol by cytochrome P450 aromatase. The hormone-receptor complex  binds to DNA and stimulates the synthesis of specific RNAs and proteins. [Note: Testosterone analogs that cannot be  converted to DFIT have less effect on the reproductive system than they do on the skeletal musculature. ]   1. Androgenic effects: Androgenic steroids are used for males with inadequate androgen secretion. [Note:  Flypogonadism can be caused by testicular dysfunction (primary hypogonadism) or due to failure of the  hypothalamus or pituitary (secondary hypogonadism). In each instance, androgen therapy is indicated. ]   2. Anabolic effects: Anabolic steroids can be used to treat senile osteoporosis and chronic wasting associated with  human immunodeficiency virus or cancer. They may also be used as adj unct therapy in severe burns and to  speed recovery from surgery or chronic debilitating diseases.   3. Endometriosis: Danazol [DAH-nah-zole], a mild androgen, is used in the treatment of endometriosis (ectopic  growth of the endometrium) and fibrocystic breast disease. It inhibits release of FSH and LH but has no effect on  the aromatase. Weight gain, acne, decreased breast size, deepening voice, increased libido, and increased hair  growth are among the adverse effects. Danazol has been reported occasionally to suppress adrenal function.   4. Unapproved use: Anabolic steroids are used to increase lean body mass, muscle strength, and endurance in  athletes and body builders (see below). In some popular publications, DHEA (a precursor of testosterone and  estrogen) has been touted as the anti-aging hormone as well as a a€oeperformance enhancer. a€§ With its ready  availability in health food stores, the drug has been abused. There is no definitive evidence that it slows aging,  however, or that it improves performance at normal therapeutic doses.   1. Testosterone: This agent is ineffective orally because of inactivation by first-pass metabolism. As with the other  sex steroids, testosterone [tes-TOS-ter-own] is rapidly absorbed and is metabolized to relatively or completely  inactive compounds that are excreted primarily in the urine. Testosterone and its Cn-esters (for example,  testosterone cypionate or enanthate) are administered intramuscularly. [Note: The addition of the esterified  lipid makes the hormone more lipid soluble, thereby increasing its duration of action. ] Transdermal patches,  topical gels, and buccal tablets of testosterone are also available. Figure 25.11 shows serum levels of  testosterone achieved by inj ection and by a transdermal patch in hypogonadal men. Testosterone and its esters  demonstrate a 1:1 relative ratio of androgenic to anabolic activity.    Figure 25.11 A. Administration and fate of androgens. B. Serum testosterone concentrations after  administration by inj ection or transdermal patch to hypogonadal men. The yellow band indicates the  upper and lower limits of normal range.   2. Testosterone derivatives: Alkylation of the 17T± position of testosterone allows oral administration of the  hormone. Agents such as fluoxymesterone [floo-ox-ee-MESS-teh-rone] have a longer half-life in the body than  that of the naturally occurring androgen. Fluoxymesterone is effective when given orally, and it has a 1:2  androgenic to anabolic ratio. Oxandrolone [ox-AN-droe-lone] is another orally active testosterone derivative  with anabolic activity 3 to 13 times that of testosterone. Hepatic adverse effects have been associated with the  17l±-alkylated androgens.   1. In females: Androgens can cause masculinization, with acne, growth of facial hair, deepening of the voice, male  pattern baldness, and excessive muscle development. Menstrual irregularities may also occur. Testosterone  should not be used by pregnant women because of possible virilization of the female fetus.   2. In males: Excess androgens can cause priapism, impotence, decreased spermatogenesis, and gynecomastia.   Cosmetic changes such as those described for females may occur as well. Androgens can also stimulate growth of  the prostate.   3. In children: Androgens can cause abnormal sexual maturation and growth disturbances resulting from premature  closing of the epiphyseal plates.   4. General effects: Androgens increase serum LDL and lower serum HDL levels; therefore, they increase the  LDL: HDL ratio and potentially increase the risk for premature coronary heart disease. Androgens can also cause  fluid retention, leading to edema.   5. In athletes: Use of anabolic steroids, (for example, DHEA or nandrolone [NAN-dro-lone]) by athletes can cause  premature closing of the epiphysis of the long bones, which stunts growth and interrupts development. The high  doses taken by these young athletes may result in reduction of testicular size, hepatic abnormalities, increased  aggression (a€oeroid ragea€^), major mood disorders, and the other adverse effects described above.   Antiandrogens counter male hormonal action by interfering with the synthesis of androgens or by blocking their  receptors. For example, at high doses, the antifungal drug ketoconazole inhibits several of the cytochrome P450  enzymes involved in steroid synthesis. Finasteride [fin-AS-ter-ide] and dutasteride [doo-TAS-ter-ride], agents used  for the treatment of benign prostatic hypertrophy, inhibit 5i±-reductase (Figure 25. 12). The resulting decrease in  formation of DHT in the prostate leads to a reduction in prostate size. Antiandrogens, such as fiutamide [FLOO-  tah-mide], act as competitive inhibitors of androgens at the target cell. Fiutamide is used in the treatment of  prostatic carcinoma in males. Two other potent antiandrogens, bicalutamide [bye-ka-LOO-ta-mide] and nilutamide  [nye-LOO-tah-mide], are effective orally for the treatment of metastatic prostate cancer.   • Terazosin, doxazosin, tamsulosin,  and alfuzosin relieve outlet  obstruction of the bladder by  reducing the tension of prostatic  smooth muscle in the prostate,  prostate capsule, and bladder  neck.    • The most important side effects  are orthostatic hypotension  and dizziness.    • The major side effects of  the 5 (/.-reductase inhibitors  are decreased libido and  ejaculatory or erectile  dysfunction.    • Finasteride and dutasteride  act by reducing the size of  the prostate gland. Treatment  for 6 to 1 2 months is generally  needed before prostate size is  sufficiently reduced to improve  symptoms.    • Combination therapy with an  O' -adrenergic antagonist plus a  5 ( /-reductase inhibitor produces  the greatest reduction in the  symptoms of BPH, such as acute  urinary retention, urinary  incontinence, renal insufficiency.   25. 1 Young athletes who abuse androgens should be made aware of the side effects of these drugs. Which one  of the following is, however, not of concern?    25.2 A 70-year-old woman is being treated with raloxifene for osteoporosis. There is an increased risk of her  developing:    25.3 A 23-year-old woman has failed to become pregnant after 2 years of unprotected intercourse. Which of  the following would be effective in treating infertility due anovulatory cycles?   D. Is most effective if instituted at the first signs of menopause.   E. Requires higher doses of estrogen than with oral contraceptive therapy.   >Table of Contents > Unit V - Drugs Affecting the Endocrine System >Chapter 26 - Adrenal Hormones   The adrenal gland consists of the cortex and the medulla. The latter secretes epinephrine, whereas the cortex, the  subj ect of this chapter, synthesizes and secretes two maj or classes of steroid hormonesa€"the  adrenocorticosteroids (glucocorticoids and mineralocorticoids; Figure 26. 1), and the adrenal androgens. The  adrenal cortex is divided into three zones that synthesize various steroids from cholesterol and then secrete them  (Figure 26.2). The outer zona glomerulosa produces mineralocorticoids (for example, aldosterone), which are  responsible for regulating salt and water metabolism. Production of aldosterone is regulated primarily by the renin-  angiotensin system (see p. 216). The middle zona fasciculata synthesizes glucocorticoids (for example, cortisol),  which are involved with normal metabolism and resistance to stress. The inner zona reticularis secretes adrenal  androgens (for example, dehydroepiandrosterone). Secretion by the two inner zones and, to some extent, the  outer zone is controlled by pituitary corticotropin adrenocorticotropic hormone [ACTH; also called cortictropin],  which is released in response to the hypothalamic corticotropin-releasing hormone (CRH; also called corticotropin-  releasing factor). Glucocorticoids serve as feedback inhibitors of corticotropin and CRH secretion. Hormones of the  adrenal cortex are used in replacement therapy; in the treatment and management of asthma as well as other  inflammatory diseases, such as rheumatoid arthritis; in the treatment of severe allergic reactions; and in the  treatment of some cancers.   The adrenocorticoids bind to specific intracellular cytoplasmic receptors in target tissues. [Note: The glucocorticoid  receptor is widely distributed throughout the body, whereas the mineralocorticoid receptor is confined mainly to  excretory organs, such as the kidney, colon, and salivary and sweat glands. ] After dimerizing, the receptor-  hormone complex translocates into the nucleus, where it attaches to gene promoter elements, acting as a  transcription factor to turn genes on or off, depending on the tissue (Figure 26. 3) 1 . This mechanism requires time to  produce an effect, but other glucocorticoid effects, such as their interaction with catecholamines to mediate  relaxation of bronchial musculature or lipolysis, have effects that are immediate. Some normal actions and some  selected mechanisms of adrenocorticoids are described in this section.   Cortisol is the principal human glucocorticoid. Normally, its production is diurnal, with a peak early in the morning  followed by a decline and then a secondary, smaller peak in the late afternoon. Factors such as stress and levels of  the circulating steroid influence secretion. The effects of cortisol are many and diverse. In general, all  glucocorticoids:   1. Promote normal intermediary metabolism: Glucocorticoids favor gluconeogenesis through increasing amino  acid uptake by the liver and kidney and elevating activities of gluconeogenic enzymes. They stimulate protein  catabolism (except in the liver) and lipolysis, thereby providing the building blocks and energy that are needed  for glucose synthesis. [Note: Glucocorticoid insufficiency may result in hypoglycemia (for example, during  stressful periods or fasting). ] Lipolysis results as a consequence of the glucocorticoid augmenting the action of  growth hormone on adipocytes, causing an increase in the activity of hormone-sensitive lipase.   2. Increase resistance to stress: By raising plasma glucose levels, glucocorticoids provide the body with the  energy it requires to combat stress caused, for example, by trauma, fright, infection, bleeding, or debilitating  disease. Glucocorticoids can cause a modest rise in blood pressure, apparently by enhancing the vasoconstrictor  action of adrenergic stimuli on small vessels. [Note: Individuals with adrenal insufficiency may respond to severe  stress by becoming hypotensive. ]   3. Alter blood cell levels in plasma: Glucocorticoids cause a decrease in eosinophils, basophils, monocytes, and  lymphocytes by redistributing them from the circulation to lymphoid tissue. In contrast to this effect, they  increase the blood levels of hemoglobin, erythrocytes, platelets, and polymorphonuclear leukocytes. [Note: The  decrease in circulating lymphocytes and macrophages compromises the body's ability to fight infections.   However, this property is important in the treatment of leukemia (see p. 478).]   4. Have anti-inflammatory action: The most important therapeutic property of the glucocorticoids is their ability  to dramatically reduce the inflammatory response and to suppress immunity. The exact mechanism is complex  and incompletely understood. However, the lowering and inhibition of peripheral lymphocytes and macrophages  is known to play a role. Also involved is the indirect inhibition of phospholipase A 2 (due to the steroid-mediated  elevation of lipocortin), which blocks the release of arachidonic acida€"the precursor of the prostaglandins and  leukotrienesa€"from membrane-bound phospholipid. Cyclooxygenase-2 synthesis in inflammatory cells is further  reduced, lowering the availability of prostaglandins. In addition, interference in mast cell degranulation results  in decreased histamine and capillary permeability.   5. Affect other components of the endocrine system: Feedback inhibition of corticotropin production by  elevated glucocorticoids causes inhibition of further glucocorticoid synthesis as well as further production of  thyroid-stimulating hormone. In contrast, growth hormone production is increased.   6. Can have effects on other systems: Adequate cortisol levels are essential for normal glomerular filtration.   However, the effects of corticosteroids on other systems are mostly associated with the adverse effects of the  hormones. High doses of glucocorticoids stimulate gastric acid and pepsin production and may exacerbate  ulcers. Effects on the central nervous system that influence mental status have been identified. Chronic  glucocorticoid therapy can cause severe bone loss. Myopathy leads patients to complain of weakness.   Mineralocorticoids help to control the body's water volume and concentration of electrolytes, especially sodium and  potassium. Aldosterone acts on kidney tubules and collecting ducts, causing a reabsorption of sodium, bicarbonate,  and water. Conversely, aldosterone decreases reabsorption of potassium, which, with H + , is then lost in the urine.  Enhancement of sodium reabsorption by aldosterone also occurs in gastrointestinal mucosa and in sweat and salivary  glands. [Note: Elevated aldosterone levels may cause alkalosis and hypokalemia, whereas retention of sodium and  water leads to an increase in blood volume and blood pressure. Hyperaldosteronism is treated with spironolactone .]  Target cells for aldosterone action contain mineralocorticoid receptors that interact with the hormones in a manner  analogous to that of the glucocorticoid receptor (see above).    A lipid-soluble steroid diffuses  across the cell membrane and  binds to a cytoplasmic receptor.   Binding to a gluco-  corticosteroid  response element  stimulates or inhibits  the activity of an  adjacent promoter,  which initiates or  inhibits transcription  of a gene.   Several semisynthetic derivatives of the glucocorticoids have been developed that vary in their anti-inflammatory  potency, degree to which they cause sodium retention, and duration of action. These are summarized in Figure  26.4.   1. Replacement therapy for primary adrenocortical insufficiency (Addison's disease): This disease is caused by  adrenal cortex dysfunction (as diagnosed by the lack of patient response to corticotropin administration).  Hydrocortisone [hye-droe-KOR-ti-sone], which is identical to natural cortisol, is given to correct the deficiency.   Failure to do so results in death. The dosage of hydrocortisone is divided so that two-thirds of the normal daily  dose is given in the morning and one-third is given in the afternoon. [Note: The goal of this regimen is to  approximate the daily hormone levels resulting from the circadian rhythm exhibited by cortisol, which causes  plasma levels to be maximal around 8 AM and then decrease throughout the day to their lowest level around 1  AM] Administration of fludrocortisone [floo-droe-KOR-tih-sone], a potent synthetic mineralocorticoid with some  glucocorticoid activity, may also be necessary to raise the mineralocorticoid activity to normal levels.   2. Replacement therapy for secondary or tertiary adrenocortical insufficiency: These deficiencies are caused  by a defect either in CRH production by the hypothalamus or in corticotropin production by the pituitary.   [Note: Under these conditions, the synthesis of mineralocorticoids in the adrenal cortex is less impaired than  that of glucocorticoids.] The adrenal cortex responds to corticotropin (ACTH) administration by synthesizing  and releasing the adrenal corticosteroids. Hydrocortisone is also used for these deficiencies.   Figure 26.4 Pharmacologic effects and duration of action of some commonly used natural and synthetic  corticosteroids. Activities are all relative to that of hydrocortisone, which is considered to be 1.    3. Diagnosis of Cushing's syndrome: Cushing's syndrome is caused by a hypersecretion of glucocorticoids that  results either from excessive release of corticotropin by the anterior pituitary or an adrenal tumor. The  dexamethasone [dex-a-METH-a-sone] suppression test is used to diagnose the cause of an individual's case of  Cushing's syndrome. This synthetic glucocorticoid suppresses cortisol release in individuals with pituitary-  dependent Cushing's syndrome, but it does not suppress glucocorticoid release from adrenal tumors. [Note:   Chronic treatment with high doses of glucocorticoid is a frequent cause of iatrogenic Cushing's syndrome.]   4. Replacement therapy for congenital adrenal hyperplasia: This is a group of diseases resulting from an enzyme  defect in the synthesis of one or more of the adrenal steroid hormones. This condition may lead to virilization in  females due to overproduction of adrenal androgens (see below). Treatment of this condition requires  administration of sufficient corticosteroids to normalize the patient's hormone levels by suppressing release of  CRH and ACTH. This decreases production of adrenal androgens. The choice of replacement hormone depends  on the specific enzyme defect.   5. Relief of inflammatory symptoms: Glucocorticoids dramatically reduce the manifestations of inflammations (for  example, rheumatoid and osteoarthritic inflammations, as well as inflammatory conditions of the skin), including  the redness, swelling, heat, and tenderness   that are commonly present at the inflammatory site. The effect of glucocorticoids on the inflammatory process  is the result of a number of actions, including the redistribution of leukocytes to other body compartments,  thereby lowering their blood concentration (their function is also compromised). Other effects include an  increase in the concentration of neutrophils; a decrease in the concentration of lymphocytes (T and B cells),  basophils, eosinophils, and monocytes; and an inhibition of the ability of leukocytes and macrophages to  respond to mitogens and antigens. The decreased production of prostaglandins and leukotrienes is believed to  be central to the anti-inflammatory action. Glucocorticoids also influence the inflammatory response by their  ability to reduce the amount of histamine that is released from basophils and mast cells, thus diminishing the  activation of the kinin system [Note: The ability of glucocorticoids to inhibit the immune response is also a result  of the other actions described above.]   6. Treatment of allergies: Glucocorticoids are beneficial in the treatment of the symptoms of bronchial asthma,  allergic rhinitis, and drug, serum, and transfusion allergic reactions. These drugs are not, however, curative.   [Note: Beclomethasone dipropionate [bek-loe-METH-ah-sone], triamcinolone [tri-am-SI N-o-lone] , and others  (see Figure 26. 4) are applied topically to the respiratory tract through inhalation from a metered-dose  dispenser. This minimizes systemic effects and allows the patient to significantly reduce or eliminate the use of  oral steroids.]   7. Acceleration of lung maturation: Respiratory distress syndrome is a problem in premature infants. Fetal cortisol  is a regulator of lung maturation. Consequently, a dose of beclomethasone is administered intramuscularly to  the mother 48 hours prior to birth, followed by a second dose 24 hours before delivery.   1. Absorption and fate: Synthetic glucocorticoid preparations with unique pharmacokinetic characteristics are  used therapeutically. Those that are administered orally are readily absorbed from the gastrointestinal tract.  Selected compounds can also be administered intravenously, intramuscularly, intra-articularly (for example, into  arthritic joints), topically, or as an aerosol for inhalation (Figure 26.5). Greater than 90 percent of the absorbed  glucocorticoids are bound to plasma proteinsa€"most to corticosteroid-binding globulin, and the remainder to  albumin. Corticosteroids are metabolized by the liver microsomal oxidizing enzymes. The metabolites are    conj ugated to glucuronic acid or sulfate, and the products are excreted by the kidney. [Note: The half-life of  adrenal steroids may increase dramatically in individuals with hepatic dysfunction. ] The only glucocorticoid that  has no effect on the fetus in pregnancy is prednisone [PRED-ni-sone], It is a prodrug that is not converted to the  active compound, prednisolone [pred-NIH-so-lene], in the fetal liver. Any prednisolone formed in the mother is  biotransformed to prednisone by the fetus.   2. Dosage: In determining the dosage of adrenocortical steroids, many factors need to be considered, including  glucocorticoid versus mineralocorticoid activity, duration of action, type of preparation, and   time of day when the steroid is administered. For example, when large doses of the hormone are required over  an extended period of time (more than 2 weeks), suppression of the hypothalamic-pituitary-adrenal (HPA) axis  occurs. To prevent this adverse effect, a regimen of alternate-day administration of the adrenocortical steroid  may be useful. This schedule allows the HPA axis to recover/ function on the days the hormone is not taken.   The common side effects of long-term corticosteroid therapy are summarized in Figure 26.6. Osteoporosis is the  most common adverse effect due to the ability of glucocorticoids to suppress intestinal Ca 2+ absorption, inhibit  bone formation, and decrease sex hormone synthesis. Alternate-day dosing does not prevent osteoporosis. Patients  are advised to take calcium and vitamin D supplements. Drugs that are effective in treating osteoporosis may also be  beneficial. [Note: Increased appetite is not necessarily an adverse effect. In fact, it is one of the reasons for the  use of prednisone in cancer chemotherapy. ] The classic Cushing-like syndromea€"redistribution of body fat, puffy  face, increased body hair growth, acne, insomnia, and increased appetitea€"are observed when excess  corticosteroids are present. Increased frequency of cataracts also occurs with long-term corticosteroid therapy.  Hyperglycemia may develop and lead to diabetes mellitus. Diabetics should monitor their blood glucose and adj ust  their medications accordingly. Hypokalemia caused by corticosteroid therapy can be counteracted by potassium  supplementation. Coadministration of medications that induce or inhibit the hepatic mixed-function oxidases may  require adj ustment of the glucocorticoid dose.   Withdrawal from these drugs can be a serious problem, because if the patient has experienced HPA suppression,  abrupt removal of the corticosteroids causes an acute adrenal insufficiency syndrome that can be lethal. This,  coupled with the possibility of psychologic dependence on the drug and the fact that withdrawal might cause an    exacerbation of the disease, means the dose must be tapered according to the individual, possibly through trial and  error. The patient must be monitored carefully.   Several substances have proven to be useful as inhibitors of the synthesis of adrenal steroids: metyrapone,  aminoglutethimide, ketoconazole, trilostane, spironolactone, and eplerenone. Mifepristone competes with  glucocorticoids for the receptor.   1. Metyrapone: Metyrapone [me-TEER-ah-pone] is used for tests of adrenal function and can be used for the  treatment of pregnant women with Cushing's syndrome. [Note: Dexamethasone suppression is now used more  commonly for diagnosis. ] Metyrapone interferes with corticosteroid synthesis by blocking the final step   (11- hydroxylation) in glucocorticoid synthesis, leading to an increase in 11-deoxycortisol as well as adrenal  androgens and the potent mineralocorticoid 11-deoxycorticosterone. The adverse effects encountered with  metyrapone include salt and water retention, hirsutism, transient dizziness, and gastrointestinal disturbances.   2. Aminoglutethimide: This drug acts by inhibiting the conversion of cholesterol to pregnenolone. As a result, the  synthesis of all hormonally active steroids is reduced. Aminoglutethimide [ah-mee-noe-glu-TETH-ih-mide] has  been used therapeutically in the treatment of breast cancer to reduce or eliminate androgen and estrogen  production. [Note: Tamoxifen has largely replaced aminoglutethimide in the treatment of breast cancer. ] In  these cases, it is used in conjunction with dexamethasone. However, it increases the clearance of  dexamethasone. Aminoglutethimide may also be useful in the treatment of malignancies of the adrenal cortex  to reduce the secretion of steroids. Recent studies indicate it is an aromatase inhibitor.    3. Ketoconazole: Ketoconazole [kee-toe-KON-ah-zole] is an antifungal agent that strongly inhibits all gonadal and  adrenal steroid hormone synthesis. It is used in the treatment of patients with Cushing's syndrome.   4. Trilostane: Trilostane [TRYE-loe-stane] reversibly inhibits 3i 2 -hydroxysteroid dehydrogenase and, thus, affects  aldosterone, cortisol, and gonadal hormone synthesis. Its side effects are gastrointestinal.   5. Mifepristone: At high doses, mifepristone [mih-feh-PRIH-stone] is a potent glucocorticoid antagonist as well as  an antiprogestin. It forms a complex with the glucocorticoid receptor, but the rapid dissociation of the drug  from the receptor leads to a faulty translocation into the nucleus. Its use is presently limited to the treatment of  inoperable patients with ectopic ACTH syndrome.   6. Spironolactone: This antihypertensive drug competes for the mineralocorticoid receptor and, thus, inhibits  sodium reabsorption in the kidney. It can also antagonize aldosterone and testosterone synthesis. It is effective  against hyperaldosteronism. Spironolactone [speer-oh-no-LAK-tone] is also useful in the treatment of hirsutism  in women, probably due to interference at the androgen receptor of the hair follicle. Adverse effects include  hyperkalemia, gynecomastia, menstrual irregularities, and skin rashes.   7. Eplerenone: Eplerenone [e-PLER-en-one] specifically binds to the mineralocorticoid receptor, where it acts as  an aldosterone antagonist. This specificity avoids the side effect of gynecomastia that is associated with the use  of spironolactone. It is approved as an antihypertensive.   26. 1 Measurements of cortisol precursors and plasma dehydroepiandrosterone sulfate confirm the diagnosis of  congenital adrenal hyperplasia (CAH) in a child. This condition can be effectively treated by:    26.2 Osteoporosis is a maj or adverse effect caused by the glucocorticoids. It is due to their ability to:   26.3 A child with asthma is being treated effectively with an inhaled preparation of beclomethasone  dipropionate. Which of the following adverse effects is of particular concern?   >Table of Contents > Unit VI - Drugs Affecting Other Organs >Chapter 27 - Respiratory System   Asthma, chronic obstructive pulmonary disease (COPD), and allergic rhinitis are commonly encountered respiratory  diseases. Each of these conditions may be associated with a troublesome cough, which may be the patient's only  presenting complaint. Asthma is a chronic disease characterized by hyperresponsive airways, affecting 10 million  patients (four to five percent of the U.S. population), and resulting annually in 2 million emergency room visits,  500,000 hospitalizations, and 5,000 deaths. COPD, also called emphysema or chronic bronchitis, affects  approximately 30 million Americans and is currently the fourth most common cause of preventable deaths in the  United States. Allergic rhinitis, characterized by itchy, watery eyes, runny nose, and a nonproductive cough, is an  extremely common condition that significantly decreases patient-reported quality of life. Allergic rhinitis affects  approximately 20 percent of the population, or over 61 million Americans. Coughing is an important defensive  respiratory response to irritants and has been cited as the number-one reason why patients seek medical care. A  troublesome cough may represent several etiologies, such as the common cold, sinusitis, and/or an underlying  chronic respiratory disease.   Each of these respiratory conditions can be adequately controlled through a combined approach of appropriate  lifestyle changes and medication management. Drugs used to treat respiratory conditions can be delivered topically  to the nasal mucosa, inhaled into the lungs, or given orally or parenteral ly for systemic absorption. Topical delivery  methods, such as nasal sprays or inhalers, are preferred so as to target affected tissues while minimizing systemic  side effects. Clinically useful drugs mitigate the specific pathology, such as by relaxing bronchial smooth muscle or  modulating the inflammatory response. Medications used to treat these commonly encountered respiratory  disorders are summarized in Figure 27. 1.   Asthma is an inflammatory disease of the airways characterized by episodes of acute bronchoconstriction causing  shortness of breath, cough, chest tightness, wheezing, and rapid respiration. These acute symptoms may resolve  spontaneously, with nonpharmacologic relaxation exercises, or with use of aCoequick reliefa€§ medications, such as    a short-acting IVadrenergic agonist (see p. 72). Unlike chronic bronchitis, cystic fibrosis, or bronchiectasis, asthma  is usually not a progressive disease; that is, it does not inevitably lead to crippled airways. Asthma is a chronic  disease with an underlying inflammatory pathophysiology that, if untreated, may incur airway remodeling, resulting  in increased severity and incidence of exacerbations and/ or death. Deaths due to asthma are relatively infrequent,  but significant morbidity results in high outpatient costs, numerous hospitalizations, and decreased quality of life.   b. Require infrequent use (a%»2 days a week) of inhaled short-acting i 2 2 agonist for quick relief of symptoms.   d. Maintain normal activity levels (including exercise and other physical activity and attendance at work or  school).   e. Meet patients' and family expectations of and satisfaction with asthma care.   a. Prevent recurrent exacerbations of asthma, and minimize the need for emergency department visits or  hospitalizations.   b. Prevent progressive loss of lung function; for children, prevent reduced lung growth.   Airflow obstruction in asthma is due to bronchoconstriction that results from contraction of bronchial smooth  muscle, inflammation of the bronchial wall, and increased mucous secretion (Figure 27.2). Asthmatic attacks may be  related to recent exposure to allergens or inhaled irritants, leading to bronchial hyperactivity and inflammation of  the airway mucosa. The symptoms of asthma may be effectively treated by several drugs, but no agent provides a  cure for this obstructive lung disease.   Recent research demonstrates a link between P-receptor polymorphism (phenotype) and response to long-acting i 2 2  agonists for approximately 16 to 20 percent of the patient population affected by asthma. Three asthma phenotypes  have been reported: homozygous glycine, heterozygous glycine/ arginine, and homozygous arginine. Evidence from  clinical trials and postmarketing analysis suggests patients with   the homozygous arginine polymorphism may be at risk for worsening symptoms with long-acting i 2 2 agonists therapy.  Because population-based genotyping to determine P-receptor phenotype is not feasible at this time, clinicians  prescribing any new long-acting i 2 2 agonists prescription should counsel patients to carefully monitor symptoms for  any signs of worsening. If the patient reports worsening symptoms, the long-acting i 2 2 agonists therapy should be  discontinued with a subsequent increase in corticosteroid dosing as clinically appropriate. Further research is  underway examining the mechanism of the various asthma phenotypes and how to appropriately target therapy to  each for improved control.   Low- to medium-dose  inhaled corticosteroids  and a long-acting |J a agonist    Figure 27.3 Treatment of asthma. In all asthmatic patients, quick relief is provided by a short-acting i * 2 2  agonist as needed for symptoms. ^Eighty percent or more of predicted function.   Inhaled adrenergic agonists with i 2 2 activity are the drugs of choice for mild asthmaa€"that is, in patients showing  only occasional, intermittent symptoms (Figure 27.3). Direct-acting i 2 2 agonists are potent bronchodilators that  relax airway smooth muscle.   1. Quick relief: Most clinically useful T 2 2 agonists have a rapid onset of action ( 5a€" 30 minutes) and provide relief  for 4 to 6 hours. They are used for symptomatic treatment of bronchospasm, providing quick relief of acute  bronchoconstriction. [Note: Epinephrine is the drug of choice for treatment of acute anaphylaxis. ] i 2 2 Agonists  have no anti-inflammatory effects, and they should never be used as the sole therapeutic agents for patients  with persistent asthma. Monotherapy with short-acting i 2 2 agonists may be appropriate only for patients  identified as having mild intermittent asthma, such as exercise-induced asthma. The direct-acting T 2 2 -selecti ve  agonists, such as pirbuterol [peer-BYOO-ter-ole], terbutaline [ter-BYOO-ta-leen], and albuterol [al-BYOO-  teh-rall], offer the advantage of providing maximally attainable bronchodilation with little of the undesired  effect of l±or l 2 i stimulation. (See p. 69 for the receptor-specific actions of adrenergic agonists.) The i 2 2  agonists are not catecholamines and, thus, are not inactivated by catechol-O-methyltransferase. Adverse  effects, such as tachycardia, hyperglycemia, hypokalemia, and hypomagnesemia are minimized with dosing via  inhalation versus systemic routes. Although tolerance to the effects of i 2 2 agonists on nonairway tissues occurs,  it is uncommon with normal dosages. All   patients with asthma should be prescribed a quick-relief inhaler and regularly assessed for appropriate inhaler  technique.   2. Long-term control: Salmeterol [sal- ME-te- rol ] xinafoate and formoterol [for-MOH-ter-ol] are long-acting i 2 2  agonists bronchodilators. They are chemical analogs of albuterol but differ by having a lipophilic side chain,  increasing the affinity of the drug for the i 2 2 -adrenoceptor. Salmeterol and formoterol have a long duration of  action, providing bronchodilation for at least 12 hours. Both salmeterol and formoterol have slower onsets of  action and should not be used for quick relief of an acute asthma attack, long-acting i 2 2 agonists should be  prescribed for routine administration. Whereas inhaled corticosteroids remain the long-term control drugs of  choice in asthma, long-acting i 2 2 agonists are considered to be useful adj unctive therapy for attaining asthma  control. Adverse effects of the long-acting i 2 2 agonists are similar to quick-relief i 2 2 agonists. Appropriate  inhaler technique with long-acting i 2 2 agonists is critical to the success of therapy, may differ from the patient's  other inhalers (metered-dose inhaler versus dry powder inhaler), and should be reassessed regularly.   Inhaled corticosteroids (ICS) are the drugs of first choice in patients with any degree of persistent asthma (mild,  moderate, or severe; see Figure 27.3). Severe persistent asthma may require the addition of a short course of oral  glucocorticoid treatment. No other medications are as effective as ICS in the long-term control of asthma in  children and adults. If appropriately prescribed and used, ICS therapy may reduce or eliminate the need for oral  glucocorticoids in patients with severe asthma. To be effective in controlling inflammation, glucocorticoids must be  taken continuously. (See p. 313 for a summary of the mechanism of action of corticosteroids. ) Current guidelines  recommend selecting ICS therapy for a newly diagnosed patient with asthma at dosing equivalent to the patient's  asthma classification (National Heart, Lung, and Blood Institute [NHLBI] a€oeStep Upa€i therapy). Patients  achieving 3 to 6 consecutive months of improved asthma control may be considered for a reduction in ICS dosing  (NHLBI a€oeStep DownaCS therapy) as clinically indicated.   1. Actions on lung: ICS do not directly affect the airway smooth muscle. Instead, ICS therapy directly targets  underlying airway inflammation by decreasing the inflammatory cascade (eosinophils, macrophages, and T  lymphocytes), reversing mucosal edema, decreasing the permeability of capillaries, and inhibiting the release of  leukotrienes. After several months of regular use, ICS reduce the hyperresponsiveness of the airway smooth  muscle to a variety of bronchoconstrictor stimuli, such as allergens, irritants, cold air, and exercise.    a. Inhalation: The development of ICS has markedly reduced the need for systemic corticosteroid treatment to  achieve asthma control. Appropriate inhalation technique is critical to the success of therapy. Metered-dose  inhalers have propellants that ej ect the active medication from the canister. Patients should be instructed  to SLOWLY and DEEPLY inhale upon activation of these inhalers to avoid impaction of the medication onto  the laryngeal mucosa rather than the bronchial smooth muscle. Improper use   of a metered-dose inhaler can result in a large fraction (typically 80a€"90 percent) of inhaled glucocorticoids  to be deposited in the mouth, pharynx, and/ or swallowed (Figure 27.4). The 10 to 20 percent of the metered  dose of inhaled glucocorticoids that is not swallowed is deposited in the airway. If ICS are inappropriately  inhaled, systemic absorption and adverse effects are much more likely. ICS delivered by dry powder inhalers  require a different inhaler technique. Patients should be instructed to inhale QUICKLY and DEEPLY to  optimize drug delivery to the lungs. Even properly administered, corticosteroid deposition on the oral and  laryngeal mucosa can cause adverse effects such as oropharyngeal candidiasis and hoarseness. Patient  counseling incorporating a rinsing of these tissues via the a€oeswish and spita€§ method should avoid these  adverse events.   b. Oral/ systemic: Patients with severe exacerbation of asthma (status asthmaticus) may require intravenous  administration of methyl prednisolone or oral prednisone. Once the patient has improved, the dose of drug  is gradually reduced, leading to discontinuance in 1 to 2 weeks. In most cases, suppression of the  hypothalamic-pituitary axis will not occur during the short course of oral prednisone a€oebursta€§ typically  prescribed for an asthma exacerbation; therefore, dose reduction is not necessary.   Large particles of aerosol are  deposited in the chamber  before the patient inhales.   inhaled aerosol is enriched in  small particles that more readily  travel to the small airways.    Figure 27.5 Effect of a spacer on the delivery of an inhaled aerosol.    c. Spacers: A spacer is a large-volume chamber attached to a metered-dose inhaler. Spacers decrease the  deposition of drug in the mouth caused by improper inhaler technique (Figure 27. 5). The chamber reduces  the velocity of the injected aerosol before entering the mouth, allowing large drug particles to be deposited  in the device. The smaller, higher-velocity drug particles are less likely to be deposited in the mouth and  more likely to reach the target airway tissue. Spacers minimize the problem of adrenal suppression by  reducing the amount of glucocorticoid deposited in the oropharynx. Spacers improve delivery of inhaled  glucocorticoids and are advised for virtually all patients, especially children less than 5 years old and elderly  patients who may have difficulty coordinating actuation with inhalation. Patients should be counseled about  regular washing and/or rinsing of spacers to reduce the risk of bacterial, mold, or mildew growth inducing an  asthma attack.   3. Adverse effects: Oral or parenteral glucocorticoids have a variety of potentially serious side effects (see p.   317); inhaled glucocorticoids, particularly if used with a spacer, have few systemic effects. Studies have  demonstrated the effect of ICS on vertical bone growth in children to be negligible, whereas the retardation of    vertical bone growth secondary to low oxygenated blood levels from uncontrolled asthma can occur in more  severe cases.   These drugs are useful for treatment of moderate to severe allergic asthma in patients who are poorly controlled by  conventional therapy or experience adverse effects secondary to high-dose or prolonged corticosteroid treatment.   These drugs should be used in conj unction with ICS therapy, not as sole therapies.   Leukotriene (LT) B 4 and the cysteinyl leukotrienes, LTC 4 , LTD 4 , and LTE 4 , are products of the 5-lipoxygenase  pathway of arachidonic acid metabolism and part of the inflammatory cascade . 1 5-Lipoxygenase is found in cells of  myeloid origin, such as mast cells, basophils, eosinophils, and neutrophils. LTB 4 is a potent chemoattractant for  neutrophils and eosinophils, whereas the cysteinyl leukotrienes constrict bronchiolar smooth muscle, increase  endothelial permeability, and promote mucous secretion. Zileuton [zye-LOO-ton] is a selective and specific  inhibitor of 5-lipoxygenase, preventing the formation of both LTB 4 and the cysteinyl leukotrienes. Zafirlukast  [za-FIR-loo-kast] and montelukast [mon-tee-LOO-kast] are selective, reversible inhibitors of the cysteinyl  leukotriene-1 receptor, thereby blocking the effects of cysteinyl leukotrienes (Figure 27.6). Montelukast, the  market leader in this pharmacologic class, claims two primary advantages: dosing recommendations for children 1  year of age and older as well as being available in chewable tablets and granule formulations. All three drugs are  approved for the prophylaxis of asthma but are not effective in situations where immediate bronchodilation is  required. Modest reductions in the doses of IVadrenergic agonists and corticosteroids, as well as improved  respiratory function, are among the therapeutic benefits.    1. Pharmacokinetics: All three drugs are orally active, although food impairs the absorption of zafirlukast.  Greater than 90 percent of each drug is bound to plasma protein. The drugs are extensively metabolized.  Zileuton and its metabolites are excreted in the urine, whereas zafirlukast and montelukast and their  metabolites undergo biliary excretion.   2. Adverse effects: Elevations in serum hepatic enzymes have occurred with all three agents, requiring periodic  monitoring and discontinuation when enzymes exceed three to five times the upper limit of normal. Although  rare, eosinophilic vasculitis (Churg-Strauss syndrome) has been reported with all agents, particularly when the  dose of concurrent glucocorticoids is reduced. Other effects include headache and dyspepsia. Both zafirlukast  and zileuton are inhibitors of cytochrome P450. Both drugs can increase serum levels of warfarin. Figure 27.6  summarizes the drugs that modify the action of leukotrienes.   Cromolyn [KROE-moe-lin] and nedocromil [ne-doe-KROE-mil] are effective prophylactic anti-inflammatory agents.  However, they are not useful in managing an acute asthma attack, because they are not direct bronchodilators.   These agents can block the initiation of immediate and delayed asthmatic reactions. For use in asthma, cromolyn is  administered either by inhalation of a microfine powder or as an aerosolized solution. Because it is poorly absorbed,  only minor adverse effects are associated with it. Pretreatment with cromolyn blocks allergen- and exercise-  induced bronchoconstriction. Cromolyn is also useful in reducing the symptoms of allergic rhinitis. A 4 to 6-week  trial is required to determine   efficacy. Given its safety, an initial trial of cromolyn is often recommended, particularly in children and pregnant  women. Toxic reactions are mild and include a bitter taste and irritation of the pharynx and larynx. Due to short  duration of action, these agents require frequent daily dosing, which has been shown to affect adherence and,  therefore, therapeutic efficacy. Neither cromolyn nor nedocromil should replace ICS or quick-relief i 2 2 agonists as  the mainstay of asthma therapy.   Anticholinergic agents are generally less effective than i 2 2 -adrenergic agonists. They block the vagal ly mediated  contraction of airway smooth muscle and mucus secretion. Inhaled ipratropium [i-pra-TROE-pee-um], a quaternary  derivative of atropine, is useful in patients who are unable to tolerate adrenergic agonists. Ipratropium is slow in  onset and nearly free of side effects. These agents are not traditionally effective for patients with asthma unless  COPD is also present.   Theophylline [thee-OFF-i-lin] is a bronchodilator that relieves airflow obstruction in chronic asthma and decreases  its symptoms. Theophylline is well absorbed by the gastrointestinal tract, and several sustained-release preparations  are available. Previously the mainstay of asthma therapy, theophylline has been largely replaced with l 2 2 agonists  and corticosteroids due to a narrow therapeutic window, high side-effect profile, and potential for drug  interactions. Overdose may cause seizures or potentially fatal arrhythmias. Theophylline is metabolized in the liver,  is a CYP1A2 and 3A4 substrate, and interacts adversely with many drugs.   Omalizumab [oh-mah-lye-ZOO-mab] is a recombinant DNAa€"derived monoclonal antibody that selectively binds to    human immunoglobulin E (IgE). This leads to decreased binding of IgE to the high-affinity IgE receptor on the  surface of mast cells and basophils. Reduction in surface-bound IgE limits the degree of release of mediators of the  allergic response. Omalizumab may be particularly useful for treatment of moderate to severe allergic asthma in  patients who are poorly controlled with conventional therapy. Due to the high cost of the drug (approximately $600  for a 150- mg vial), limitations on dosage, and available clinical trial data, it is not presently used as first-line  therapy.   Chronic obstructive pulmonary disease is a chronic, irreversible obstruction of airflow. Smoking is the greatest risk  factor for COPD and is directly linked to the progressive decline of lung function as demonstrated by forced  expiratory volume (FEV). Smoking cessation and/ or continued avoidance should be recommended regardless of  stage/ severity of COPD and age of patient. Inhaled bronchodilators, such as anticholinergic agents ( ipratropium  and tiotropium) and i 2 2 -adrenergic agonists, are the foundation of therapy for COPD (Figure 27. 7). These drugs  increase airflow, alleviate symptoms, and decrease exacerbation of disease. Combinations of an anticholinergic plus  a T 2 2 agonist may be helpful in patients for whom a single inhaled bronchodilator has failed to provide an adequate  response. For example, the combination   of albuterol and ipratropium provides greater bronchodilation than with either drug alone. Longer-acting drugs,  such as salmeterol and tiotropium [tee-oh-TROE-pee-um], have the advantage of less frequent dosing. ICS should  be restricted to patients with an FEV in 1 second (FEVi) of less than 50 percent of predicted and three or more  exacerbations in the last 3 years (Stage III or IV). Whereas the addition of ICS may provide symptomatic relief, the  progressive decline in FEVi is not impacted. Addition of a long-acting l 2 2 agonists such as salmeterol, improves lung  function compared to either a short-acting i 2 2 agonist or steroid alone.   Antibiotics for acute exacerbations of COPD characterized by  increased volume and purulence of secretions    Figure 27.7 Treatment of stable chronic obstructive pulmonary disease (COPD). FEVi =forced expiratory  volume in one second.   Rhinitis is an inflammation of the mucous membranes of the nose and is characterized by sneezing, itchy nose/ eyes,  watery rhinorrhea, and nasal congestion. An attack may be precipitated by inhalation of an allergen (such as dust,  pollen, or animal dander). The foreign material interacts with mast cells coated with IgE generated in response to a  previous allergen exposure (Figure 27.8). The mast cells release mediators, such as histamine, leukotrienes, and  chemotactic factors, that promote bronchiolar spasm and mucosal thickening from edema and cellular infiltration.  Combinations of oral antihistamines with decongestants are the first-line therapies for allergic rhinitis. Systemic   effects associated with these oral preparations (sedation, insomnia, and, rarely, cardiac arrhythmias) have  prompted interest in topical intranasal delivery of drugs.   Antihistamines are the most frequently used agents in the treatment of sneezing and watery rhinorrhea associated  with allergic rhinitis. Hi-histamine receptor blockers, such as diphenhydramine, chlorpheniramine, loratadine,  and fexofenadine, are useful in treating the symptoms of allergic rhinitis caused by histamine release. Ocular and  nasal antihistamine delivery devices are available over-the-counter for more targeted tissue delivery. Combinations  of antihistamines with decongestants (see below) are effective when congestion is a feature of rhinitis.  Antihistamines differ in their ability to cause sedation and in their duration of action. In general, anticholinergic  side effects of the first-generation antihistamines (dry eyes/ mouth, difficulty urinating and/or defecating) are  transient and may resolve in 7 to 10 days. Constipation associated with chronic use of the first-generation  antihistamines is not    transient and may require treatment with a stool softener, especially in more susceptible patients.   Short-acting i±-adrenergic agonists (aCoenasal decongestantsaC^), such as phenylephrine, constrict dilated  arterioles in the nasal mucosa and reduce airway resistance. Longer-acting oxymetazoline [ok-see-met-AZ-oh-leen]  is also available. When administered as an aerosol, these drugs have a rapid onset of action and show few systemic  effects. Oral administration results in longer duration of action but also increased systemic effects. Combinations of  these agents with antihistamines are frequently used. The l±-adrenergic agonists should be used no longer than  several days due to the risk of rebound nasal congestion (rhinitis medicamentosa). I±-Adrenergic agents have no  place in the long-term treatment of allergic rhinitis.   First exposure to antigen causes  the production of specific IgE  antibodies, which attach to the  surface of tissue mast cells and    Subsequent exposure to antigen  results in binding to surface-bound  IgE molecules. The sensitized mast  cells are stimulated to release  granules containing histamine.    Figure 27.8 Hypersensitivity reactions mediated by immunoglobulin E (IgE) molecules can cause rhinitis.   Corticosteroids, such as bed omethasone, budesonide, fluticasone, flunisolide, and triamcinolone, are effective  when administered as nasal sprays. [Note: Systemic absorption is minimal, and side effects of intranasal  corticosteroid treatment are localized. These include nasal irritation, nosebleed, sore throat, and rarely,  candidiasis.] To avoid systemic absorption, patient counseling should emphasize the importance of topical  deposition of the drug (tell patients NOT to deeply inhale while administering these drugs because the target tissue  is in the nose, not in the lungs or the throat). Topical steroids may be more effective than systemic antihistamines  in relieving the nasal symptoms of both allergic and nonallergic rhinitis. The effects of long-term usage are  unknown, but these agents are considered to be generally safe. Periodic assessment of the patient is advised.   Treatment of chronic rhinitis may not result in improvement until 1 to 2 weeks after starting therapy.   Intranasal cromolyn may be useful, particularly when administered before contact with an allergen. To optimize the  therapeutic effect of cromolyn, dosing should occur at least 1 to 2 weeks prior to allergen exposure. Due to a short  duration of action, cromolyn requires multiple daily dosing, which may deleteriously impact adherence and,  therefore, therapeutic efficacy.   Codeine [KOE-deen] is the gold-standard treatment for cough suppression due to its long history of availability and  use. Codeine decreases the sensitivity of cough centers in the central nervous system to peripheral stimuli and  decreases mucosal secretion. These therapeutic effects occur at doses lower than those required for analgesia but  still incur common sides effects like constipation, dysphoria, and fatigue, in addition to its addictive potential. (See  p. 159 for a more complete discussion of the opiates. ) Dextromethorphan [dek-stroe-METH-or-fan] is a synthetic  derivative of morphine that suppresses the response of the central cough center. It has no analgesic effects, has a  low addictive profile, but may cause dysphoria at high doses, which may explain its status as a potential drug of  abuse. Dextromethorphan has a significantly better side effect profile than codeine and has been demonstrated to  be equally effective for cough suppression.   27.1 A 12-year-old girl with a childhood history of asthma complained of cough, dyspnea, and wheezing after  visiting a riding stable. Her symptoms became so severe that her parents brought her to the emergency room.  Physical examination revealed diaphoresis, dyspnea, tachycardia, and tachypnea. Her respiratory rate was 42  breaths per minute, pulse rate 110 beats per minute, and blood pressure 132/65 mm Hg. Which of the  following is the most appropriate drug to rapidly reverse her bronchoconstriction?    27. 2 A 9-year-old girl has severe asthma, which required three hospitalizations in the last year. She is now  receiving therapy that has greatly reduced the frequency of these severe attacks. Which of the following  therapies is most likely responsible for this benefit?    27. 3 A 68-year-old male retired police officer who has smoked a 1/2 pack of cigarettes a day for the past 40  years is diagnosed with chronic obstructive pulmonary disease (COPD). He has a difficulty in expiration during  breathing, but the symptms are mild and intermittent. Which one of the following agents would most  appropratate initial therapy.   >Table of Contents > Unit VI - Drugs Affecting Other Organs >Chapter 28 - Gastrointestinal and Antiemetic Drugs   This chapter describes drugs used to treat three common medical conditions involving the gastrointestinal tract:  peptic ulcers and gastroesophageal reflux disease (GERD), chemotherapy-induced emesis, and diarrhea and  constipation. Many drugs described in other chapters also find application in the treatment of gastrointestinal  disorders. For example, the meperidine derivative diphenoxylate, which decreases peristaltic activity of the gut, is  useful in the treatment of severe diarrhea, and the corticosteroid dexamethasone has excellent antiemetic  properties. Other drugs, (for example, H 2 -receptor antagonists and proton-pump inhibitors (PPIs), are employed to  heal peptic ulcers; the selective inhibitors of the serotonin receptors, such as ondansetron or granisetron, which  prevent vomiting, are used almost exclusively to treat gastrointestinal tract disorders.   _ Amoxicillin  _ Bismuth compounds  _ Clarithromycin  _ Metronidazole  - Tetracycline    Figure 28.1 Summary of drugs used to treat peptic ulcer disease.   Although the pathogenesis of peptic ulcer disease is not fully understood, several maj or causative factors are  recognized: nonsteroidal anti-inflammatory drug (NSAID) use, infection with gram-negative Helicobacter pylori ,  increased hydrochloric acid secretion, and inadequate mucosal defense against gastric acid. Treatment approaches  include 1) eradicating the H. pylori infection, 2) reducing secretion of gastric acid with the use of H 2 -receptor  antagonists or PPIs, and/ or 3) providing agents that protect the gastric mucosa from damage, such as misoprostol  and sucralfate. (Note: If patients are unable to tolerate the above therapies, neutralizing gastric acid with  nonabsorbable antacids is an option). Figure 28.1 summarizes agents that are effective in treating peptic ulcer  disease.   Optimal therapy for patients with peptic ulcer disease (both duodenal and gastric ulcers) who are infected with Fh_  pylori requires antimicrobial treatment. To document infection with H. pylori, endoscopic biopsy of the gastric  mucosa or various noninvasive methods are utilized, including serologic tests and urea breath tests. Figure 28.2  shows a biopsy sample in which H. pylori is closely associated with the gastric mucosa. Eradication of H. pylori  results in rapid healing of active peptic ulcers and low recurrence rates (less than 15 percent compared with 60 to  100 percent per year for patients with initial ulcers healed by traditional antisecretory therapy). Successful  eradication of H. pylori (80a€"90 percent) is possible with various combinations   of antimicrobial drugs. Currently, either triple therapy consisting of a PPI with either metronidazole or amoxicillin  plus clarithromycin, or quadruple therapy of bismuth subsalicylate and metronidazole plus tetracycline plus a  PPI, are administered for a 2-week course. This usually results in a 90 percent or greater eradication rate. Bismuth  salts do not neutralize stomach acid, but they inhibit pepsin and increase the secretion of mucus, thus helping to  form a barrier against the diffusion of acid in the ulcer. Treatment with a single antimicrobial drug is less effective  (20 to 40 percent eradication rates), results in antimicrobial resistance and is absolutely not recommended;  switching of antibiotics is also not recommended (that is, do not substitute amoxicillin for ampicillin or  erythromycin for clarithromycin or doxycycline for tetracycline). [Note: GERD (that is, a heartburn-like sensation)  is not associated with H. pylori infection and does not respond to treatment with antibiotics.]   Gastric acid secretion by parietal cells of the gastric mucosa is stimulated by acetylcholine, histamine, and gastrin  (Figure 28. 3). The receptor-mediated binding of acetylcholine, histamine, or gastrin results in the activation of  protein kinases, which in turn stimulates the H + / K + a€" adenosine triphosphatase (ATPase) proton pump to secrete  hydrogen ions in exchange for K + into the lumen of the stomach. A Cl" channel couples chloride efflux to the release  of H + . In contrast, receptor binding of prostaglandin E 2 and somatostatin diminish gastric acid production. [Note:   Histamine binding causes activation of adenylyl cyclase, whereas binding of prostaglandin E 2 inhibits this enzyme.   Gastrin and acetylcholine act by inducing an increase in intracellular calcium levels.]   Although antagonists of the histamine H 2 receptor block the actions of histamine at all H 2 receptors, their chief  clinical use is to inhibit gastric acid secretion, being particularly effective against nocturnal acid secretion. By  competitively blocking the binding of histamine to H 2 receptors, these agents reduce the intracellular  concentrations of cyclic adenosine monophosphate and, thereby, secretion of gastric acid. The four drugs used in    the United Statesa €"cimetidine [si-MET-ih-deen], ranitidine [ra-NI-tih-deen], famotidine [fa-MOE-ti-deen], and  nizatidine [nye-ZA-ti-deen]a€" potently inhibit (greater than 90 percent) basal, food-stimulated, and nocturnal  secretion of gastric acid after a single dose. Cimetidine is the prototype histamine h^-receptor antagonist;  however, its utility is limited by its adverse effect profile and drug interactions.   1. Actions: The histamine H 2 -receptor antagonistsaC" cimetidine, ranitidine, famotidine, and nizatidine a€"act  selectively on H 2 receptors in the stomach, blood vessels, and other sites, but they have no effect on Hi  receptors. They are competitive antagonists of histamine and are fully reversible. These agents completely  inhibit gastric acid secretion induced by histamine or gastrin. However, they only partially inhibit gastric acid  secretion induced by acetylcholine or bethanechol .   2. Therapeutic uses: The use of these agents has decreased with the advent of the PPIs.   a. Peptic ulcers: All four agents are equally effective in promoting healing of duodenal and gastric ulcers.   However, recurrence is common after treatment with H 2 antagonists is stopped (60a€" 100   percent per year). Patients with NSAID-induced ulcers should be treated with PPIs, because these agents  heal and prevent future ulcers better than H 2 antagonists.    b. Acute stress ulcers: These drugs are useful in managing acute stress ulcers associated with maj or physical  trauma in high-risk patients in intensive care units. They are usually inj ected intravenously.   c. Gastroesophageal reflux disease: Low doses of H 2 antagonists, recently released for over-the-counter sale,  appear to be effective for prevention and treatment of heartburn (gastroesophageal reflux). However,  about 50 percent of patients do not find benefit, and PPIs are now used preferentially in the treatment of  this disorder. Because H 2 -receptor antagonists act by stopping acid secretion, they may not relieve  symptoms for at least 45 minutes. Antacids more efficiently, but temporarily, neutralize secreted acid  already in the stomach. Finally, tolerance to the effects of H 2 antagonists can be seen within 2 weeks of  therapy.   a. Cimetidine: Cimetidine and the other H 2 antagonists are given orally, distribute widely throughout the body  (including into breast milk and across the placenta), and are excreted mainly in the urine (Figure 28.4).   Cimetidine normally has a short serum half-life, which is increased in renal failure. Approximately 30  percent of a dose of cimetidine is slowly inactivated by the liver's   microsomal mixed-function oxygenase system (see p. 14) and can interfere in the metabolism of many other  drugs; the other 70 percent is excreted unchanged in the urine. The dosage of all these drugs must be  decreased in patients with hepatic or renal failure. Cimetidine inhibits cytochrome P450 and can slow  metabolism (and, thus, potentiate the action) of several drugs (for example, warfarin, diazepam,  phenytoin, quinidine, carbamazepine, theophylline, and imipramine-, Figure 28.5), sometimes resulting in  serious adverse clinical effects.    b. Ranitidine: Compared to cimetidine, ranitidine is longer acting and is five- to ten-fold more potent.  Ranitidine has minimal side effects and does not produce the antiandrogenic or prolactin-stimulating effects  of cimetidine. Unlike cimetidine, it does not inhibit the mixed-function oxygenase system in the liver and,  thus, does not affect the concentrations of other drugs.   c. Famotidine: Famotidine is similar to ranitidine in its pharmacologic action, but it is 20 to 50 times more  potent than cimetidine, and 3 to 20 times more potent than ranitidine.   d. Nizatidine: Nizatidine is similar to ranitidine in its pharmacologic action and potency. In contrast to  cimetidine, ranitidine, and famotidine, which are metabolized by the liver, nizatidine is eliminated  principally by the kidney. Because little first-pass metabolism occurs with nizatidine, its bioavailability is  nearly 100 percent. No intravenous preparation is available.   4. Adverse effects: The adverse effects of cimetidine are usually minor and are associated mainly with the maj or  pharmacologic activity of the druga€"namely, reduced gastric acid production. Side effects occur only in a small  number of patients and generally do not require discontinuation of the drug. The most common side effects are  headache, dizziness, diarrhea, and muscular pain. Other central nervous system effects (confusion,  hallucinations) occur primarily in elderly patients or after intravenous administration. Cimetidine can also have  endocrine effects, because it acts as a nonsteroidal antiandrogen. These effects include gynecomastia,  galactorrhea (continuous release/ discharge of milk), and reduced sperm count. Except for famotidine, all these  agents inhibit the gastric first-pass metabolism of ethanol. Drugs such as ketoconazole, which depend on an  acidic medium for gastric absorption, may not be efficiently absorbed if taken with one of these antagonists.   Omeprazole [oh-MEH-pra-zole] is the first of a class of drugs that bind to the H + / K + -ATPase enzyme system (proton  pump) of the parietal cell, thereby suppressing secretion of hydrogen ions into the gastric lumen. The  membrane-bound proton pump is the final step in the secretion of gastric acid (see Figure 28.3). Four additional  PPIsare now available: lansoprazole [lan-SO-pra-zole], rabeprazole [ rah- BEH- pra-zole] , pantoprazole [pan-TOE-  pra-zole], and esomeprazole [es-oh-MEH-pra-zole],   1. Actions: These agents are prodrugs with an acid-resistant enteric coating to protect them from premature  degradation by gastric acid. The coating is removed in the alkaline duodenum, and the prodrug, a weak base, is  absorbed and transported to the parietal cell canaliculus.   There, it is converted to the active form, which reacts with a cysteine residue of the H + / K + -ATPase, forming a  stable covalent bond. It takes about 18 hours for the enzyme to be resynthesized. At standard doses, all PPIs  inhibit both basal and stimulated gastric acid secretion by more than 90 percent. Acid suppression begins within  1 to 2 hours after the first dose of lansoprazole and slightly earlier with omeprazole. There is also an oral  product containing omeprazole combined with sodium bicarbonate for faster absorption. It is available in  powder to be dissolved in water and taken orally as well as in capsule form.   2. Therapeutic uses: The superiority of the PPIs over the H 2 antagonists for suppressing acid production and  healing peptic ulcers has made them the preferred drugs for treating erosive esophagitis and active duodenal  ulcer and for long-term treatment of pathologic hypersecretory conditions (for example, Zol I i nger- El I ison  syndrome, in which a gastrin-producing tumor causes hypersecretion of HCI ) . They are approved for the  treatment of GERD. Clinical studies have shown that PPIs reduce the risk of bleeding from an ulcer caused by  aspirin and other NSAIDs. They are also successfully used with antimicrobial regimens to eradicate H. pylori. For  maximum effect, PPIs should be taken 30 minutes before breakfast or the largest meal of the day. If an   ^-receptor antagonist is also needed, it should be taken well after the PPI for best effect. The H 2 antagonists  will reduce the activity of the proton pump, and PPIs require active pumps to be effective. In patients with  GERD in whom once-daily PPI is partially effective, increasing to a twice-daily regimen or keeping the PPI in the  morning and adding an H 2 antagonist in the evening may improve symptom control.   3. Pharmacokinetics: All these agents are delayed-release formulations and are effective orally. [Note: Some are  also available for intravenous inj ection. ] Metabolites of these agents are excreted in urine and feces.   4. Adverse effects: The PPIs are generally well tolerated, but concerns about long-term safety have been raised  due to the increased secretion of gastrin. In animal studies, the incidence of gastric carcinoid tumors increased,  possibly related to the effects of prolonged hypochlorhydria and secondary hypergastrinemia. However, this has  not been found in humans. Increased concentrations of viable bacteria in the stomach have been reported with  continued use of these drugs. Omeprazole inhibits the metabolism of warfarin, phenytoin, diazepam, and  cyclosporine. However, drug interactions are not a problem with the other PPIs. Prolonged therapy with agents  that suppress gastric acid, such as the PPIs and H 2 antagonists, may result in low vitamin B 12 , because acid is  required for its absorption. Another problem with prolonged elevation of gastric pH is that calcium carbonate  products require low gastric pH to be absorbed in the upper intestine. Increasing gastric pH increases the  potential for incomplete absorption of calcium carbonate products. An effective option would be to use calcium  citrate as a source of calcium by patients taking prolonged acid-suppressing medications. The absorption of the  citrate salt is not affected by gastric pH. There are increased reports of diarrhea and Clostridium difficile colitis  in community patients receiving PPIs; therefore, patients must be counseled to discontinue PPI therapy if they  have diarrhea for several days and to contact their physicians for further follow-up.   Prostaglandin E 2 , produced by the gastric mucosa, inhibits secretion of HCI and stimulates secretion of mucus and  bicarbonate (cytoprotective effect). A deficiency of prostaglandins is thought to be involved in the pathogenesis of  peptic ulcers. Misoprostol [mye-soe-PROST-ole], a stable analog of prostaglandin Ei, as well as some PPIs, are  approved for prevention of gastric ulcers induced by NSAIDs (Figure 28.6). It is less effective than H 2 antagonists  and the PPIs for acute treatment of peptic ulcers. Although misoprostol has cytoprotective actions, it is clinically  effective only at higher doses that diminish gastric acid secretion. Routine prophylactic use of misoprostol may not  be j ustified except in patients who are taking NSAIDs and are at high risk of NSAID-induced ulcers, such as the  elderly or patients with ulcer complications. Like other prostaglandins, misoprostol produces uterine contractions  and is contraindicated during pregnancy. Dose-related diarrhea and nausea are the most common adverse effects  and limit the use of this agent.    Figure 28.6 Misoprostol reduces serious gastrointestinal (Gl) complications in patients with rheumatoid  arthritis receiving nonsteroidal antiinflammatory drugs.   Muscarinic receptor stimulation increases gastrointestinal motility and secretory activity. A cholinergic antagonist,   such as dicyclomine [dye-SYE-kloe-meen], can be used as an adj unct in the management of peptic ulcer disease and   Zollinger-Ellison syndrome, particularly in patients who are refractory to standard therapies. However, its many side   effects (for example, cardiac arrhythmias, dry mouth, constipation, and urinary retention) limit its use.   Antacids are weak bases that react with gastric acid to form water and a salt, thereby diminishing gastric acidity.   Because pepsin is inactive at a pH greater than 4, antacids also reduce pepsin activity.   1. Chemistry of antacids: Antacid products vary widely in their chemical composition, acid-neutralizing capacity,  sodium content, palatability, and price. The acid-neutralizing ability of an antacid depends on its capacity to  neutralize gastric HCI and on whether the stomach is full or empty (food delays stomach emptying, allowing  more time for the antacid to react). Commonly used antacids are salts of aluminum and magnesium, such as  aluminum hydroxide (usually a mixture of AlfOHh and aluminum oxide hydrates) or magnesium hydroxide  [MgfOHhL either alone or in combination. Calcium carbonate [CaC 03 ] reacts with HCI to form CO 2 and CaCl 2  and is a commonly used preparation. Systemic absorption of sodium bicarbonate [NaHCOs] can produce  transient metabolic alkalosis; therefore, this antacid is not recommended for long-term use.   2. Therapeutic uses: Aluminum- and magnesium-containing antacids are used for symptomatic relief of peptic  ulcer disease and GERD; they may promote healing of duodenal ulcers, but the evidence for efficacy in the  treatment of acute gastric ulcers is less compelling; therefore, these agents are used as last-line therapy. [Note:  Calcium carbonate preparations are also used as calcium supplements for the treatment of osteoporosis. ]   3. Adverse effects: Aluminum hydroxide tends to be constipating, and magnesium hydroxide tends to produce  diarrhea. Preparations that combine these agents aid in normalizing bowel function. The   binding of phosphate by aluminum-containing antacids can lead to hypophosphatemia. In addition to the  potential for systemic alkalosis, sodium bicarbonate liberates CO 2 , causing belching and flatulence. Absorption  of the cations from antacids (Mg 2+ , Al 3+ , Ca 2+ ) is usually not a problem in patients with normal renal function,  but the sodium content of antacids can be an important consideration in patients with hypertension or  congestive heart failure. Adverse effects may also occur in patients with renal impairment, caused by  accumulation of magnesium, calcium, sodium, and other electrolytes. Excessive intake of calcium carbonate  along with calcium foods can result in hypercalcemia.   These compounds, known as cytoprotective compounds, have several actions that enhance mucosal protection  mechanisms, thereby preventing mucosal inj ury, reducing inflammation, and healing existing ulcers.   I. Sucralfate: This complex of aluminum hydroxide and sulfated sucrose binds to positively charged groups in  proteins of both normal and necrotic mucosa. By forming complex gels with epithelial cells, sucralfate  [soo-KRAL-fate] creates a physical barrier that impairs diffusion of HCI and prevents degradation of mucus by  pepsin and acid. It also stimulates prostaglandin release as well as mucus and bicarbonate output, and it inhibits  peptic digestion. By these and other mechanisms, sucralfate effectively heals duodenal ulcers and is used in  long-term maintenance therapy to prevent their recurrence. Because it requires an acidic pH for activation,    sucralfate should not be administered with H 2 antagonists or antacids. Little of the drug is absorbed  systemically. It is very well tolerated, but it can interfere with the absorption of other drugs by binding to them.  This agent does not prevent NSAID-induced ulcers, nor does it heal gastric ulcers.   2. Bismuth subsalicylate: Preparations of this compound effectively heal peptic ulcers. In addition to their  antimicrobial actions, they inhibit the activity of pepsin, increase secretion of mucus, and interact with  glycoproteins in necrotic mucosal tissue to coat and protect the ulcer crater.   Although nausea and vomiting may occur in a variety of conditions (for example, motion sickness, pregnancy, or  hepatitis) and are always unpleasant for the patient, it is the nausea and vomiting produced by many  chemotherapeutic agents that demand effective management. Nearly 70 to 80 percent of all patients who undergo  chemotherapy experience nausea or vomiting. Several factors influence the incidence and severity of  chemotherapy-induced emesis (Figure 28.7), including the specific chemotherapeutic drug, dose, route, schedule  of administration, and patient variables. For example, the young and women are more susceptible than older  patients and men, and 10 to 40 percent of patients experience nausea or vomiting in anticipation of their  chemotherapy (anticipatory vomiting). Emesis not only affects the quality of life but can lead to rej ection of  potentially curative antineoplastic treatment. In addition, uncontrolled vomiting can produce dehydration,  profound metabolic imbalances, and nutrient depletion.   Two brainstem sites have key roles in the vomiting reflex pathway. The chemoreceptor trigger zone, which is  located in the area postrema (a circumventricular structure at the caudal end of the fourth ventricle) is outside the  blood-brain barrier. Thus, it can respond directly to chemical stimuli in the blood or cerebrospinal fluid. The second  important site, the vomiting center, which is located in the lateral reticular formation of the medulla, coordinates   the motor mechanisms of vomiting. The vomiting center also responds to afferent input from the vestibular system,  the periphery (pharynx and gastrointestinal tract), and higher brainstem and cortical structures. The vestibular  system functions mainly in motion sickness.   Figure 28.8 Summary of drugs used to treat chemotherapy-induced nausea and vomiting. 5 -HT 3 =serotonin  Type 3.   Chemotherapeutic agents (or their metabolites) can directly activate the medullary chemoreceptor trigger zone or  vomiting center; several neuroreceptors, including dopamine receptor Type 2 and serotonin Type 3 ( 5 -HT 3 ), play  critical roles. Often, the color or smell of chemotherapeutic drugs (and even stimuli associated with chemotherapy,  such as cues in the treatment room or the physician or nurse who administers the therapy) can activate higher brain  centers and trigger emesis. Chemotherapeutic drugs can also act peripherally by causing cell damage in the  gastrointestinal tract and releasing serotonin from the enterochromaffin cells of the small intestinal mucosa. The  released serotonin activates 5 -HT 3 receptors on vagal and splanchnic afferent fibers, which then carry sensory  signals to the medulla, leading to the emetic response.   Considering the complexity of the mechanisms involved in emesis, it is not surprising that antiemetics represent a  variety of classes (Figure 28.8) and offer a range of efficacies (Figures 28.9). Anticholinergic drugs, especially the  muscarinic receptor antagonist, scopolamine, and Fli-receptor antagonists, such as dimenhydrinate, meclizine,  and cyclizine, are very useful in motion sickness but are ineffective against substances that act directly on the  chemoreceptor trigger zone. The maj or categories of drugs used to control chemotherapy-induced nausea and  vomiting include the following:   1. Phenothiazines: The first group of drugs shown to be effective antiemetic agents, phenothiazines, such as  prochlorperazine [proe-klor-PER-ah-zeen], acts by blocking dopamine receptors. It is effective against low or  moderately emetogenic chemotherapeutic agents (for example, fluorouracil and doxorubicin ; see Figure 28. 7).  Although increasing the dose improves antiemetic activity, side effects, including hypotension and restlessness,  are dose limiting. Other adverse reactions include extrapyramidal symptoms and sedation.   2. 5-HT3 receptor blockers: This class of agents commands an important place in treating emesis linked with  chemotherapy. They have the advantage of a long duration of action. The specific antagonists of the 5- HT 3  receptora€" ondansetron [on-DAN-seh-tron], granisetron [gra-NI-seh-tron], palonosetron [pa-low-NO-seh-tron]  and dolasetron [dol-A-se-tron]a€"selectively block 5- HT 3 receptors in the periphery (visceral vagal afferent  fibers) and in the brain (chemoreceptor trigger zone). These drugs can be administered as a single dose prior to  chemotherapy (intravenously or orally) and are efficacious against   all grades of emetogenic therapy. One trial reported ondansetron and granisetron prevented emesis in 50 to 60  percent of cisplatin- treated patients. These agents are extensively metabolized by the liver, with  hydroxydolasetron being an active metabolite of dolasetron. Thus, doses of these agents should be adj usted in  patients with hepatic insufficiency. Elimination is through the urine. Fleadache is a common side effect.  Electrocardiographic changes, such as prolongation of the QT interval, can occur with dolasetron; therefore,  patients who may be at risk should receive this medication with caution. These drugs are costly.   3. Substituted benzamides: One of several substituted benzamides with antiemetic activity, metoclopramide  [met-oh-kloe-PRAH-mide], is highly effective at high doses against the highly emetogenic cisplatin, preventing  emesis in 30 to 40 percent of patients and reducing emesis in the maj ority. Antidopaminergic side effects,  including sedation, diarrhea, and extrapyramidal symptoms, limit its high-dose use.   4. Butyrophenones: Droperidol [ droe- PER- i-dol I ] and haloperidol [ hal-oh-PER- i-doll] act by blocking dopamine  receptors. The butyrophenones are moderately effective antiemetics. Droperidol had been used most often for  sedation in endoscopy and surgery, usually in combination with opiates or benzodiazepines. Flowever, it may    prolong the QT interval, and current practice reserves it for patients whose response to other agents is  inadequate. High-dose haloperidol was found to be nearly as effective as high-dose metoclopramide in  preventing c/sp/at/n-induced emesis.   5. Benzodiazepines: The antiemetic potency of lorazepam [lor-A-ze-pam] and alprazolam [al-PRAH-o-lam] is  low. Their beneficial effects may be due to their sedative, anxiolytic, and amnesic properties. These same  properties make benzodiazepines useful in treating anticipatory vomiting.   6. Corticosteroids: Dexamethasone [dex-a-MEH-tha-sone] and methyl prednisolone [meth-i ll-pred-NIH-so- lone],  used alone, are effective against mildly to moderately emetogenic chemotherapy. Most frequently, however,  they are used in combination with other agents. Their antiemetic mechanism is not known, but it may involve  blockade of prostaglandins. These drugs can cause insomnia as well as hyperglycemia in patients with diabetes  mellitus.   7. Cannabinoids: Marij uana derivatives, including dronabinol [droe-NAB-i-nol] and nabilone [NAB-il-own], are  effective against moderately emetogenic chemotherapy. However, they are seldom first-line antiemetics  because of their serious side effects, including dysphoria, hallucinations, sedation, vertigo, and disorientation.  In spite of their psychotropic properties, the antiemetic action of cannabinoids may not involve the brain,  because synthetic cannabinoids, which have no psychotropic activity, nevertheless are antiemetic.   8. Substance P/neurokinin-1 receptor blocker: Aprepitant [ah-PRE-pih-tant] belongs to a new family of  antiemetic agents. It targets the neurokinin receptor in the brain and blocks the actions of the natural  substance. Aprepitant is usually administered orally with dexamethasone and palonosetron. It undergoes  extensive metabolism, primarily by CYP3A4. Thus, as would be expected, it can affect the metabolism of other   drugs that are metabolized by this enzyme. Aprepitant can also induce this enzyme and, thus, affect responses   to other agents; for example, concomitant use with warfarin can shorten the half-life of the anticoagulant.  Constipation and fatigue appear to be the maj or side effects.   9. Combination regimens: Antiemetic drugs are often combined to increase antiemetic activity or decrease  toxicity (Figure 28. 10). Corticosteroids, most commonly dexamethasone, increase antiemetic activity when  given with high-dose metoclopramide, a 5 -HT 3 antagonist, phenothiazine, butyrophenone, a cannabinoid, or a  benzodiazepine. Antihistamines, such as diphenhydramine, are often administered in combination with  high-dose metoclopramide to reduce extrapyramidal reactions or with corticosteroids to counter  metoclopramide- induced diarrhea.   Increased motility of the gastrointestinal tract and decreased absorption of fluid are maj or factors in diarrhea.  Antidiarrheal drugs include antimotility agents, adsorbents, and drugs that modify fluid and electrolyte transport  (Figure 28.11).    Figure 28.10 Effectiveness of antiemetic activity of some drug combinations against emetic episodes in the  first 24 hours after cisplatin chemotherapy.   Two drugs that are widely used to control diarrhea are diphenoxylate [dye-fen-OX-see-late] and loperamide  [loe-PER-ah-mide], Both are analogs of meperidine and have opioid-like actions on the gut, activating presynaptic  opioid receptors in the enteric nervous system to inhibit acetylcholine release and decrease peristalsis. At the usual  doses, they lack analgesic effects. Side effects include drowsiness, abdominal cramps, and dizziness. Because these  drugs can contribute to toxic megacolon, they should not be used in young children or in patients with severe  colitis.   Adsorbent agents, such as bismuth subsalicylate, methyl cellulose [meth-ill-CELL-you-lowse], and aluminum  hydroxide are used to control diarrhea. Presumably, these agents act by adsorbing intestinal toxins or  microorganisms and/or by coating or protecting the intestinal mucosa. They are much less effective than  antimotility agents. They can interfere with the absorption of other drugs.   Bismuth subsalicylate, used for traveler's diarrhea, decreases fluid secretion in the bowel. Its action may be due to  its salicylate component as well as its coating action.   Laxatives are commonly used to accelerate the movement of food through the gastrointestinal tract. These drugs  can be classified on the basis of their mechanism of action as irritants or stimulants of the gut, bulking agents, and  stool softeners. They all have a risk of being habit-forming. Laxatives also increase the potential of loss of  pharmacologic effect of poorly absorbed, delayed-acting, and extended-release oral preparations by accelerating  their transit through the intestines. They may cause electrolyte imbalances when used chronically.   Senna is a widely used stimulant laxative. Its active ingredient is a group of sennosides, a natural complex of  anthraquinone glycosides. Taken orally, it causes evacuation of the bowels within 8 to 10 hours. It also causes water  and electrolyte secretion into the bowel. In combination products with a docusate-containing stool softener, it is  useful in treating opioid-induced constipation. Bisacodyl, available as suppositories and enteric-coated tablets, is a  potent stimulant of the colon. It acts directly on nerve fibers in the mucosa of the colon. Adverse effects include  abdominal cramps and the potential for atonic colon with prolonged use. Antacids should not be taken at the same  time as the enteric-coated tablets. The antacid would cause the enteric coating to dissolve prematurely in the  stomach, resulting in stomach irritation and pain. The same adverse effects could be expected with milk,  H 2 -receptor antagonists, and PPIs. Castor oil is broken down in the small intestine to ricinoleic acid, which is very  irritating to the gut, and promptly increases peristalsis. It should be avoided by pregnant patients, because it may  stimulate uterine contractions.   Figure 28.11 Summary of drugs used to treat diarrhea and constipation.   The bulk laxatives include hydrophilic colloids (from indigestible parts of fruits and vegetables). They form gels in  the large intestine, causing water retention and intestinal distension, thereby increasing peristaltic activity. Similar  actions are produced by methylcellulose, psyllium seeds, and bran. They should be used cautiously in patients who  are bed-bound, due to the potential for intestinal obstruction.   Saline cathartics, such as magnesium citrate, magnesium sulfate, sodium phosphate, and magnesium hydroxide,    are nonabsorbable salts (anions and cations) that hold water in the intestine by osmosis and distend the bowel,  increasing intestinal activity and producing defecation in a few hours. Electrolyte solutions containing polyethylene  glycol (PEG) are used as colonic lavage solutions to prepare the gut for radiologic or endoscopic procedures. PEG  powder for solution is available as a prescription and also an over-the-counter laxative. Lactulose is a semisynthetic  disaccharide sugar that also acts as an osmotic laxative. It is a product that cannot be hydrolyzed by intestinal  enzymes. Oral doses are degraded in the colon by colonic bacteria into lactic, formic, and acetic acids. This  increases osmotic pressure, thereby accumulating fluid, distending the colon, creating a soft stool, and causing  defecation.   Surface-active agents that become emulsified with the stool produce softer feces and ease passage. These include  docusate sodium, docusate calcium, and docusate potassium. They may take days to become effective. They  should not be taken together with mineral oil because of the potential for absorption of the mineral oil.   Mineral oil and glycerin suppositories are considered to be lubricants. They facilitate the passage of hard stools.   Mineral oil should be taken orally in an upright position to avoid its aspiration and potential for lipid or lipoid  pneumonia.   28. 1 A 68-year-old patient with cardiac failure is diagnosed with ovarian cancer. She is started on cisplatin but  becomes nauseous and suffers from severe vomiting. Which of the following medications would be most  effective to counteract the emesis in this patient without exacerbating her cardiac problem?    28. 2 A 45-year-old woman is distressed by the dissolution of her marriage. She has been drinking heavily and  overeating. She complains of persistent heartburn and an unpleasant, acid-like taste in her mouth. The  clinician suspects gastrointestinal reflux disease and advises her to raise the head of her bed 6 to 8 inches, not  to eat for several hours before retiring, to avoid alcohol, and to eat smaller meals. Two weeks later, she  returns and says the symptoms have subsided slightly but still are a concern. The clinician prescribes:    28.3 Which of the following agents interferes with most of the cytochrome P450 enzymes and, thus, leads to   28.4 A couple celebrating their fortieth wedding anniversary is given a trip to Peru to visit Machu Picchu. Due  to past experiences while traveling, they ask their doctor to prescribe an agent for diarrhea. Which of the  following would be effective?   >Table of Contents > Unit VI - Drugs Affecting Other Organs >Chapter 29 - Other Therapies   Erectile dysfunction (ED)a€"that is, the inability to maintain penile erection for the successful performance of  sexual activitya€"has many physical and psychological causes, including vascular disease, diabetes, medications,  depression, and sequelae to prostatic surgery. ED is estimated to affect more than 30 million men in the United  States. Previous therapies have included penile implants, intrapenile injections of alprostadil, and intraurethral  suppositories of alprostadil. However, because of their efficacy, ease of use, and safety, oral phosphodiesterase  (PDE) inhibitors are now considered to be first-line therapy for men with ED. Three PDE-5 inhibitors, sildenafil  [sil-DEN-a-fil], vardenafil [var-DEN-na-fil], and tadalafil [ta-DAL-a-fil], are approved for the treatment of ED  (Figure 29.1).   Figure 29.1 Summary of drugs used in the treatment of erectile dysfunction, osteoporosis, and obesity.   All three PDE-5 inhibitors are equally effective in treating ED, and the adverse effect profiles of the drugs are  similar. However, the duration of action of PDE-5 inhibitors differ, as do the effects of food on the rates of drug  absorption.   1. Mechanism of penile erection: Sexual stimulation results in smooth muscle relaxation of the corpus   cavernosum, increasing the inflow of blood (Figure 29.2). The mediator of this response is nitric oxide (NO). NO  activates guanylyl cyclase, which forms cyclic guanosine monophosphate (cGMP) from guanosine triphosphate.  cGMP produces smooth muscle relaxation through a reduction in the intracellular Ca 2+ concentration, The  duration of action of cyclic nucleotides is controlled by the action of PDE. At least 11 isozymes of PDE have  been characterized. Sildenafil, vardenafil, and tadalafil inhibit PDE-5, the isozyme responsible for    degradation of cGMP in the corpus cavernosum. The action of PDE-5 inhibitors is to increase the flow of blood  into the corpus cavernosum at any given level of sexual stimulation (Figure 29.3). At recommended doses, PDE-5  inhibitors have no effect in the absence of sexual stimulation. PDE-5 inhibitors are indicated for the treatment  of ED due to organic or psychogenic causes.   2. Pharmacokinetics: Sildenafil and vardenafil have similar pharmacokinetic properties. Both drugs should be  taken approximately 1 hour prior to anticipated sexual activity, with erectile enhancement observed up to 4  hours after administration. Thus, administration of sildenafil and vardenafil must be timed so that sexual  activity occurs within 1 to 4 hours. The absorption of both drugs   is delayed by consumption of food, particularly high-fat meals. By contrast, tadalafil has a slower onset of  action (Figure 29.4) but a significantly longer half-life of approximately 18 hours, resulting in enhanced erectile  function for at least 36 hours. Furthermore, the absorption of tadalafil is not clinically influenced by food. The  timing of sexual activity is less critical for tadalafil because of its prolonged duration of effect. All three PDE-5  inhibitors are metabolized by the cytochrome P450 3A4 (CYP3A4) enzyme. Dosage adj ustments are  recommended in patients with hepatic dysfunction.    Sexual stimulation causes  the smooth muscle cells of  the arteries in the penis to  relax. As a result, more blood  flows into the sinusoids,  and their volume Increases.  The penis becomes swollen  and erect    3. Adverse effects: The most frequent adverse effects reported for PDE inhibitors are headache, flushing,   dyspepsia, and nasal congestion. These effects are generally mild, and men with ED rarely discontinue treatment  because of side effects. Disturbances in color vision (loss of blue/ green discrimination) occur with sildenafil,  probably because of inhibition of PDE-6 (a PDE found in the retina that is important in color vision). Tadalafil  does not appear to disrupt PDE-6, and reports of changes in color vision have been rare with this medication.   The incidence of these reactions appears to be dose dependent. Because there is an inherent cardiac risk  associated with sexual activity, PDE-5 inhibitors should be used with caution in patients with a history of  cardiovascular disease (CVD) or those with strong risk factors for CVD. PDE-5 inhibitors should not be used more  than once per day.   Figure 29.3 Effect of phosphodiesterase inhibitors on cyclic guanosine monophosphate (cGMP) levels in  the smooth muscle of the corpus cavernosum. GTP =guanosine triphosphate.    4. Drug interactions: Because of the ability of PDE inhibitors to potentiate the activity of NO, administration of  these agents in patients taking any form of organic nitrates is contraindicated. PDE-5 inhibitors may produce  additive blood pressurea€"lowering effects when used in patients taking l±-adrenergic antagonists (used to  alleviate symptoms associated with benign prostatic hyperplasia). The combination of PDE-5 inhibitors and  i±-adrenergic antagonists should be used with caution. Patients should be on a stable dose of the i±-adrenergic  antagonist prior to the initiation of the PDE-5 inhibitor, and the PDE-5 inhibitor should be started at a low dose  if this combination is to be used. Doses of PDE-5 inhibitors may need to be reduced in the presence of potent  inhibitors of CYP3A4, such as protease inhibitors, clarithromycin, and erythromycin.   Osteoporosis is a condition of skeletal fragility due to progressive loss of bone mass. It occurs in the elderly of both  sexes but is most pronounced in postmenopausal women. Osteoporosis is characterized by frequent bone fractures,  which are a maj or cause of disability among the elderly. Nondrug strategies to reduce bone loss in postmenopausal  women include a diet adequate in calcium and vitamin D, weight-bearing exercise, and cessation of smoking. In  addition, patients at risk for osteoporosis should avoid drugs that increase bone loss, such as glucocorticoids. Figure  29.5 shows the changes in bone morphology seen in osteoporosis.    Sildenafil Q 3-4 hrs  Vardenafil  4-5 hrs  Tadalafil | 18 hrs    Figure 29.4 Some properties of phosphodiesterase inhibitors, ^elay in time to reach peak drug  concentration when taken with high-fat foods.   These analogs of pyrophosphate, including etidronate [e-TID-row-nate], risedronate [rih-SED-row-nate],  alendronate [a-LEND-row-nate], ibandronate [eye-BAN-dro-nate], pamidronate [pah-MID-row-nate], tiludronate  [till-UH-droe-nate], and zoledronic [zole-DROE-nick] acid, comprise an important drug group used for the  treatment of disorders of bone remodeling, such as osteoporosis and Paget's disease, as well as for treatment of  bone metastases and hypercalcemia of malignancy. In addition, alendronate, risedronate, and ibandronate have  been approved for the prevention and treatment of osteoporosis. Zoledronic acid is also approved for the  treatment of postmenopausal osteoporosis. The bisphosphonates decrease osteoclastic bone resorption via several  mechanisms, including 1) inhibition of the osteoclastic proton pump necessary for dissolution of hydroxyapatite, 2)  decrease in osteoclastic formation/ activation, 3) increase in osteoclastic apoptosis (programmed cell death), and 4)  inhibition of the cholesterol biosynthetic pathway important for osteoclast function. The relative importance of the  mechanisms may differ among the individual bisphosphonates. The decrease in osteoclastic bone resorption results  in a small but significant net gain in bone mass in osteoporotic patients, because the bone-forming osteoblasts are  not inhibited. The beneficial effects of alendronate persist over several years of therapy (Figure 29.6), but  discontinuation results in a gradual loss of its effects. Treatment with bisphosphonates decreases the risk of bone  fracture in patients with osteoporosis. Bisphosphonates are preferred agents for the prevention and treatment of  postmenopausal osteoporosis.   1. Pharmacokinetics: Alendronate, risedronate, and ibandronate are orally active agents for osteoporosis,  although less than one percent of the administered dose is absorbed. Alendronate and risedronate may be  dosed once daily or once weekly, whereas ibandronate is administered once monthly. Food significantly    interferes with absorption. Bisphosphonates should be administered with 6 to 8 ounces of plain water at least 30  minutes (60 minutes for ibandronate) before eating breakfast or taking other medications. The bisphosphonates  are rapidly cleared from the plasma, primarily because they avidly bind to the hydroxyapatite mineral of bone.  Once bound to bone, they are cleared over a period of hours to years. Elimination from the body is primarily  through renal clearance, and the bisphosphonates should not be given to individuals with severe renal  impairment. For patients unable to tolerate oral bisphosphonates, intravenous ibandronate and zoledronic acid  are alternative treatments for osteoporosis. Intravenous ibandronate is administered once every 3 months, and  zoledronic acid is administered once yearly.   2. Adverse effects: These include diarrhea, abdominal pain, and musculoskeletal pain. Alendronate, risedronate,  and ibandronate are associated with esophagitis and esophageal ulcers. To minimize the risk of esophageal  irritation, patients should remain upright for at least 30 minutes (60 minutes for ibandronate ) after taking a  bisphosphonate. Osteonecrosis of the j aw has been reported with bisphosphonates. Etidronate is the only  member of the class that causes osteomalacia following long-term, continuous administration. Figure 29.7 shows  the relative potencies of the bisphosphonates.   Estrogen replacement is an effective therapy for the prevention of postmenopausal bone loss. When initiated in the  immediate postmenopausal period, estrogen therapy prevents osteoporosis and reduces the risk of hip fracture.  [Note: Estrogen-progestogen therapy is no longer the therapy of choice for the treatment of osteoporosis in  postmenopausal women because of increased risk of breast cancer, stroke, venous thromboembolism, and coronary  disease. ] Raloxifene [rah- LOX- i h-feen ] is a selective estrogen-receptor modulator approved for the prevention and  treatment of osteoporosis. It increases bone density without increasing the risk of endometrial cancer. In addition,  raloxifene may reduce the risk of invasive breast cancer. Raloxifene is a first-line alternative for postmenopausal  osteoporosis in women who are intolerant to bisphosphonates. Raloxifene reduces serum total and low-density    lipoprotein cholesterol concentrations. The risk of venous thromboembolism appears to be comparable to that with  estrogen. Other adverse effects include hot flashes and leg cramps.    Figure 29.6 Effect of alendronate therapy on the bone mineral density of the lumbar spine.   Salmon calcitonin [cal-SIH-toe-nin], administered intranasally, is effective and well tolerated in the treatment of  postmenopausal osteoporosis. The drug reduces bone resorption, but it is less effective than the bisphosphonates. A  unique property of calcitonin is the relief of pain associated with osteoporotic fracture. Therefore, calcitonin may  be beneficial in patients who have recently suffered a vertebral fracture. Common adverse effects of the intranasal  formulation include rhinitis and other nasal symptoms. A parenteral formulation of calcitonin is available for  intramuscular or subcutaneous inj ection, but it is infrequently used in the treatment of osteoporosis. Resistance to  the effects of calcitonin has been observed with long-term use in patients with Paget's disease .   Teriparatide [ter-ih-PAR-a-tide] is a recombinant segment of human parathyroid hormone that is administered  subcutaneously for the treatment of osteoporosis. Parathyroid hormone given continuously leads to dissolution of  bone, but when it is given subcutaneously once daily, bone formation is the predominant effect. It increases spinal  bone density and decreases the risk of vertebral fracture. Teriparatide is the first approved treatment for  osteoporosis that stimulates bone formation. Other drugs approved for this indication inhibit bone resorption. It is  also effective in the treatment of glucocorticoid-induced osteoporosis. Teriparatide has been associated with an  increased risk of osteosarcoma in rats. The safety and efficacy of this agent have not been evaluated beyond 24  months. Teriparatide should be reserved for patients at high risk of fractures or who cannot tolerate other  osteoporosis therapies.   Two classes of drugs are used in treating obesity: the anorexiants (appetite suppressants) phentermine,  diethylpropion, and sibutramine, and a lipase inhibitor, orlistat. Phentermine and diethylpropion are indicated  for short-term management of obesity. Sibutramine and orlistat have been approved for up to 2 and 4 years of use,  respectively.   Phentermine [FEN-ter-meen] exerts its pharmacologic action by increasing release of norepinephrine and dopamine  from the nerve terminals and by inhibiting reuptake of these neurotransmitters, thereby increasing levels of  neurotransmitters in the brain. Diethylpropion [ dye-eth- i 1 1- PROE- pee-on ] has similar effects on norepinephrine.  Sibutramine [si-BYOO-tra-meen] inhibits central reuptake of serotonin, norepinephrine, and to a lesser extent,  dopamine. Unlike the other agents, sibutramine does not cause the release of neurotransmitters. Figure 29.8 shows  the effect of sibutramine treatment.   1. Pharmacokinetics: Limited information is available regarding the pharmacokinetics of phentermine. The  duration of activity is dependent on the formulation, and the primary route of excretion is via the kidney.  Diethylpropion is rapidly absorbed and undergoes extensive first-pass metabolism. Many of the metabolites are  active. Diethylpropion and its metabolites are excreted mainly via the kidney. The half-life of the metabolites is  4 to 8 hours. Sibutramine undergoes first-pass demethylation to active metabolites, which are primarily  responsible for its pharmacologic effects. The active metabolites are biotransformed further in the liver and  excreted primarily in the urine. The half-life of the active metabolites is about 15 hours.   2. Adverse effects and contraindications: All of the appetite suppressants are Schedule IV controlled agents due  to potential for dependence or abuse. Dry mouth, headache, insomnia, and constipation are common problems.  Heart rate and blood pressure may be increased with these agents, and they should be avoided in patients with a  history of hypertension, CVD, arrhythmias, congestive heart failure, or stroke. In addition, phentermine has  been associated with heart valve disorders and pulmonary hypertension. Concomitant use of appetite  suppressants and monoamine oxidase inhibitors should be avoided. Sibutramine should also be avoided in  patients who are taking selective serotonin inhibitors such as fluoxetine, serotonin agonists for migraine such as  sumatriptan, as well as lithium, dextromethorphan, or pentazocine. Drug interactions can occur when  sibutramine is administered with drugs that inhibit CYP3A4, such as ketoconazole, erythromycin, and  cimetidine. The clinical relevance of these interactions is not known.   Orlistat [OR-lih-stat] is the first drug in a class of antiobesity drugs known as lipase inhibitors. Orlistat is a  pentanoic acid ester that inhibits gastric and pancreatic lipases, thus decreasing the breakdown of dietary fat into  smaller molecules that can be absorbed. Fat absorption is decreased by about 30 percent. The loss of calories is the  main cause of weight loss, but adverse gastrointestinal effects associated with the drug may also contribute to a  decreased intake of food. Orlistat is administered   three times daily with meals. Figure 29.9 shows the effects of orlistat treatment. The most common adverse effects  associated with orlistat are gastrointestinal symptoms, such as oily spotting, flatulence with discharge, fecal  urgency, and increased defecation. It interferes with the absorption of fat-soluble vitamins and i 2 -carotene. Thus,  patients should be advised to take a multivitamin supplement that contains vitamins A, D, E, and K and also  f 2 -carotene. The vitamin supplement should not be taken within 2 hours of orlistat. Orlistat is contraindicated in  patients with chronic malabsorption syndrome or cholestasis.   29. 1 A 66-year-old man complained of decreased libido and difficulty maintaining an erection. He is concerned  about the use of drugs to restore sexual function, particularly about the need to time therapy with anticipated  sexual activity. Which one of the following therapeutic options is indicated for this patient?   A. Sildenafil is indicated because of its long duration of action.   B. Vardenafil is indicated because its absorption is not affected by food.   C. Tadalafil is indicated because of its long duration of action   D. Tadalafil is not indicated because of its short duration of action.   29.2 Which of the following drugs causes osteomalacia and bone pain when administered chronically?   29.3 A 58-year-old male has been effectively treated for Paget's disease for approximately 6 months. He is now  beginning to experience renewed bone pain and radiologic evidence of advancing disease. Which of the  following drugs is most likely to have resulted in this failure of therapy?   >Table of Contents > Unit VII - Chemotherapeutic Drugs >Chapter 30 - Principles of Anti-microbial Therapy   Antimicrobial therapy takes advantage of the biochemical differences that exist between microorganisms and human  beings. Antimicrobial drugs are effective in the treatment of infections because of their selective toxicity; that is,  they have the ability to inj ure or kill an invading microorganism without harming the cells of the host. In most  instances, the selective toxicity is relative rather than absolute, requiring that the concentration of the drug be  carefully controlled to attack the microorganism while still being tolerated by the host.    Figure 30.1 Some laboratory techniques that are useful in the diagnosis of microbial diseases.   Selection of the most appropriate antimicrobial agent requires knowledge of 1) the organism's identity, 2) the  organism's susceptibility to a particular agent, 3) the site of the infection, 4) patient factors, 5) the safety of the  agent, and 6) the cost of therapy. However, some critically ill patients require empiric therapya€"that is, immediate  administration of drug(s) prior to bacterial identification and susceptibility testing.   Characterization of the organism is central to selection of the proper drug. A rapid assessment of the nature of the  pathogen can sometimes be made on the basis of the Gram stain, which is particularly useful in identifying the  presence and morphologic features of microorganisms in body fluids that are normally sterile (cerebrospinal fluid  [CSF], pleural fluid, synovial fluid, peritoneal fluid, and urine). However, it is generally necessary to culture the  infective organism to arrive at a conclusive diagnosis and to determine the susceptibility of the bacteria to  antimicrobial agents. Thus, it is essential to obtain a sample culture of the organism prior to initiating treatment.  Definitive identification of the infecting organism may require other laboratory techniques, such as detection of  microbial antigens, microbial DNA    or RNA, or detection of an inflammatory or host immune response to the microorganism (Figure 30. 1). 1   Ideally, the antimicrobial agent used to treat an infection is selected after the organism has been identified and its  drug susceptibility established. However, in the critically ill patient, such a delay could prove fatal, and immediate  empiric therapy is indicated.    Tubes containing varying  concentrations of antibiotic  are inoculated with test  organism.    Minimum inhibitory concentration (MIC)  is the lowest concentration of antibiotic  that inhibits bacterial growth (equals 2  in this example).    Subculture in antibiotic-free  medium, and measure growth  after 24 hours of incubation.   Minimum bactericidal concentration  (MBC) is the lowest concentration of  antibiotic that kills 99.9 percent of  bacteria (equals 32 in this example).   Figure 30.2 Determination of minimum inhibitory concentration (MIC) and minimum bactericidal  concentration (MBC) of an antibiotic.    1. Timing: Acutely ill patients with infections of unknown ori gi na€"f or example, a neutropenic patient (one who  has a reduction in neutrophils, predisposing the patient to infections), or a patient with severe headache, a  rigid neck, and sensitivity to bright lights (symptoms characteristic of meningitis)a€"require immediate  treatment. Therapy is initiated after specimens for laboratory analysis have been obtained but before the  results of the culture are available.   2. Selecting a drug: The choice of drug in the absence of susceptibility data is influenced by the site of infection  and the patient's history (for example, whether the infection was hospital- or community-acquired, whether the  patient is immunocompromised, as well as the patient's travel record and age). Broad-spectrum therapy may be  needed initially for serious infections when the identity of the organism is unknown or the site makes a  polymicrobial infection likely. The choice of agents may also be guided by known association of particular  organisms with infection in a given clinical setting. For example, a gram-positive coccus in the spinal fluid of a  newborn infant is unlikely to be Streptococcus pneumoniae (pneumococcus) and most likely to be Streptococcus  aqalactiae (Group B), which is sensitive to penicillin G. By contrast, a gram-positive coccus in the spinal fluid of  a 40-year-old patient is most likely to be S. pneumoniae . This organism is frequently resistant to penicillin G and  often requires treatment with a third-generation cephalosporin (such as cefotaxime or ceftriaxone ) or  vancomycin.   After a pathogen is cultured, its susceptibility to specific antibiotics serves as a guide in choosing antimicrobial  therapy. Some pathogens, such as Streptococcus pyogenes and Neisseria meningitidis , usually have predictable  susceptibility patterns to certain antibiotics. In contrast, most gram-negative bacilli, enterococci, and  staphylococcal species often show unpredictable susceptibility patterns to various antibiotics and require  susceptibility testing to determine appropriate antimicrobial therapy. The minimum inhibitory and bactericidal  concentrations of a drug can be experimentally determined (Figure 30.2).   1. Bacteriostatic vs. bactericidal drugs: Antimicrobial drugs are classified as either bacteriostatic or bactericidal.  Bacteriostatic drugs arrest the growth and replication of bacteria at serum levels achievable in the patient, thus  limiting the spread of infection while the body's immune system attacks, immobilizes, and eliminates the  pathogens. If the drug is removed before the immune system has   scavenged the organisms, enough viable organisms may remain to begin a second cycle of infection. Bactericidal  drugs kill bacteria at drug serum levels achievable in the patient. Because of their more aggressive antimicrobial  action, these agents are often the drugs of choice in seriously ill patients. Figure 30. 3 shows a laboratory  experiment in which the growth of bacteria is arrested by the addition of a bacteriostatic agent. Note that  viable organisms remain even in the presence of the bacteriostatic drug. By contrast, addition of a bactericidal  agent kills bacteria, and the total number of viable organisms decreases. Although practical, this classification  may be too simplistic, because it is possible for an antibiotic to be bacteriostatic for one organism and  bactericidal for another. For example, chloramphenicol is bacteriostatic against gram-negative rods and is  bactericidal against other organisms, such as S. pneumoniae .    Figure 30.3 Effects of bactericidal and bacteriostatic drugs on the growth of bacteria i n vitro .    2. Minimum inhibitory concentration: To determine the minimum inhibitory concentration (MIC), tubes  containing serial dilutions of an antibiotic are inoculated with the organism whose susceptibility is to be tested  (see Figure 30.2). The tubes are incubated and later observed to determine the MICa€"that is, the lowest  concentration of antibiotic that inhibits bacterial growth. To provide effective antimicrobial therapy, the  clinically obtainable antibiotic concentration in body fluids should be greater than the MIC. [Note: This assay is  now done automatically using microtiter plates.]   3. Minimum bactericidal concentration: This quantitative assay determines the minimum concentration of  antibiotic that kills the bacteria under investigation. The tubes that show no growth in the MIC assay are  subcultured into antibiotic-free media. The minimum bactericidal concentration is the lowest concentration of  antimicrobial agent that results in a 99.9 percent decline in colony count after overnight broth dilution  incubations (see Figure 30.2).    D. Effect of the site of infection on therapy: The blood-brain barrier   Adequate levels of an antibiotic must reach the site of infection for the invading microorganisms to be effectively  eradicated. Capillaries with varying degrees of permeability carry drugs to the body tissues. For example, the  endothelial cells comprising the walls of capillaries of many tissues have fenestrations (openings that act like  windows) that allow most drugs not bound by plasma proteins to penetrate. Flowever, natural barriers to drug  delivery are created by the structures of the capillaries of some tissues, such as the prostate, the vitreous body of  the eye, and the central nervous system (CNS). Of particular significance are the capillaries in the brain, which help  to create and maintain the blood-brain barrier. This barrier is formed by the single layer of tile-like endothelial cells  fused by tight j unctions that impede entry from the blood to the brain of virtually all molecules, except those that  are small and lipophilic (Figure 30.4). This barrier can be demonstrated by inj ecting dyes into laboratory animals.  Dyes inj ected into the circulation stain all tissues except brain. Flowever, the same dyes injected into the CSF stain  only the cells of the CNS (Figure 30.5). The blood- brain barrier prevents the dye from escaping from the blood  vessels in the brain, although they readily leak from the vessels throughout the rest of the body. The penetration  and concentration of an antibacterial agent in the CSF is particularly influenced by the following:   1. Lipid solubility of the drug: All compounds without a specific transporter must pass intracellularly from the  blood to the CSF (through two endothelial cell membranes; see Figure 30.5). The lipid solubility of a drug is  therefore a major determinant of its ability to penetrate into the brain. For example, lipid-soluble drugs, such  as the quinolones and metronidazole, have significant penetration into the CNS. In contrast, l * 1 2 3 -lactam  antibiotics, such as penicillin, are ionized at physiologic pH and have low solubility in lipids. They therefore  have limited penetration through the intact blood-brain barrier under normal circumstances. In infections such  as meningitis, in which the brain becomes inflamed, the barrier does not function effectively, and local  permeability is increased. Some l 2 -lactam antibiotics can then enter the CSF in therapeutic amounts.   2. Molecular weight of the drug: A compound with a low molecular weight has an enhanced ability to cross the  blood-brain barrier, whereas compounds with a high molecular weight (for example, vancomycin) penetrate  poorly, even in the presence of meningeal inflammation.   3. Protein binding of the drug: A high degree of protein binding of a drug in the serum restricts its entry into the   CSF. Therefore, the amount of free (unbound) drug in serum, rather than the total amount of drug present, is  important for CSF penetration.   In selecting an antibiotic, attention must be paid to the condition of the patient. For example, the status of the  patient's immune system, kidneys, liver, circulation, and age must be considered. In women, pregnancy or breast-  feeding also affects selection of the antimicrobial agent.    1. Immune system: Elimination of infecting organisms from the body depends on an intact immune system.   Antibacterial drugs decrease the microbial population (bactericidal) or inhibit further bacterial growth  (bacteriostatic), but the host defense system must ultimately eliminate the invading organisms. Alcoholism,  diabetes, infection with the human immunodeficiency virus, malnutrition, or advanced age can affect a patient's  immunocompetence, as can therapy with immunosuppressive drugs. Higher-than-usual doses of bactericidal  agents or longer courses of treatment are required to eliminate infective organisms in these individuals.   2. Renal dysfunction: Poor kidney function (10 percent or less of normal) causes accumulation in the body of  antibiotics that ordinarily are eliminated by this route. This may lead to serious adverse effects unless drug  accumulation is controlled by adj usting the dose or the dosage schedule of the antibiotic. Serum creatinine  levels are frequently used as an index of renal function for adj ustment of drug regimens. * 2 3 4 5 6 7 However, direct  monitoring of serum levels of some antibiotics (for example, aminoglycosides) is preferred to identify maximum  and minimum values. Rising minimum values alert the physician to potential toxicity. [Note: The number of  functioning nephrons   decreases with age. Thus, elderly patients are particularly vulnerable to accumulation of drugs eliminated by the  kidneys. Antibiotics that undergo extensive metabolism or are excreted via the biliary route may be favored in  such patients.]   3. Hepatic dysfunction: Antibiotics that are concentrated or eliminated by the liver (for example, erythromycin  and tetracycline ) are contraindicated in treating patients with liver disease.   4. Poor perfusion: Decreased circulation to an anatomic area, such as the lower limbs of a diabetic, reduces the  amount of antibiotic that reaches that area, making infections notoriously difficult to treat.   5. Age: Renal or hepatic elimination processes are often poorly developed in newborns, making neonates  particularly vulnerable to the toxic effects of chloramphenicol and sulfonamides. Young children should not be  treated with tetracyclines, which affect bone growth.   6. Pregnancy: All antibiotics cross the placenta. Adverse effects to the fetus are rare, except the for tooth  dysplasia and inhibition of bone growth encountered with the tetracyclines. However, some anthelmintics are  embryotoxic and teratogenic. Aminoglycosides should be avoided in pregnancy because of their ototoxic effect  on the fetus. Figure 30.6 summarizes the U.S. Food and Drug Administration (FDA) categories of antibiotic use  during pregnancy. The drug examples listed in Figure 30.6 are not all inclusive; they merely represent an  example from each category. This current U.S. Food and Drug Administration category system can be difficult to  apply to combination medications with many active ingredients and does not take into consideration the  potential for any drug interactions. Of course, all drugs should be used only during pregnancy under the  supervision of a patient's physician. Moreover, clinicians should reference the most current literature before  prescribing medications for pregnant patients, to stay up-to-date for risk assessment reasons.   7. Lactation: Drugs administered to a lactating mother may enter the nursing infant via the breast milk. Although  the concentration of an antibiotic in breast milk is usually low, the total dose to the infant may be enough to  cause problems.   No controlled  studies show  human risk;  animal studies  suggest  potential  toxicity   [i-Lactams  ji-Lactams with  inhibitors  Cephalosporins  Aztreonam  Clindamycin  Erythromycin  Azithromycin  Metronidazole  Nitrofurantoin  Sulfonamides   Human fetal  risk present  but does not  outweigh  benefits;  contraindicated  in pregnancy   Figure 30.6 United States Food and Drug Administration categories of antimicrobials and fetal risk.   Many of the antibiotics, such as the penicillins, are among the least toxic of all drugs, because they interfere with a  site unique to the growth of microorganisms. Other antimicrobial agents (for example, chloramphenicol) are less  microorganism specific and are reserved for life-threatening infections because of the drug's potential for serious  toxicity to the patient. [Note: As discussed above, safety is related not only to the inherent nature of the drug but  also to patient factors that can predispose to toxicity.]   Often, several drugs may show similar efficacy in treating an infection but vary widely in cost. Figure 30. 7 illustrates  the cost of some antibacterial agents showing similar efficacy in eradicating the gram- negative bacillus FHel icobacter  pylori from the gastric mucosa. None of these agents shows a clear therapeutic superiority; thus, a combination of   metronidazole with bismuth subsalicylate plus one other antibiotic is usually employed in the treatment of K_    gyloriaC" induced peptic ulcers. Selecting clarithromycin instead as the drug of choice would clearly make a  considerable cost impact.   The oral route of administration is chosen for infections that are mild and can be treated on an outpatient basis. In  addition, economic pressures have prompted the use of oral antibiotic therapy in all but the most serious infectious  diseases. In patients requiring a course of intravenous therapy initially, the switch to oral agents occurs as soon as  possible. However, some antibiotics, such as vancomycin, the aminoglycosides, and amphotericin B, are so poorly  absorbed from the gastrointestinal tract that adequate serum levels cannot be obtained by oral administration.  Parenteral administration is used for drugs that are poorly absorbed from the gastrointestinal tract and for  treatment of patients with serious infections, for whom it is necessary to maintain higher serum concentrations of  antimicrobial agents than can be reliably obtained by the oral route.    Figure 30.7 Relative cost of some drugs used for the treatment of peptic ulcers causedby Helicobacter  pylori .   Rational dosing of antimicrobial agents is based on their pharmacodynamics (the relationship of drug concentrations  to antimicrobial effects) as well as their pharmacokinetic properties (the absorption, distribution, and elimination  of the drug by the body). Three important properties that have a significant influence on the frequency of dosing  are concentration-dependent killing, time-dependent killing, and postantibiotic effect. Utilizing these properties to  optimize antibiotic dosing regimens will improve clinical outcomes and possibly decrease the development of  resistance.   Rate of bacterial killing increases  as the concentration exceeds 4- to  64-fold the MIC of the drug for the  organism.   Figure 30.8 A. Significant dose-dependent killing effect shown by tobramycin. B. Nonsignificant  dose-dependent killing effect shown by ticarcill in. cfu =colony forming units; MIC =minimum inhibitory  concentration.   Certain antimicrobial agents, including aminoglycosides, fluoroquinolones, and carbapenems show a significant  increase in the rate of bacterial killing as the concentration of antibiotic increases from 4- to 64-fold the MIC of the  drug for the infecting organism (Figure 30. 8A). Giving drugs that exhibit this concentration-dependent killing by a   once-a-day bolus infusion achieves high peak levels, favoring rapid killing of the infecting pathogen.   By contrast, F-lactams, glycopeptides, macrolides, clindamycin, and linezolid do not exhibit this property; that is,  increasing the concentration of antibiotic to higher multiples of the MIC does not significantly increase the rate of  kill (Figure 30. 8B). The clinical efficacy of antimicrobials that have a nonsignificant, dose-dependent killing effect is  best predicted by the percentage of time that blood concentrations of a drug remain above the MIC. This effect is  sometimes called concentration-independent or time-dependent killing. For example, for the penicillins and  cephalosporins, dosing schedules that ensure blood levels greater than the MIC 60 to 70 percent of the time have  been demonstrated to be clinically effective. Some experts therefore suggest that some severe infections are best  treated by continuous infusion of these agents rather than by intermittent dosing.   The postantibiotic effect (PAE) is a persistent suppression of microbial growth that occurs after levels of antibiotic  have fallen below the MIC. To measure the PAE of an antibiotic, a test culture is first incubated in antibiotic-  containing medium and then transferred to antibiotic-free medium. The PAE is defined as the length of time it takes  (after the transfer) for the culture to achieve log-phase growth. 3 Antimicrobial drugs exhibiting a long PAE (several  hours) often require only one dose per day. For example, antimicrobials, such as aminoglycosides and  fluoroquinolones, exhibit a long PAE, particularly against gram-negative bacteria.   In this book, the clinically useful antibacterial drugs are organized into six familiesaC" penicillins, cephalosporins,  tetracyclines, aminoglycosides, macrolides, and fluoroquinolonesa€"plus a seventh group labeled a€oeOthera€§ that  is used to represent any drug not included in one of the other six drug families (Figure 30. 9A). Here and throughout  this book, these seven groups are graphically presented as a bar chart (as a a€oedrug stacka€i). The drug(s) of  choice within each family that is/ are used for treating a specific bacterial infection are shown in bold print, as  illustrated for Staphylococcus aureus in Figure 30. 9B. A key to additional antibiotic symbols used in this book is  shown in Figure 30. 9C.    Figure 30.9 A. Bar chart showing the six most commonly used drug families. B. An example of the bar chart  with the drugs of choice for the treatment of Staphylococcus aureus shown in bold print. C. Key to symbols  used in this book.   In this book, the clinically important bacteria have been organized into eight groups based on Gram stain,  morphology, and biochemical or other characteristics, and they are represented as wedges of a a€oepie chartaCS  (Figure 30. 10A). The ninth section of the bacterial pie chart is labeled a€oeOther,a€^ : and it is used to represent any  organism not included in one of the other eight categories. In this chapter, the pie chart is used to illustrate the  spectra of bacteria for which a particular class of antibiotics is therapeutically effective.   Chemotherapeutic agents acting only on a single or a limited group of microorganisms are said to have a narrow  spectrum. For example, isoniazid is active only against mycobacteria (Figure 30. 10B).   Extended spectrum is the term applied to antibiotics that are effective against gram-positive organisms and also  against a significant number of gram-negative bacteria. For example, ampicillin is considered to have an extended  spectrum, because it acts against gram-positive and some gram-negative bacteria (Figure 30. 10C).   Drugs such as tetracycline and chloramphenicol affect a wide variety of microbial species and are referred to as  broad-spectrum antibiotics    (Figure 30. 10D). Administration of broad-spectrum antibiotics can drastically alter the nature of the normal  bacterial flora and precipitate a superinfection of an organism such as Candida albicans , the growth of which is  normally kept in check by the presence of other microorganisms. 4   It is therapeutically advisable to treat patients with the single agent that is most specific for the infecting organism.  This strategy reduces the possibility of superinfection, decreases the emergence of resistant organisms (see below),  and minimizes toxicity. Flowever, situations in which combinations of drugs are employed do exist. For example, the  treatment of tuberculosis benefits from drug combinations.    Figure 30.10 A. Color-coded representation of medically important microorganisms. B. Isoniazid, a narrow-  spectrum antimicrobial agent. C. Ampicillin, an extended-spectrum antimicrobial agent. D. Tetracycline, a  broadspectrum antimicrobial agent.   Certain combinations of antibiotics, such asi 2 -lactams and aminoglycosides, show synergism; that is, the  combination is more effective than either of the drugs used separately. Because such synergism among antimicrobial  agents is rare, multiple drugs used in combination are only indicated in special situationsa€"for example, when an  infection is of unknown origin.   A number of antibiotics act only when organisms are multiplying. Thus, coadministration of an agent that causes  bacteriostasis plus a second agent that is bactericidal may result in the first drug interfering with the action of the  second. For example, bacteriostatic tetracycline drugs may interfere with the bactericidal effect of penicillins and  cephalosporins.   Bacteria are said to be resistant to an antibiotic if the maximal level of that antibiotic that can be tolerated by the  host does not halt their growth. Some organisms are inherently resistant to an antibiotic. For example,  gram-negative organisms are inherently resistant to vancomycin. However, microbial species that are normally  responsive to a particular drug may develop more virulent, resistant strains through spontaneous mutation or  acquired resistance and selection. Some of these strains may even become resistant to more than one antibiotic.   Acquired antibiotic resistance requires the temporary or permanent gain or alteration of bacterial genetic  information. Resistance develops due to the ability of DNA to undergo spontaneous mutation or to move from one  organism to another (Figure 30. 11).   1. Spontaneous mutations of DNA: Chromosomal alteration may occur by insertion, deletion, or substitution of  one or more nucleotides within the genome. 5 The resulting mutation may persist, be corrected by the organism,  or be lethal to the cell. If the cell survives, it can replicate and transmit its mutated properties to progeny cells.   Some spontaneous mutations have little or no effect on the susceptibility of the organism to antimicrobial  agents. However, mutations that produce antibiotic-resistant strains can result in organisms that may proliferate  under certain selective pressures. An example is the emergence of rifampin- resistant Mycobacterium  tuberculosis when rifampin is used as a single antibiotic.   2. DNA transfer of drug resistance: Of particular clinical concern is resistance acquired due to DNA transfer from  one bacterium to another. Resistance properties are usually encoded in extrachromosomal R factors (resistance  plasmids). In fact, most resistance genes are plasmid mediated, although plasmid-mediated traits can become  incorporated into host bacterial DNA. Plasmids may enter cells by processes such as transduction (phage  mediated), transformation, or bacterial conjugation. 6   Drug resistance may be mediated by a variety of mechanisms, such as a lack of or an alteration in an antibiotic    target site, lowered penetrability of the drug due to decreased permeability, increased efflux of the drug, or  presence of antibiotic-inactivating enzymes (see Figure 30. 11).    Alteration in the target  enzyme, ONA gyrase,  has resulted in  resistance to fluoro-  quinoloocs.   [5-LacUms enter gram-  negative cells through  porin channels.  Entcrobactcr is largely  resistant to cephalo-  sporins by producing  [5-lactamases. However,  resistant organisms  may also have altered  porin channels through  which cephalosporins  do not pass.    Tetracycline was  effective against gyne-  cologic infection due  «o BgcttfPjdM. but now  these organisms are  resistant due to the  presence of plasmid-  mediated protein that  promotes efflux of the  drug.   Neisseria gonorrhoeae  is now largely resistant to  penicillin because of  penicillinase activity.   1. Modification of target sites: Alteration of an antibiotic's target site through mutation can confer organismal  resistance to one or more related antibiotics. For example, S. pneumoniae resistance to i 2 -lactam antibiotics  involves alterations in one or more of the maj or bacterial pen/c////n- binding proteins, resulting in decreased  binding of the antibiotic to its target.    Prevention of strepto-  coccal infections in  patients with a history of  rheumatic heart disease.  Patients may require  years of treatment.    Pretreatment of patients  undergoing dental  extractions who have  implanted prosthetic  devices, such as artificial  heart valves, to prevent  seeding of the prosthesis.    Prevention of tuber-  culosis or meningitis  among individuals who  are in close contact  with infected patients.    Treatment prior to certain  surgical procedures (such  as bowel surgery, joint  replacement, and some  gynecologic inter-  ventions) to prevent  infection.    Treatment of the mother  with zidovudine to protect  the fetus in the case of an  HIV-infected, pregnant  woman.   Figure 30.12 Some clinical situations in which prophylactic antibiotics are indicated.    2. Decreased accumulation: Decreased uptake or increased efflux of an antibiotic can confer resistance, because  the drug is unable to attain access to the site of its action in sufficient concentrations to inj ure or kill the  organism. For example, gram-negative organisms can limit the penetration of certain agents, including i 2 -lactam  antibiotics, tetracyclines, and chloramphenicol , as a result of an alteration in the number and structure of  porins (channels) in the outer membrane. Also, the presence of an efflux pump can limit levels of a drug in an  organism.   3. Enzymic inactivation: The ability to destroy or inactivate the antimicrobial agent can also confer resistance on  microorganisms. Examples of antibiotic-inactivating enzymes include 1) P-lactamases (a€oepenicillinasesa€i)  that hydrolytically inactivate the l 2 -lactam ring of penicillins, cephalosporins, and related drugs; 2)  acetyltransferases that transfer an acetyl group to the antibiotic, inactivating chloramphenicol or  aminoglycosides; and 3) esterases that hydrolyze the lactone ring of macrolides.   Certain clinical situations require the use of antibiotics for the prevention rather than the treatment of infections  (Figure 30. 12). Because the indiscriminate use of antimicrobial agents can result in bacterial resistance and  superinfection, prophylactic use is restricted to clinical situations in which the benefits outweigh the potential  risks. The duration of prophylaxis is dictated by the duration of the risk of infection.   Because the mechanism of action of a particular antibiotic is selectively toxic to an invading organism does not  insure the host against adverse effects. For example, the drug may produce an allergic response or be toxic in ways  unrelated to the drug's antimicrobial activity.   Hype rse n si t i vi ty reactions to antimicrobial drugs or their metabolic products frequently occur. For example, the  penicillins, despite their almost absolute selective microbial toxicity, can cause serious hypersensitivity problems,  ranging from urticaria (hives) to anaphylactic shock.   High serum levels of certain antibiotics may cause toxicity by directly affecting cellular processes in the host. For  example, aminoglycosides can cause ototoxicity by interfering with membrane function in the hair cells of the organ  of Corti.   Drug therapy, particularly with broad-spectrum antimicrobials or combinations of agents, can lead to alterations of  the normal microbial flora of the upper respiratory, intestinal, and genitourinary tracts, permitting the overgrowth  of opportunistic organisms, especially fungi or resistant bacteria. These infections are often difficult to treat.   Antimicrobial drugs can be classified in a number of ways. These include 1) by their chemical structure (for  example, l 2 -lactams or aminoglycosides), 2) by their mechanism of action (for example, cell wall synthesis  inhibitors), or 3) by their activity against particular types of organisms (for example, bacteria, fungi, or viruses).  Chapters 31 through 33 are organized by the mechanisms of action of the drug, and Chapters 34 through 38 are  organized according to the type of organisms affected by the drug (Figure 30. 13).    Figure 30.13 Classification of some antibacterial agents by their sites of action, (THFA =tetrahydrofolic acid;  PABA =p-aminobenzoic acid)   30. 1 Which one of the following patients is least likely to require antimicrobial treatment tailored to the  individual's condition?    30. 2 In which one of the following clinical situations is the prophylactic use of antibiotics not warranted?   A. Prevention of meningitis among individuals in close contact with infected patients.   B. Patient with a hip prosthesis who is having a tooth removed.    30.3 Which one of the following is the best route of administration/dosing schedule for treatment with  aminoglycosides based on the drug's concentration-dependent killing property?   >Table of Contents > Unit VII - Chemotherapeutic Drugs >Chapter 31 - Cell Wall Inhibitors   Some antimicrobial drugs selectively interfere with synthesis of the bacterial cell wallaC'a structure that mammalian  cells do not possess. The cell wall is composed of a polymer called peptidoglycan that consists of glycan units j oined  to each other by peptide cross-links. To be maximally effective, inhibitors of cell wall synthesis require actively  proliferating microorganisms; they have little or no effect on bacteria that are not growing and dividing. The most  important members of this group of drugs are the i 2 -lactam antibiotics (named after the P-lactam ring that is  essential to their activity) and vancomycin. Figure 31. 1 shows the classification of agents affecting cell wall  synthesis.    Figure 31.1 Summary of antimicrobial agents affecting cell wall synthesis. *Cilastatin is not an antibiotic but  a peptidase inhibitor that protects imipenem from degradation.   The penicillins are among the most widely effective antibiotics and also the least toxic drugs known, but increased    resistance has limited their use. Members of this family differ from one another in the R substituent attached to the  6- ami nopeni ci 1 1 ani c acid residue (Figure 31.2). The nature of this side chain affects the antimicrobial spectrum,  stability to stomach acid, and susceptibility to bacterial degradative enzymes (i 2 -lactamases).    Nature of the R group  determines the drug's  stability to enzymatic or  acidic hydrolysis, and  affects its antibacterial  spectrum.   The penicillins interfere with the last step of bacterial cell wall synthesis (transpeptidation or cross-linkage 1 ),  resulting in exposure of the osmotically less stable membrane. Cell lysis can then occur, either through osmotic  pressure or through the activation of autolysins. These drugs are thus bactericidal. The success of a penicillin  antibiotic in causing cell death is related to the antibiotic's size, charge, and hydrophobicity. Penicillins are only  effective against rapidly growing organisms that synthesize a peptidoglycan cell wall. Consequently, they are  inactive against organisms devoid of this structure, such as mycobacteria, protozoa, fungi, and viruses.   1. Penicillin-binding proteins: Penicillins inactivate numerous proteins on the bacterial cell membrane. These  penicillin-binding proteins (PBPs) are bacterial enzymes involved in the synthesis of the cell wall and in the  maintenance of the morphologic features of the bacterium. Exposure to these antibiotics can therefore not only  prevent cell wall synthesis but also lead to morphologic changes or lysis of susceptible bacteria. The number of  PBPs varies with the type of organism. Alterations in some of these target molecules provide the organism with  resistance to the penicillins. [Note: Metfi/c////n-resistant Staphylococcus aureus (MRSA) apparently arose  because of such an alteration.]   2. Inhibition of transpeptidase: Some PBPs catalyze formation of the cross-linkages between peptidoglycan chains  (Figure 31.3). Penicillins inhibit this transpeptidase-catalyzed reaction, thus hindering the formation of  cross-links essential for cell wall integrity. As a result of this blockade of cell wall synthesis, the a€oePark  nucleotideaCS (formerly called the a€oePark peptidea€§), UDP-acetylmuramyl-l-Ala-D-GIn-L-Lys-D-Ala-D-Ala,    3. Production of autolysins: Many bacteria, particularly the gram-positive cocci, produce degradative enzymes  (autolysins) that participate in the normal remodeling of the bacterial cell wall. In the presence of a penicillin,  the degradative action of the autolysins proceeds in the absence of cell wall synthesis. [Note: The exact  autolytic mechanism is unknown, but it may be due to a disinhibition of the autolysins. ] Thus, the antibacterial  effect of a penicillin is the result of both inhibition of cell wall synthesis and destruction of existing cell wall by  autolysins.    The PEP side chains are cross-  linked as the final step in the  synthesis of peptidoglycan.  This process is blocked by  penicillin.    H NAM | 1 NAG | 1 NAM | 1 NAG |—    Figure 31.3 Bacterial cell wall of gram-positive bacteria. NAM =N-acetylmuramic acid; NAG =  N-acetylglucosamine; PEP = cross- linking peptide.   The antibacterial spectrum of the various penicillins is determined, in part, by their ability to cross the bacterial  peptidoglycan cell wall to reach the PBPs in the periplasmic space. Factors that determine the susceptibility of PBPs  to these antibiotics include the size, charge, and hydrophobicity of the particular P-lactam antibiotic. In general,  gram-positive microorganisms have cell walls that are easily traversed by penicillins and, therefore, in the absence  of resistance are susceptible to these drugs. Gram-negative microorganisms have an outer lipopolysaccharide  membrane (envelope) surrounding the cell wall that presents a barrier to the water-soluble penicillins. However,  gram-negative bacteria have proteins inserted in the lipopolysaccharide layer that act as water-filled channels  (called porins) to permit transmembrane entry. [Note: Pseudomonas aeruginosa lacks porins, making these  organisms intrinsically resistant to many antimicrobial agents. ]   1. Natural penicillins: These penicillins, which include those classified as antistaphylococcal, are obtained from  fermentations of the mold Penicillium chrysogenum . Other penicillins, such as ampicillin, are called  semisynthetic, because the different R groups are attached chemically to the 6-aminopenicillanic acid nucleus    obtained from fermentation broths of the mold. Penicillin [pen-i-SILL-in] G ( benzylpenicillin ) is the  cornerstone of therapy for infections caused by a number of gram-positive and gram-negative cocci,  gram-positive bacilli, and spirochetes (Figure 31.4). Penicillin G is susceptible to inactivation by l * 2 3 -lactamases  (penicillinases). Penicillin V has a spectrum similar to that of penicillin G, but it is not used for treatment of  bacteremia because of its higher minimum bactericidal concentration (the minimum amount of the drug needed  to eliminate the infection; see p. 343). Penicillin V is more acid-stable than penicillin G. It is often employed  orally in the treatment of infections, where it is effective against some anaerobic organisms.   2. Antistaphylococcal penicillins; Methicillin [meth-i-SILL-in], nafcillin [naf-SILL-in], oxacillin [ox-a-SILL-in], and  dicloxacillin [dye-klox-a-SILL-in] are penicillinase-resistant penicillins. Their use is restricted to the treatment  of infections caused by penicillinase-producing staphylococci. [Note: Because of its toxicity, methicillin is not  used clinically except to identify resistant strains of S. aureus]. Currently a serious source of nosocomial  (hospital-acquired) infections, MRSA is usually susceptible to vancomycin and, rarely, to ciprofloxacin or  rifampin.   3. Extended-spectrum penicillins; Ampicillin [am-pi-SILL-in] and amoxicillin [a-mox-i-SILL-in] have an  antibacterial spectrum similar to that of penicillin G but are more effective against gram- negative bacilli. They  are therefore referred to as extended-spectrum penicillins (Figure 31. 5A). Ampicillin is the drug of choice for  the gram-positive bacillus Listeria monocytogenes . These agents are also widely used in the treatment of  respiratory infections, and amoxicillin is employed prophyl act ical ly by dentists for patients with abnormal heart  valves who are to undergo extensive oral surgery. Resistance to these antibiotics is now a maj or clinical problem  because of inactivation by plasmid-mediated penicillinase. [Note: Escherichia coli and Plaemophilus influenzae  are frequently resistant. ] Formulation with a l 2 -lactamase inhibitor, such as clavulanic acid or sulbactam,  protects amoxicillin or ampicillin, respectively, from enzymatic hydrolysis and extends their antimicrobial  spectrum.    Enterobacter species  Escherichia coli  Proteus mirabilis  Proteus (indole positive)  Haemophilus influenzae  Pseudomonas aeruginosa    Figure 31.5 Typical therapeutic applications of ampicillin (A) and the antipseudomonal penicillins (B).    4. Antipseudomonal penicillins: Carbenicillin [kar-ben-i-SILL-in], ticarcillin [tye-kar-SILL-in], and piperacillin  [pip-er-a-SILL-in] are called antipseudomonal penicillins because of their activity against P. aeruginosa (Figure  31. 5B). Piperacillin is the most potent of these antibiotics. They are effective against many gram-negative  bacilli, but not against klebsiella, because of its constitutive penicillinase. Formulation of ticarcillin or  piperacillin with clavulanic acid or tazobactam, respectively, extends the antimicrobial spectrum of these  antibiotics to include penicillinase-producing organisms. (Figure 31.6 summarizes of the stability of the  penicillins to acid or the action of penicillinase. )   5. Penicillins and aminoglycosides: The antibacterial effects of all the P-lactam antibiotics are synergistic with  the aminoglycosides. Because cell wall synthesis inhibitors alter the permeability of bacterial cells, these drugs    can facilitate the entry of other antibiotics (such as aminoglycosides) that might not ordinarily gain access to  intracellular target sites. This can result in enhanced antimicrobial activity, [Note: Although the combination of  a penicillin plus an aminoglycoside is used clinically, these drug types should never be placed in the same  infusion fluid, because on prolonged contact, the positively charged aminoglycosides form an inactive complex  with the negatively charged penicillins. ]   Natural resistance to the penicillins occurs in organisms that either lack a peptidoglycan cell wall (for example,  mycoplasma) or have cell walls that are impermeable to the drugs. Acquired resistance to the penicillins by plasmid  transfer has become a significant clinical problem, because an organism may become resistant to several antibiotics  at the same   time due to acquisition of a plasmid that encodes resistance to multiple agents. Multiplication of such an organism  will lead to increased dissemination of the resistance genes. By obtaining a resistance plasmid, bacteria may acquire  one or more of the following properties, thus allowing it to withstand i 2 -lactam antibiotics.   Figure 31.6 Stability of the penicillins to acid or the action of penicillinase.    1. i 1 2 -Lactamase activity: This family of enzymes hydrolyzes the cyclic amide bond of the i 2 -lactam ring, which  results in loss of bactericidal activity (see Figure 31.2). They are the maj or cause of resistance to the penicillins  and are an increasing problem. f 2 -Lactamases are either constitutive or, more commonly, are acquired by the   transfer of plasmids. Some of the i 2 -lactam antibiotics are poor substrates for l 2 -lactamases and resist cleavage,  thus retaining their activity against l 2 -lactamase producing organisms. [Note: Certain organisms may have  chromosome-associated l 2 -lactamases that are inducible by l 2 -lactam antibiotics (for example, cefoxitin). ]  Gram-positive organisms secrete l 2 -lactamases extracellularly, whereas gram-negative bacteria confine the   enzymes in the periplasmic space between the inner and outer membranes.   2. Decreased permeability to the drug: Decreased penetration of the antibiotic through the outer cell membrane  prevents the drug from reaching the target PBPs. The presence of an efflux pump can also reduce the amount of  intracellular drug.   3. Altered PBPs: Modified PBPs have a lower affinity for P-lactam antibiotics, requiring clinically unattainable  concentrations of the drug to effect inhibition of bacterial growth. This mechanism may explain MRSA, although  it does not explain its resistance to non-f 2 -lactam antibiotics like erythromycin, to which they are also  refractory.   1. Administration: The route of administration of a i 2 -lactam antibiotic is determined by the stability of the drug  to gastric acid and by the severity of the infection.   a. Routes of administration: Ticarcillin, carbenicillin, piperacillin, and the combinations of ampicillin with  sulbactam, ticarcillin with clavulanic acid, and piperacillin with tazobactam, must be administered  intravenously (IV) or intramuscularly (IM). Penicillin V, amoxicillin, amoxicillin combined with clavulanic  acid, and the indanyl ester of carbenicillin (for treatment of urinary tract infections) are available only as  oral preparations. Others are effective by the oral, IV, or IM routes (see Figure 31.6).   b. Depot forms: Procaine penicillin G and benzathine penicillin G are administered IM and serve as depot  forms. They are slowly absorbed into the circulation and persist at low levels over a long time period.   2. Absorption: Most of the penicillins are incompletely absorbed after oral administration, and they reach the  intestine in sufficient amounts to affect the composition of the intestinal flora. However, amoxicillin is almost  completely absorbed. Consequently, it is not appropriate therapy for the treatment of shigella- or salmonella-  derived enteritis, because therapeutically effective levels do not   reach the organisms in the intestinal crypts. Absorption of all the penicillinase-resistant penicillins is decreased  by food in the stomach, because gastric emptying time is lengthened, and the drugs are destroyed in the acidic  environment. Therefore, they must be administered 30 to 60 minutes before meals or 2 to 3 hours  postprandially. Other penicillins are less affected by food.    3. Distribution: The l 2 -lactam antibiotics distribute well throughout the body. All the penicillins cross the placental  barrier, but none has been shown to be teratogenic. However, penetration into certain sites, such as bone or  cerebrospinal fluid (CSF), is insufficient for therapy unless these sites are inflamed (Figures 31.7 and 31.8).   [Note: During the acute phase of infection, the inflamed meninges are more permeable to the penicillins,  resulting in an increased ratio of the amount of drug in the central nervous system compared to the amount in  the serum. As the infection abates, inflammation subsides, and permeability barriers are reestablished.]  Penicillin levels in the prostate are insufficient to be effective against infections.   4. Metabolism: Host metabolism of the i 2 -lactam antibiotics is usually insignificant, but some metabolism of  penicillin G has been shown to occur in patients with impaired renal function.    5. Excretion: The primary route of excretion is through the organic acid (tubular) secretory system of the kidney  as well as by glomerular filtration. Patients with impaired renal function must have dosage regimens adj usted.  Thus, the half-life of penicillin G can increase from a normal of between 30 minutes and 1 hour, to 10 hours in  individuals with renal failure. Probenecid inhibits the secretion of penicillins by competing for active tubular  secretion via the organic acid transporter and, thus, can increase blood levels. Nafcillin is eliminated primarily  through the biliary route. [Note: This is also the preferential route for the acylureido penicillins in cases of renal  failure. ] The penicillins are also excreted into breast milk.   Penicillins are among the safest drugs, and blood levels are not monitored. However, the following adverse  reactions may occur (Figure 31.9).   Figure 31.8 Enhanced penetration of penicillin into the cerebral spinal fluid (CSF) during inflammation.    1. Hypersensitivity: This is the most important adverse effect of the penicillins. The major antigenic determinant  of penicillin hypersensitivity is its metabolite, penicilloic acid, which reacts with proteins and serves as a hapten  to cause an immune reaction. Approximately five percent of patients have some kind of reaction, ranging from  maculopapular rash (the most common rash seen with ampicillin hypersensitivity) to angioedema (marked  swelling of the lips, tongue, and periorbital area) and anaphylaxis. Among patients with mononucleosis who are  treated with ampicillin, the incidence of maculopapular rash approaches 100 percent. Cross-allergic reactions  occur among the i * 2 3 4 -lactam antibiotics.   2. Diarrhea: This effect, which is caused by a disruption of the normal balance of intestinal microorganisms, is a  common problem. It occurs to a greater extent with those agents that are incompletely   absorbed and have an extended antibacterial spectrum. As with some other antibiotics, pseudomembranous  colitis 2 may occur.   3. Nephritis: All penicillins, but particularly methicillin, have the potential to cause acute interstitial nephritis.   4. Neurotoxicity: The penicillins are irritating to neuronal tissue, and they can provoke seizures if inj ected    intrathecally or if very high blood levels are reached. Epileptic patients are particularly at risk.   5. Hematologic toxicities: Decreased coagulation may be observed with the antipseudomonal penicillins   ( carbenicillin and ticarcillin) and, to some extent, with penicillin G. It is generally a concern when treating  patients who are predisposed to hemorrhage (for example, uremics) or those receiving anticoagulants.  Additional toxicities include eosinophilia.   6. Cation toxicity: Penicillins are generally administered as the sodium or potassium salt. Toxicities may be caused  by the large quantities of sodium or potassium that accompany the penicillin. Sodium excess may result in  hypokalemia. This can be avoided by using the most potent antibiotic, which permits lower doses of drug and  accompanying cations.   The cephalosporins are i 2 -lactam antibiotics that are closely related both structurally and functionally to the  penicillins. Most cephalosporins are produced semisynthetically by the chemical attachment of side chains to  7-aminocephalosporanic acid. Cephalosporins have the same mode of action as penicillins, and they are affected by  the same resistance mechanisms. However, they tend to be more resistant than the penicillins to certain  l 2 -lactamases.   Cephalosporins have been classified as first, second, third, or fourth generation, based largely on their bacterial  susceptibility patterns and resistance to P-lactamases (Figure 31. 10). [Note: Cephalosporins are ineffective against  MRSA, L. monocytogenes , Clostridium difficile , and the enterococci.]    1. First generation: The first-generation cephalosporins act as penicillin G substitutes. They are resistant to the  staphylococcal penicillinase and also have activity against Proteus mirabilis , E. coli , and Klebsiella pneumoniae  (the acronym PEcK has been suggested).   2. Second generation: The second-generation cephalosporins display greater activity against three additional  gram-negative organisms: H. influenzae , Enterobacter aeroqenes , and some Neisseria species, whereas activity  against gram-positive organisms is weaker (the acronym HENPEcK has been suggested with the second  generation's   increased coverage). [Note: The exception to this generalization is the structurally related cephamycin,  cefoxitin [sef-OX-i-tin], which has little activity against H. influenzae yet is effective against the anaerobe  Bacteroides fragilis [with some resistance occurring per 2007 antimicrobial guidelines.]   3. Third generation: These cephalosporins have assumed an important role in the treatment of infectious disease.  Although inferior to first-generation cephalosporins in regard to their activity against gram-positive cocci, the  third-generation cephalosporins have enhanced activity against gram-negative bacilli, including those mentioned  above, as well as most other enteric organisms plus Serratia marcescens . Ceftriaxone [sef-trye-AKS-own] or  cefotaxime [sef-oh-TAKS-eem] have become agents of choice in the treatment of meningitis. Ceftazidime  [sef-TA-zi-deem] has activity against P. aeruginosa .   4. Fourth generation: Cefepime [SEF-eh-peem] is classified as a fourth-generation cephalosporin and must be  administered parenterally. Cefepime has a wide antibacterial spectrum, being active against streptococci and  staphylococci (but only those that are methicillin- susceptible). Cefepime is also effective against aerobic  gram-negative organisms, such as enterobacter, E. coli . K. pneumoniae , P. mirabilis. and P. aeruginosa .   Mechanisms of bacterial resistance to the cephalosporins are essentially the same as those described for the  penicillins. [Note: Although they are not susceptible to hydrolysis by the staphylococcal penicillinase,  cephalosporins may be susceptible to extended-spectrum i 2 -lactamases. ]    Staphylococcus aureus *  Staphylococcus epidermidis  Streptococcus pneumoniae  Streptococcus pyogenes  Anaerobic streptococci   1. Administration: Many of the cephalosporins must be administered IV or IM (Figure 31. 11) because of their poor  oral absorption. Exceptions are noted in Figure 31.12.   2. Distribution: All cephalosporins distribute very well into body fluids. Flowever, adequate therapeutic levels in  the CSF, regardless of inflammation, are achieved only with the third-generation cephalosporins. For example,  ceftriaxone or cefotaxime are effective in the treatment of neonatal and childhood meningitis caused by Fh_  influenzae . Cefazolin [se-FA-zo-lin] finds application as a single prophylaxis dose prior to surgery because of its  1.8-hour half-life and its activity against penicillinase-producing S. aureus . Flowever, additional intraoperative  cefazolin doses may be required if the surgical procedure lasts longer than 3 hours. Cefazolin is effective for  most surgical procedures, including orthopedic surgery because of its ability to penetrate bone. All  cephalosporins cross the placenta.   3. Fate: Biotransformation of cephalosporins by the host is not clinically important. Elimination occurs through  tubular secretion and/or glomerular filtration (see Figure 31.11). Therefore doses must be adj usted in cases of  severe renal failure to guard against accumulation and toxicity. Ceftriaxone is excreted through the bile into  the feces and, therefore, is frequently employed in patients with renal insufficiency.   The cephalosporins produce a number of adverse affects, some of which are unique to particular members of the  group.    Most cephalosporins  do not penetrate  into the CSF; third-  generation agents  achiei  levels    1. Allergic manifestations: Patients who have had an anaphylactic response to penicillins should not receive  cephalosporins. The cephalosporins should be avoided or used with caution in individuals who are allergic to  penicillins (about 5a€"15 percent show cross-sensitivity). In contrast, the incidence of allergic reactions to  cephalosporins is one to two percent in patients without a history of allergy to penicillins.   Carbapenems are synthetic P-lactam antibiotics that differ in structure from the penicillins in that the sulfur atom  of the thiazolidine ring (see Figure 31.2) has been externalized and replaced by a carbon atom (Figure 31.13).  Imipenem [i-mi-PEN-em], meropenem [mer-oh-PEN-em] and ertapenem [er-ta-PEN-em] are the only drugs of this  group currently available. Imipenem is compounded with cilastatin to protect it from metabolism by renal  dehydropeptidase.   1. Antibacterial spectrum: Imipenem/ cilastatin and meropenem are the broadest-spectrum i 2 -lactam antibiotic  preparations currently available (Figure 31. 14). Imipenem resists hydrolysis by most F-lactamases, but not the  metallo-i 2 -lactamases. The drug plays a role in empiric therapy because it is active against penicillinase-  producing gram-positive and gram-negative organisms, anaerobes, and P. aeruginosa (although other  pseudomonal strains are resistant, and resistant strains of P. aeruginosa have been reported to arise during  therapy). Meropenem has antibacterial activity similar to that of imipenem. Ertapenem is not an alternative for  P. aeruginosa coverage, because most strains exhibit resistance.   2. Pharmacokinetics: Imipenem and meropenem are administered IV and penetrate well into body tissues and  fluids, including the CSF when the meninges are inflamed. They are excreted by glomerular filtration. Imipenem  undergoes cleavage by a dehydropeptidase found in the brush border of the proximal renal tubule. This enzyme  forms an inactive metabolite that is potentially nephrotoxic. Compounding the imipenem with cilastatin  protects the parent drug and, thus, prevents the formation of the toxic metabolite. This allows the drug to be  used in the treatment of urinary tract infections. Meropenem does not undergo metabolism. Ertapenem can be  administered via IV or IM inj ection. [Note: Doses of these agents must be adj usted in patients with renal  insufficiency.]   3. Adverse effects: Imipenem/cilastatin can cause nausea, vomiting, and diarrhea. Eosinophilia and neutropenia  are less common than with other i 2 -lactams. High levels of imipenem may provoke seizures, but meropenem is  less likely to do so.    This first-generation parenteral cephalosporin  has a longer duration of action, and a similar  spectrum of action, compared to other first-  generation drugs. It penetrates well Into bone.   Figure 31.12 Characteristics of some clinically useful cephalosporins. [Note: Drugs that can be administered  orally are shown in reverse type. More useful drugs shown in bold.] CSF =cerebrospinal fluid.   The monobactams, which also disrupt bacterial cell wall synthesis, are unique, because the l 2 -lactam ring is not  fused to another ring (see Figure 31. 13). Aztreonam [az-TREE-oh-nam], which is the only commercially available   monobactam, has antimicrobial activity directed primarily against the enterobacteriaceae, but it also acts against  aerobic gram-negative rods, including P. aeruginosa . It lacks activity against gram-positive organisms and anaerobes.  This narrow antimicrobial spectrum precludes its use alone in empiric therapy (see p. 342). Aztreonam is resistant  to the action of I 2 - lactamases. It is administered either IV or IM and is excreted in the urine. It can accumulate in  patients with renal failure. Aztreonam is relatively nontoxic, but it may cause phlebitis, skin rash, and occasionally,  abnormal liver function tests. This drug has a low immunogenic potential, and it shows little cross-reactivity with  antibodies induced by other f 2 -lactams. Thus, this drug may offer a safe alternative for treating patients who are  allergic to penicillins and/ or cephalosporins.   Hydrolysis of the i 2 -lactam ring, either by enzymatic cleavage with a f 2 -lactamase or by acid, destroys the  antimicrobial activity of a l 2 -lactam antibiotic. i 2 -Lactamase inhibitors, such as clavulanic [cla-vue-LAN-ick] acid,  sulbactam [sul-BACK-tam], and tazobactam [ta-zoh-BACK-tam], contain a i 2 -lactam ring but, by themselves, do not  have significant antibacterial activity. Instead, they bind to and inactivate i 2 -lactamases, thereby protecting the  antibiotics that are normally substrates for these enzymes. The H-lactamase inhibitors are therefore formulated in  combination with i 2 -lactamase sensitive antibiotics. For example, Figure 31. 15 shows the effect of clavulanic acid  and amoxicillin on the growth of i 2 -lactamase producing E. coli . [Note: Clavulanic acid alone is nearly devoid of  antibacterial activity. ]   Vancomycin [van-koe-MYE-sin] is a tricyclic glycopeptide that has become increasingly important because of its   effectiveness against multiple drug-resistant organisms, such as MRSA and enterococci. The medical community is  presently concerned with emergence of vancomycin resistance in these organisms. [Note: Bacitracin [bass-  i-TRAY-sin] is a mixture of polypeptides that also inhibits bacterial cell wall synthesis. It is active against a wide  variety of gram-positive organisms. Its use is restricted to topical application because of its potential for  nephrotoxicity with systemic use. ]    Aanetobacter species  Gtrobacter species  Enterobacter species  Escherichia coH  Gardnerella vaginalis  Haemophilus influenzae  Klebsiella species  Proteus species  Providencia species  Pseudomonas aeruginosa  Salmonella species  Serratia species   Vancomycin inhibits synthesis of bacterial cell wall phospholipids as well as peptidoglycan polymerization by binding  to the D-Ala-D-Ala side chain of the precursor pentapeptide. This prevents the t ransglycosyl ati on step in  peptidoglycan polymerization, thus weakening the cell wall and damaging the underlying cell membrane.   Vancomycin is effective primarily against gram-positive organisms (Figure 31. 16). It has been lifesaving in the   treatment of MRSA and methicillin- resistant Staphylococcus epidermidis (MRSE) infections as well as enterococcal  infections. With the emergence of resistant strains,    it is important to curtail the increase in vancomycin- resistant bacteria (for example, Enterococcus faecium and  Enterococcus faecalis) by restricting the use of vancomycin to the treatment of serious infections caused by  i 2 -lactam resistant, gram-positive microorganisms or for patients with gram- positive infections who have a serious  allergy to the i 2 -lactams. Oral vancomycin is limited to treatment for potentially life-threatening, antibiotic-  associated colitis due to C. difficile or staphylococci. Vancomycin is used in individuals with prosthetic heart valves  and in patients undergoing implantation with prosthetic devices. [Note: The latter is of particular concern in those  hospitals where there is a problem with MRSA or MRSE. Daptomycin, a cyclic lipopeptide antibiotic, and two protein  synthesis inhibitorsa €"quinopristin/dalfopristin and linezolid a€"are currently available for the treatment of  vancomyc/n-resistant organisms.] Vancomycin acts synergistically with the aminoglycosides, and this combination  can be used in the treatment of enterococcal endocarditis.    Figure 31.15 The in vitro growth of Escherichia coli in the presence of amoxicillin, with and without  clavulanic acid.   Vancomycin resistance can be caused by plasmid-mediated changes in permeability to the drug or by decreased  binding of vancomycin to receptor molecules. [Note: An example of the latter is caused by the replacement of a  D-Ala by D-lactate in resistant organisms.]    Slow IV infusion (60a€"90 minutes) is employed for treatment of systemic infections or for prophylaxis. Because  vancomycin is not absorbed after oral administration, this route is employed only for the treatment of antibiotic-  induced colitis due to C. difficile when metronidazole has proven to be ineffective. Inflammation allows  penetration into the meninges. However, it is often necessary to combine vancomycin with other antibiotics, such  as ceftriaxone for synergistic effects when treating menigits. Metabolism of the drug is minimal, and 90 to 100  percent is excreted by glomerular filtration (Figure 31. 17). [Note: Dosage must be adj usted in renal failure, because  the drug will accumulate. The normal half-life of vancomycin is 6 to 10 hours, compared to over 200 hours in  end-stage renal disease.]   Side effects are a serious problem with vancomycin and include fever, chills, and/ or phlebitis at the infusion site.  Flushing (a€oered man syndromea€§) and shock results from histamine release associated with a rapid infusion. If an  infusion-related reaction occurs, slow the infusion rate to administer vancomycin over 2 hours, increase the dilution  volume, or pretreat with an antihistamine 1 hour prior to administration. Additionally, reactions can be treated with  antihistamines and steroids (Figure 31. 18). Dose-related hearing loss has occurred in patients with renal failure who  accumulate the drug. Ototoxicity and nephrotoxicity are more common when vancomycin is administered with  another drug (for example, an aminoglycoside) that can also produce these effects.   Daptomycin [DAP-toe-mye-sin] is a cyclic lipopeptide antibiotic that is an alternative to other agents, such as   linezolid and quinupristin/ dalfopristin, for treating infections caused by resistant gram-positive organisms,  including MRSA and vancomycin-resistant enterococci (VRE).   Upon binding to the bacterial cytoplasmic membrane, daptomycin induces rapid depolarization of the membrane,  thus disrupting multiple aspects of membrane function and inhibiting intracellular synthesis of DNA, RNA, and  protein. Daptomycin is bactericidal, and bacterial killing is concentration dependent.   Daptomycin has a spectrum of activity limited to gram-positive organisms, which includes methicillin-su sceptible  and methicillin-resistant S. aureus , penicillin-resistant Streptococcus pneumoniae , Streptococcus pyogenes ,  Corynebacterium jeikeium , E. faecalis , and E. faecium (including VRE). Daptomycin is indicated for the treatment  of complicated skin and skin structure infections and bacteremia caused by S. aureus, including those with  right-sided infective endocarditis. Efficacy of treatment with daptomycin in left-sided endocarditis has not been  demonstrated. Additionally, daptomycin is inactivated by pulmonary surfactants; thus, it is not indicated in the  treatment of pneumonia.    Does not penetrate non-  inflamed meninges, but  does enter CSF if  meninges are inflamed   Daptomycin is 90 to 95 percent protein bound and does not appear to undergo hepatic metabolism; however, the  dosing interval needs to be adj usted in patients with renal impairment (creatinine clearance less than 30  mL/ minute). In skin and soft tissue infections, daptomycin is administered at 4 mg/ kg IV daily via a 30- minute  infusion. Nevertheless, when treating bacteremia and endocarditis, dose should be increased to 6 mg/ kg.   The most common adverse effects reported in clinical trials included constipation, nausea, headache, and insomnia.  Increased hepatic transaminases and also elevations in creatin phosphokinases occurred, suggesting weekly  monitoring while the patient is receiving daptomycin. Although no clinically significant interactions have been  identified, it is recommended to temporarily discontinue 3-hydroxy- 3- methylglutary coenzyme A reductase  inhibitors (statins) while receiving daptomycin due to the potential for additive muscle toxicity.    31.1 An elderly diabetic patient is admitted to the hospital with pneumonia. The sputum culture stains for a    gram-negative rod. The patient is started on IV ampicillin. Two days later, the patient is not improving, and the  microbiology laboratory reports the organism to be a i 2 -lactamase producing H, influenzae . What course of  treatment is indicated?    31.2 A 70-year-old alcoholic male with poor dental hygiene is to have his remaining teeth extracted for  subsequent dentures. He has mitral valve stenosis with mild cardiac insufficiency and is being treated with  captopril, digoxin, and furosemide. The dentist decides that his medical history warrants prophylactic  antibiotic therapy prior to the procedure and prescribes which of the following drugs?    31.3 A patient with degenerative joint disease is to undergo insertion of a hip prosthesis. To avoid  complications due to postoperative infection, the surgeon will pretreat this patient with an antibiotic. This  hospital has a significant problem with MRSA. Which of the following antibiotics should the surgeon select?    31.4 A 25-year-old male returns home from a holiday in the Far East and complains of 3 days of dysuria and a  purulent urethral discharge. You diagnose this to be a case of gonorrhea. Which of the following is appropriate  treatment?   >Table of Contents > Unit VII - Chemotherapeutic Drugs >Chapter 32 - Protein Synthesislnhibitors   A number of antibiotics exert their antimicrobial effects by targeting the bacterial ribosome, which has components  that differ structurally from those of the mammalian cytoplasmic ribosome. In general, the bacterial ribosome is  smaller (70S) than the mammalian ribosome (80S) and is composed of 50S and 30S subunits (as compared to 60S and  40S subunits). The mammalian mitochondrial ribosome, however, more closely resembles the bacterial ribosome.  Thus, although drugs that interact with the bacterial target usually spare the host cells, high levels of drugs such as  chloramphenicol or the tetracyclines may cause toxic effects as a result of interaction with the host mitochondrial  ribosomes. Figure 32. 1 lists the drugs discussed in this chapter.   The tetracyclines are a group of closely related compounds that, as the name implies, consist of four fused rings  with a system of conj ugated double bonds. Substitutions on these rings are responsible for variation in the drugs'  individual pharmacokinetics, which cause small differences in their clinical efficacy.    Entry of these agents into susceptible organisms is mediated both by passive diffusion and by an energy-dependent  transport protein mechanism unique to the bacterial inner cytoplasmic membrane. Nonresistant strains concentrate  the tetracyclines intracellularly. The drug binds reversibly to the 30S subunit of the bacterial ribosome, thereby  blocking access of the amino acyl-tRNA to the mRNA- ribosome complex at the acceptor site. By this mechanism,  bacterial protein synthesis is inhibited (Figure 32.2).   As broad-spectrum, bacteriostatic antibiotics, the tetracyclines are effective against gram-positive and  gram-negative bacteria as well as against organisms other than bacteria. Tetracyclines are the drugs of choice for  infections such as those shown in Figure 32.3.   Widespread resistance to the tetracyclines limits their clinical use. The most commonly encountered, naturally  occurring resistance   (a€oeRa€i) factor confers an inability of the organism to accumulate the drug, thus producing resistance. This is  accomplished by Mg 2+ -dependent, active efflux of the drug, mediated by the plasmid-encoded resistance protein,   TetA. Other less important mechanisms of bacterial resistance to tetracyclines include enzymatic inactivation of the  drug and production of bacterial proteins that prevent tetracyclines from binding to the ribosome. Any organism  resistant to one tetracycline is resistant to all. The maj ority of penicillinase-producing staphylococci are now  insensitive to tetracyclines.   Figure 32.2 Tetracyclines binds to the 30S ribosomal subunit, thus preventing the binding of aminoacyl-tRNA  to the ribosome, aa =amino acid.   1. Absorption: All tetracyclines are adequately but incompletely absorbed after oral ingestion (Figure 32.4).  Flowever, taking these drugs concomitantly with dairy foods in the diet decreases absorption due to the  formation of nonabsorbable chelates of the tetracyclines with calcium ions. Nonabsorbable chelates are also    formed with other divalent and trivalent cations (for example, those found in magnesium and aluminum antacids  and in iron preparations). [Note: This presents a problem if a patient self-treats the epigastric upsets caused by  tetracycline ingestion with antacids (Figure 32.5).] Doxycycline [dox-i-SYE-kleen] and minocycline [min-oh-  SYE-kleen] are almost totally absorbed on oral administration. Currently, doxycycline is the preferred  tetracycline for parenteral administration.   • Chlamydia trachomatis Is the major cause of sexually transmitted disease In the  United States. It causes nongonococcal urethritis, pelvic inflammatory disease,  and lymphogranuloma venereum.    • This disease, caused by Rickettsia  rickettsii. is characterized by fever,  chills, and aches in bones and joints.   • Chlamydia psittaci causes psittacosis, which usually takes the form of pneumonia.  Other clinkal forms include hepatitis, myocarditis, and coma.    • Response to tetracyclines is prompt if  the drug is started early in the disease   • Mycooplasm pneumoniae is a c  causa of pneumonia in young  adults and in people who live  in close confines, such as in  military camps.   • Treatment leads to a shorter  duration of fever, cough, and  malaise.   • Infection results in skin lesions, headache, and fever, followed  by meningoencephalitis and, eventually, arthritis.   • A single, 200 -mg dose of doxycycline, given within 72 hours after  a tick bite, can prevent development of the disease.   > Cholera is caused by Yibr to cholera t  ingested as part of fecally contaminated  food or water.   > The organism multiplies in the gastro-  intestinal tract, where it secretes an  enterotoxin that produces diarrhea.   I Treatment includes doxycycline, which  reduces the number of intestinal vibrios,  and fluid replacement.   2. Distribution: The tetracyclines concentrate in the liver, kidney, spleen, and skin, and they bind to tissues  undergoing calcification (for example, teeth and bones) or to tumors that have a high calcium content (for  example, gastric carcinoma). Penetration into most body fluids is adequate. Although all tetracyclines enter the  cerebrospinal fluid (CSF), levels are insufficient for therapeutic efficacy, except for minocycline. Minocycline  enters the brain in the absence of inflammation and also appears in tears and saliva. Although useful in  eradicating the meningococcal carrier state, minocycline is not effective for central nervous system infections.   All tetracyclines cross the placental barrier and concentrate in fetal bones and dentition.    3. Fate: All the tetracyclines concentrate in the liver, where they are, in part, metabolized and conj ugated to  form soluble glucuronides. The parent drug and/or its metabolites are secreted into the bile. Most tetracyclines  are reabsorbed in the intestine via the enterohepatic circulation and enter the urine by glomerular filtration.  Obstruction of the bile duct and hepatic or renal dysfunction can increase their half-lives. Unlike other  tetracyclines, doxycycline can be employed for treating infections in renal ly compromised patients, because it is  preferentially excreted via the bile into the feces. [Note: Tetracyclines are also excreted in breast milk.]   Figure 32.5 Effect of antacids and milk on the absorption of tetracyclines.    1. Gastric discomfort: Epigastric distress commonly results from irritation of the gastric mucosa (Figure 32.6) and is  often responsible for noncompliance in patients treated with these drugs. The discomfort can be controlled if  the drug is taken with foods other than dairy products.   2. Effects on calcified tissues: Deposition in the bone and primary dentition occurs during calcification in growing  children. This causes discoloration and hypoplasia of the teeth and a temporary stunting of growth.   3. Fatal hepatotoxicity: This side effect has been known to occur in pregnant women who received high doses of  tetracyclines, especially if they were experiencing pyelonephritis.   4. Phototoxicity: Phototoxicity, such as severe sunburn, occurs when a patient receiving a tetracycline is exposed  to sun or ultraviolet rays. This toxicity is encountered most frequently with tetracycline [tet-rah-SYE-kleen],  doxycycline, and demeclocycline [dem-e-kloe-SYE-kleen],   5. Vestibular problems: These side effects (for example, dizziness, nausea, and vomiting) occur particularly with  minocycline, which concentrates in the endolymph of the ear and affects function. Doxycycline may also cause  vestibular effects.   6. Pseudotumor cerebri: Benign, intracranial hypertension characterized by headache and blurred vision may  occur rarely in adults. Although discontinuation of the drug reverses this condition, it is not clear whether  permanent sequelae may occur.   7. Superinfections: Overgrowths of Candida (for example, in the vagina) or of resistant staphylococci (in the  intestine) may occur. Pseudomembranous colitis due to an overgrowth of Clostridium difficile has also been  reported.   8. Contraindications: Renal ly impaired patients should not be treated with any of the tetracyclines except  doxycycline. Accumulation of tetracyclines may aggravate preexisting azotemia (a higher-than-normal level of    urea or other nitrogen-containing compounds in the blood)by interfering with protein synthesis, thus promoting  amino acid degradation. The tetracyclines should not be employed in pregnant or breast-feeding women or in  children less than 8 years of age.   Tigecycline [tye-ge-SYE-kleen] is the first available member of a new class of antimicrobial agents called  glycylcyclines. Tigecycline, a derivative of minocycline, is structurally similar to the tetracyclines and has a broad-  spectrum activity against multidrug-resistant gram-positive pathogens, some gram-negative organisms, and  anaerobic organisms. Tigecycline is indicated for treatment of complicated skin and soft tissue infections as well as  complicated intra-abdominal infections.   Tigecycline exhibits bacteriostatic action by reversibly binding to the 30S ribosomal subunit and inhibiting protein  translation.   Tigecycline exhibits expanded broad-spectrum activity that includes methici 1 1 i n- resistant staphylococci, multidrug-  resistant Streptococcus pneumoniae , and other susceptible strains of streptococcal species, vancomycin-resistant  enterococci, extended-spectrum i 2 -lactamase producing gram-negative bacteria, Acinetobacter baumannii, and  many anaerobic organisms. However, tigecycline is not active against Proteus , Providencia , and Pseudomonas  species.   Tigecycline was developed to overcome the recent emergence of tetracycline classa€"resistant organisms that  utilize efflux and ribosomal protection to infer resistance.   Following a 30- to 60- minute intravenous infusion every 12 hours, tigecycline is extensively distributed throughout  plasma and body tissue. It does not undergo significant liver metabolism, but it is primarily eliminated via  biliary/fecal excretion. No dose adj ustment is necessary for patients who are renally impaired. However, dose  adj ustment is needed in severe hepatic dysfunction.   Tigecycline is well tolerated, with the main adverse effects being similar to those of the tetracycline class. In  clinical trials, the most commonly reported-class adverse effects were nausea and vomiting. Other similar  tetracycline adverse effects that may occur with tigecycline include photosensitivity, pseudotumor cerebri,  discoloration of permanent teeth when used during tooth development, and fetal harm when administered to a  pregnant woman.    The aminoglycosides bind to the 30S  ribosomal subunit and distort its  structure, thus interfering with the  initiation of protein synthesis. They  also allow misreading of the mRNA,  causing mutations or premature chain  termination.   The cytochrome P450 liver enzymes do not metabolize tigecycline-, therefore, it will not be affected by medications    that induce or inhibit these enzymes. Although tigecycline does not affect prothrombin time significantly, it has  been found to inhibit the clearance of warfarin. Therefore, it is recommended that anticoagulation be monitored  closely when tigecycline is coadministered with warfarin. No dose adj ustment of digoxin is necessary with  concomitant use of tigecycline even though digoxin C max is increased. However, another method of contraception  is suggested when tigecycline and oral contraceptives are coadministered, because the oral contraceptives may  become less effective.   Aminoglycoside antibiotics had been the mainstays for treatment of serious infections due to aerobic gram-negative  bacilli. However, because their use is associated with serious toxicities, they have been replaced to some extent by  safer antibiotics, such as the third- and fourth-generation cephalosporins, the fluoroquinolones, and the  carbapenems. Aminoglycosides that are derived from Streptomvces have -mycin suffixes, whereas those derived  from Micromonospora end in -micin. The terms a€oeaminoglycosidea€' : and a€oeaminocyclitola€'- stem from their  structurea€"two amino sugarsjoined by a glycosidic linkage to a central hexose (aminocyclitol) nucleus. Their  polycationic nature precludes their easy passage across tissue membranes. All members of this family are believed to  inhibit bacterial protein synthesis by the mechanism determined for streptomycin [strep-toe-MYE-sin] as described  below.   • Tularemia is commonly acquired  during rabbit-hunting season by  hunters skinning infected animals.   • Pneumonic tularemia results from  infection by the respiratory route  or by bacteremic seeding of lung.   Enterococci are intrinsically  resistant to most antibiotic  classes and require two  synergistic antibiotics for  effective therapy.   Recommended therapy is with  gentamicin or streptomycin  plus vancomycin or a (i-lactam,  such as penicillin G.   t Pseudomonas aeruginosa rarely  attacks healthy individuals, but  can cause infections under special  circumstances, for example, in  immunocompromised patients,  and in burn victims.   Susceptible gram-negative organisms allow aminoglycosides to diffuse through porin channels in their outer  membranes. These organisms also have an oxygen-dependent system that transports the drug across the cytoplasmic  membrane. The antibiotic then binds to the 30S ribosomal subunit prior to ribosome formation (Figure 32. 7). There,  it interferes with assembly of the functional ribosomal apparatus and/ or can cause the 30S subunit of the completed  ribosome to misread the genetic code. Polysomes become depleted, because the aminoglycosides interrupt the  process of polysome disaggregation and assembly. [Note: The aminoglycosides synergize with l 2 -lactam antibiotics  because of the latter's action on cell wall synthesis, which enhances diffusion of the aminoglycosides into the  bacterium. ]   The aminoglycosides are effective in the empirical treatment of infections suspected of being due to aerobic  gram-negative bacilli, including Pseudomonas aeruginosa . To achieve an additive or synergistic effect,  aminoglycosides are often combined with a i 2 -lactam antibiotic, or vancomycin, or a drug active against anaerobic  bacteria. All aminoglycosides are bactericidal. The exact mechanism of their lethality is unknown because other  antibiotics that affect protein synthesis are generally bacteriostatic. [Note: The aminoglycosides are effective only  against aerobic organisms because strict anaerobes lack the oxygen-requiring drug transport system. ] Some  therapeutic applications of four commonly used aminoglycosidesa€"am/kadn [am-i KAY-sin], gentamicin [jen-ta-  MYE-sin], tobramycin [toe-bra-MYE-sin], and streptomycina €" are shown in Figure 32.8.   Resistance can be caused by 1) decreased uptake of drug when the oxygen-dependent transport system for  aminoglycosides or porin channels are absent and 2) plasmid-associated synthesis of enzymes (for example, acetyl  transferases, nucleotidyltransferases, and phosphotransferases) that modify and inactivate aminoglycoside  antibiotics. Each of these enzymes has its own aminoglycoside specificity; therefore, cross-resistance is not an  invariable rule. [Note: Amikacin is less vulnerable to these enzymes than are the other antibiotics of this group. ]   1. Administration: The highly polar, polycationic structure of the aminoglycosides prevents adequate absorption  after oral administration (Figure 32.9). Therefore, all aminoglycosides (except neomycin [nee-oh-MYE-sin]) must  be given parenterally to achieve adequate serum levels. [Note: The severe nephrotoxicity associated with  neomycin precludes parenteral administration, and its current use is limited to topical application for skin  infections or oral administration to prepare the bowel prior to surgery. ] The bactericidal effect of  aminoglycosides is concentration and time dependent; that is, the greater the concentration of drug, the  greater the rate at which the organisms die. They also have a postantibiotic effect. Because of these properties,  once-daily dosing with the aminoglycosides can be employed. This results in fewer toxicities and is less  expensive to administer. The exceptions are pregnancy, neonatal infections, and bacterial endocarditis, in  which these agents are administered in divided doses every 8 hours. [Note: The dose that is administered is  calculated based on lean body mass, because these drugs do not distribute into fat. ]   2. Distribution: All the aminoglycosides have similar pharmacokinetic properties. Levels achieved in most tissues  are low, and penetration into most body fluids is variable. Concentrations in CSF are inadequate, even when the  meninges are inflamed. Except for neomycin, the aminoglycosides may be administered intrathecally or   i ntraventricu larly. High concentrations accumulate in the renal cortex and in the endolymph and perilymph of  the inner ear, which may account for their nephrotoxic and ototoxic potential. All aminoglycosides cross the  placental barrier and may accumulate in fetal plasma and amniotic fluid.   3. Fate: Metabolism of the aminoglycosides does not occur in the host. All are rapidly excreted into the urine,  predominantly by glomerular filtration (see Figure 32.9). Accumulation occurs in patients with renal failure and  requires dose modification.   It is important to monitor plasma levels of gentamicin, tobramycin, and amikacin to avoid concentrations that    cause dose-related toxicities (Figure 32. 10). [Note: When the drugs are administered two to three times daily, both  peak and trough levels are measured. Peak levels are defined as those obtained 30 minutes to 1 hour after infusion.  Trough levels are obtained immediately before the next dose. When once-daily dosing is employed, only the trough  concentrations are monitored.] Patient factors, such as old age, previous exposure to aminoglycosides, and liver  disease, tend to predispose patients to adverse reactions. The elderly are particularly susceptible to nephrotoxicity  and ototoxicity.   1. Ototoxicity: Ototoxicity (vestibular and cochlear) is directly related to high peak plasma levels and the duration  of treatment. The antibiotic accumulates in the endolymph and perilymph of the inner ear, and toxicity  correlates with the number of destroyed hair cells in the organ of Corti. Deafness may be irreversible and has  been known to affect fetuses in utero. Patients simultaneously receiving another ototoxic drug, such as  cisplatin or the loop diuretics, furosemide, bumetanide, or ethacrynic acid, are particularly at risk. Vertigo  and loss of balance (especially in patients receiving streptomycin) may also occur, because these drugs affect  the vestibular apparatus.    2. Nephrotoxicity: Retention of the aminoglycosides by the proximal tubular cells disrupts calcium-mediated  transport processes, and this results in kidney damage ranging from mild, reversible renal impairment to severe,  acute tubular necrosis, which can be irreversible.   3. Neuromuscular paralysis: This side effect most often occurs after direct intraperitoneal or intrapleural  application of large doses of aminoglycosides. The mechanism responsible is a decrease in both the release of  acetylcholine from prej unctional nerve endings and the sensitivity of the postsynaptic site. Patients with  myasthenia gravis are particularly at risk. Prompt administration of calcium gluconate or neostigmine can  reverse the block.   4. Allergic reactions: Contact dermatitis is a common reaction to topically applied neomycin.   The macrolides are a group of antibiotics with a macrocyclic lactone structure to which one or more deoxy sugars  are attached. Erythromycin [er-ith-roe-MYE-sin] was the first of these drugs to find clinical application, both as a  drug of first choice and as an alternative to penicillin in individuals who are allergic to i 2 -lactam antibiotics. The  newer members of this family, clarithromycin [kla-rith-roe-MYE-sin] (a methylated form of erythromycin ) and  azithromycin [az-ith-roe-MYE-sin] (having a larger lactone ring), have some features in common with, and others    that improve on, erythromycin. Telithromycin [tel-ith-roe-MYE-sin], a semisynthetic derivative of erythromycin, is  the first a€oeketolidea€§] antimicrobial agent that has been approved and is now in clinical use. Ketolides and  macrolides have very similar antimicrobial coverage. However, the ketolides are active against many macrolide-  resistant gram-positive strains.   The macrolides bind irreversibly to a site on the 50S subunit of the bacterial ribosome, thus inhibiting the  translocation steps of protein synthesis (Figure 32. 11). They may also interfere at other steps, such as  transpeptidation. Generally considered to be bacteriostatic, they may be bactericidal at higher doses. Their binding  site is either identical or in close proximity to that for clindamycin and chloramphenicol .   1. Erythromycin: This drug is effective against many of the same organisms as penicillin G (Figure 32. 12);  therefore, it is used in patients who are allergic to the penicillins.   Azithromycin Is an alternative to tetracycline In treating  uncomplicated urethral, endocervlcal, rectal, or epldldymal  infections due to Chlamydia .   i erythromycin is the drug of choice for urogenital infections  due to Chlamydia occurlng during pregnancy.    • Erythromycin is used to treat  syphilis in patients who are  allergic to penicillin G.   • Legionellosis represents 0.5 to  2.0 percent of all pneumonia In  the United States. Undiagnosed  or asymptomatic infections are  common.    2. Clarithromycin: This antibiotic has a spectrum of antibacterial activity similar to that of erythromycin, but it is  also effective against Haemophilus influenzae . Its activity against intracellular pathogens, such as Chlamydia ,  Legionella , Moraxella , and Ureaplasma species and Helicobacter pylori , is higher than that of erythromycin.   3. Azithromycin: Although less active against streptococci and staphylococci than erythromycin, azithromycin is  far more active against respiratory infections due to H. influenzae and Moraxella catarrhalis . Azithromycin is  now the preferred therapy for urethritis caused by Chlamydia trachomatis. It also has activity against  Mycobacterium avium-intracellulare complex in patients with acquired immunodeficiency syndrome and  disseminated infections.   4. Telithromycin: This ketolide drug has an antibacterial spectrum similar to that of azithromycin. Moreover, the  structural modification within ketolides neutralizes the most common resistance mechanisms (methylase-  mediated and efflux-mediated) that make macrolides ineffective.   Resistance to erythromycin is becoming a serious clinical problem. For example, most strains of staphylococci in  hospital isolates are resistant to this drug. Several mechanisms have been identified: 1) the inability of the organism  to take up the antibiotic or the presence of an efflux pump, both of which limit the amount of intracellular drug; 2)  a decreased affinity of the 50S ribosomal subunit for the antibiotic, resulting from the methylation of an adenine in  the 23S bacterial ribosomal RNA; and 3) the presence of a plasmid-associated erythromycin esterase. Both  clarithromycin and azithromycin show cross- resistance with erythromycin, but telithromycin can be effective  against macrolide-resistant organisms.    1. Administration: The erythromycin base is destroyed by gastric acid. Thus, either enteric-coated tablets or  esterified forms of the antibiotic are administered. All are adequately absorbed upon oral administration (Figure  32.13). Clarithromycin, azithromycin, and telithromycin are stable to stomach acid and are readily absorbed.  Food interferes with the absorption of erythromycin and azithromycin but can increase that of clarithromycin.  Azithromycin is available for intravenous infusion, but intravenous administration of erythromycin is associated  with a high incidence of thrombophlebitis.   2. Distribution: Erythromycin distributes well to all body fluids except the CSF. It is one of the few antibiotics that  diffuses into prostatic fluid, and it has the unique characteristic of accumulating in macrophages. All four drugs  concentrate in the liver. Inflammation allows for greater tissue penetration. Similarly, clarithromycin,  azithromycin, and telithromycin are widely distributed in the tissues. Serum levels of azithromycin are low;  the drug is concentrated in neutrophils, macrophages, and fibroblasts. Azithromycin has the longest half-life  and largest volume of distribution of the four drugs (Figure 32. 14).   3. Fate: Erythromycin and telithromycin are extensively metabolized and are known to inhibit the oxidation of a  number of drugs through their interaction with the cytochrome P450 system (see p. 14). Interference with the  metabolism of drugs such as theophylline and carbamazepine has been reported for clarithromycin (see Figure  32. 16). Clarithromycin is oxidized to the 14-hydroxy derivative, which retains antibiotic activity.   4. Excretion: Erythromycin and azithromycin are primarily concentrated and excreted in an active form in the  bile (see Figure 32.13). Partial reabsorption occurs through the enterohepatic circulation. Inactive metabolites  are excreted into the urine. In contrast, clarithromycin and its metabolites are eliminated by the kidney as well  as the liver, and it is recommended that the dosage of this drug be adj usted in patients with compromised renal  function.    1. Epigastric distress: This side effect is common and can lead to poor patient compliance for erythromycin.  Clarithromycin and azithromycin seem to be better tolerated by the patient, but gastrointestinal problems are  their most common side effects (Figure 32.15).   2. Cholestatic jaundice: This side effect occurs especially with the estolate form of erythromycin, presumably as  the result of a hypersensitivity reaction to the estolate form (the lauryl salt of the propionyl ester of  erythromycin). It has also been reported for other forms of the drug.   3. Ototoxicity: Transient deafness has been associated with erythromycin, especially at high dosages.   4. Contraindications: Patients with hepatic dysfunction should be treated cautiouslya€" if at all a€" with  erythromycin, telithromycin, or azithromycin, because these drugs accumulate in the liver. Recent cases of  severe hepatotoxicity with telithromycin use have emphasized   the caution needed when utilizing this agent. Additionally, telithromycin has the potential to prolongate the  QTc interval in some patients. Therefore, it should be avoided in patients with congenital prolongation of the  QTc interval and in those patients with proarrhythmic conditions. Similarly, patients who are renal ly  compromised should be given telithromycin with caution. Telithromycin is contraindicated in patients with  myasthenia gravis.   5. Interactions: Erythromycin, telithromycin, and clarithromycin inhibit the hepatic metabolism of a number of  drugs, which can lead to toxic accumulations of these compounds (Figure 32. 16). An interaction with digoxin  may occur in some patients. In this case, the antibiotic eliminates a species of intestinal flora that ordinarily  inactivates digoxin, thus leading to greater reabsorption of the drug from the enterohepatic circulation. No  interactions have been reported for azithromycin.   Figure 32.16 Inhibition of the cytochrome P450 system by erythromycin, clarithromycin, and  telithromycin.   Chloramphenicol [ klor-am- FEN- i- kol e] is active against a wide range of gram-positive and gram- negative organisms.  However, because of its toxicity, its use is restricted to life-threatening infections for which no alternatives exist.   The drug binds to the bacterial 50S ribosomal subunit and inhibits protein synthesis at the peptidyl transferase  reaction (Figure 32.17). Because of the similarity of mammalian mitochondrial ribosomes to those of bacteria,  protein synthesis in these organelles may be inhibited at high circulating chloramphenicol levels, producing bone    Chloramphenicol , a broad-spectrum antibiotic, is active not only against bacteria but also against other  microorganisms, such as rickettsiae. Pseudomonas aeruginosa is not affected, nor are the chlamydiae.  Chloramphenicol has excellent activity against anaerobes. The drug is either bactericidal or (more commonly)  bacteriostatic, depending on the organism.   Resistance is conferred by the presence of an R factor that codes for an acetyl coenzyme A transferase. This  enzyme inactivates chloramphenicol. Another mechanism for resistance is associated with an inability of the  antibiotic to penetrate the organism. This change in permeability may be the basis of multidrug resistance.   Chloramphenicol may be administered either intravenously or orally (Figure 32. 18). It is completely absorbed via  the oral route because of its lipophilic nature, and is widely distributed throughout the body. It readily enters the  normal CSF. The drug inhibits the hepatic mixed-function oxidases. Excretion of the drug depends on its conversion  in the liver to a glucuronide, which is then secreted by the renal tubule. Only about 10 percent of the parent  compound is excreted by glomerular filtration. Chloramphenicol is also secreted into breast milk.   The clinical use of chloramphenicol is limited to life-threatening infections because of the serious adverse effects  associated with its administration. In addition to gastrointestinal upsets, overgrowth of Candida albicans may appear  on mucous membranes.    1. Anemias: Hemolytic anemia occurs in patients with low levels of glucose 6-phosphate dehydrogenase. Other  types of anemia occurring as a side effect of chloramphenicol include reversible anemia, which is apparently  dose-related and occurs concomitantly with therapy, and aplastic anemia, which although rare is idiosyncratic  and usually fatal. [Note: Aplastic anemia is independent of dose and may occur after therapy has ceased. ]   2. Gray baby syndrome: This adverse effect occurs in neonates if the dosage regimen of chloramphenicol is not  properly adj usted. Neonates have a low capacity to glucuronylate the antibiotic, and they have underdeveloped  renal function. Therefore, neonates have a decreased ability to excrete the drug, which accumulates to levels  that interfere with the function of mitochondrial ribosomes. This leads to poor feeding, depressed breathing,  cardiovascular collapse, cyanosis (hence the term a€oegray babya€§), and death. Adults who have received very  high doses of the drug can also exhibit this toxicity.   3. Interactions: Chloramphenicol is able to inhibit some of the hepatic mixed-function oxidases and, thus, blocks  the metabolism of such drugs as warfarin, phenytoin, tolbutamide, and chlorpropamide, thereby elevating  their concentrations and potentiating their effects (Figure 32.19).   Figure 32.19 Inhibition of the cytochrome P450 system by chloramphenicol .   Clindamycin [klin-da-MYE-sin] has a mechanism of action that is the same as that of erythromycin. Clindamycin is  employed primarily in the treatment of infections caused by anaerobic bacteria, such as Bacteroides fragilis , which  often causes abdominal infections associated with trauma. However, it is also significantly active against  nonenterococcal, gram-positive cocci. Resistance mechanisms are the same as those for erythromycin, and cross-  resistance has been described. [Note: Clostridium difficile is always resistant to clindamycin. ] Clindamycin is well  absorbed by the oral route. It distributes well into all body fluids except the CSF. Adequate levels of clindamycin  are not achieved in the brain, even when meninges are inflamed. Penetration into bone occurs even in the absence  of inflammation. Clindamycin undergoes extensive oxidative metabolism to inactive products. The drug is excreted  into the bile or urine by glomerular filtration, but therapeutically effective levels of the parent drug are not  achieved in the urine (Figure 32.20). Accumulation has been reported in patients with either severely compromised  renal function or hepatic failure. In addition to skin rashes, the most serious adverse effect is potentially fatal  pseudomembranous colitis caused by overgrowth of C. difficile , which elaborates necrotizing toxins. Oral  administration of either metronidazole or vancomycin is usually effective in controlling this serious problem.   [Note: Vancomycin should be reserved for a condition that does not respond to metronidazole. ] Impaired liver  function has also been reported.   Quinupristin/ dalfopristin [ KWI N-yoo- pris-ti n/ DAL-foh-pris-tin] is a mixture of two streptogramins in a ratio of  thirty to seventy, respectively. They are derived from a streptomycete and then chemically modified. The drug is  normally reserved for the treatment of vancomyc/n- resistant Enterococcus faecium (VRE).   Each component of this combination drug binds to a separate site on the 50S bacterial ribosome, forming a stable  ternary complex. Thus, they synergisti cal ly interrupt protein synthesis. The combination drug is bactericidal and has  a long postantibiotic effect.   Enzymatic processes commonly account for resistance to these agents. For example, the presence of a ribosomal  enzyme that methylates the target bacterial 23S ribosomal RNA site can interfere in quinupristin binding. In some  cases, the enzymatic modification can change the action from bactericidal to bacteriostatic. Plasmid-associated  acetyltransferase inactivates dalfopristin. An active efflux pump can also decrease levels of the antibiotics in  bacteria.    The combination drug is active primarily against gram- positive cocci, including those resistant to other antibiotics  (for example, methicillin-resistant staphylococci). Its primary use is in the treatment of E. faecium infections,  including VRE strains. [Note: In the latter case, the effect is bacteriostatic rather than bactericidal. ] The drug is not  effective against Enterococcus faecalis .   Quinupristin/ dalfopristin is injected intravenously in a 5 percent dextrose solution (the drug is incompatible with a  saline medium). The combination drug penetrates macrophages and polymorphonucleocytes, a property that is  important, because VRE are intracellular. Levels in the CSF are low. Both compounds undergo metabolism. The  products are less active than the parent in the case of quinupristin and are equally active in the case of  dalfopristin. Most of the parent drugs and metabolites are cleared through the liver and eliminated via the bile into  the feces (Figure 32.21). Urinary excretion is secondary.   1. Venous irritation: This commonly occurs when quinupristin/ dalfopristin is administered through a peripheral  rather than a central line.   2. Arthralgia and myalgia: These have been reported when higher levels of the drugs are employed.   3. Hyperbilirubinemia: Total bilirubin is elevated in about 25 percent of patients, resulting from a competition  with the antibiotic for excretion.   4. Interactions: Because of the ability of quinupristin/ dalfopristin to inhibit the cytochrome P450 (CYP3A4)  isozyme, concomitant administration with drugs that are metabolized by this pathway may lead to toxicities  (Figure 32.22). A drug interaction with digoxin appears to occur by the same mechanism as that caused by  erythromycin.   Linezoiid [ I i h- NEH-zo- lid] was introduced recently to combat resistant gram- positive organisms, such as methicillin-  and i/ancomyc/n-resistant Staphylococcus aureus , vancomycin-resistant E. faecium and E. faecalis , and penicillin-  resistant streptococci. Linezolid is a totally synthetic oxazolidinone.   The drug inhibits bacterial protein synthesis by inhibiting the formation of the 70S initiation complex. Linezolid  binds to a site on the 50S subunit near the interface with the 30S subunit (Figure 32.23).   Decreased binding to the target site confers resistance on the organism. Cross- resistance with other antibiotics does  not occur.   The antibacterial action of linezolid is directed primarily against gram-positive organisms, such as staphylococci,  streptococci, and enterococci, as well as Corynebacterium species and Listeria monocytogenes (Figure 32.24). It is  also moderately active against Mycobacterium tuberculosis . Flowever, its main clinical use is against the resistant  organisms mentioned above. Like other agents that interfere with bacterial protein synthesis, linezolid is  bacteriostatic. Flowever, it is cidal against the streptococci and Clostridium perfringens .   Linezolid is completely absorbed on oral administration. An intravenous preparation is also available. The drug is   widely distributed throughout the body, having a volume of distribution of 40 to 50 liters. Two metabolites that are  oxidation products have been identified, one of which has antimicrobial activity. However, cytochrome P450  enzymes are not involved in their formation. The drug is excreted both by renal and nonrenal routes. The  metabolites rely on the kidney for elimination.   Linezolid is well-tolerated, with some reports of gastrointestinal upset, nausea, and diarrhea, as well as headaches  and rash. Thrombocytopenia was found to occur in about 2 percent of patients who were on the drug for longer  than 2 weeks. Although no reports have appeared that linezolid inhibits monoamine oxidase activity, patients are  cautioned not to consume large quantities of tyramine-containing foods. Early oxazolidinones had been shown to  inhibit monoamine oxidase activity. The condition was reversible when the drug was suspended. Reversible  enhancement of the pressor effects of pseudoephedrine was shown to occur.    32.1 A patient with a gunshot wound to the abdomen, which has resulted in spillage of intestinal contents, is  brought to the emergency room. Which antibiotic would you select to effectively treat an infection due to  Bacteroides fraqilis ?   32.2 A pregnant woman was hospitalized and catheterized with a Foley catheter. She developed a urinary  tract infection caused by Pseudomonas aeruginosa and was treated with gentamicin. Which of the following  adverse effects was a risk to the fetus when the woman was on gentamicin?   32.3 Children younger than 8 years of age should not receive tetracyclines because these agents:   32.4 A 46-year-old woman is in the intensive care unit for treatment of a vancomycin-resistant strain of  Enterococcus faecium a€"caused bacteremia. You want to limit the risk of drug interactions in this woman, who  is receiving five other medications. Which one of the following antibiotics would you choose?   >Table of Contents > Unit VII - Chemotherapeutic Drugs >Chapter 33 - Quinolones, Folic AcidAntagonists, and UrinaryTract Antiseptics   Introduction of the first fluorinated quinolone, norfloxacin, was rapidly followed by development of other members  of this group, such as ciprofloxacin, which has had wide clinical application. Newer fluorinated quinolones offer  greater potency, a broader spectrum of antimicrobial activity, greater in vitro efficacy against resistant organisms,  and in some cases, a better safety profile than older quinolones and other antibiotics. Compared to ciprofloxacin,  the new compounds are more active against gram-positive organisms, yet retain favor able activity against  gram-negative microorganisms. It seems likely that the number of drugs in this class of antibiotics will increase due  to its wide antibacterial spectrum, favorable pharmacokinetic properties, and relative lack of adverse reactions.  Unfortunately, their overuse has already led to the emergence of resistant strains, resulting in limitations to their  clinical usefulness. The fluoroquinolones and other antibiotics discussed in this chapter are listed in Figure 33. 1.   The fluoroquinolones enter the bacterium by passive diffusion through water-filled protein channels (porins) in the  outer membrane. Once inside the cell, they inhibit the replication of bacterial DNA by interfering with the action of  DNA gyrase (topoisomerase II) and topoisomerase IV during bacterial growth and reproduction. [Note:   Topoisomerases are enzymes that change the configuration or topology of DNA by a nicking, pass-through, and  resealing mechanism. They do not change the DNA's primary sequence 1 (Figure 33.2).] Binding of the quinolone to  both the enzyme and the DNA forms a ternary complex that inhibits the resealing step, and can cause cell death by  inducing cleavage of the DNA. Because DNA gyrase is a bacteriospecific target for antimicrobial therapy, cross-  resistance with other, more commonly used antimicrobial drugs is rare, but this is increasing in the case of  multidrug-resistant organisms. The second site blocked by the fluoroquinolonesa€"topoisomerase IVa€" is required  by bacteria for cell division. It has been implicated in the process of segregating newly replicated DNA. In  gram-negative organisms (for example, Escherichia coli ), the inhibition of DNA gyrase is more significant than that  of topoisomerase IV, whereas in gram-positive organisms (for example, the staphylococci), the opposite is true.   All the fluoroquinolones are bactericidal. Like aminoglycosides, the quinolones exhibit concentration-dependent  bacterial killing. Bactericidal activity becomes more pronounced as the serum drug concentration increases to  approximately 30-fold the minimum inhibitory concentration. In general, they are effective against gram-negative  organisms such as the Enterobacteriaceae, Pseudomonas species, Haemophilus influenzae , Moraxella catarrhalis ,  Legionellaceae, chlamydia, and mycobacteria (except for Mycobacterium avium-intracellulare complex) . They are  effective in the treatment of gonorrhea but not syphilis. The newer agents (for example, levofloxacin and  moxifloxacin ) also have good activity against some gram- positive organisms, such as Streptococcus pneumoniae .  Moxifloxacin has activity against many anaerobes. If used prophylactically before transurethral surgery,  fluoroquinolones lower the incidence of postsurgical urinary tract infections (UTIs). It has become common practice  to classify the fluoroquinolones into a€oegenerations,a€§ based on their antimicrobial targets (Figure 33. 3). The  nonfluorinated quinolone nalidixic acid is considered to be first generation, with a narrow spectrum of susceptible  organisms usually confined to the urinary tract. Ciprofloxacin and norfloxacin are assigned to the second  generation because of their activity against aerobic gram-negative and atypical bacteria. In addition, these  fluoroquinolones exhibit significant intracellular penetration, allowing therapy for infections in which a bacterium  spends part or all of its life cycle inside a host cell (for example, chlamydia, mycoplasma, and legionella).  Levofloxacin is classified as third generation because of its increased activity against gram-positive bacteria. Lastly,  the fourth generation includes only moxifloxacin because of its activity against anaerobic as well as gram-positive  organisms.    1. Ciprofloxacin: This is the most frequently used fluoroquinolone in the United States (Figure 33.4). The serum  levels of ciprofloxacin [sip-row-FLOX-a-sin] that are achieved are effective against many systemic infections,  with the exception of serious infections caused by metfi/c////n-resistant Staphylococcus aureus (MRSA), the  enterococci, and pneumococci. Ciprofloxacin is also particularly useful in treating infections caused by many  Enterobacteriaceae and other gram-negative bacilli. For example, traveler's diarrhea caused by E. coli can be  effectively treated. Ciprofloxacin is also the drug of choice for prophylaxis and treatment of anthrax. It is the  most potent of the fluoroquinolones for Pseudomonas aeruginosa infections and, therefore, is used in the  treatment of pseudomonal infections associated with cystic fibrosis. The drug is also used as an alternative to  more toxic drugs, such as the aminoglycosides. It may act synergisti cal ly with i 2 -lactams and is also of benefit in  treating resistant tuberculosis.   2. Norfloxacin: Norfloxacin (nor-FLOX-a-sin] is effective against both gram-negative (including P. aeruginosa) and  gram-positive organisms in treating complicated and uncomplicated UTIs and prostatitis. It is not effective in  systemic infections.   3. Levofloxacin: Levofloxacin [leave-oh-FLOX-a-sin] is an isomer of ofloxacin [oh-FLOX-a-sin] and has largely  replaced it clinically. It can be used in the treatment of prostatitis due to E. coli and of sexually transmitted  diseases, with the exception of syphilis. It may be used as alternative therapy in patients with gonorrhea.   Additionally, due to its broad spectrum of activity, levofloxacin is utilized in a wide   range of infections, including skin infections, acute sinusitis, acute exacerbation of chronic bronchitis,  community-acquired pneumonia, as well as nosocomial pneumonia. Levofloxacin has excellent activity against  respiratory infections due to S. pneumoniae .    First generation quinolonos, which  are used less often today, have  moderate gram-negative activity.  They achieve minimal serum  concentrations and are restricted  to the treatment of uncomplicated  urinary tract infections.    Third -generation fluoroquinolones  retain expanded gram-negative  activity and show improved activity  against atypical organisms and  specific gram-positive bacter ia.    Second -generation fluoroquinolones  have expanded gram-negative activity  and also have some activity against  gram-positive and atypical organisms,  such as Mycoplasma pneumoniae  and Chlamydia pneumoniae .    This fourth-generation fluoroquinolone  shows improved gram-positive coverage,  maintains gram-negative activity, and  gains anaerobic coverage.    Figure 33.3 Summary of antimicrobial spectrum of quinolones. [Note: The antimicrobial spectrum of specific  agents may differ from the generalizations shown in this figure.]   • Ciprofloxacin Is often  effective in treating  Infections unresponsive  to p-lactam antibiotics,  such as amplclllln.   • Ciprofloxacin is not the  drug of first choice for  pneumonia or sinusitis,  because the fluoroquinolones  have only weak activity  against Streptococcus  pneumoniae, a common  causatlvo agent.    4. Moxifloxacin: Moxifloxacin [moxie-FLOX-a-sin] not only has enhanced activity against gram-positive organisms   (for example, S. pneumoniae) but also has excellent activity against many anaerobes. It has very poor activity  against P. aeruginosa .   When the fluoroquinolones were first introduced, there was optimism that resistance would not develop. Although  no plasmid-mediated resistance has been reported, resistant MRSA, pseudomonas, coagulase-negative  staphylococci, and enterococci have unfortunately emerged due to chromosomal mutations. Cross-resistance exists  among the quinolones. The mechanisms responsible for this resistance include the following.   1. Altered target: Mutations in the bacterial DNA gyrase have been associated with a decreased affinity for  fluoroquinolones. Topoisomerase IV also undergoes mutations. Resistance is frequently associated with  mutations in both gyrase and topoisomerase IV.   2. Decreased accumulation: Reduced intracellular concentration of the drugs in the bacterial cell is linked to two  mechanisms. One involves a decreased number of porin proteins in the outer membrane of the resistant cell,  thereby impairing access of the drugs to the intracellular topoisomerases. The other mechanism is associated  with an energy-dependent efflux system in the cell membrane.   1. Absorption: Only 35 to 70 percent of orally administered norfloxacin is absorbed, compared with 85 to 95  percent of the other fluoroquinolones (Figure 33. 5). Intravenous preparations of ciprofloxacin, levofloxacin,  and ofloxacin are available. Ingestion of the fluoroquinolones with sucralfate, antacids containing aluminum or    magnesium, or dietary supplements containing iron or zinc can interfere with the absorption of these  antibacterial drugs. Calcium and other divalent cations have also been shown to interfere with the absorption of  these agents (Figure 33.6). The fluoroquinolones with the longest half-lives (levofloxaci n and moxifloxacin)  permit once-daily dosing.   2. Fate: Binding to plasma proteins ranges from 10 to 40 percent. [Note: Achieved plasma levels of free   norfloxacin are insufficient for treatment of systemic infections. ] All the fluoroquinolones distribute well into  all tissues and body fluids. Levels are high in bone, urine, kidney, and prostatic tissue (but not prostatic fluid),  and concentrations in the lung exceed those in serum. Penetration into cerebrospinal fluid is low except for  ofloxacin, for which concentrations can be as high as 90 percent of those in the serum. The fluoroquinolones  also accumulate in macrophages and polymorphonuclear leukocytes, thus being effective against intracellular  organisms such as Legionella pneumophila . They are excreted by the renal route.   Figure 33.6 Effect of dietary calcium on the absorption of ciprofloxaxin.   In general, these agents are very well tolerated. Toxicities similar to those for nalidixic acid have been reported for  the fluoroquinolones (Figure 33.7).   1. Gastrointestinal: The most common adverse effects of the fluoroquinolones are nausea, vomiting, and diarrhea,  which occur in three to six percent of patients.    2. Central nervous system problems: The most prominent central nervous system (CNS) effects of   fluoroquinolone treatment are headache and dizziness or light-headedness. Thus, patients with CNS disorders,  such as epilepsy, should be treated cautiously with these drugs. [Note: Ciprofloxacin interferes in the  metabolism of theophylline and may evoke seizures.]    3. Phototoxicity: Patients taking fluoroquinolones are advised to avoid excessive sunlight and to apply sunscreens.  However, the latter may not protect completely. Thus, it is advisable that the drug should be discontinued at  the first sign of phototoxicity.    4. Connective tissue problems: Fluoroquinolones should be avoided in pregnancy, in nursing mothers, and in   children under 18 years of age, because articular cartilage erosion (arthropathy) occurs in immature  experimental animals. [Note: Children with cystic fibrosis who receive ciprofloxacin have had few problems, but  careful monitoring is indicated. ] In adults, fluoroquinolones can infrequently cause ruptured tendons.   5. Contraindications: Moxifloxacin may prolong the QTc interval and, thus, should not be used in patients who are  predisposed to arrhythmias or are taking antiarrhythmic medications.   6. Drug interactions: The effect of antacids and cations on the absorption of these agents was considered above.  Ciprofloxacin and ofloxacin can increase the serum levels of theophylline by inhibiting its metabolism (Figure  33.8). This is not the case with the third- and fourth-generation fluoroquinolones, which may raise the serum  levels of warfarin, caffeine, and cyclosporine.   Enzymes requiring folate-derived cofactors are essential for the synthesis of purines and pyrimidines 2 (precursors of  RNA and DNA) and other compounds necessary for cellular growth and replication. Therefore, in the absence of  folate, cells cannot grow or divide. To synthesize the critical folate derivative, tetrahydrofolic acid, humans must  first obtain preformed folate in the form of folic acid as a vitamin from the diet. In contrast, many bacteria are  impermeable to folic acid and other folates and, therefore, must rely on their ability to synthesize folate de novo.  The sulfonamides (sulfa drugs) are a family of antibiotics that inhibit this de novo synthesis of folate. A second type  of folate antagonista€"tr;met/iopr;ma€"prevents microorganisms from converting dihydrofolic acid to  tetrahydrofolic acid, with minimal effect on a human cell's ability to make this conversion. Thus, both sulfonamides  and trimethoprim interfere with the ability of an infecting bacterium to divide. Compounding the sulfonamide  sulfamethoxazole with trimethoprim (the generic name for the combination is cotrimoxazole) provides a  synergistic combination that is used as effective treatment of a variety of bacterial infections.   The sulfa drugs are seldom prescribed alone except in developing countries, where they are still employed because  of their low cost and their efficacy in certain bacterial infections, such as trachoma and those of the urinary tract.  However, when cotrimoxazole was introduced in the mid-1970s, there was a renewed interest in the sulfonamides.  Sulfa drugs differ from each other not only in their chemical and physical properties but also in their  pharmacokinetics.   In many microorganisms, dihydrofolic acid is synthesized from p-aminobenzoic acid (PABA), pteridine, and  glutamate (Figure 33.9). All the sulfonamides currently in clinical use are synthetic analogs of PABA. 3 Because of  their structural similarity to PABA, the sulfonamides compete with this substrate for the bacterial enzyme,  dihydropteroate synthetase. They thus inhibit the synthesis of bacterial dihydrofolic acid and, thereby, the  formation of its essential cofactor forms. 4 The sulfa drugs, including cotrimoxazole, are bacteriostatic.   Sulfa drugs are active against selected enterobacteria in the urinary tract and nocardia. In addition, sulfadiazine  [sul-fa-DYE-a-zeen], in combination with the dihydrofolate reductase inhibitor pyrimethamine [ py-ri- METH-a-  meen], is the preferred form of treatment for toxoplasmosis and chloroquine-resistant malaria.   Only organisms that synthesize their folate requirements de novo are sensitive to the sulfonamides. Thus, humans,  who synthesize critical folate cofactors from dietary folic acid, are not affected, and bacteria that can obtain  folates from their environment are naturally resistant to these drugs. Acquired bacterial resistance to the sulfa  drugs can arise   from plasmid transfers or random mutations. [Note: Organisms resistant to one member of this drug family are  resistant to all. ] Resistance is generally irreversible and may be due to 1) an altered dihydropteroate synthetase, 2)  decreased cellular permeability to sulfa drugs, or 3) enhanced production of the natural substrate, PABA.    1. Administration: After oral administration, most sulfa drugs are well absorbed via the small intestine (Figure  33. 10). An exception is sulfasalazine [sul-fa-SAL-a-zeen], It is not absorbed when administered orally or as a  suppository and, therefore, is reserved for treatment of chronic inflammatory bowel disease (for example,  Crohn's disease or ulcerative colitis). [Note: Local intestinal flora split sulfasalazine into sulfapyridine and  5-aminosalicylate, with the latter exerting the anti-inflammatory effect. Absorption of the sulfapyridine can  lead to toxicity in patients who are slow acetylators (see below). ] Intravenous sulfonamides are generally  reserved for patients who are unable to take oral preparations. Because of the risk of sensitization, sulfas are  not usually applied topically. However, in burn units, creams of silver sulfadiazine or mafenide [mah-FEN-ide]  acetate (l±-amino-p-toluene-sulfonamide) have been effective in reducing burn-associated sepsis, because  they prevent colonization of bacteria. Superinfections with resistant bacteria or fungi may still occur. [Note:  Silver sulfadiazine is preferred, because mafenide produces pain on application. Furthermore, mafenide can  be absorbed in burn patients, causing an increased risk of acid-base imbalance. ]   2. Distribution: Sulfa drugs are bound to serum albumin in the circulation, where the extent of binding depends on  the particular agent's pK a . In general, the lower the pK a , the greater the binding. Sulfa drugs distribute  throughout the body's water and penetrate well into cerebrospinal fluida€"even in the absence of inflammation.  They can also pass the placental barrier and enter fetal tissues.   3. Metabolism: The sulfa drugs are acetylated, primarily in the liver. The product is devoid of antimicrobial activity  but retains the toxic potential to precipitate at neutral or acidic pH. This causes crystalluria (a€oestone  formationaCi; see below) and, therefore, potential damage to the kidney.   4. Excretion: Sulfa drugs are eliminated by glomerular filtration. Therefore, depressed kidney function causes  accumulation of both the parent compounds and their metabolites. The sulfonamides may also be eliminated in  breast milk.    1. Crystallu ria : Nephrotoxicity develops as a result of crystalluria (Figure 33. 11). Adequate hydration and  alkalinization of urine prevent the problem by reducing the concentration of drug and promoting its ionization.   Agents, such as sulfisoxazole [sul-fi-SOX-a-zole] and sulfamethoxazole [sul-fa-meth-OX-a-zole] are more  soluble at urinary pH than are the older sulfonamides (for example, sulfadiazine ) and are less liable to cause  crystalluria .   2. Hypersensitivity: Hypersensitivity reactions, such as rashes, angioedema, and Stevens-J ohnson syndrome, are  fairly common. The latter occurs more frequently with the longer-acting agents.   3. Hemopoietic disturbances: Hemolytic anemia is encountered in patients with glucose 6-phosphate  dehydrogenase deficiency.Granulocytopenia and thrombocytopenia can also occur.   4. Kernicterus: This disorder may occur in newborns, because sulfa drugs displace bilirubin from binding sites on   serum albumin. The bilirubin is then free to pass into the CNS, because the baby's blood-brain barrier is not fully  developed (see below).    5. Drug potentiation: Transient potentiation of the hypoglycemic effect of tolbutamide or the anticoagulant  effect of warfarin results from their displacement from binding sites on serum albumin. Free methotrexate  levels may also rise through displacement.   6. Contraindications: Due to the danger of kernicterus, sulfa drugs should be avoided in newborns and infants less  than 2 months of age as well as in pregnant women at term. Because sulfonamides condense with formaldehyde,  they should not be given to patients receiving methenamine for UTIs (Figure 33. 12).   Trimethoprim [trye METH-oh-prim], a potent inhibitor of bacterial dihydrofolate reductase, exhibits an  antibacterial spectrum similar to that of the sulfonamides. Trimethoprim is most often compounded with  sulfamethoxazole, producing the combination called cotrimoxazole.   The active form of folate is the tetrahydro-derivative that is formed through reduction of dihydrofolic acid by  di hydrofolate reductase. 5 This enzymatic reaction (see Figure 33.9) is inhibited by trimethoprim, leading to a  decreased availability of the tetrahydrofolate coenzymes required for purine, pyrimidine, and amino acid synthesis.  The bacterial reductase has a much stronger affinity for trimethoprim than does the mammalian enzyme, which  accounts for the drug's selective toxicity. [Note: Examples of other drugs that function as folate reductase  inhibitors include pyrimethamine, which is used with sulfonamides in treating parasitic infections, and  methotrexate, which is used in the treatment of cancer, rheumatoid arthritis, and psoriasis],   The antibacterial spectrum of trimethoprim is similar to that of sulfamethoxazole. Flowever, trimethoprim is 20-  to 50-fold more potent than the sulfonamide. Trimethoprim may be used alone in the treatment of acute UTIs and  in the treatment of bacterial prostatitis (although fluoroquinolones are preferred) and vaginitis.   Resistance in gram-negative bacteria is due to the presence of an altered dihydrofolate reductase that has a lower   affinity for trimethoprim. Overproduction of the enzyme may also lead to resistance, because this can decrease  drug permeability.   The half-life of trimethoprim is similar to that of sulfamethoxazole. However, because the drug is a weak base,  higher concentrations of trimethoprim are achieved in the relatively acidic prostatic and vaginal fluids. The drug  also penetrates the cerebrospinal fluid. Trimethoprim undergoes some O-demethylation, but most of it is excreted  unchanged through the kidney.   Trimethoprim can produce the effects of folic acid deficiency. 6 These effects include megaloblastic anemia,  leukopenia, and granulocytopenia, especially in pregnant patients and those having very poor diets. These blood  disorders can be reversed by the simultaneous administration of folinic acid, which does not enter bacteria.   The combination of trimethoprim with sulfamethoxazole, called cotrimoxazole [co-try-MOX-a-zole], shows  greater antimicrobial activity than equivalent quantities of either drug used alone (see Figure 33. 13). The  combination was selected because of the similarity in the half-lives of the two drugs.   Figure 33.13 Synergism between trimethoprim and sulfamethoxazole on the inhibition of growth of  Escherichia coli.   The synergistic antimicrobial activity of cotrimoxazole results from its inhibition of two sequential steps in the  synthesis of tetrahydrofolic acid: Sulfamethoxazole inhibits the incorporation of PABA into dihydrofolic acid  precursors, and trimethoprim prevents reduction of dihydrofolate to tetrahydrofolate (see Figure 33.9).   Cotrimoxazole has a broader spectrum of antibacterial action than the sulfa drugs (Figure 33. 14). It is effective in  treating UTIs and respiratory tract infections as well as in Pneumocystis j iroveci pneumonia and ampicillin- or  chloramphenicol -resistant systemic salmonella infections.   Resistance to the trimethoprim-sulfamethoxazole combination is less frequently encountered than resistance to  either of the drugs alone, because it would require that the bacterium have simultaneous resistance to both drugs.   Trimethoprim is more lipid soluble than sulfamethoxazole and has a greater volume of distribution. Administration  of one part trimethoprim to five parts of the sulfa drug produces a ratio of the drugs in the plasma of twenty parts  sulfamethoxazole to one part trimethoprim. This ratio is optimal for the antibiotic effect. Cotrimoxazole is  generally administered orally (Figure 33. 15). An exception involves intravenous administration to patients with  severe pneumonia caused by P. i iroveci or to patients who cannot take the drug by mouth. Both agents distribute  throughout the body. Trimethoprim concentrates in the relatively acidic   milieu of prostatic and vaginal fluids, and it accounts for the use of the trimethoprim-sulfamethoxazole  combination in infections at these sites. Both parent drugs and their metabolites are excreted in the urine.   • This Is a common opportunistic infection  complicating AIDS. Cotrimoxazole is the most  effective therapy.   • Prophylaxis with cotrimoxazole is recommended  for HIV-infected patients with fewer than 200 CD4r  cefls/mL.   Ampicillin or cotrimoxazole is  effective In treating the septicemia  and meningitis caused by Listeria  monocytogenes.   • Cotrimoxazole is useful in the treatment  of shigellosis and nontyphoid salmonella.   • The drug Is also effective In the management  of carriers of Salmonella typhi .   In prostatlc and vaginal fluids,  making it effective in treating  Infections at these sites.   Figure 33.14 Typical therapeutic applications of co-trimoxazole ( sulfamethoxazole plus trimethoprim).    1. Dermatologic: Reactions involving the skin are very common and may be severe in the elderly (Figure 33. 16).   2. Gastrointestinal: Nausea, vomiting, as well as glossitis and stomatitis are not unusual.   3. Hematologic: Megaloblastic anemia, leukopenia, and thrombocytopenia may occur. All these effects may be  reversed by the concurrent administration of folinic acid, which protects the patient and does not enter the  microorganism. Hemolytic anemia may occur in patients with glucose 6-phosphate dehydrogenase deficiency due  to the sulfamethoxazole.   4. Patients infected with human immunodeficiency virus: Immuno-compromised patients with P. i iroveci  pneumonia frequently show drug-induced fever, rashes, diarrhea, and/or pancytopenia.   5. Drug interactions: Prolonged prothrombin times in patients receiving both trimethoprim and warfarin have  been reported. The plasma half-life of phenytoin may be increased due to an inhibition of its metabolism.  Methotrexate levels may rise due to displacement from albumin-binding sites by sulfamethoxazole.   Urinary tract infections (most commonly uncomplicated acute cystitis and pyelonephritis) in women of child-bearing  age and in the elderly are one of the most common problems seen by primary care physicians. Escherichia coli is the  most common pathogen, causing about 80 percent of uncomplicated upper and lower UTIs. Staphylococcus  saprophyticus is the second most common bacterial pathogen causing UTIs, with other common causes including  Klebsiella pneumoniae and Proteus mirabilis These infections may be treated with any one of a group of agents  called urinary tract antiseptics, including methenamine, nitrofurantoin, and the quinolone nalidixic acid. These  drugs do not achieve antibacterial levels in the circulation, but because they are concentrated in the urine,   1. Mechanism of action: To act, methenamine [meth-EN-a-meen] must decompose at an acidic pH of 5. 5 or less in  the urine, thus producing formaldehyde, which is toxic to most bacteria (Figure 33. 17). The reaction is slow,  requiring 3 hours to reach 90 percent decomposition. Methenamine should not be used in patients with  indwelling catheters. Bacteria do not develop resistance to formaldehyde. [Note: Methenamine is frequently  formulated with a weak acid, such as mandelic acid or hippuric acid.]   2. Antibacterial spectrum: Methenamine is primarily used for chronic suppressive therapy. Urea-splitting bacteria  that alkalinize the urine, such as Proteus species, are usually resistant to the action of methenamine.  Methenamine is used to treat lower UTIs but is not effective in upper UTIs.   3. Pharmacokinetics: Methenamine is administered orally. In addition to formaldehyde, ammonium ion is  produced in the bladder. Because the liver rapidly metabolizes ammonia to form urea, methenamine is  contraindicated in patients with hepatic insufficiency, in which elevated levels of circulating ammonium ions  would be toxic to the CNS. Methenamine is distributed throughout the body fluids, but no decomposition of the   drug occurs at pH 7.4. Thus, systemic toxicity does not occur. The drug is eliminated in the urine.   4. Adverse effects: The major side effect of methenamine treatment is gastrointestinal distress, although at  higher doses, albuminuria, hematuria, and rashes may develop. Methenamine mandelate is contraindicated in  patients with renal insufficiency, because mandelic acid may precipitate. [Note: Sulfonamides react with  formaldehyde and must not be used concomitantly with methenamine.]   Nitrofurantoin [nye-troe-FYOOR-an-toyn] is less commonly employed for treating UTIs because of its narrow  antimicrobial spectrum and its toxicity. Sensitive bacteria reduce the drug to an active agent that inhibits various  enzymes and damages DNA. Antibiotic activity is greater in acidic urine. The drug is bacteriostatic. It is useful  against E. coli , but other common urinary tract gram-negative bacteria may be resistant. Gram-positive cocci are  susceptible. Adverse effects include gastrointestinal disturbances, acute pneumonitis, and neurologic problems.   33. 1 A 30-year-old male is diagnosed to be human immunodeficiency virus (HIV) positive. His CD4+ count is  200 cells/mm 3 and his viral load is 10,000 copies/mL. In addition to receiving antiviral therapy, which of the  following is indicated to protect him against pneumonia due to Pneumocystis jiroveci ?   33. 2 A 26-year-old young man presents with the symptoms of gonorrhea. Because this condition is often  associated with an infection due to Chlamydia trachomatis, which of the following quinolones would be the  best choice for treating him?   A. Urinary tract infections due to a P-lactamase producing strain of Klebsiella.   >Table of Contents > Unit VII - Chemotherapeutic Drugs >Chapter 34 - Antimycobacterials   Mycobacteria are slender, rod-shaped bacteria with lipid-rich cell walls that stain poorly with the Gram stain, but  once stained, the walls cannot be easily decolorized by treatment with acidified organic solvents. Hence, they are  termed a€oe acid-fast. a€^ The most widely encountered mycobacterial infections is tuberculosisa€"the leading  cause worldwide of death from infection. Members of the genus Mycobacterium also cause leprosy as well as several  tuberculosis-like human infections. Mycobacterial infections are intracellular and, generally, result in the formation  of slow-growing granulomatous lesions that are responsible for major tissue destruction. 1 There are four currently  recommended first-line agents utilized for antituberculosis therapy (Figure 34. 1). Second-line medications are  either less effective, more toxic, or have not been studied as extensively. They are useful in patients who cannot  tolerate the first-line drugs or who are infected with myobacteria that are resistant to the first-line agents.   Mycobacterium tuberculosis, one of a number of mycobacteria, can lead to serious infections of the lungs,  genitourinary tract, skeleton, and meninges. Treating tuberculosis as well as other mycobacterial infections  presents therapeutic problems. The organism grows slowly; thus, the disease may have to be treated for 6 months to  2 years. Resistant organisms readily emerge, particularly in patients who have had prior therapy or who fail to  adhere to the treatment protocol. It is currently estimated that about one-third of the world's population is  infected with M. tuberculosis , with 30 million people having active disease. Worldwide, 8 million new cases occur,  and approximately 2 million people die of the disease each year.   Strains of M. tuberculosis that are resistant to a particular agent emerge during treatment with a single drug. For  example, Figure 34. 2 shows that resistance rapidly develops in patients given only streptomycin. Therefore,  multidrug therapy is employed when treating tuberculosis in an effort to delay or prevent the emergence of    resistant strains. Isoniazid, rifampin (or rifabutin or rifapentine), ethambutol, and pyrazinamide   are the principal or so-called a€oefirst-linea€§ drugs because of their efficacy and acceptable degree of toxicity.   Today, however, because of poor patient compliance and other factors, the number of multidrug-resistant  organisms has risen. Some bacteria have been identified that are resistant to as many as seven antitubercular  agents. Therefore, although treatment regimens vary in duration and in the agents employed, they always include a  minimum of two drugs, preferably with both being bactericidal (see p. 348). The combination of drugs should  prevent the emergence of resistant strains. The multidrug regimen is continued well beyond the disappearance of  clinical disease to eradicate any persistent organisms. For example, the initial short-course chemotherapy for  tuberculosis includes isoniazid, rifampin, ethambutol, and pyrazinamide for 2 months and then isoniazid and  rifampin for the next 4 months (the a€oecontinuation phasea€§; Figure 34.3). Before susceptibility data are  available, more drugs may be added to the first-line ones for patients who have previously had tuberculosis or those  in whom multidrug-resistant tuberculosis is suspected. The added drugs normally include an aminoglycoside  ( streptomycin , kanamycin, or amikacin) or capreomycin (inj ectable agents), a fluoroquinolone, and perhaps a  second-line antituberculosis agent such as cycloserine, ethionamide, or para-aminosalicylic acid. Once  susceptibility data are available, the drug regimen can be individually tailored to the patient. Patient compliance is  often low when multidrug schedules last for 6 months or longer. One successful strategy for achieving better  treatment completion rates is a€oedi rectly observed therapy, a€§ also known as DOT, in which patients take their  medication while being supervised and observed. DOT have been shown to decrease drug resistance as well as  relapse and mortality rates and to improve cure rates. Most local and state health departments offer DOT services.   Figure 34.2 Cumulative percentage of strains of Mycobacterium tuberculosis showing resistance to  streptomycin.   Isoniazid [eye-soe-NYE-a-zid], the hydrazide of isonicotinic acid, is a synthetic analog of pyridoxine. It is the most  potent of the antitubercular drugs but is never given as a single agent in the treatment of active tuberculosis. Its  introduction revolutionized the treatment of tuberculosis.    Figure 34.3 One of several recommended multidrug schedules for the treatment of tuberculosis.    1. Mechanism of action: Isoniazid, often referred to as INH, is a prodrug that is activated by a mycobacterial  catalase-peroxidase (KatG). Genetic and biochemical evidence has implicated at least two different target  enzymes for isoniazid within the unique Type II fatty acid synthase system involved in the production of mycolic  acids. [Note: Mycolic acid is a unique class of very-long-chain, l 2 -hydroxylated fatty acids found in  mycobacterial cell walls. Decreased mycolic acid synthesis corresponds with the loss of acid-fastness after  exposure to isoniazid. ] The targeted enzymes are enoyl acyl carrier protein reductase (InhA) and a  i 2 -ketoacyl-ACP synthase (KasA). The activated drug covalently binds to and inhibits these enzymes, which are  essential for the synthesis of mycolic acid.   2. Antibacterial spectrum: For bacilli in the stationary phase, isoniazid is bacteriostatic, but for rapidly dividing  organisms, it is bactericidal. It is effective against intracellular bacteria. Isoniazid is specific for treatment of ML  tuberculosis , although Mycobacterium kansasii (an organism that causes three percent of the clinical illness  known as tuberculosis) may be susceptible at higher drug levels. When it is used alone, resistant organisms  rapidly emerge.   3. Resistance: This is associated with several different chromosomal mutations, each of which results in one of the  following: mutation or deletion of KatG (producing mutants incapable of prodrug activation), varying mutations  of the acyl carrier proteins, or overexpression of InhA. Cross-resistance does not occur between isoniazid and  other antitubercular drugs.   Figure 34.4 Bimodal distribution of isoniazid half-lives caused by rapid and slow acetylation of the drug.    4. Pharmacokinetics: Orally administered isoniazid is readily absorbed. Absorption is impaired if isoniazid is taken  with food, particularly carbohydrates, or with aluminum-containing antacids. The drug diffuses into all body  fluids, cells, and caseous material (necrotic tissue resembling cheese that is produced in tubercles). Drug levels  in the cerebrospinal fluid (CSF) are about the same as those in the serum. The drug readily penetrates host cells  and is effective against bacilli growing intracel lularly. Infected tissue tends to retain the drug longer. Isoniazid  undergoes N-acetylation and hydrolysis, resulting in inactive products. [Note: Acetylation is genetically  regulated, with the fast acetylator trait being autosomally dominant. A bimodal distribution of fast and slow  acetylators exists (Figure 34.4). ] Chronic liver disease decreases metabolism, and doses must be reduced.  Excretion is through glomerular filtration, predominantly as metabolites (Figure 34.5). Slow acetylators excrete  more of the parent compound. Severely depressed renal function results in accumulation of the drug, primarily  in slow acetylators.   5. Adverse effects: The incidence of adverse effects is fairly low. Except for hypersensitivity, adverse effects are  related to the dosage and duration of administration.    a. Peripheral neuritis: Peripheral neuritis (manifesting as paresthesias of the hands and feet), which is the  most common adverse effect, appears to be due to a relative pyridoxine deficiency. Most of the toxic  reactions are corrected by supplementation of 25 to 50 mg per day of pyridoxine (vitamin Be). [Note:  Isoniazid can achieve levels in breast milk that are high enough to cause a pyridoxine deficiency in the  infant unless the mother is supplemented with the vitamin. 2 ]   b. Hepatitis and idiosyncratic hepatotoxicity: Potentially fatal hepatitis is the most severe side effect  associated with isoniazid. It has been suggested that this is caused by a toxic metabolite of  monoacetylhydrazine, formed during the metabolism of isoniazid. Its incidence increases among patients  with increasing age, among patients who also take rifampin, or among those who drink alcohol daily.   c. Drug interactions: Because isoniazid inhibits metabolism of phenytoin (Figure 34.6), isoniazid can  potentiate the adverse effects of that drug (for example, nystagmus and ataxia). Slow acetylators are  particularly at risk .   d. Other adverse effects: Mental abnormalities, convulsions in patients prone to seizures, and optic neuritis  have been observed. Hypersensitivity reactions include rashes and fever.   Rifampin, rifabutin, and rifapentine are all considered to be rifamycins, a group of structurally similar macrocyclic  antibiotics, which are first-line drugs for tuberculosis. Any of these rifamycins must always be used in conj unction  with at least one other antituberculosis drug to which the isolate is susceptible.    Figure 34.7 Administration and fate of rifampin. [Note: Patient should be warned that urine and tears may  be orange-red in color, ]    1. Rifampin: Rifampin [ rif-AM- pin], which is derived from the soil mold Streptomyces , has a broader antimicrobial   activity than isoniazid and has found application in the treatment of a number of different bacterial infections.   Because resistant strains rapidly emerge during therapy, it is never given as a single agent in the treatment of   a. Mechanism of action: Rifampin blocks transcription by interacting with the I 2 subunit of bacterial but not  human DNA-dependent RNA polymerase. [Note: The drug is thus specific for prokaryotes. ] Rifampin inhibits  mRNA synthesis by suppressing the initiation step.   b. Antimicrobial spectrum: Rifampin is bactericidal for both intracellular and extracellular mycobacteria,  including M. tuberculosis , and atypical mycobacteria, such as M. kansasii . It is effective against many  gram-positive and gram- negative organisms and is frequently used prophyl actically for individuals exposed to  meningitis caused by meningococci or Haemophilus influenzae . Rifampin is the most active antileprosy drug  at present, but to delay the emergence of resistant strains, it is usually given in combination with other  drugs. Rifabutin, an analog of rifampin, has some activity against Mycobacterium avium-intracellulare  complex but is less active against tuberculosis.   c. Resistance: Resistance to rifampin can be caused by a mutation in the affinity of the bacterial  DNA-dependent RNA polymerase for the drug or by decreased permeability.   d. Pharmacokinetics: Absorption is adequate after oral administration. Distribution of rifampin occurs to all  body fluids and organs. Adequate levels are attained in the CSF even in the absence of inflammation. The  drug is taken up by the liver and undergoes enterohepatic cycling. Rifampin itself can induce the hepatic  mixed-function oxidases (see p. 14), leading to a shortened half-life. Elimination of metabolites and the  parent drug is via the bile into the feces or via the urine (Figure 34.7). [Note: Urine and feces as well as  other secretions have an orange-red color; patients should be forewarned. Tears may permanently stain soft   e. Adverse effects: Rifampin is generally well tolerated. The most common adverse reactions include nausea,  vomiting, and rash. Hepatitis and death due to liver failure is rare; however, the drug should be used   j udiciously in patients who are alcoholic, elderly, or have chronic liver disease due to the increased  incidence of severe hepatic dysfunction when rifampin is administered alone or concomitantly with  isoniazid. Often, when rifampin is dosed intermittently, or in daily doses of 1.2 grams or greater, a flu-like  syndrome is associated with fever, chills, and myalgias   and sometimes is associated with acute renal failure, hemolytic anemia, and shock.   f. Drug interactions: Because rifampin can induce a number of cytochrome P450 enzymes (see p. 14), it can  decrease the half-lives of other drugs that are coadministered and metabolized by this system (Figure 34.8).   2. Rifabutin: Rifabutin [rif-a-BYOO-tin], a derivative of rifampin, is the preferred drug for use in tuberculosis-  infected with the human immunodeficiency virus (HIV) patients who are concomitantly treated with protease  inhibitors or nonnucleoside reverse transcriptase inhibitors, because it is a less potent inducer of cytochrome  P450 enzymes. Rifabutin has adverse effects similar to those of rifampin but can also cause uveitis, skin  hyperpigmentation, and neutropenia.   3. Rifapentine: Rifapentine [rih-fa-PEN-teen] has activity comparable to that of rifampin but has a longer  half-life than rifampin and rifabutin, which permits weekly dosing. However, for the intensive phase (initial 2  months) of the short-course therapy for tuberculosis, rifapentine is given twice weekly. In the subsequent  phase, rifapentine is dosed once per week for 4 months. To avoid resistance issues, rifapentine should not be  used alone but, rather, be included in a three to four-drug regimen.    Figure 34.8 Rifampin induces cytochrome P450, which can decrease the half-lives of coadministered drugs   Pyrazinamide [peer-a-ZIN-a-mide] is a synthetic, orally effective, bactericidal, antitubercular agent used in  combination with isoniazid, rifampin, and ethambutol. It is bactericidal to actively dividing organisms, but the  mechanism of its action is unknown. Pyrazinamide must be enzymatically hydrolyzed to pyrazinoic acid, which is  the active form of the drug. Some resistant strains lack the pyrazinamidase. Pyrazinamide is active against tubercle  bacilli in the acidic environment of lysosomes as well as in macrophages. Pyrazinamide distributes throughout the  body, penetrating the CSF. It undergoes extensive metabolism. About one to five percent of patients taking  isoniazid, rifampin, and pyrazinamide may experience liver dysfunction. Urate retention can also occur and may  precipitate a gouty attack (Figure 34.9).    Figure 34.9 Pyrazinamide and ethambutol may cause urate retention and gouty attacks.   Ethambutol [e-TFIAM-byoo-tole] is bacteriostatic and specific for most strains of M. tuberculosis and M. kansasii .  Ethambutol inhibits arabinosyl transferasea€"an enzyme that is important for the synthesis of the mycobacterial  arabinogalactan cell wall. Resistance is not a serious problem if the drug is employed with other antitubercular  agents. Ethambutol can be used in combination with pyrazinamide, isoniazid, and rifampin to treat tuberculosis.  Absorbed on oral administration, ethambutol is well distributed throughout the body. Penetration into the central  nervous system (CNS) is therapeutically adequate in tuberculous meningitis. Both parent drug and metabolites are  excreted by glomerular filtration and tubular secretion. The most important adverse effect is optic neuritis, which  results in diminished visual acuity and loss of ability to discriminate between red and green. Visual acuity should be  periodically examined. Discontinuation of the drug results in reversal of the optic symptoms. In addition, urate  excretion is decreased by the drug; thus, gout may be exacerbated (see Figure 34.9). Figure 34. 10 summarizes   some of the characteristics of first-line drugs. [Note: As with any drug, antitubercular drugs have a therapeutic  margin, which is the difference between the minimum drug concentration required to inhibit the growth of JVL  tuberculosis and the maximum concentration that can be given without provoking drug toxicity. ]   Take baseline hepatic enzyme measurements; repeat if abnormal  or patient is at risk or symptomatic.   Take baseline hepatic enzymes and uric acid measurements;  repeat if abnormal or patient is at risk or symptomatic.   Hepatitis, Gl upset, rash, flu-like  syndrome, significant interaction  with several drugs   Take baseline hepatic enzyme measurements and CBC count;  repeat if abnormal or patient is at risk or symptomatic. Warn  patient that urine and tears may turn red-orange in color.    Figure 34.10 Some characteristics of first-line drugs used in treating tuberculosis. CBC =complete blood  count.   A number of drugsa €" streptomycin, [strep-toe-MY-sin], para-aminosalicylic acid [ a- mee- noe- sal-i-SIL- i k] ,  ethionamide [e-thye-ON-am-ide], cycloserine [sye-kloe-SER-een], capreomycin [kap-ree-oh-MYE sin],  fluoroquinolones, and macrolidesa€"are considered to be second-line drugs, either because they are no more  effective than the first-line agents and their toxicities are often more serious or because they are particularly  active against atypical strains of mycobacteria.   Figure 34.11 Aminosalicylic acid and ethionamide can inhibit the acetylation of isoniazid.    1. Streptomycin: This is the first antibiotic effective in the treatment of tuberculosis and is discussed with the  aminoglycosides (see p. 377). Its action is directed against extracellular organisms. Infections due to  streptomycin- resistant organisms may be treated with kanamycin or amikacin, to which these bacilli remain  sensitive.    2. Capreomycin: This is a peptide that inhibits protein synthesis. It is administered parenteral ly. Capreomycin is  primarily reserved for the treatment of multidrug-resistant tuberculosis. Careful monitoring of the patient is  necessary to prevent its nephrotoxicity and ototoxicity.   3. Cycloserine is an orally effective, tuberculostatic agent that appears to antagonize the steps in bacterial cell  wall synthesis involving D-alanine. It distributes well throughout body fluids, including the CSF. Cycloserine is  metabolized, and both parent and metabolite are excreted in urine. Accumulation occurs with renal  insufficiency. Adverse effects involve CNS disturbances, and epileptic seizure activity may be exacerbated.   Peripheral neuropathies are also a problem, but they respond to pyridoxine.   4. Ethionamide: This is a structural analog of isoniazid, but it is not believed to act by the same mechanism.   Ethionamide can inhibit acetylation of isoniazid (Figure 34.11). It is effective after oral administration and is  widely distributed throughout the body, including the CSF. Metabolism is extensive, and the urine is the main  route   of excretion. Adverse effects that limit its use include gastric irritation, hepatotoxicity, peripheral  neuropathies, and optic neuritis. Supplementation with vitamin Bg (pyridoxine) may lessen the severity of the  neurologic side effects.   5. Fluoroquinolones: The fluoroquinolones, such as moxif I oxacin and levofloxacin, have an important place in  the treatment of multidrug-resistant tuberculosis. Some atypical strains of mycobacteria are also susceptible.   6. Macrolides: The macrolides, such as azithromycin and clarithromycin, are part of the regimen that includes  ethambutol and rifabutin used for the treatment of infections by M. avium-intracellulare complex.   Azithromycin is preferred for HIV- infected patients because it is least likely to interfere with the metabolism of  antiretroviral drugs. Details about the pharmacology of macrolides are found in Chapter 32.   Leprosy (or, as it is specified by the U.S. Public Health Service, Hansen's disease) is rare in the United States, but a  small number of cases, both imported and domestically acquired, are reported each year. Worldwide, it is a much  larger problem (Figure 34. 12). Approximately 70 percent of all cases in the world are located in India. Bacilli from  skin lesions or nasal discharges of infected patients enter susceptible individuals via abraded skin or the respiratory  tract. The World Health Organization recommends the triple-drug regimen of dapsone, clofazimine, and rifampin    for 6 to 24 months. Figure 34, 13 shows the effects of multi-drug therapy.   Dapsone [DAP-sone] is structurally related to the sulfonamides and similarly inhibits folate synthesis via  dihydropteroate synthetase inhibiton. It is bacteriostatic for Mycobacterium leprae, but resistant strains are  encountered. Dapsone is also employed in the treatment of pneumonia caused by Pneumocystis i iroveci in patients  infected with the HIV. The drug is well absorbed from the gastrointestinal tract and is distributed throughout the  body, with high levels concentrated in the skin. The parent drug enters the enterohepatic circulation and  undergoes hepatic acetylation. Both parent drug and metabolites are eliminated through the urine. Adverse  reactions include hemolysis, especially in patients with glucose 6-phosphate dehydrogenase deficiency, as well as  methemoglobinemia, peripheral neuropathy, and the possibility of developing erythema nodosum leprosum (a  serious and severe skin complication of leprosy). [Note: The latter is treated with corticosteroids or thalidomide. ]   Figure 34. 13 Leprosy patient. A. Before therapy, B. After 6 months of multidrug therapy.   Clofazimine [kloe-FA-zi-meen] is a phenazine dye that binds to DNA and prevents it from serving as a template for  future DNA replication. Its redox properties may lead to the generation of cytotoxic oxygen radicals that are also  toxic to the bacteria. Clofazimine is bactericidal to M. leprae and has some activity against M. avium-intracellulare  complex. Following oral absorption, the drug accumulates in tissues, allowing intermittent therapy, but it does not  enter the CNS. Patients may develop a red-brown discoloration of the skin. Eosinophilic enteritis has been reported  as an adverse effect. The drug also has some anti-inflammatory activity; thus, erythema nodosum leprosum does not  develop.   34. 1 A 31-year-old white intravenous drug user was admitted to the hospital with a 4-week history of cough  and fever. A chest radiograph showed left upper lobe cavitary infiltrate. Cultures of sputum yielded  tuberculosis susceptible to all antimycobacterial drugs. The patient received isoniazid, rifampin, and  pyrazinamide. The patient's sputum remained culture- positive for the subsequent 4 months. Which one of the  following is the most likely cause of treatment failure?    34. 2 A 40-year-old man has been on primary therapy for active pulmonary tuberculosis for the past 2 months.  At his regular clinic visit, he complains of a aCcepins and needlesaC - sensation in his feet. You suspect that he  might be deficient in which one of the following vitamins?    34.3 A 35-year-old male, formerly a heroin abuser, has been on methadone maintenance for the last 13  months. Two weeks ago, he had a positive tuberculosis skin test (PPD test), and a chest radiograph showed  evidence of right upper lobe infection. He was started on standard antimycobacterial therapy. He has come to  the emergency department complaining of aCoewithdrawal symptoms. a€ Which of the following  antimycobacterial drugs is likely to have caused this patient's acute withdrawal reaction?   >Table of Contents > Unit VII - Chemotherapeutic Drugs >Chapter 35 - Antifungal Drugs   Infectious diseases caused by fungi are called mycoses, and they are often chronic in nature. 1 Many common  mycotic infections are superficial and only involve the skin (cutaneous mycoses), but fungi may also penetrate the  skin, causing subcutaneous infections. The fungal infections that are most difficult to treat are the systemic  mycoses, which are often life-threatening. Unlike bacteria, fungi are eukaryotic. They have rigid cell walls  composed largely of chitina€"a polymer of N-acetylglucosaminea€" rather than peptidoglycan (a characteristic  component of most bacterial cell walls). The fungal cell membrane contains ergosterol rather than the cholesterol  found in mammalian membranes. These chemical characteristics are useful in targeting chemotherapeutic agents  against fungal infections. Fungal infections are generally resistant to antibiotics used in the treatment of bacterial  infections, and conversely, bacteria are resistant to the antifungal agents. The last two decades have seen a rise in  the incidence of fungal infections so that candidemia is the fourth most common cause of septicemia. This increased  incidence of fungal infections is associated with greater numbers of individuals who are on chronic immune  suppression following organ transplant, undergoing chemotherapy for myelogenous and solid tumors, or infected  with the human immunodeficiency virus (HIV). During this same period, there have been significant changes in the  therapeutic options available to the clinician. For example, the ongoing development of new azole antifungal drugs  offers effective therapy for all but the most serious mycotic infections. Clinically useful antifungal agents are listed  in Figure 35. 1.   The drugs used in the treatment of subcutaneous and systemic mycoses are listed in Figure 35. 1. [Note: Additional  azole drugs are effective in the topical treatment of candidiasis or dermatophytic infections.] The echinocandins  are a new class of antifungal agents that exert their fungicidal activity by inhibiting 1, 3-I 2 -gl ucan synthesis for the  fungal cell wall.   Amphotericin [am-foe-TER-i-sin] 6 is a naturally occurring, polyene macrolide antibiotic produced by Streptomyces  nodosus . In spite of its toxic potential, amphotericin B is the drug of choice for the treatment    of life-threatening, systemic mycoses. [Note: Conventional amphotericin ( amphotericin B deoxycholate, the    nonlipid formulation) has undergone several formulation improvements to reduce the incidence of side effects,  particularly nephrotoxicity. ] The drug is also sometimes used in combination with flucytosine so that lower (less  toxic) levels of amphotericin B are possible.   Figure 35.2 Model of a pore formed by amphotericin B in the lipid bilayer membrane.    1. Mechanism of action: Several amphotericin B molecules bind to ergosterol in the plasma membranes of  sensitive fungal cells. There, they form pores (channels) that require hydrophobic interactions between the  lipophilic segment of the polyene antibiotic and the sterol (Figure 35.2). The pores disrupt membrane function,  allowing electrolytes (particularly potassium) and small molecules to leak from the cell, resulting in cell death.  [Note: Because the polyene antibiotics bind preferentially to ergosterol rather than to cholesterola€"the sterol  found in mammalian membranesa€"a relative (but not absolute) specificity is conferred. ]   2. Antifungal spectrum: Amphotericin B is either fungicidal or fungistatic, depending on the organism and the  concentration of the drug. It is effective against a wide range of fungi, including Candida albicans, Histo plasma  capsulatum , Cryptococcus neoformans , Coccidioides immitis , Blastomyces dermatitidis , and many strains of  aspergi 1 1 us. [Note: Amphotericin B is also used in the treatment of the protozoal infection, leishmaniasis.]   3. Resistance: Fungal resistance, although infrequent, is associated with decreased ergosterol content of the  fungal membrane.   4. Pharmacokinetics: Amphotericin B is administered by slow, intravenous infusion (Figure 35.3). Amphotericin B  is insoluble in water, and inj ectable preparations require the addition of sodium deoxycholate, which produces  a soluble colloidal dispersion. The more dangerous intrathecal route is sometimes chosen for the treatment of  meningitis caused by fungi that are sensitive to the drug. Amphotericin B has also been formulated with a  variety of artificial lipids that form liposomes. The three amphotericin B lipid formulations marketed in the  United States are AmphotecA®, AbelcetA®, and AmBisomeA®. For example, the simplest and smallest of the    liposome preparations, AmBisomeA®, is produced by the incorporation of amphotericin B into a single liposomal  bilayer composed of phospholipids and cholesterol (Figure 35.4). These liposomal preparations have the primary  advantage of reduced renal and infusion toxicity. However, because of their high cost, they are reserved mainly  as salvage therapy for those individuals who cannot tolerate conventional amphotericin B. Amphotericin B is  extensively bound to plasma proteins and is distributed throughout the body, becoming highly tissue bound.  Inflammation favors penetration into various body fluids, but little of the drug is found in the cerebrospinal fluid  (CSF), vitreous humor, or amniotic fluid. However, amphotericin B does cross the placenta. Low levels of the  drug and its metabolites appear in the urine over a long period of time; some are also eliminated via the bile.  Dosage adj ustment is not required in patients with compromised hepatic function, but when renal dysfunction is  due to the use of conventional amphotericin B, the total daily dose is decreased by 50%. Sodium loading with  infusions of normal saline and the lipid-based amphotericin B products are alternatives utilized to minimize  nephrotoxicity.   Patient survival is similar  with conventional and  liposomal preparations,  but liposomal amphotericin B  shows lower toxicity.    Figure 35.4 A. Amphotericin B intercalated between the phospholipids of a spherical liposome  (AmBisomeA®). B. Outcomes of antifungal therapy in febrile, neutropenic cancer patients treated with  conventional amphotericin B and liposomal amphotericin B.    5. Adverse effects: Amphotericin B has a low therapeutic index. A total adult daily dose should not exceed 1.5  mg/ kg. Small test doses are usually administered to assess the degree of a patient's negative responses, such as  anaphylaxis or convulsions. Other toxic manifestations include the following (Figure 35. 5).   a. Fever and chills: These occur most commonly 1 to 3 hours after starting the intravenous administration, but  they usually subside with repeated administration of the drug. Premedication with a corticosteroid or an  antipyretic helps to prevent this problem.    b. Renal impairment: Despite the low levels of the drug excreted in the urine, patients may exhibit a decrease  in glomerular filtration rate and renal tubular function. Creatinine clearance can drop, and potassium and  magnesium are lost. [Note: Nephrotoxicity may be potentiated by sodium depletion; thus, a bolus infusion of  normal saline before and after amphotericin B infusion may reduce the incidence of drug-induced  nephrotoxicity. ] Normal renal function usually returns on suspension of the drug, but residual damage is  likely at high doses. Azotemia (elevated blood urea) is exacerbated by other nephrotoxic drugs, such as  aminoglycosides, cyclosporine, or pentamidine, although adequate hydration can decrease its severity.    c. Hypotension: A shock-like fall in blood pressure accompanied by hypokalemia may occur, requiring  potassium supplementation. Care must be exercised in patients taking digoxin.   d. Anemia: Normochromic, normocytic anemia caused by a reversible suppression of erythrocyte production  may occur. This may be exacerbated in patients infected with HIV who are taking zidovudine.    e. Neurologic effects: Intrathecal administration can cause a variety of serious neurologic problems.   f. Thrombophlebitis: Adding heparin to the infusion can alleviate this problem.   Flucytosine [floo-SYE-toe-seen] (5-FC) is a synthetic pyrimidine antimetabolite that is often used in combination  with amphotericin B. This combination of drugs is administered for the treatment of systemic mycoses and for  meningitis caused by Cryptococcus neoformans and Candida albicans .   Figure 35.6 Mode of action of flucytosine. 5-FdUMP =5-fluorodeoxyuridine 5'-monophosphate; dTMP =  deoxythymidine 5'-monophosphate.    1. Mechanism of action: 5-FC enters fungal cells via a cytosine-specific permeasea€"an enzyme not found in  mammalian cells. 5-FC is then converted by a series of steps to 5-fluorodeoxyuridine 5'-monophosphate. This    false nucleotide inhibits thymidylate synthase, thus depriving the organism of thymidylic acida€"an essential  DNA component (Figure 35.6). The unnatural mononucleotide is further metabolized to a trinucleotide  (5-fluorodeoxyuridine 5-tri phosphate) and is incorporated into fungal RNA, thus disrupting nucleic acid and  protein synthesis. [Note: Amphotericin B increases cell permeability, allowing more 5-FC to penetrate the cell.  Thus, 5-FC and amphotericin B are synergistic (Figure 35.7).]   2. Antifungal spectrum: 5-FC is fungistatic. It is effective in combination with itraconazole for treating  chromoblastomycosis and in combination with amphotericin B for treating candidiasis or cryptococcosis.   3. Resistance: Resistance due to decreased levels of any of the enzymes in the conversion of 5-FC to  5-fluorouracil ( 5-FU ) and beyond, or increased synthesis of cytosine, can develop during therapy. This is the  primary reason that 5-FC is not used as a single antimycotic drug. The rate of emergence of resistant fungal cells  is lower with a combination of 5-FC plus a second antifungal agent than it is with 5-FC alone.   4. Pharmacokinetics: 5-FC is well absorbed by the oral route. It distributes throughout the body water and  penetrates well into the CSF. 5-FU is detectable in patients and is probably the result of metabolism of 5-FC by  intestinal bacteria. Excretion of both the parent drug and its metabolites is by glomerular filtration, and the  dose must be adjusted in patients with compromised renal function.   5. Adverse effects: 5-FC causes reversible neutropenia, thrombo-cytopenia, and dose-related bone marrow  depression. Caution must be exercised in patients undergoing radiation or chemotherapy with drugs that depress  bone marrow. Reversible hepatic dysfunction with elevation of serum transaminases and alkaline phosphatase  may occur. Gastrointestinal disturbances, such as nausea, vomiting, and diarrhea, are common, and severe  enterocolitis may occur. [Note: Some of these adverse effects may be related to 5-FU formed by intestinal  organisms from 5-FC. ]   Ketoconazole [kee-toe-KON-a-zole] was the first orally active azole available for the treatment of systemic  mycoses.    1. Mechanism of action: Azoles are predominantly fungistatic. They inhibit C-14 l±-demethylase (a cytochrome  P450 enzyme), thus blocking the demethylation of lanosterol to ergosterola€"the principal sterol of fungal  membranes (Figure 35.8). This inhibition disrupts membrane structure and function and, thereby, inhibits fungal  cell   growth. [Note: Unfortunately, as is often the case for the initial member of a class of drugs, the selectivity of  ketoconazole toward its target is not as precise as those of later azoles. For example, in addition to blocking  fungal ergosterol synthesis, the drug also inhibits human gonadal and adrenal steroid synthesis, leading to  decreased testosterone and cortisol production. In addition, ketoconazole inhibits cytochrome  P450a€"dependent hepatic drug- metabolizing enzymes.]   2. Antifungal spectrum: Ketoconazole is active against many fungi, including Histoplasma , Blastomyces , Candida ,  and Coccidioides , but not aspergil lus species. Although itraconazole has largely replaced ketoconazole in the  treatment of most mycoses because of its broader spectrum, greater potency, and fewer adverse effects,  ketoconazole, as a second-line drug, is a less expensive alternative for the treatment of mucocutaneous  candidiasis. Strains of several fungal species that are resistant to ketoconazole have been identified.    3. Resistance: This is becoming a significant clinical problem, particularly in the protracted therapy required for  those with advanced HIV infection. Identified mechanisms of resistance include mutations in the C-14  i±-demethylase gene, which cause decreased azole binding. Additionally, some strains of fungi have developed  the ability to pump the azole out of the cell.   4. Pharmacokinetics: Ketoconazole is only administered orally (Figure 35.9). It requires gastric acid for dissolution  and is absorbed through the gastric mucosa. Drugs that raise gastric pH, such as antacids, or that interfere with  gastric acid secretion, such as H 2 -histamine receptor blockers and proton-pump inhibitors, impair absorption.  Administering acidifying agents, such as cola drinks, before taking the drug can improve absorption in patients  with achlorhydria. Ketoconazole is extensively bound to plasma proteins. Although penetration into tissues is  limited, it is effective in the treatment of histoplasmosis in lung, bone, skin, and soft tissues. The drug does not  enter the CSF. Extensive metabolism occurs in the liver, and excretion is primarily through the bile. Levels of  parent drug in the urine are too low to be effective against mycotic infections of the urinary tract.    5. Adverse effects: In addition to allergies, dose-dependent gastrointestinal disturbances, including nausea,  anorexia, and vomiting, are the most common adverse effects of ketoconazole treatment. Endocrine effects,  such as gynecomastia, decreased libido, impotence, and menstrual irregularities, result from the blocking of  androgen and adrenal steroid synthesis by ketoconazole. Transient increases in serum transaminases are found  in from 2 to 10 percent of patients. Frank hepatitis occurs rarely but requires immediate cessation of treatment.   [Note: Ketoconazole may accumulate in patients with hepatic dysfunction. Plasma concentrations of the drug  should be monitored in these individuals.]   6. Drug interactions and contraindications: By inhibiting cytochrome P450, ketoconazole can potentiate the  toxicities of drugs such as cyclosporine, phenytoin, tolbutamide, and warfarin, among others (Figure 35.10).  Rifampin, an inducer of the cytochrome P450 system, can shorten the duration of action of ketoconazole and  the other azoles. Drugs that decrease gastric acidity, such as Pl 2 -receptor   blockers, antacids, proton-pump inhibitors, and sucralfate, can decrease absorption of ketoconazole.   Ketoconazole and amphotericin B should not be used together, because the decrease in ergosterol in the fungal  membrane reduces the fungicidal action of amphotericin B (Figure 35.11). Finally, ketoconazole is teratogenic  in animals, and it should not be given during pregnancy.   Fluconazole [floo-KON-a-zole] is clinically important because of its lack of the endocrine side effects of  ketoconazole and its excellent penetrability into the CSF of both normal and inflamed meninges. Fluconazole is  employed prophylactically, with some success, for reducing fungal infections in recipients of bone marrow  transplants. It inhibits the synthesis of fungal membrane ergosterol in the same manner as ketoconazole and is the  drug of choice for Cryptococcus neoformans, for candidemia, and for coccidioidomycosis. Fluconazole is effective  against all forms of mucocutaneous candidiasis. [Note: Treatment failures due to resistance have been reported in  some HI V- inf ected patients.] Fluconazole is administered orally or intravenously. Its absorption is excellent and,  unlike that of ketoconazole, is not dependent on gastric acidity. Binding to plasma proteins is minimal. Unlike    ketoconazole, fluconazole is poorly metabolized. The drug is excreted via the kidney, and doses must be reduced  in patients with compromised renal function. The adverse effects caused by fluconazole treatment are less of a  problem than those with ketoconazole. Fluconazole has no endocrinologic effects, because it does not inhibit the  cytochrome P450 system responsible for the synthesis of androgens. However, it can inhibit the P450 cytochromes  that metabolize other drugs listed in Figure 35. 10. Nausea, vomiting, and rashes are a problem. Hepatitis is rare.  Fluconazole is teratogenic, as are other azoles, and should not be used in pregnancy.   Figure 35.10 By inhibiting cytochrome P450, ketoconazole can potentiate the toxicities of other drugs.   Itraconazole [it-ra-KON-a-zole] is an azole antifungal agent with a broad antifungal spectrum. Like fluconazole, it  a synthetic triazole and also lacks the endocrinologic side effects of ketoconazole. Its mechanism of action is the  same as that of the other azoles. Itraconazole is now the drug of choice for the treatment of blastomycosis,  sporotrichosis, paracoccidioidomycosis, and histoplasmosis. Unlike ketoconazole, it is effective in acquired  immunodeficiency syndromea€" associated histoplasmosis. Itraconazole is well-absorbed orally, but it requires acid  for dissolution. Food increases the bioavailability of some preparations. The drug is extensively bound to plasma  proteins and distributes well throughout most tissues, including bone and adipose tissues. However, therapeutic  concentrations are not attained in the CSF. Like ketoconazole, itraconazole is extensively metabolized by the  liver, but it does not inhibit androgen synthesis. Its maj or metabolite, hydroxyitraconazole, is biologically active,  with a similar antifungal spectrum. Little of the parent drug appears in the urine; thus, doses do not have to be  reduced in renal failure. Adverse effects include nausea and vomiting, rash (especially in immunocompromised  patients), hypokalemia, hypertension, edema, and headache. Itraconazole should be avoided in pregnancy.  Itraconazole inhibits the metabolism of many drugs, including oral anticoagulants, statins, and quini dine. Inducers  of the cytochrome P450 system increase the metabolism of itraconazole.    Figure 35.11 Ketoconazole and amphotericin B should not be used together.   Voriconazole [vor-i-KON-a-zole] has the advantage of being a broad-spectrum antifungal agent. It is available for  intravenous administration and also for oral administration and is approximately 96% bi oavai I abl e. Voriconazole is  approved for the treatment of invasive aspergillosis and seems to have replaced amphotericin B as the treatment of  choice for this indication. Voriconazole is also approved for treatment of serious infections caused by Scedosporium  apiospermum and Fusarium species. Voriconazole penetrates tissues well, including the CNS. Elimination is primarily  by metabolism through the cytochrome P450 2C19, 2C9, and 3A4 enzymes. The significant number of drug  interactions due to its metabolism through the various hepatic enzymes may limit its use. Side effects are similar to  those of the other azoles. One unique problem is a transient visual disturbance that occurs within 30 minutes of  dosing.   Posaconazole [poe-sa-kon-a-zole] is a new oral, broad-spectrum antifungal agent with a chemical structure similar  to that of itraconazole. It was approved in 2006 to prevent Candida and Aspergillus infections in severely  immunocompromised patients and for the treatment of oropharyngeal candidiasis. Due to its spectrum of activity,  posaconazole could possibly be used in the treatment of fungal infections caused by Mucor species and other  zygomycetes. To date, amphotericin B formulations are the only other antifungal agents available for treatment of  zygomycete infections. Overall, posaconazole is relatively well tolerated. The most common side effects observed  were gastrointestinal issues (nausea, vomiting, diarrhea, and abdominal pain) and headaches. Like other azoles,  posaconazole can cause an elevation of liver function tests aspartate aminotransferase and alanine  aminotransferase. Additionally, in patients who are receiving concomitant cyclosporine or tacrolimus for  management of transplant rej ection, rare cases of hemolytic uremic syndrome, thrombotic thrombocytopenic  purpura, and pulmonary embolus have been reported. Due to its inhibition of cytochrome P450 3A4 enzyme,  posaconazole may increase the effect and toxicity of many drugs, including cyclosporine, tacrolimus, and  sirolumus. Concomitant use of posaconazole with ergot alkaloids, pimozide, and quinidine is contraindicated. To  be effective, posaconazole must be administered with a full meal or nutritional supplement. For treatment of  oropharyngeal   candidiasis, dosing is daily. However, for prophylaxis of Candida and Aspergillus infections, posaconazole must be  dosed three times a day. Figure 35. 12 summarizes the azole antifungal agents.   I. Caspofungin: Caspofungin [kas-poh-FUN-j in] is the first approved member of the echinocandins class of  antifungal drugs. Echinocandins interfere with the synthesis of the fungal cell wall by inhibiting the synthesis of  T 2 ( 1, 3)- D-gl ucan, leading to lysis and cell death. This drug's spectrum is limited to Aspergillus and Candida  species. Caspofungin is not active by the oral route. The drug is highly bound to serum proteins and has a  half-life of 9 to 11 hours. It is slowly metabolized by hydrolysis and N-acetylation. Elimination is approximately  equal between the urinary and fecal routes. Adverse effects include fever, rash, nausea, and phlebitis. Flushing  occursa€"probably due to the release of histamine from mast cells. Caspofungin should not be coadministered  with cyclosporine. Caspofungin is a second-line antifungal for those who have failed or cannot tolerate  amphotericin B or an azole.   2. Micafungin and anidulafungin: Micafungin (mi-ka-FUN-gin) and anidulafungin (ay-nid-yoo-la-FUN-j in) are the  newer members of the echinocandins class of antifungal drugs. Like caspofungin, they are not orally active, are  only available via intravenous infusion, and have histamine-mediated side effects. Micafungin and  anidulafungin have similar efficacy against Candida species, but the efficacy for treatment of other fungal  infections has not been established. Also, they are not substrates for cytochrome P450 enzymes and do not have  any associated drug interactions.   Fungi that cause superficial skin infections are called dermatophytes. Common dermatomycoses, such as tinea  infections, are often referred to as a€oeringworm.a€§This is a misnomer, because fungi rather than worms cause  the disease.   Terbinafine [TER-bin-a-feen] is the drug of choice for treating dermatophytoses and, especially, onychomycoses   (fungal infections of nails). It is better tolerated, requires shorter duration of therapy, and is more effective than   1. Mechanism of action: Terbinafine inhibits fungal squalene epoxidase, thereby decreasing the synthesis of  ergosterol (Figure 35. 13). This plus the accumulation of toxic amounts of squalene result in the death of the  fungal cell. [Note: Significantly higher concentrations of terbinafine are needed to inhibit human squalene  epoxidase, an enzyme required for the cholesterol synthetic pathway. ]   2. Antifungal spectrum: The drug is primarily fungicidal. Antifungal activity is limited to dermatophytes and  Candida albicans . Therapy is prolongeda€"usually about 3 monthsa€"but considerably shorter than that with  griseofulvin.   3. Pharmacokinetics: Terbinafine is orally active, although its bioavailability is only 40 percent due to first-pass  metabolism. Absorption is not significantly enhanced by food. Terbinafine is greater than 99 percent bound to  plasma proteins. It is deposited in the skin, nails, and   fat. Terbinafine accumulates in breast milk and, therefore, should not be given to nursing mothers. A prolonged  terminal half-life of 200 to 400 hours may reflect the slow release from these tissues. Terbinafine is extensively  metabolized prior to urinary excretion (Figure 35. 14). Patients with either moderate renal impairment or  hepatic cirrhosis have reduced clearance.   4. Adverse effects: The most common adverse effects due to terbinafine are gastrointestinal disturbances  (diarrhea, dyspepsia, and nausea), headache, and rash. Taste and visual disturbances have been reported as well  as transient elevations in serum liver enzyme levels. All adverse effects resolve upon drug discontinuation.   Rarely, terbinafine may cause hepatotoxicity and neutropenia. Although terbinafine is extensively  metabolized, there does not seem to be a significant risk of reduced clearance of other drugs. Rifampin  decreases blood levels of terbinafine, whereas ci met i dine increases blood levels of terbinafine.   Griseofulvin [gris-e-oh-FUL-vin] has been largely replaced by terbinafine for the treatment of dermatophytic  infections of the nails. Griseofulvin requires treatment of 6 to 12 months in duration. It is only fungistatic, and it  causes a number of significant drug interactions. Griseofulvin accumulates in newly synthesized, keratin-containing  tissue, where it causes disruption of the mitotic spindle and inhibition of fungal mitosis (Figure 35. 15). Duration of  therapy is dependent on the rate of replacement of healthy skin or nails. Ultrafine crystalline preparations are  absorbed adequately from the gastrointestinal tract; absorption is enhanced by high-fat meals. Griseofulvin induces  hepatic cytochrome P450 activity (Figure 35.16). It also increases the rate of metabolism of a number of drugs,  including anticoagulants. It may exacerbate intermittent porphyria. Patients should not drink alcoholic beverages  during therapy, because griseofulvin potentiates the intoxicating effects of alcohol.   Nystatin [nye-STAT-in] is a polyene antibiotic, and its structure, chemistry, mechanism of action, and resistance  resemble those of amphotericin B. Its use is restricted to topical treatment of Candida infections because of its  systemic toxicity. The drug is negligibly absorbed from the gastrointestinal tract, and it is never used parenteral ly. It  is administered as an oral agent (a€oeswish and swallowa€[? or a€oeswish and spita€§) for the treatment of oral  candidiasis. Excretion in the feces is nearly quantitative. Adverse effects are rare because of its lack of absorption,  but nausea and vomiting occasionally occur.   Miconazole [my-KON-a-zole], clotrimazole [kloe-TRIM-a-zole], butoconazole [byoo-toe-KON-a-zole], and  terconazole [ter-KON-a-zole] are topically active drugs that are only rarely administered parenteral ly because of  their severe toxicity. Their mechanism of action and antifungal spectrum are the same as those of ketoconazole.   Topical use is associated with contact dermatitis, vulvar irritation, and edema. Miconazole is a potent inhibitor of  warfarin metabolism and has produced bleeding in warfarin-treated patients even when miconazole is applied  topically. No significant difference in clinical outcomes is associated with any azole or nystatin in the treatment of  vulvar candidiasis.   35. 1 A 25-year-old male patient with acquired immunodeficiency syndrome has a fever of 102A° F and  complains of severe headaches during the past week. Staining of his CSF with India ink reveals Cryptococcus  neoformans . The patient is admitted to the hospital and is treated with:    35. 2 A 30-year-old male has had a heart transplant and is being maintained on the immunosuppressant   cyclosporine. He develops a Candida infection and is treated with ketoconazole. Why is this poor therapy?   35.3 A 22-year-old male has been treating his aCoeathlete's footaC with an over-the-counter drug without  much success. Upon examination, it is found that the nail bed of both great toes is infected. Which one of the  following antifungal agents would be most appropriate for this patient?   >Table of Contents > Unit VII - Chemotherapeutic Drugs >Chapter 36 - Antiprotozoal Drugs   Protozoal infections are common among people in underdeveloped tropical and subtropical countries, where  sanitary conditions, hygienic practices, and control of the vectors of transmission are inadequate. However, with  increased world travel, protozoal diseases, such as malaria, amebiasis, leishmaniasis, trypanosomiasis,  trichomoniasis, and giardiasis, are no longer confined to specific geographic locales. Because they are eukaryotes,  the unicellular protozoal cells have metabolic processes closer to those of the human host than to prokaryotic  bacterial pathogens. Protozoal diseases are thus less easily treated than bacterial infections, and many of the  antiprotozoal drugs cause serious toxic effects in the host, particularly on cells showing high metabolic activity,  such as neuronal, renal tubular, intestinal, and bone marrow stem cells. Most antiprotozoal agents have not proved  to be safe for pregnant patients. Drugs used to treat protozoal infections are summarized in Figure 36. 1.   Amebiasis (also called amebic dysentery) is an infection of the intestinal tract caused by Entamoeba histolytica . The    disease can be acute or chronic, with patients showing varying degrees of illness, from no symptoms to mild diarrhea  to fulminating dysentery. The diagnosis is established by isolating E. histolytica from fresh feces. Therapy is aimed  not only at the acutely ill patient but also at those who are asymptomatic carriers, because dormant E. histolytica  may cause future infections in the carrier and be a potential source of infection for others.   Entamoeba histolytica exists in two forms: cysts that can survive outside the body, and labile but invasive  trophozoites that do not persist outside the body. Cysts, ingested through feces-contaminated food or water, pass  into the lumen of the intestine, where the trophozoites are liberated. The trophozoites multiply, and they either  invade and ulcerate the mucosa of the large intestine or simply feed on intestinal bacteria. [Note: One strategy for  treating luminal amebiasis is to add antibiotics, such as tetracycline, to the treatment regimen, resulting in a  reduction in intestinal floraa€"the ameba's maj or food source. ] The trophozoites within the intestine are slowly  carried toward the rectum, where they return to the cyst form and are excreted in feces.   Large numbers of trophozoites within the colon wall can also lead to systemic invasion. A summary of the life cycle  of E. histolytica is presented in Figure 36.2.   Therapeutic agents are classified as luminal, systemic, or mixed (luminal and systemic) amebicides according to the  site where the drug is effective (see Figure 36.2). For example, luminal amebicides act on the parasite in the lumen  of the bowel, whereas systemic amebicides are effective against amebas in the intestinal wall and liver. Mixed    amebicides are effective against both the luminal and systemic forms of the disease, although luminal  concentrations are too low for single-drug treatment.    1. Metronidazole: Metronidazole [me-troe-NYE-da-zole], a nitroimidazole, is the mixed amebicide of choice for  treating amebic infections; it kills the E. histolytica trophozoites. [Note: Metronidazole also finds extensive use  in the treatment of infections caused by Giardia lamblia, Trichomonas vaginalis, anaerobic cocci, and anaerobic  gram-negative bacilli (for example, Bacteroides species). Metronidazole is the drug of choice for the treatment  of pseudomembranous colitis    caused by the anaerobic, gram-positive bacillus Clostridium difficile and is also effective in the treatment of  brain abscesses caused by these organisms. ]   a. Mechanism of action: Some anaerobic protozoal parasites (including amebas) possess ferrodoxin-like,  low-redox-potential, electron-transport proteins that participate in metabolic electron removal reactions.  The nitro group of metronidazole is able to serve as an electron acceptor, forming reduced cytotoxic  compounds that bind to proteins and DNA, resulting in cell death.    b. Pharmacokinetics: Metronidazole is completely and rapidly absorbed after oral administration (Figure  36.3). [Note: For the treatment of amebiasis, it is usually administered with a luminal amebicide, such as  iodoquinol or paromomycin. This combination provides cure rates of greater than 90 percent.]  Metronidazole distributes well throughout body tissues and fluids. Therapeutic levels can be found in  vaginal and seminal fluids, saliva, breast milk, and cerebrospinal fluid (CSF). Metabolism of the drug depends  on hepatic oxidation of the metronidazole side chain by mixed-function oxidase, followed by  glucuronylation. Therefore, concomitant treatment with inducers of this enzymatic system, such as  phenobarbital , enhances the rate of metabolism. Conversely, those drugs that inhibit this system, such as    cimetidine, prolong the plasma half-life of metronidazole. The drug accumulates in patients with severe  hepatic disease. The parent drug and its metabolites are excreted in the urine.   c. Adverse effects: The most common adverse effects are those associated with the gastrointestinal tract,  including nausea, vomiting, epigastric distress, and abdominal cramps (Figure 36.4). An unpleasant, metallic  taste is often experienced. Other effects include oral moniliasis (yeast infection of the mouth) and, rarely,  neurotoxicologic problems, such as dizziness, vertigo, and numbness or paresthesias in the peripheral  nervous system. [Note: The latter are reasons for discontinuing the drug. ] If taken with alcohol, a  disulfiram- like effect occurs (114).   d. Resistance: Resistance to metronidazole is not a therapeutic problem, although strains of trichomonads  resistant to the drug have been reported.   2. Tinidazole: Tinidazole [tye-NI-da-zole] is a second-generation nitroimidazole that is similar to metronidazole  in spectrum of activity, absorption, adverse effects and drug interactions. It was approved by the U. S. Food and  Drug Administration in 2004 for treatment of amebiasis, amebic liver abcess, giardiasis, and trichomoniasis but  was used outside the United States for decades prior to approval. Tinidazole is as effective as metronidazole,  with a shorter course of treatment, yet is more expensive than generic metronidazole.   After treatment of invasive intestinal or extraintestinal amebic disease is complete, a luminal agent, such as  iodoquinol, diloxanide furoate, or paromomycin, should be administered for treatment of asymptomatic  colonization state.   1. Iodoquinol: Iodoquinol [eye-oh-doe-QUIN-ole], a halogenated 8-hydroxy quinolone, is amebicidal against   histolytica , and is effective against the luminal trophozoite and cyst forms. Side effects from iodoquinol include  rash, diarrhea, and dose-related peripheral neuropathy, including a rare optic neuritis. Long-term use of this  drug should be avoided.   2. Paromomycin: Paromomycin [par-oh-moe-MYE-sin], an aminoglycoside antibiotic, is only effective against the  intestinal (luminal) forms of E. histolytica and tapeworm, because it is not significantly absorbed from the  gastrointestinal tract. It is an alternative agent for cryptosporidiosis. Although directly amebicidal,  paromomycin also exerts its antiamebic actions by reducing the population of intestinal flora. Its direct  amebicidal action is probably due to the effects it has on cell membranes, causing leakage. Very little of the  drug is absorbed on oral ingestion, but that which is absorbed is excreted in the urine. Gastrointestinal distress  and diarrhea are the principal adverse effects.   These drugs are useful for treating liver abscesses or intestinal wall infections caused by amebas.    Figure 36.5 Some commonly used therapeutic options for the treatment of amebiasis.    1. Chloroquine: Chloroquine [KLOR-oh-kwin] is used in combination with metronidazole and diloxanide furoate  to treat and prevent amebic liver abscesses. It eliminates trophozoites in liver abscesses, but it is not useful in  treating luminal amebiasis. Chloroquine is also effective in the treatment of malaria.   2. Emetine and dehydroemetine: Emetine [EM-e-teen] and dehydroemetine [de-hye-dro-EM-e-teen] are  alternative agents for the treatment of amebiasis. They inhibit protein synthesis by blocking chain elongation. 1 2  Intramuscular injection is the preferred route. Emetine is concentrated in the liver, where it persists for a  month after a single dose. It is slowly metabolized and excreted, and it can accumulate. Its half-life in plasma is  5 days. The use of these ipecac alkaloids is limited by their toxicities ( dehydroemetine is less toxic than  emetine), and close clinical observation is necessary when these drugs are administered. They should not be    taken for more than 5 days. Dehydroemetine is only available under a compassionate investigational new drug  protocol through the Centers of Disease Control and Prevention. Among the untoward effects are pain at the  site of inj ection, transient nausea, cardiotoxicity (for example, arrhythmias or congestive heart failure),  neuromuscular weakness, dizziness, and rashes. A summary of the treatment of amebiasis is shown in Figure  36.5.   Malaria is an acute infectious disease caused by four species of the protozoal genus Plasmodium . The parasite is  transmitted to humans through the bite of a female Anopheles mosquito, which thrives in humid, swampy areas.   acute, rapidly fulminating disease that is characterized by persistent high fever, orthostatic hypotension, and  massive erythrocytosis (an abnormal elevation in the number of red blood cells accompanied by swollen and reddish  condition of the limbs). P. falciparum infection can lead to capillary obstruction and death if treatment is not  instituted promptly. Plasmodium vivax causes a milder form of the disease. Plasmodium malariae is common to many  tropical regions, but Plasmodium ovale is rarely encountered. Resistance acquired by the mosquito to insecticides,  and by the parasite to drugs, has led to new therapeutic challenges, particularly in the treatment of P. falciparum .   When an infected mosquito bites, it injects Plasmodium sporozoites into the bloodstream (Figure 36.6). The  sporozoites migrate through the blood to the liver, where they form cyst-like structures containing thousands of  merozoites. [Note: Diagnosis depends on laboratory identification of the parasites in red blood cells of peripheral  blood smears. ] Upon release, each merozoite invades a red blood cell, becoming a trophozoite and using  hemoglobin as a nutrient. The trophozoites multiply and become merozoites. Eventually, the infected cell ruptures,  releasing heme and merozoites that can enter other erythrocytes. [Note: Alternatively, released merozoites can  become gametocytes,   which are picked up by mosquitoes from the blood they ingest. The cycle thus begins again, with the gametocytes  becoming sporozoites in the insect. ] The effectiveness of a drug treatment is related to the particular species of  infecting plasmodium and the stage of its life cycle that is targeted. A summary of the life cycle of the parasite and  the sites of therapeutic interventions are presented in Figure 36.6.    The female mosquito picks  up gametocytes from an  infected human. The sexual  cycle occurs in the mosquito,  where sporozoites are formed.   Infection can also  result from use  of a Wood  contaminated  needle    Figure 36.6 Life cycle of the malarial parasite, Plasmodium falciparum , showing the sites of action of  antimalarial drugs.   Primaquine [PRIM-a-kwin] is an 8-aminoquinoline that eradicates primary exoerythrocytic forms of P. falciparum  and P. vivax and the secondary exoerythrocytic forms of recurring malarias ( P. vivax and P. ovale ). [Note:  Primaquine is the only agent that can lead to radical cures of the P. vivax and P. ovale malarias, which may remain  in the liver in the exoerythrocytic form after the erythrocytic form of the disease is eliminated.] The sexual  (gametocytic) forms of all four plasmodia are destroyed in the plasma or are prevented from maturing later in the  mosquito, thus interrupting the transmission of the disease. [Note: Primaquine is not effective against the  erythrocytic stage of malaria and, therefore, is often used in conj unction with a blood schizonticide, such as  chloroquine, quinine, mefloquine, or pyrimethamine.]    1. Mechanism of action: This is not completely understood. Metabolites of primaquine are believed to act as  oxidants that are responsible for the schizonticidal action as well as for the hemolysis and methemoglobinemia  encountered as toxicities.   2. Pharmacokinetics: Primaquine is well absorbed on oral administration and is not concentrated in tissues. It is  rapidly oxidized to many compounds, the maj or one being the deaminated drug. It has not been established  which compound possesses the schizontocidal activity. Metabolites appear in the urine (Figure 36. 7).   3. Adverse effects: Primaquine has a low incidence of adverse effects, except for drug-induced hemolytic anemia  in patients with genetically low levels of glucose-6-phosphate dehydrogenase 2 (Figure 36.8). Other toxic  manifestations observed after large doses of the drug include abdominal discomfort, especially when  administered in combination with chloroquine (which may affect patient compliance), and occasional  methemoglobinemia. Granulocytopenia and agranulocytosis are rarely seen, except in patients with lupus or  arthritis (both conditions are aggravated by the drug). Primaquine is contraindicated during pregnancy. All  Plasmodium species may develop resistance to primaquine.   Chloroquine [KLOR-oh-kwin] is a synthetic 4-aminoquinoline that has been the mainstay of antimalarial therapy, and  it is the drug of choice in the treatment of erythrocytic P. falciparum malaria, except in resistant strains.   Chloroquine is less effective against P. vivax malaria. It is highly specific for the asexual form of plasmodia.   Chloroquine is also effective in the treatment of extraintestinal amebiasis. [Note: The anti-inflammatory   action of chloroquine explains its occasional use in rheumatoid arthritis and discoid lupus erythematosus. ]    Glucose 6-P-dehydrogenase  deficiency results in a decrease  in NADPH and GSH synthesis,  making the cell more sensitive  to oxidative agents, such as  primaquine. This causes hemolysis.    Primaquine oxidizes GSH  to GSSG. Therefore, less  GSH is available to neutralize  toxic compounds.   Figure 36.8 Mechanism of pr/magu/ne-induced hemolytic anemia. GSH =reduced glutathione; GSSG =  oxidized glutathione; NADP+ = nicotinamide adenine dinucleotide phosphate; NADPH =reduced nicotinamide  adenine dinucleotide phosphate.   The parasite digests the host cell's  hemoglobin to obtain essential  amino acids.    The process releases large  amounts of heme, which  is toxic to the parasite.    To protect itself, the  parasite ordinarily  polymerizes the  heme to nontoxic  hemozoin, which  is sequestered in  the parasite's food  vacuole.    | Chloroquint prevents the  | polymerization to hemozoin.  The accumulation of heme  results in lysis of both the  parasite and the red blood  cell.   Figure 36.9 Action of chloroquine on the formation of hemozoin by Plasmodium species.    1. Mechanism of action: Although a detailed explanation of the mechanisms by which chloroquine kills plasmodial  parasites is still incomplete, the following processes are essential for the drug's lethal action (Figure 36.9). After  traversing the erythrocytic and plasmodial membranes, chloroquine (a diprotic weak base) is concentrated in  the organism's acidic food vacuole, primarily by ion trapping. It is in the food vacuole that the parasite digests  the host cell's hemoglobin to obtain essential amino acids. However, this process also releases large amounts of  soluble heme (ferriprotoporphyrin IX), which is toxic to the parasite. To protect itself, the parasite ordinarily  polymerizes the heme to hemozoin (a pigment), which is sequestered in the parasite's food vacuole.   Chloroquine specifically binds to heme, preventing its polymerization to hemozoin. The increased pH and the  accumulation of heme result in oxidative damage to the membranes, leading to lysis of both the parasite and the  red blood cell. The binding to heme and prevention of its polymerization appear to be a crucial step in the  drug's antiplasmodial activity, and this may represent a unifying mechanism for such diverse compounds as  chloroquine, quinidine, and mefloquine.    2. Pharmacokinetics: Chloroquine is rapidly and completely absorbed following oral administration. Usually, 4  days of therapy suffice to cure the disease. The drug concentrates in erythrocytes, liver, spleen, kidney, lung,  melanin-containing tissues, and leukocytes. Thus, it has a very large volume of distribution. It persists in  erythrocytes (see a€oeMechanism of actionaCp above). The drug also penetrates into the central nervous system  (CNS) and traverses the placenta. Chloroquine is dealkylated by the hepatic mixed-function oxidase system, but  some metabolic products retain antimalarial activity. Both parent drug and metabolites are excreted  predominantly in the urine (Figure 36. 10). The excretion rate is enhanced as urine is acidified.   3. Adverse effects: Side effects are minimal at the low doses used in the chemosuppression of malaria. At higher    doses, many more toxic effects occur, such as gastrointestinal upset, pruritus, headaches, and blurring of vision  (Figure 36.11). [Note: An ophthalmologic examination should be routinely performed.] Discoloration of the nail  beds and mucous membranes may be seen on chronic administration. Chloroquine should be used cautiously in  patients with hepatic dysfunction or severe gastrointestinal problems or in patients with neurologic or blood  disorders. Chloroquine can cause electrocardiographic changes, because it has a quinidine-Uke effect. It may  also exacerbate dermatitis produced by gold or phenylbutazone therapy. [Note: Patients with psoriasis or  porphyria should not be treated with chloroquine, because an acute attack may be provoked.]   4. Resistance: Resistance of plasmodia to available drugs has become a serious medical problem throughout Africa,  Asia, and most areas of Central and South America. Chloroquine- resistant P. falciparum exhibit multigenic  alterations that confer a high level of resistance. [Note: When a c/i/orogu/'ne-resistant organism is encountered,  therapy usually consists of an orally administered combination of quinine, pyrimethamine, and a sulfonamide,  such as sulfadoxine. ]   Mefloquine [MEF-lo-kween] appears to be promising as an effective single agent for suppressing and curing  infections caused by multidrug-resistant forms of P. falciparum . Its exact mechanism of action remains to be   determined, but like quinine, it can apparently damage the parasite's membrane. Resistant strains have been  identified. Mefloquine is absorbed well after oral administration and concentrates in the liver and lung. It has a long  half-life (17 days) because of its concentration in various tissues and its continuous circulation through the  enterohepatic and enterogastric systems. The drug undergoes extensive metabolism. Its maj or excretory route is  the feces. Adverse reactions at high doses range from nausea, vomiting, and dizziness to disorientation,  hallucinations, and depression. Electrocardiographic abnormalities and cardiac arrest are possible if mefloquine is  taken concurrently with quinine or quinidine.   Quinine [KWYE-nine] and its stereoisomer, quinidine [KWIH-ni-deen], interfere with heme polymerization,  resulting in death of the erythrocytic form of the plasmodial parasite. These drugs are reserved for severe  infestations and for malarial strains that are resistant to other agents, such as chloroquine. Taken orally, quinine is  well distributed throughout the body and can reach the fetus. Alkalinization of the urine decreases its excretion.   The maj or adverse effect of quinine is cinchonisma€"a syndrome causing nausea, vomiting, tinnitus, and vertigo.   These effects are reversible and are not considered to be reasons for suspending therapy. However, quinine  treatment should be suspended if a positive Coombs' test for hemolytic anemia occurs. Drug interactions include  potentiation of neuromuscular-blocking agents and elevation of digoxin levels if taken concurrently with quinine.   Quinine absorption is retarded when the drug is taken with aluminum-containing antacids. Quinine is fetotoxic.   Artemisinin [ar-te-MIS-in-in] is derived from the qinghaosu plant, which has been used in Chinese medicine for  more than two millennia in the treatment of fevers and malaria. Artemisinin (or one of its derivatives) is available  for the treatment of severe, multidrug-resistant P. falciparum malaria. Its antimalarial action involves the  production of free radicals within the plasmodium food vacuole, following cleavage of the drug's endoperoxide  bridge by heme iron in parasitized erythrocytes. It is also believed to covalently bind to and damage specific  malarial proteins. Oral, rectal, and intravenous preparations are available, but the short half-lives preclude their  use in chemoprophylaxis. They are metabolized in the liver and are excreted primarily in the bile. Adverse effects  include nausea, vomiting, and diarrhea, but overall, artemisinin is remarkably safe. Extremely high doses may cause  neurotoxicity and prolongation of the QT interval.   The antifolate agent pyrimethamine [peer-i-METH-a-meen] is frequently employed to effect a radical cure as a  blood schizonticide. It also acts as a strong sporonticide in the mosquito's gut when the mosquito ingests it with the  blood of the human host. Pyrimethamine inhibits plasmodial dihydrofolate reductase 3 at much lower concentrations  than those needed to inhibit the mammalian enzyme. The inhibition deprives the protozoan of tetrahydrofolatea€"a  cofactor required in the de novo biosynthesis of purines and pyrimidines and in the interconversions of certain  amino acids. Pyrimethamine alone is effective against P. falciparum. In combination with a sulfonamide, it is also  used against P. malariae and Toxoplasma gondii. If megaloblastic anemia occurs with pyrimethamine treatment, it  may be reversed with leucovorin. Figure 36. 12 shows some therapeutic options in the treatment of malaria.   Trypanosomiasis refers to two chronic and, eventually, fatal diseases caused by species of Trypanosoma : African  sleeping sickness, and American sleeping sickness (Figure 36. 13). In African sleeping sickness, the causative  organisms, Trypanosoma brucei qambiense and Trypanosoma brucei rhodiense , initially live and grow in the blood.  The parasite invades the CNS, causing an inflammation of the brain and spinal cord that produces the characteristic  lethargy and, eventually, continuous sleep. Chagas 1 disease (American sleeping sickness) is caused by Trypanosoma  cruzi and occurs in South America.   Melarsoprol [mel-AR-so-prol] is a derivative of mersalyl oxide, a trivalent arsenical. Its use is limited to the    treatment of trypanosomal infectionsa€"usually in the late stage with CNS involvementa€"and it is lethal to these  parasites.   1. Mechanism of action: The drug reacts with sulfhydryl groups of various substances, including enzymes in both  the organism and host.   The parasite's enzymes may be more sensitive than those of the host. There is evidence that mammalian cells  may be less permeable to the drug and, thus, are protected from its toxic effects. Trypanosomal resistance may  also be due to decreased permeability of the drug.    2. Pharmacokinetics: Melarsoprol usually is slowly administered intravenously through a fine needle, even though    it is absorbed from the gastrointestinal tract. Because it is very irritating, care should be taken not to infiltrate  surrounding tissue. Adequate trypanocidal concentrations appear in the CSF, in contrast to nonpenetration of  the CSF by pentamidine. Melarsoprol is therefore the agent of choice in the treatment of T. brucei  rhodesiense , which rapidly invades the CNS, as well as for meningoencephalitis caused by T. brucei qambiense .  The host readily oxidizes melarsoprol to a relatively nontoxic, pentavalent arsenic compound. The drug has a  very short half-life and is rapidly excreted into the urine (Figure 36. 14).   3. Adverse effects: CNS toxicities are the most serious side effects of melarsoprol treatment. Encephalopathy  may appear soon after the first course of treatment but usually subsides. It may, however, be fatal.  Hypersensitivity reactions may also occur, and fever may follow inj ection. Gastrointestinal disturbances, such as  severe vomiting and abdominal pain, can be minimized if the patient is in the fasting state during drug  administration and for several hours thereafter. Melarsoprol is contraindicated in patients with influenza.  Hemolytic anemia has been seen in patients with glucose 6-phosphate dehydrogenase deficiency.   Pentamidine [pen-TAM-i-deen] is active against a variety of protozoal infections, including many trypanosomes,  such as T. brucei qambiense , for which pentamidine is used to treat and prevent the organism's hematologic stage.  Flowever, some trypanosomes, including T. cruzi, are resistant. Pentamidine is also effective in the treatment of  systemic blastomycosis (caused by the fungus Blastomyces dermatitidis ) and in treating infections caused by  Pneumocystis j iroveci (formerly called Pneumocystis carini ia€"a name now used to refer to the organism in animals).  [Note: It is now considered to be a fungus, but it is not susceptible to antifungal drugs. Trimethoprim-  sulfamethoxazole is preferred in the treatment of P. j iroveci infections. Flowever, pentamidine is the drug of  choice in treating patients with pneumonia caused by P. j iroveci who have failed to respond to trimethoprim-  sulfamethoxazole. The drug is also used in treating P. j irovecia€"infected individuals who are allergic to  sulfonamides. Because of the increased incidence of pneumonia caused by this organism in immunocompromised  patients, such as those infected with human immunodeficiency virus, pentamidine has assumed an important place    in chemotherapy.] Pentamidine is also an alternative drug to stibogluconate in the treatment of leishmaniasis.    1. Mechanism of action: Trypanosoma brucei concentrates pentamidine by an energy-dependent, high-affinity   uptake system. [Note: Resistance is associated with an inability of the trypanosome to concentrate the drug.]   Although its mechanism of action has not been defined, evidence exists that the drug binds to the parasite's DNA   and interferes with the synthesis of RNA, DNA, phospholipid, and protein by the parasite.    2. Pharmacokinetics: Fresh solutions of pentamidine are administered intramuscularly or as an aerosol (Figure  36. 15). [Note: The intravenous route is avoided because of severe adverse reactions, such as a sharp fall in  blood pressure and tachycardia. ] The drug is concentrated and stored in the liver and kidney for a long period of  time. Because it does not enter the CSF, it is ineffective against the meningoencephalitic stage of  trypanosomiasis. The drug is not metabolized, and it is excreted very slowly into the urine. Its half-life in the  plasma is about 5 days.   3. Adverse effects: Serious renal dysfunction may occur, which reverses on discontinuation of the drug. Other  adverse reactions are hypotension, dizziness, rash, and toxicity to i 2 * cells of the pancreas.   Nifurtimox [nye-FER-tim-oks] has found use only in the treatment of acute T. cruzi infections (Chagas 1 disease),  although treatment of the chronic stage of such infections has led to variable results. [Note: Nifurtimox is  suppressive, not curative.] Being a nitroaromatic compound, nifurtimox undergoes reduction and, eventually,  generates intracellular oxygen radicals, such as superoxide radicals and hydrogen peroxide 4 (Figure 36. 16). These  highly reactive radicals are toxic to T. cruzi , which lacks catalase. 5 [Note: Mammalian cells are partially protected  from such substances by the presence of enzymes such as catalase, glutathione peroxidase, and superoxide  dismutase. ] Nifurtimox is administered orally, and it is rapidly absorbed and metabolized to unidentified products    that are excreted in the urine. Adverse effects are common following chronic administration, particularly among  the elderly. Maj or toxicities include immediate hypersensitivity reactions such as anaphylaxis, delayed  hypersensitivity reactions such as dermatitis and icterus, and gastrointestinal problems that may be severe enough  to cause weight loss. Peripheral neuropathy is relatively common, and disturbances in the CNS may also occur. In  addition, cell-mediated immune reactions may be suppressed.   Suramin [SOO-ra-min] is used primarily in the early treatment and, especially, the prophylaxis of African  trypanosomiasis. It is very reactive and inhibits many enzymes, among them those involved in energy metabolism  (for example, glycerol phosphate dehydrogenase 6 ), which appears to be the mechanism most closely correlated with  trypanocidal activity. The drug must be inj ected intravenously. It binds to plasma proteins and remains in the plasma  for a long time, accumulating in the liver and in the proximal tubular cells of the kidney. The severity of the adverse  reactions demands that the patient be carefully followed, especially if he or she is debilitated. Although infrequent,  adverse reactions include nausea and vomiting (which cause further debilitation of the patient), shock and loss of  consciousness, acute urticaria, and neurologic problems, including paresthesia, photophobia, palpebral edema  (edema   of the eyelids), and hyperesthesia of the hands and feet. Albuminuria tends to be common, but when cylindruria  (the presence of renal casts in the urine) and hematuria occur, treatment should cease.   Benznidazole [benz-NI-da-zole] is a nitroimidazole derivative that inhibits protein synthesis and ribonucleic acid  synthesis in the T. cruzi cells. It is an alternative choice for treatment of acute and indeterminate phases of Chagas 1  disease, but therapy with benznidazole does not offer any significant efficacy or toxicity advantages over that with  nifurtimox. However, benznidazole is recommended as prophylaxis for preventing infections caused byT. cruzi  among hematopoietic stem cell transplant, recipients because treatment in potential donors is not always effective.   There are three types of leishmaniasis: cutaneous, mucocutaneous, and visceral. [Note: In the visceral type (liver  and spleen), the parasite is in the bloodstream and can cause very serious problems. ] Leishmaniasis is transmitted  from animals to humans (and between humans) by the bite of infected sandflies. The diagnosis is established by  demonstrating the parasite in biopsy material and skin lesions. The treatments of leishmaniasis and trypanosomiasis  are difficult, because the effective drugs are limited by their toxicities and failure rates. Pentavalent antimonials,  such as sodium stibogluconate, are the conventional therapy used in the treatment of leishmaniasis, with  pentamidine and amphotericin B as backup agents. Allopurinol has also been reported to be effective (it is  converted to a toxic metabolite by the amastigote form 7 of the organism).   The sandfly transfers the flagellated promastigote form of the protozoa, which is rapidly phagocytized by  macrophages. In the macrophage, the promastigotes rapidly change to nonf lagel lated amastigotes and multiply,  killing the cell. The newly released amastigotes are again phagocytized, and the cycle continues.   Sodium stibogluconate [stib-o-GLOO-koe-nate] is not effective in vitro . Therefore, it has been proposed that  reduction to the trivalent antimonial compound is essential for activity. The exact mechanism of action has not  been determined. Evidence for inhibition of glycolysis in the parasite at the phosphofructokinase reaction 8 has been  found. Because it is not absorbed on oral administration, sodium stibogluconate must be administered parenteral ly,  and it is distributed in the extravascular compartment. Metabolism is minimal, and the drug is excreted in the urine  (Figure 36. 17). Adverse effects include pain at the inj ection site, gastrointestinal upsets, and cardiac arrhythmias.   One of the most common infections in humans is caused by the protozoan Toxoplasma gondii , which is transmitted  to humans when they consume raw or inadequately cooked, infected meat. 9 An infected pregnant woman can  transmit the organism to her fetus. Cats are the only animals that shed oocysts, which can infect other animals as  well as humans. The treatment of choice for this condition is the antifolate drug pyrimethamine. A combination of  sulfadiazine and pyrimethamine is also efficacious. Leucovorin is often administered to protect against folate  deficiency. Other inhibitors of folate biosynthesis, such as trimethoprim and sulfamethoxazole, are without  therapeutic efficacy in toxoplasmosis. [Note: At the first appearance of a rash, pyrimethamine should be  discontinued, because hypersensitivity to this drug can be severe.]   Both cysts and trophozoites can  be found in the feces. Infection  occurs by the ingestion of cysts  in contaminated water or food, or   In the small intestine, excystation  releases trophozoites. Trophozoites  multiply in the lumen of the proximal  small bowel, where they can be free  or attached to the mucosa by a sucking  disk. Encystation occurs as the  parasites transit toward the colon.   Giardia lamblia is the most commonly diagnosed intestinal parasite in the United States. 10 It has only two life-cycle  stages: the binucleate trophozoite with four flagellae, and the drug-resistant, four-nucleate cyst (Figure 36. 18).  Ingestion, usually from contaminated drinking water, leads to infection. The trophozoites exist in the small intestine  and divide by binary fission. Occasionally, cysts are formed that pass out in the stool. Although some infections are  asymptomatic, severe diarrhea can occur, which can be very serious in immune-suppressed patients. The treatment  of choice is metronidazole for 5 days. One alternative agent is tinidazole, which is equally effective as  metronidazole in treatment of giardiasis but with a much shorter course of treatment (2 g given once).  Nitazoxanide [nye-ta-ZOX-a-nide], a nitrothiazole derivative structurally similar to aspirin, was recently approved  for treatment of giardiasis. Nitazoxanide is also equally efficacious as metronidazole and, in comparison, has a 2  day shorter course of therapy.   36.1 A 36-year-old male of Lebanese ancestry is being treated for Plasmodium vivax malaria. He experiences  severe fatigue, back pain, and darkened urine. Which one of the following antimalarial drugs is most likely to  have caused his symptoms?   36. 2 Tinnitus, dizziness, blurred vision, and headache are indicative of toxicity to which one of the following  antimalarial drugs?   37.3 Which of the following drugs is recommended for the treatment of severe, multidrug- resistant  Plasmodium falciparum malaria?   37.4 A 22-year-old man, who frequently backpacks, complains of diarrhea and fatigue. Examination of stool  specimens shows binucleate organisms with four flagellae. Which one of the following drugs would be effective  in treating this patient's infestation?   >Table of Contents > Unit VII - Chemotherapeutic Drugs >Chapter 37 - Anthelmintic Drugs   Three major groups of helminths (worms)a€"the nematodes, trematod, and cestodesa€"infect humans. As in all  antibiotic regimens, the anthelmintic drugs (Figure 37.1) are aimed at metabolic targets that are present in the  parasite but are either absent from or have different characteristics than those of the host. Figure 37.2 illustrates  the high incidence of helmintic infections.   Nematodes are elongated roundworms that possess a complete digestive system, including both a mouth and an  anus. They cause infections of the intestine as well as the blood and tissues.    _ Diethylcarbamazine  _ Ivermectin  _ Mebendazole  _ Pyrantel pamoate  _ Thiabendazole   Mebendazole [me-BEN-da-zole], a synthetic benzimidazole compound, is effective against a wide spectrum of  nematodes. It is a drug of choice in the treatment of infections by whipworm (Trichuris trichiura), pinworm  (Enterobius vermicularis), hookworms (Necator americanus and Ancylostoma duodenale), and roundworm (Ascariasis  lumbricoides). Mebendazole acts by binding to and interfering with the assembly of the parasites' microtubules and  also by decreasing glucose uptake. Affected parasites are expelled with the feces. Mebendazole is nearly insoluble  in aqueous solution. Little of an oral dose (that is chewed) is absorbed by the body, unless it is taken with a high-fat  meal. It undergoes first-pass metabolism to inactive compounds. Mebendazole is relatively free of toxic effects,  although patients may complain of abdominal pain and diarrhea. It is, however, contraindicated in pregnant women  (Figure 37.3), because it has been shown to be embryotoxic and teratogenic in experimental animals.   Pyrantel pamoate [pi-RAN-tel PAM-oh-ate], along with mebendazole, is effective in the treatment of infections  caused by roundworms, pinworms, and hookworms (Figure 37.4). Pyrantel pamoate is poorly absorbed orally and  exerts its effects in the intestinal tract. It acts as a depolarizing, neuromuscular-blocking agent, causing persistent  activation of the parasite's nicotinic receptors. The paralyzed worm is then expelled from the host's intestinal tract.  Adverse effects are mild and include nausea, vomiting, and diarrhea.   Thiabendazole [thye-a-BEN-da-zole], another synthetic benzimidazole, is effective against strongyloidiasis caused  by Strongyloides stercoralis (threadworm), cutaneous larva migrans, and early stages of trichinosis (caused by  Trichinella spiralis; see Figure 37,4). Thiabendazole, like the other benzimidazoles, affects microtubular  aggregation. Although nearly insoluble in water, the drug is readily absorbed on oral administration. It is  hydroxylated in the liver and excreted in the urine. The adverse effects most often encountered are dizziness,  anorexia, nausea, and vomiting. There have been reports of central nervous system (CNS) symptomatology. Among  the cases of erythema multiforme and Stevens-J ohnson syndrome reportedly caused by thiabendazole, there have  been a number of fatalities. Its use is contraindicated during pregnancy.   Ivermectin [eye-ver-MEK-tin] is the drug of choice for the treatment of onchocerciasis (river blindness) caused by  Onchocerca volvulus and is a drug of first choice for cutaneous larva migrans and strongyloides. Ivermectin targets  the parasite's glutamate-gated Cf channel receptors. Chloride influx is enhanced, and hyperpolarization occurs,  resulting in paralysis of the worm. The drug is given orally. It does not cross the blood-brain barrier and, thus, has  no pharmacologic effects in the CNS. However, it is contraindicated in patients with meningitis, because their  blood-brain barrier is more permeable and CNS effects might be expected. Ivermectin is also contraindicated in  pregnancy (see Figure 37,3). The killing of the microfilaria can result in a Mazotti-like reaction (fever, headache,  dizziness, somnolence, and hypotension).   Diethylcarbamazine [dye-eth-il-kar-BAM-a-zeen] is used in the treatment of filariasis because of its ability to  immobilize microfilariae and render them susceptible to host defense mechanisms. Combined with albendazole,  diethylcarbamazine is effective in the treatment of Wucheria bancrofti and Brugia malayi infections. It is rapidly  absorbed following oral administration with meals and is excreted primarily in the urine. Urinary alkalosis or renal  impairment may require dosage reduction. Adverse effects are primarily caused by host reactions to the killed  organisms. The severity of symptoms is related to the parasite load and include fever, malaise, rash, myalgias,  arthralgias, and headache. Most patients have leukocytosis. Antihistamines or steroids may be given to ameliorate  many of the symptoms. Figure 37. 4 summarizes the maj or infections caused by nematodes and the common  therapies for them.   The trematodes (flukes) are leaf-shaped flatworms that are generally characterized by the tissues they infect. For  example, they may be categorized as liver, lung, intestinal, or blood flukes (Figure 37.5).   Trematode infections are generally treated with praziquantel [ pray-zi-KWON-tel ]. This drug is an agent of choice  for the treatment of all forms of schistosomiasis and other trematode infections and for cestode infections like  cysticercosis. Permeability of the cell membrane to calcium is increased, causing contracture and paralysis of the  parasite.   Praziquantel is rapidly absorbed after oral administration and distributes into the cerebrospinal fluid. High levels  occur in the bile. The drug is extensively metabolized oxidatively, resulting in a short half-life. The metabolites are  inactive and are excreted through the urine and bile. Common adverse effects include drowsiness, dizziness,  malaise, and anorexia, as well as gastrointestinal upsets. The drug is not recommended for pregnant women or  nursing mothers. Drug interactions due to increased metabolism have been reported with dexamethasone,  phenytoin, and carbamazepine. Cimetidine, which inhibits cytochrome P450 isozymes, causes increased  praziquantel levels. Praziquantel is contraindicated for the treatment of ocular cysticercosis, because destruction  of the organism in the eye may damage the organ.   # Common in areas of Mexico, South America,  and tropical Africa.   # Characterized by subcutaneous nodules, a  pruritic skin rash, and ocular lesions often  resulting in blindness.   # Second only to pinworms as the most  preval entmulticellular parasite in the United  States; approximately one third of the world's  population b infected with this worm.   # Ingested larvae grow in the intestine, causing  abdominal symptoms, including intestinal  obstruction; roundworms may pass to blood  and infect the lungs.   # Worms cause blockage of lymph flow.  Ultimately, local inflammation and fibrosis of  the lymphatics occurs.   # After years of infestation, the arms, legs, and  scrotum AM with fluid, causing elephantiasis.   # Infection is usually asymptomatic; however,  abdominal pain, diarrhea, and flatulence can  occur.   • Worm attache, to the intestinal mucosa,  causing anorexia, ulcer-llke symptoms, and  chronic intestinal blood loss that leads to   Relatively uncommon compared with other  intestinal nematodes;a relatively benign  disease in normal individuals that can  progress to a fatal outcome in immuno-  compromised patients.   • Usually caused by consumption of insufficiently  cooked meat especially pork,   The cestodes, or a€oetrue tapeworms, a€i typically have a flat, segmented body and attach to the host's intestine  (Figure 37.6). Like the trematodes, the tapeworms lack a mouth and a digestive tract throughout their life cycle.    Niclosamide [ni-KLOE-sa-mide] is the drug of choice for most cestode (tapeworm) infections. Its action has been  ascribed to inhibition of the   parasite's mitochondrial phosphorylation of adenosine diphospate, which produces usable energy in the form of  adenosine triphospate. Anaerobic metabolism may also be inhibited. The drug is lethal for the cestode's scolex and  segments of cestodes but not for the ova. A laxative is administered prior to oral administration of niclosamide. This  is done to purge the bowel of all dead segments and so preclude digestion and liberation of the ova, which may lead  to cysticercosis. Alcohol should be avoided within 1 day of niclosamide.   Figure 37.5 Characteristics of and therapy for commonly encountered trematode infections.    0 This form of schistosomiasis is diagnosed  by identifying characteristic eggs in the  urine or bladder wall.   0 This disease is caused by Paraqonimus  westerman i (lung fluke). The organisms  move from the gastrointestinal tract to  the lung, which is the primary site of  damage. Secondary bacterial infections  can result in a cough that produces  bloody sputum.   0 Paragonimiasis is diagnosed by  identifying eggs in the sputum and  stool.   0 This disease is caused by Clo norchis  sin ensis (Oriental liver flulceTTFe  primary site of infection is the biliary  tract, where the resulting inflammatory  response can cause fibrosis and  hyperplasia.   0 This disease is caused by Schistosoma  haematobium. The primary sites of  infection are veins of the urinary bladder,  where the organism's eggs can induce  fibrosis, granulomas, and hematuria.   0 This disease is caused by Schistosoma  mansoni and Schistosoma j aponicum. The  primary site of infection is the  gastrointestinal tract. Damage to the  intestinal wall is caused by the host's  inflammatory response to eggs deposited  at that site. The eggs also secrete  proteolytic enzymes that further damage  the tbsue.   • This form of schistosomiasis is diagnosed  by identification of characteristic eggs in  the stool.   Albendazole [al-BEN-da-zole] is a benzimidazole that, like the others, inhibits microtubule synthesis and glucose  uptake in nematodes. Its primary therapeutic application, however, is in the treatment of cestodal infestations,  such as cysticercosis (caused by Taenia solium larvae) and hydatid disease (caused by Echinococcus granulosis).  Albendazole is erratically absorbed after oral administration, but absorption is enhanced by a high-fat meal. It  undergoes extensive first-pass metabolism, including formation of the sulfoxide, which is also active. Albendazole  and its metabolites are primarily excreted in the urine. When used in short-course   therapy (la€"3 days) for nematodal infestations, adverse effects are mild and transient and include headache and  nausea. Treatment of hydatid disease (3 months) has a risk of hepatotoxicity and, rarely, agranulocytosis or  pancytopenia. Medical treatment of neurocysticercosis is associated with inflammatory responses to dying parasites  in the CNS, including headache, vomiting, hyperthermia, convulsions, and mental changes. The drug should not be    given during pregnancy (see Figure 37.3) or to children under 2 years of age.   • This disease (also called hydatid  disease) is caused by Echinococcus  granulosis (dog tapeworm). Infection  produces large, hydatid cysts in the  liver, lung, and brain. Anaphylactic  reaction to worm antigens can occur if  the cyst ruptures.    • This disease is caused by Taenia solium  larvae. Infection produces cvsticerci in  the brain (causing seizures, headache,  and vomiting) and in the eyes.    0 The disease follows ingestion of eggs in  dog feces. Sheep often serve as an  intermediate host.    • Echinococcosis is diagnosed by CT scan  or biopsy of infected tissue and is  treated by surgical excision of cysts.   • This disease is caused by the larval form  of Taenia saqinata (beef tapeworm). The  organism primarily infects tho intestines  and does not produce cysticerci. Most  infected individuals are asymptomatic.   0 This form of the disease Is caused by  the adult Taenia solium (pork  tapeworm), intestines are the primary  site of infection, where (he organism  can cause diarrhea. Most of those  infections, however, are asymptomatic    • The disease is transmitted by larvae in  undercooked pork or by ingestion of  tapeworm eggs.    • This disease is caused by Plphyllobothrium latum Irish  tapeworm). The adult worm in a host's intestine can bo as long  as 1 5 meters.    • Taeniasis is diagnosed by detection of  proglottids in the stool.    % The disease is transmitted by larvae in raw or undercooked fish.   0 DiphyllobothHasis is diagnosed by detection of characteristic eggs in  the stool.    > The disease is transmitted by larvae in  undercooked or raw beef.   ) Taeniasis is diagnosed by detection of  proglottids in tho stool    Figure 37.6 Characteristics of and therapy for commonly encountered cestode infections.   37. 1 A 48-year-old immigrant from Mexico presents with seizures and other neurologic symptoms. Eggs of  Taenia solium are found upon examination of a stool specimen. A magnetic resonance image of the brain shows  many cysts, some of which are calcified. Which one of the following drugs would be of benefit to this  individual?    37. 2 A 56-year-old man from South America is found to be parasitized by both schistosomes and Taenia  soliuma€”the pork tapeworm. Which of the following anthelmintic drugs would be effective for both  infestations?   >Table of Contents > Unit VII - Chemotherapeutic Drugs >Chapter 38 - Antiviral Drugs   Viruses are obligate intracellular parasites. They lack both a cell wall and a cell membrane, and they do not carry  out metabolic processes. Viral reproduction uses much of the host's metabolic machinery, and few drugs are  selective enough to prevent viral replication without inj ury to the host. Therapy for viral diseases is further  complicated by the fact that the clinical symptoms appear late in the course of the disease, at a time when most of  the virus particles have replicated. [Note: This contrasts with bacterial diseases, in which the clinical symptoms are  usually coincident with bacterial proliferation.] At this late, symptomatic stage of the viral infection, administration  of drugs that block viral replication has limited effectiveness. However, some antiviral agents are useful as  prophylactic agents. Only a few virus groups, including those that cause the viral infections discussed in this  chapter, respond to available antiviral drugs. To assist in the review of these drugs, they are grouped according to  the organisms that are affected (Figure 38.1).   Viral respiratory tract infections for which treatments exist include those of influenza A and B and respiratory  syncytial virus (RSV). [Note: Immunization against influenza A is the preferred approach. However, antiviral agents  are employed when patients are allergic to the vaccine, when the outbreak is due to an immunologic variant of the  virus not covered by vaccines, or when outbreaks occur among unvaccinated individuals who are at risk and in  closed settings (for example, in nursing homes). ]   Orthomyxoviruses that cause influenza contain the enzyme neuraminidase, which is essential to the life cycle of the  virus. Viral neuraminidase can be selectively inhibited by the sialic acid analogs, oseltamivir [os-el-TAM-i-veer] and    zanamivir [za-NA-mi-veer], These drugs prevent the release of new virions and their spread from cell to cell.   Unlike the adamantine analogs discussed below, oseltamivir and zanamivir are effective against both Type A and  Type B influenza viruses. They do not interfere with the immune response to influenza A vaccine. Administered  prior to exposure, neuraminidase inhibitors prevent infection, and when administered within the first 24 to 48 hours  after the onset of infection, they have a modest effect on the intensity and duration of symptoms.   1. Mode of action: Influenza viruses employ a specific neuraminidase that is inserted into the host cell membrane  for the purpose of releasing newly formed virions. Oseltamivir and zanamivir are transition-state analogs of the  sialic acid substrate and serve as inhibitors of the enzyme activity. Virions accumulate at the internal infected  cell surface.   2. Pharmacokinetics: Oseltamivir is an orally active prodrug that is rapidly hydrolyzed by the liver to its active  form. Zanamivir, on the other hand, is not active orally and is either inhaled or administered intranasally. Both  drugs are eliminated unchanged in the urine (Figure 38.2).   3. Adverse effects: The most common side effects of oseltamivir are gastrointestinal discomfort and nausea,  which can be alleviated by taking the drug with food. Zanamivir is not associated with gastrointestinal  disturbance, because it is administered directly to the airways. Irritation of the respiratory tract does occur,  however. Zanamivir should be avoided in individuals with severe reactive asthma or chronic obstructive  respiratory disease, because bronchospasm may occur with the risk of fatality. Neither drug has been reported  to have clinically significant drug interactions.   4. Resistance: Mutations of the neuraminidase have been identified in adults treated with either of the  neuraminidase inhibitors. These mutants, however, are often less infective and virulent than the wild type.   The therapeutic spectrum of the adamantine derivatives, amantadine [a-MAN-ta-deen] and rimantadine [ri-MAN-  ta-deen], is limited to influenza A infections, for which the drugs have been shown to be equally effective in both  treatment and prevention. For example, these drugs are 70 to 90 percent effective in preventing infection if  treatment is begun at the time ofa€"or prior toa€"exposure to the virus. Also, both drugs reduce the duration and  severity of systemic symptoms if started within the first 48 hours after exposure to the virus (Figure 38.3). Neither  impairs the immune response to influenza A vaccine, and either can be administered as a supplement to  vaccination, thus providing protection until antibody response occurs (usually 2 weeks in healthy adults). Treatment  is particularly useful in high-risk patients who have not been vaccinated and during epidemics. [Note: Amantadine  is also effective in the treatment of some cases of Parkinson's disease (see p. 101).]   The drug provides a modest  therapeutic effect in patients with  uncomplicated, naturally occurring  influenza A.    Figure 38.3 Improvement in symptoms of individuals with naturally occurring influenza infections treated  with amantadine.    1. Mode of action: The primary antiviral mechanism of amantadine and rimantadine is to block the viral   membrane matrix protein, M2, which functions as a channel for hydrogen ion. This channel is required for the  fusion of the viral membrane with the cell membrane that ultimately forms the endosome (created when the  virus is internalized by endocytosis). [Note: The acidic environment of the endosome is required for viral  uncoating. ] These drugs may also interfere with the release of new virions.    2. Pharmacokinetics: Both drugs are well absorbed orally. Amantadine distributes throughout the body and    readily penetrates into the central nervous system (CNS), whereas rimantadine does not cross the blood-brain  barrier to the same extent. Amantadine is not extensively metabolized. It is excreted into the urine and may  accumulate    to toxic levels in patients with renal failure. On the other hand, rimantadine is extensively metabolized by the  liver, and both the metabolites and the parent drug are eliminated by the kidney (Figure 38.4).   3. Adverse effects: The side effects of amantadine are mainly associated with the CNS. Minor neurologic  symptoms include insomnia, dizziness, and ataxia. More serious side effects have been reported (for example,  hallucinations and seizures). The drug should be employed cautiously in patients with psychiatric problems,  cerebral atherosclerosis, renal impairment, or epilepsy. Rimantadine causes fewer CNS reactions, because it  does not efficiently cross the blood-brain barrier. Both drugs cause gastrointestinal intolerance. Amantadine  and rimantadine should be used with caution in pregnant and nursing mothers, because they have been found  to be embryotoxic and teratogenic in rats.   4. Resistance: Resistance can develop rapidly in up to 50 percent of treated individuals, and resistant strains can  be readily transmitted to close contacts. Resistance has been shown to result from a change in one amino acid of  the M2 matrix protein. Cross-resistance occurs between the two drugs.   Ribavirin [rye-ba-VYE-rin] is a synthetic guanosine analog. It is effective against a broad spectrum of RNA and DNA  viruses. For example, ribavirin is used in treating infants and young children with severe RSV infections. [Note: It is  not indicated for use in adults. ] Ribavirin is also effective in chronic hepatitis C infections when used in  combination with interferon-J±-2b. Ribavirin may reduce the mortality and viremia of Lassa fever.    1. Mode of action: The mode of action of ribavirin has been studied only for the influenza viruses. The drug is    first converted to the 5'-phosphate derivatives, the major product being the compound ribavirin-triphosphate,  which exerts its antiviral action by inhibiting guanosine triphosphate formation, preventing viral mRNA capping, 1  and blocking RNA-dependent RNA polymerase. [Note: Rhinoviruses and enteroviruses, which contain preformed  mRNA and do not need to synthesize mRNA in the host cell to initiate an infection, are relatively resistant to the  action of ribavirin. ]   2. Pharmacokinetics: Ribavirin is effective orally and intravenously. Absorption is increased if the drug is taken  with a fatty meal. An aerosol is used in certain respiratory viral conditions, such as the treatment of RSV  infection. Studies of drug distribution in primates have shown retention in all tissues, except brain. The drug  and its metabolites are eliminated in the urine (Figure 38.5).   3. Adverse effects: Side effects reported for oral or parenteral use of ribavirin have included dose-dependent  transient anemia. Elevated bilirubin has been reported. The aerosol may be safer, although respiratory function  in infants can deteriorate quickly after initiation of aerosol treatment. Therefore, monitoring is essential.  Because of teratogenic effects in experimental animals, ribavirin is contraindicated in pregnancy (Figure 38.6).    The hepatitis viruses thus far identif ieda€"A, B, C, D, and Ea€"each have a pathogenesis specifically involving  replication in and destruction of hepatocytes. Of this group, hepatitis B and hepatitis C are the most common causes  of chronic hepatitis, cirrhosis, and hepatocellular carcinoma (Figure 38.7) and are the only hepatic viral infections  for which therapy is currently available. [Note: Hepatitis A is a commonly encountered infection, but it is not a  chronic disease.] Chronic hepatitis B is usually treated with peginterferon-~\±-2a, which is inj ected subcutaneously  once weekly. [Note: lnterferon-~\±-2b inj ected intramuscularly or subcutaneously three times weekly is also useful  in the treatment of hepatitis B, but pegi nterefron-\±-2a has similar or slightly better efficacy.] Oral therapy  includes lamivudine, adefovir, enetecavir, or telbivudine. Combination therapy of an interferon plus lamivudine  is no more effective than monotherapy with lamivudine. Patients with acquired immunodeficiency syndrome (AIDS)  who are coinfected with hepatitis B are usually poor responders to interferon therapy. In the treatment of chronic  hepatitis C, the preferred treatment is the combination of pegi nterferon-~\±-2a or pegi nterferon-~\±-2b plus  ribavirin, which is more effective than the combination of standard interferons and ribavirin.   Interferon [in-ter-FEER-on] is a family of naturally occurring, inducible glycoproteins that interfere with the ability  of viruses to infect cells. Although interferon inhibits the growth of many viruses in vitro, its activity in vivo against  viruses has been disappointing. The interferons are synthesized by recombinant DNA technology. At least three  types of interferon exist, i+ i 2 , and I 3 (Figure 38. 8). One of the 15 interferon-\±glycoproteinsa€"interferon-  i±-2ba€"has been approved for treatment of hepatitis B and C, condylomata acuminata, and cancers such as  hairy-cell leukemia and Kaposi's sarcoma, interferon-! 2 has some effectiveness in the treatment of multiple  sclerosis. In so-called a€oepegylateda€§ formulations, bis-monomethoxy polyethylene glycol has been covalently  attached to either interferon- i±-2a or -I±-2b to increase the size of the molecule. The larger molecular size delays  absorption from the inj ection site, lengthening the duration of action of the drug, and also decreases its clearance.    Figure 38.7 The prevalence of chronic hepatitis B and C in the United States.    1. Mode of action: The antiviral mechanism is incompletely understood. It appears to involve the induction of host  cell enzymes that inhibit viral RNA translation, ultimately leading to the degradation of viral mRNA and tRNA.   2. Pharmacokinetics: Interferon is not active orally, but it may be administered intralesionally, subcutaneously,  or intravenously. Very little active compound is found in the plasma, and its presence is not correlated with  clinical responses. Cellular uptake and metabolism by the liver and kidney account for the disappearance of  interferon from the plasma. Negligible renal elimination occurs.   3. Adverse effects: Adverse effects include flu-like symptoms on inj ection, such as fever, chills, myalgias,  arthralgias, and gastrointestinal disturbances. Fatigue and mental depression are common. These symptoms  subside with subsequent administrations. The principal dose-limiting toxicities are bone marrow suppression  including granulocytopenia, neurotoxicity characterized by somnolence and behavioral disturbances, severe  fatigue and weight loss, autoimmune   disorders such as thyroiditis, and rarely, cardiovascular problems such as congestive heart failure. Acute  hypersensitivity reactions and hepatic failure are rare.   4. Drug interactions: Interferon interferes with hepatic drug metabolism, and toxic accumulations of  theophylline have been reported. Interferon may also potentiate the myelosuppression caused by other bone  marrowa€"depressing agents, such as zidovudine.   This cytosine analog is an inhibitor of both hepatitis B virus (HBV) DNA polymerase and human immunodeficiency  virus (HIV) reverse transcriptase. Lamivudine [la-MI-vyoo-deen] must be phosphorylated by host cellular enzymes to  the triphosphate (active) form. This compound competitively inhibits HBV DNA polymerase at concentrations that  have negligible effects on host DNA polymerase. As with many nucleotide analogs, the intracellular half-life of the  triphosphate is many hours longer than its plasma half-life, which permits infrequent dosing. Chronic treatment is  associated with decreased plasma HBV DNA levels, improved biochemical markers, and reduced hepatic  inflammation. Lamivudine is well absorbed orally and is widely distributed. Its plasma half-life is about 9 hours.    Seventy percent is excreted unchanged in the urine. Dose reductions are necessary when there is moderate renal  insufficiency (creatinine clearance less than 50 mL/ min). Lamivudine is well tolerated, with rare occurrences of  headache and dizziness.   Adefovir dipivoxil [ah- DEH-f or- veer-d ie- pi h- VOCKS- ill] is a nucleotide analog that is phosphorylated to adefovir  diphosphate, which is then incorporated into viral DNA. This leads to termination of further DNA synthesis and  prevents viral replication. Adefovir is administered once a day and is excreted in the urine, with 45 percent as the  active compound. Clearance is influenced by renal function. Both decreased viral load and improved liver function  have occurred in patients treated with adefovir. As with other agents, discontinuation of adefovir results in severe  exacerbation of hepatitis in about 25 percent of patients. Adefovir does not seem to have significant drug  interactions. The drug should be used cautiously in patients with existing renal dysfunction.   Entecavir [en-TECK-ah-veer] is a guanosine analog approved for the treatment of HBV infections. Following  intracellular phosphorylation to the triphosphate, it competes with the natural substrate, deoxyguanosine  triphosphate, for viral reverse transcriptase. Entecavir has been shown to be effective against lamivudine- resistant  strains of HBV. Liver inflammation and scarring are improved. Entecavir need only be given once a day. Entecavir  undergoes both glomerular filtration and tubular secretion. Very little, if any, drug is metabolized. Renal function  must be assessed periodically, and drugs that have renal toxicity should be avoided. Patients should be monitored  closely for several months after discontinuation of therapy because of the possibility of severe hepatitis.   Telbivudine [tel- BlV-yoo-d i ne ] is a thymidine analog that can be used in the treatment of HBV. Unlike lamivudine  and adefovir, telbivudine is not effective against HIV or other viruses. The drug is phosphorylated i ntracel I u larly   to the triphosphate, which can either compete with endogenous thymidine triphosphate for incorporation into DNA  or else be incorporated into viral DNA, where it serves to terminate further elongation of the DNA chain. The drug is  administered orally, once a day, with or without food. Telbivudine is eliminated by glomerular filtration as the  unchanged drug, and no metabolites have been detected. The dose must be adj usted in renal failure. Combination  of telbivudine with lamivudine has been no more effective than telbivudine alone.   Herpesviruses are associated with a broad spectrum of diseasesa€"for example, cold sores, viral encephalitis, and  genital infections (the latter being a hazard to the newborn during parturition). The drugs that are effective against  these viruses exert their actions during the acute phase of viral infections and are without effect during the latent  phase. Except for foscarnet and fomivirsen, all are purine or pyrimidine analogs that inhibit viral DNA synthesis.   Acyclovir [ay-SYE-kloe-ver] (acycloguanosine) is the prototypic antiherpetic therapeutic agent. It has a greater  specificity than vidarabine against herpesviruses. Herpes simplex virus (HSV) Types 1 and 2, varicella-zoster virus  (VZV), and some Epstein-Barr virusaC" mediated infections are sensitive to acyclovir. It is the treatment of choice in  HSV encephalitis, and is more efficacious than vidarabine at increasing the rate of survival. The most common use  of acyclovir is in therapy for genital herpes infections. It is also given prophylactically to seropositive patients  before bone marrow and after heart transplants to protect such individuals during posttransplant  immunosuppressive treatments.    Thymidine kinase,  coded for by the viral  genome, phosphor-  ylates acyclovir more  than 100- fold faster  than does the host  cell enzyme.   Subsequent phosphor-  ylations are catalyzed  by the enzymes of the  host cell.    dGTP is not  incorporated  into the grow-  ing strand of  viral DNA.    Incorporation of acyclo-GMP  from acydo-GTP into the  growing strand of viral DNA  causes chain termination,  because acyclo-GMP lacks  a 3'-hydroxyl group.   Figure 38.9 Incorporation of acyclovir into replicating viral DNA, causing chain termination. dGTP =  deoxyguanosine triphosphate    1. Mode of action: Acyclovir, a guanosine analog that lacks a true sugar moiety, is monophosphorylated in the cell  by the herpes virusa€"encoded enzyme, thymidine kinase (Figure 38.9). Therefore, virus-infected cells are most  susceptible. The monophosphate analog is converted to the di- and triphosphate forms by the host cells.   Acyclovir triphosphate competes with deoxyguanosine triphosphate as a substrate for viral DNA polymerase and  is itself incorporated into the viral DNA, causing premature DNA-chain termination (see Figure 38.9). Irreversible  binding of the acyc/ov/'r-containing template primer to viral DNA polymerase inactivates the enzyme. The drug is  less effective against the host enzyme.   2. Pharmacokinetics: Administration of acyclovir can be by an intravenous, oral, or topical route. [Note: The  efficacy of topical applications is doubtful. ] The drug distributes well throughout the body, including the  cerebrospinal fluid (CSF). Acyclovir is partially metabolized to an inactive product. Excretion into the urine  occurs both by glomerular filtration and by tubular secretion (Figure 38. 10). Acyclovir accumulates in patients  with renal failure. The valyl ester, valacyclovir [val-a-SYE-kloe-veer], has greater oral bioavailability than  acyclovir. This ester is rapidly hydrolyzed to acyclovir and achieves levels of the latter comparable to those  from intravenous acyclovir administration.   3. Adverse effects: Side effects of acyclovir treatment depend on the route of administration. For example, local  irritation may occur from topical application; headache, diarrhea, nausea, and vomiting may result after oral  administration. Transient renal dysfunction may   occur at high doses or in a dehydrated patient receiving the drug intravenously. High-dose valacyclovir can  cause gastrointestinal problems and thrombotic thrombocytopenia purpura in patients with AIDS.   4. Resistance: Altered or deficient thymidine kinase and DNA polymerases have been found in some resistant viral  strains and are most commonly isolated from immunocompromised patients. Cross- resistance to the other  cyclovirs occurs. [Note: Cytomegalovirus (CMV) is resistant, because it lacks a specific viral thymidine kinase. ]   Cidofovir [si-DOE-foe-veer] is approved for treatment of CMV-induced retinitis in patients with AIDS. Cidofovir is a  nucleotide analog of cytosine, the phosphorylation of which is not dependent on viral enzymes. It inhibits viral DNA  synthesis. Slow elimination of the active intracellular metabolite permits prolonged dosage intervals and eliminates  the permanent venous access used for ganciclovir therapy. Cidofovir is available for intravenous, intravitreal  (inj ection into the eye's vitreous humor between the lens and the retina), and topical administration. Cidofovir  produces significant toxicity to the kidney (Figure 38. 11), and it is contraindicated in patients with preexisting renal  impairment or in those who are taking concurrent nephrotoxic drugs, including nonsteroidal anti-inflammatory  drugs. Neutropenia, metabolic acidosis, and ocular hypotony also occur. Probenecid must be coadministered with  cidofovir to reduce the risk of nephrotoxicity, but probenecid itself causes rash, headache, fever, and nausea.  Since the introduction of HAART (highly active antiretroviral therapy), the prevalence of CMV infections in  immunocompromised hosts has markedly declined, and the importance of cidofovir in the treatment of these  patients has also diminished.   Fomivirsen [foe-MI-veer-sen] is an antisense oligonucleotide directed against CMV mRNA. Its use is limited to those  who cannot toleratea€"or have faileda€"other therapies for CMV retinitis. A 2- to 4-week hiatus after discontinuing  cidofovir is desirable to reduce toxicity. The drug is administered intravitreally. The common adverse effects  include iritis, vitritis, and changes in vision.   Unlike most of the antiviral agents, foscarnet [fos-KAR-net] is not a purine or pyrimidine analog. Instead, it is  phosphonoformatea€"a pyrophosphate derivativea€"and does not require activation by viral (or human) kinases.  Foscarnet has broad in vitro antiviral activity. It is approved for CMV retinitis in immunocompromised hosts and for    acyclovir- resistant HSV and herpes zoster infections. Foscarnet works by reversibly inhibiting viral DNA and RNA  polymerases, thereby interfering with viral DNA and RNA synthesis. Mutation of the polymerase structure is  responsible for resistant viruses. [Note: Cross-resistance between foscarnet and ganciclovir or acyclovir is  uncommon.] Foscarnet is poorly absorbed orally and must be injected intravenously. It must also be given  frequently to avoid relapse when plasma levels fall. It is dispersed throughout the body, and greater than 10 percent  enters the bone matrix, from which it slowly leaves. The parent drug is eliminated by glomerular filtration and  tubular secretion into the urine (Figure 38. 12). Adverse effects include nephrotoxicity, anemia, nausea, and fever.  Due to chelation with divalent    cations, hypocalcemia and hypomagnesemia are also seen. In addition, hypokalemia, hypo- and hyperphosphatemia,  seizures, and arrhythmias have been reported.   Ganciclovir [gan-SYE-kloe-veer] is an analog of acyclovir that has 8- to 20-times greater activity against CMVa€"the  only viral infection for which it is approved. It is currently available for treatment of CMV retinitis in  immunocompromised patients and for CMV prophylaxis in transplant patients.    1. Mode of action: Like acyclovir, ganciclovir is activated through conversion to the nucleoside triphosphate by  viral and cellular enzymes, with the actual pathway depending on the virus. CMV is deficient in thymidine kinase  and, therefore, forms the triphosphate by another route. The nucleotide competitively inhibits viral DNA  polymerase and can be incorporated into the DNA, thereby decreasing the rate of chain elongation.   2. Pharmacokinetics: Ganciclovir is administered intravenously and distributes throughout the body, including the  CSF. Excretion into the urine occurs through glomerular filtration and tubular secretion (Figure 38. 13). Like  acyclovir, ganciclovir accumulates in patients with renal failure. V a! ganciclovir [val-gan-SYE-kloe-veer] is the  valyl ester of ganciclovir. Like valacyclovir, valganciclovir has high oral bioavailability, because rapid hydrolysis  in the intestine and liver after oral administration leads to high levels of ganciclovir.    3. Adverse effects: Adverse effects include severe, dose-dependent neutropenia. [Note: Combined treatment    with zidovudine, azathioprine, or mycophenolate mofetil can result in additive neutropenia. ] Ganciclovir is  carcinogenic as well as embryotoxic and teratogenic in experimental animals.   4. Resistance: Resistant CMV strains have been detected that have lower levels of ganciclovir triphosphate.   Penciclovir [pen-SYE-kloe-veer] is an acyclic guanosine nucleoside derivative that is active against HSV-I, HSV-2,  and VZV. Penciclovir is only administered topically (Figure 38. 14). It is monophosphorylated by viral thymidine  kinase, and cellular enzymes form the nucleoside triphosphate, which inhibits HSV DNA polymerase. Penciclovir  triphosphate has an intracellular half-life 20- to 30-fold longer than does acyclovir triphosphate. Penciclovir is  negligibly absorbed upon topical application and is well tolerated. Both pain and healing are shortened  approximately one-half day in duration compared to placebo-treated subjects. Famciclovir [fam-SYE-kloe-veer],  another acyclic analog of 2'-deoxyguanosine, is a prodrug that is metabolized to the active penciclovir. The antiviral  spectrum is similar to that of ganciclovir, but it is presently approved only for treatment of acute herpes zoster.   The drug is effective orally (see Figure 38. 14). Adverse effects include headaches and nausea. Studies in  experimental animals have shown an increased incidence of mammary adenocarcinomas and testicular toxicity.   Vidarabine [vye-DARE-a-been] (arabi nofur anosyl adenine, ara-A, adenine arabinoside) is one of the most  effective of the nucleoside analogs.   However, it has been supplanted clinically by acyclovir, which is more efficacious and safe. Although vidarabine is  active against HSV-1, HSV-2, and VZV, its use is limited to treatment of immunocompromised patients with herpetic  and vaccinial keratitis and in HSV keratoconj unctivitis. [Note: Vidarabine is only available as an ophthalmic  ointment. ] Vidarabine, an adenosine analog, is converted in the cell to its 5'-tri phosphate analog (ara-ATP), which  is postulated to inhibit viral DNA synthesis. Some resistant HSV mutants have been detected that have altered  polymerase.   Trifluridine [trye-FLURE-i-deen] is a fluorinated pyrimidine nucleoside analog. It is structurally very similar to  thymidine, the only difference being the replacement of a methyl group on the pyrimidine ring of thymidine with a  trifluoromethyl group. Once converted to the triphosphate, the agent is believed to competitively inhibit the  incorporation of thymidine triphosphate into viral DNA and, to a lesser extent, to be   incorporated into viral DNA, leading to the synthesis of a defective DNA that renders the virus unable to reproduce.  Trifluridine monophosphate is an irreversible inhibitor of viral thymidine synthase. Trifluridine is active against  HSV-1, HSV-2, and vaccina virus. It is generally considered to be the drug of choice for treatment of HSV  keratoconconj unctivitis and recurrent epithelial keratitis. Because the triphosphate form of trifluridine can also  incorporate to some degree into cellular DNA, the drug is considered to be too toxic for systemic use; therefore,  the use of trifluridine is restricted to topical application as a solution to the eye. A short half-life of approximately  12 minutes necessitates that the drug be applied frequently. Side effects include a transient irritation of the eye  and palpebral (eyelid) edema.   Blockage of the M2 protein ion channel  and its ability to modulate intracellular pH   Inhibition of viral DNA polymerase and  reverse transcriptase at the  pyrophosphate-binding site   Lassa fever, hantavirus (hemorrhagic fever renal syndrome),  hepatitis C (in chronic cases in combination with interferon «t   Blockage of the M2 protein ion channel  and its ability to modulate intracellular pH   HSV-1, HSV-2, and VZV; its use is limited to treatment of  immunocompromised patients with HSV keratitis   Prior to approval of zidovudine in 1987, treatment of HIV infections focused on decreasing the occurrence of  opportunistic infections that caused a high degree of morbidity and mortality in AIDS patients rather than on  inhibiting HIV itself. Today, the viral life cycle is understood (Figure 38. 16), and a highly active regimen is employed  that uses combinations of drugs to suppress replication of HIV and restore the number of CD4+ cel Is and  immunocompetency to the host. 2 This multi drug regimen is commonly referred to as a€oehighly active antiretroviral  therapy, a€§ or HAART (Figure 38. 17). There are five classes of antiretroviral drugs, each of which targets one of  four viral processes. These classes of drugs are nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs),  non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors, entry inhibitors and the integrase  inhibitors. The current recommendation for primary therapy is to administer two NRTIs with either a protease  inhibitor or an NNRTI. Selection of the appropriate combination is based on 1) avoiding the use of two agents of the  same nucleoside analog, 2) avoiding overlapping toxicities and genotypic and phenotypic characteristics of the  virus, 3) patient factors such as disease symptoms and concurrent illnesses, 4) impact of drug interactions, and 5)  ease of adherence to a frequently complex administration regimen. The goals of therapy are to maximally and    durably suppress viral load replication, to restore and preserve immunologic function, to reduce HIV-related  morbidity and mortality, and to improve quality of life.    After the viral RNA is  released Into the host  cell, it is transcribed  into a ONA copy by  viral reverse tran-  scriptase. NRTIs and  NNRTIs inhibit this  enzyme and, thus,  prevent the synthesis  of the essential DN A  intermediate.    As the virion buds from the surface,  the viral protease is activated and  cleaves the polyproteins into their  component proteins, which then  assemble into the mature virion.  Protease inhibitors prevent this  essential step in virus maturation.   Figure 38.16 Drugs used to prevent HIV from replicating. [NRTI =nucleoside and nucleotide reverse  transcriptase inhibitor; NNRTI =nonnucleoside reverse transcriptase inhibitor.   1. Mechanism of action: Nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs) are analogs of native  ribosides (nucleosides or nucleotides containing ribose), which all lack a 3'- hydroxyl group. Once they enter  cells, they are phosphorylated by a variety of cellular enzymes to the corresponding triphosphate analog, which  is preferentially incorporated into the viral DNA by virus reverse transcriptase. Because the 3'-hydroxyl group is  not present, a 3'-5'-phosphodiester bond between an incoming nucleoside triphosphate and the growing DNA  chain cannot be formed, and DNA chain elongation   is terminated. Affinities of the drugs for many host cell DNA polymerases are lower than they are for HIV reverse  transcriptase, although mitochondrial DNA polymerase i * 2 3 4 5 appears to be susceptible at therapeutic  concentrations.   2. Pharmacokinetics: The NRTIs are primarily renal ly excreted, and all require dosage adj ustment in renal  insufficiency except abacavir, which is metabolized by alcohol dehydrogenase and glucuronyl transferase.   Dosage adj ustment is required when the creatinine clearance drops below 50 mL/ min.   3. Adverse effects: Many of the toxicities of the NRTIs are believed to be due to inhibition of the mitochondrial  DNA polymerase in certain tissues. Asa general rule, the dideoxynucleosides, such as zalcitabine, didanosine,  and stavudine, have a greater affinity for the mitochondrial DNA polymerase, leading to such toxicities as  peripheral neuropathy, pancreatitis, and lipoatrophy. When more than one NRTI is given, care is taken not to  have overlapping toxicities. All the NRTIs have been associated with a potentially fatal liver toxicity  characterized by lactic acidosis and hepatomegaly with steatosis.   4. Drug interactions: Due to the renal excretion of the NRTIs, there are not many drug interactions encountered  with these agents except for zidovudine and tenofovir (see below).   5. Resistance: NRTI resistance is well characterized, and the most common mutation is the mutation at viral codon  184, which confers a high degree of resistance to lamivudine but, more importantly, restores sensitivity to  zidovudine and tenofovir. Cross- resistance and antagonism occur between agents of the same analog class  (thymidine, cytosine, guanosine and adenosine) so concomitant use of agents in the same class is  contraindicated (for example, zidovudine plus stavudine).   Approved in 1987, the first agent available for treatment of HIV infection is the pyrimidine analog, 3'- azi do-   3'-deoxythymidine (AZT). AZT has the generic name of zidovudine [zye-DOE-vyoo-deen], AZT is approved for use in  children and adults and to prevent prenatal infection in pregnancy. It is also recommended for prophylaxis in  individuals exposed to HIV infection. The drug is well absorbed after oral administration. If taken with food, peak  levels may be lower, but the total amount of drug absorbed is not affected. Penetration across the blood-brain  barrier is excellent, and the drug has a half-life of 1 hour. The intracellular half-life, however, is approximately 3  hours. Most of the AZT is glucuronylated by the liver and then excreted in the urine (Figure 38. 18). In spite of its  seeming specificity, AZT is toxic to bone marrow. Headaches are also common. The toxicity of AZT is potentiated if  glucuronylation is decreased by coadministration of drugs like probenecid, acetaminophen, lorazepam,  indomethacin, and cimetidine. They should be avoided or used with caution in patients receiving AZT. Both  stavudine and ribavirin are activated by the same intracellular pathways and should not be given with AZT.    Stavudine [STAV-yoo-deen] is an analog of thymidine, in which a double bond j oins the 2' and 3' carbons of the  sugar. Stavudine is a strong inhibitor of cellular enzymes such as the i 2 and I 3 DNA polymerases, thus    reducing mitochondrial DNA synthesis, resulting in toxicity. The drug is almost completely absorbed on oral ingestion  and is not affected by food. Stavudine penetrates the blood-brain barrier. About half of the parent drug can be  accounted for in the urine. Renal impairment interferes with clearance. The major and most common clinical  toxicity is peripheral neuropathy along with lipoatrophy and hyperlipidemia.   The second drug approved to treat HIV-1 infection was didanosine [dye-DAN-oh-seen] (dideoxyinosine, ddl), which  is missing both the 2'- and 3'- hyd roxyl groups. Upon entry into the host cell, ddl is biotransformed into  dideoxyadenosine triphosphate (ddATP) through a series of reactions that involve phosphorylation of the ddl,  amination to dideoxyadenosine monophosphate, and further phosphorylation. Like AZT, the resulting ddATP is  incorporated into the DNA chain, causing termination of chain elongation. Due to its acid lability, absorption is best  if ddl is taken in the fasting state. The drug penetrates into the CSF, but to a lesser extent than does AZT. About 55  percent of the parent drug appears in the urine (Figure 38. 19). Pancreatitis, which may be fatal, is a maj or toxicity  of ddl treatment and requires monitoring of serum amylase. The dose-limiting toxicity of ddl is peripheral  neuropathy. Because of its similar adverse effect profile, concurrent use of stavudine is not recommended.   Tenofovir [te-NOE-fo-veer] is the first approved drug that is a nucleotide analoga€"namely, an acyclic nucleoside  phosphonate analog of adenosine 5'-monophosphate. It is converted by cellular enzymes to the diphosphate, which  is the inhibitor of HIV reverse transcriptase. Cross-resistance with other NRTIs may occur, but some AZT-resistant  strains retain susceptibility to tenofovir. Tenofovir should be taken with a meal to increase bioavailability.   Tenofovir has a long half-life, allowing once-daily dosing. Most of the drug is recovered unchanged in the urine, and  elimination is by filtration and active secretion. Serum creatinine must be monitored and doses adj usted in renal  insufficiency. Gastrointestinal complaints are frequent and include nausea, diarrhea, and vomiting. (Figure 38.20).  Tenofovir is the only NRTI with significant drug interactions. Tenofovir increases the concentrations of ddl to the  point that ddl dosage reductions are required if the two are given together; however, these two agents are no  longer recommended for combined use. Tenofovir decreases the concentrations of atazanavir such that  atazanavir must be boosted with ritonavir (see p. 452) if given with tenofovir to maintain effective atazanavir  concentrations.   Lamivudine [la-MI-vyoo-deen] ( 2 d eoxy- 3'- 1 h i acyt i d i n e , 3TC) is approved for treatment of HIV in combination with  AZT, but it should not be used with other cytosine analogs due to antagonism. Lamivudine terminates the synthesis  of the proviral DNA chain, and it inhibits the reverse transcriptase of both HIV and HBV. However, it does not affect  mitochondrial DNA synthesis or bone marrow precursor cells. It has good bioavailability on oral administration,  depends on the kidney for excretion, and is well tolerated.   Emtricitabine [em-tri-SIGH-ta-been], a fluoro-derivative of lamivudine, inhibits both HIV and HBV reverse  transcriptase. In a small clinical trial,   it was shown to be at least as effective as lamivudine in the treatment of HIV-infected individuals. Emtricitabine is  orally active, with a mean bioavailability of 93 percent. Plasma half-life is about 10 hours, whereas it has a long  intracellular half-life of 39 hours. Emtricitabine is eliminated essentially unchanged in the urine. It does not affect  cytochrome P450 isozymes, and has no significant interactions with other drugs. Headache, diarrhea, nausea, and  rash are its most common adverse effects. Emtricitabine causes hyperpigmentation of the soles and palms, and it has  been associated with lactic acidosis, fatty liver, and hepatomegaly. Withdrawal of emtricitabine in HBV-infected  patients may result in worsening of the hepatitis.   Zacitabine [zal-SIGH-ta- been] , was the first cytosine analog developed; however, due to severe toxicity, it was  removed from the market.   Abacavir [a-BA-ka-veer] is a guanosine analog. There may be some cross-resistance with strains resistant to AZT and  lamivudine. Abacavir is well absorbed orally, and metabolites appear in the urine (Figure 38.21). Most of the drug is  metabolized by non-cytochrome P450a€"dependent reactions. A carboxylic acid derivative and a glucuronylated  form have been identified. Common side effects include gastrointestinal disturbances, headache, and dizziness.  Approximately 5 percent of patients exhibit the a€oehypersensitivity reaction, a€^ : which is characterized by drug  fever, plus one or more of the following symptoms of rash, gastrointestinal symptoms, malaise, and respiratory  distress (Figure. 38.22). Sensitized individuals should NEVER be rechallenged because of rapidly appearing, severe  reactions that lead to death. There is a newly approved H LA genetic test available to screen patients for the  potential of this reaction. Figure 38. 23 show some adverse reactions commonly seen with nucleoside analogs.   Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are highly selective, noncompetitive inhibitors of HIV-1  reverse transcriptase. They bind to HIV reverse transcriptase at a site adjacent to the active site, inducing a  conformational change that results in enzyme inhibition. They do not require activation by cellular enzymes. Their  maj or advantage is their lack of effect on the host blood-forming elements and their lack of cross- resistance with  NRTIs. These drugs, however, do have common characteristics that include cross- resistance within the NNRTI class,  drug interactions, and a high incidence of hypersensitivity reactions, including rash.    Nevirapine [ne-VYE-ra-peen] is used in combination with other antiretroviral drugs for the treatment of HIV-1  infections in adults and children. Due to potential severe hepatotoxicity, nevirapine should not be initiated in  women with CD4+T-cell counts of greater than 250 cells/ mm 3 or in men with CD4+T cell counts greater than 400    cells/ mm 3 . Nevirapine is well absorbed orally, and its absorption is not affected by food and antacids. The lipophilic    nature of nevirapine accounts for its entrance into the fetus and mother's milk and for its wide tissue distribution,  including the CNS. Nevirapine is dependent upon metabolism for elimination; most of the drug is excreted in the  urine as the    glucuronides of hydroxylated metabolites (Figure 38.24). Nevirapine is an inducer of the CYP3A4 family of  cytochrome P450 drug- metabolizing enzymes. Nevirapine does increase the metabolism of protease inhibitors, but  most combinations do not require dosage adj ustment. Nevirapine increases the metabolism of a number of drugs,  such as oral contraceptives, ketoconazole, methadone, metronidazole, quinidine, theophylline, and warfarin. The  most frequently observed side effects are rash, fever, headache, and elevated serum transaminases and fatal  hepatotoxicity. Severe dermatologic effects have been encountered, including Stevens-J ohnson syndrome and  toxic epidermal necrolysis. A 14-day titration period at half the dose is mandatory to reduce the risk of serious  epidermal reactions.   Delavirdine [de-LA-vir-deen] has not undergone clinical trials as extensive as those of nevirapine and is not  recommended as a preferred or alternate agent in the U.S. Department of Health and Human Services (DHHS)   guidelines for initial therapy. Delavirdine is rapidly absorbed after oral administration and is unaffected by the  presence of food. Delavirdine is extensively metabolized, and very little is excreted as the parent compound. Fecal  and urinary excretion each account for approximately half the elimination. Delavirdine is an inhibitor of cytochrome  P450a€" mediated drug metabolism, including that of protease inhibitors. Fluoxetine and ketoconazole increase  plasma levels of delavirdine, whereas phenytoin, phenobarbital, and carbamazepine result in substantial decreases  in plasma levels of delavirdine. Rash is the most common side effect of delavirdine.    Efavirenz [e-FA-veer-enz] treatment results in increases in CD4+ cel I counts and a decrease in viral load comparable  to that achieved by protease inhibitors when used in combination with NRTIs; and therefore, it is the preferred  NNRTI on the DHHS guidelines. Following oral administration, efavirenz is well distributed, including to the CNS  (Figure 38.25). Bioavailability is enhanced when taken with a high-fat meal. Most of the drug is bound to plasma  albumin (99 percent) at therapeutic doses. A half-life of more than 40 hours accounts for its recommended  once-a-day dosing. Efavirenz is extensively metabolized to inactive products. Efavirenz is a potent inducer of  cytochrome P450 enzymes; therefore, it may reduce the concentrations of drugs that are substrates of the  cytochrome P450. Most adverse effects are tolerable and are associated with the CNS, including dizziness,  headache, vivid dreams, and loss of concentration (Figure 38.26). Nearly half of the patients experience these  complaints, which usually resolve within a few weeks. Rash is the other most common side effect, with an incidence  of approximately 25 percent. Severe, life-threatening reactions are rare. Efavirenz should be avoided in pregnant  women.   See p. 455 for a discussion of the second-generation NNRTI entravirine.   Inhibitors of HIV protease have significantly altered the course of this devastating viral disease. Within a year of  their introduction in 1995, the number of deaths in the United States due to AIDS declined, although the trend   These potent agents have several common features that characterize their pharmacology.   1. Mechanism of action: All the drugs in this group are reversible inhibitors of the HIV aspartyl proteasea€"the  viral enzyme responsible for cleavage of the viral polyprotein into a number of essential enzymes (reverse  transcriptase, protease, and integrase) and several structural proteins. The protease inhibitors exhibit at least a  thousand-fold greater affinity for HIV-1 and HIV-2 enzymes than they have for comparable human proteases,  such as renin and cathepsin D/E. This accounts for their selective toxicity. The inhibition prevents maturation of  the viral particles and results in the production of non-infectious virions. Treatment of anti retrovi ral ly naA've  patients (that is, patients who have never had HIV therapy) with a protease inhibitor and two NRTIs as  recommended by the DHHS guidelines, results in a decrease in the plasma viral load to undetectable levels in 60  to 95 percent of patients. Treatment failures under these conditions are most likely due to a lack of patient  adherence.   Figure 38.27 Estimated number of AIDS cases and deaths due to AIDS in the United States. Green  background indicates years in which combination antiretroviral therapy came into common usage.    2. Pharmacokinetics: Most protease inhibitors have poor oral bioavailability. High-fat meals substantially increase  the bioavailability of some, such as nelfinavir and saquinavir, whereas the bioavailability of indinavir is  decreased and others are essentially unaffected. All are substrates for the CYP3A4 isozyme of cytochrome P450,  and individual protease inhibitors are also metabolized by other P450 isozymes. Metabolism is extensive, and  very little of the protease inhibitors are excreted unchanged in the urine. Dosage adj ustments are unnecessary  in renal impairment. Distribution into some tissues may be affected by the fact that the protease inhibitors are  substrates for the P-glycoprotein multidrug efflux pump. The presence of this pump in endothelial cells of  capillaries in the brain may limit protease inhibitor access to the CNS. The HIV protease inhibitors are all  substantially bound to plasma proteins, specifically i±L-acid glycoprotein. This may be clinically important,  because the concentration of l^-acid glycoprotein increases in response to trauma and surgery.    3. Adverse effects: Protease inhibitors commonly cause parathesias, nausea, vomiting, and diarrhea (Figure  38.28). Disturbances in glucose and lipid metabolism also occur, including diabetes, hypertriglyceridemia, and  hypercholesterolemia. Chronic administration results in fat redistribution, including loss of fat from the  extremities and its accumulation in the abdomen and the base of the neck (a€oebuffalo humpa€§; Figure 38.29),   and breast enlargement. These physical changes may indicate to others that an individual is HIV positive.   4. Drug interactions: Drug interactions are a common problem for all protease inhibitors, because they are not  only substrates but also potent inhibitors of CYP isozymes. The inhibitory potency of the compounds lies  between that of ritonavir, the most potent, and that of saquinavir, the least potent inhibitor of CYP isozymes.   Drug interactions are therefore quite common. Drugs that rely on metabolism for their termination of action  may accumulate to toxic levels. Examples of potentially dangerous interactions from drugs that are  contraindicated with protease inhibitors include rhabdomyolysis from simvastatin or iovastatin, excessive  sedation from midazolam or   triazolam, and respiratory depression from fentanyl (Figure 38. 30). Other drug interactions that require dosage  modification and cautious use include warfarin, sildenafil and phenytoin (Figure 38.31). In addition, inducers  of CYP isozymes may result in the lowering of protease plasma concentrations to suboptimal levels, contributing  to treatment failures. Thus, drugs such as rifampin and St. J ohn's wort are also contraindicated with protease  inhibitors. Meticulous attention must be paid to all these detrimental interactions.   5. Resistance: Resistance occurs as an accumulation of stepwise mutations of the protease gene. Initial mutations  result in decreased ability of the virus to replicate, but as the mutations accumulate, virions with high levels of  resistance to the protease emerge. Suboptimal concentrations result in the more rapid appearance of resistant  strains.   Figure 38.29 Accumulation of fat at the base of the neck in a patient receiving a protease inhibitor.   Ritonavir [ri-TOE-na-veer] is no longer used as a single protease inhibitor but, instead, is used as a  a€oepharmacokinetic enhancer or boostera€§ of other protease inhibitors. Ritonavir is a potent inhibitor of CYP3A,  and concomitant ritonavir administration (at low doses) increases the bioavailability of the second protease inhibitor  and often allows for longer dosing intervals. The resulting higher Cmin levels of the a€oe boosted protease  inhibitorsa€i also help to prevent the development of resistance. Therefore, the a€oeboosted protease  inhibitorsa€i are the preferred agents in the DHHS treatment guidelines. Metabolism and biliary excretion are the  primary methods of elimination. Ritonavir has a half-life of 3 to 5 hours. Because it is primarily an inhibitor of  cytochrome P450 isozymes, numerous drug interactions have been identified. Ritonavir is also a self-inducer of its  own metabolism as well as that of some substrates. Nausea, vomiting, diarrhea, headache, and circumoral  parethesias are among the more common adverse effects.    Figure 38.30 Drugs that should not be coadministered with any protease inhibitor.   To maximize bioavailability, saquinavir [sa-KWIH-na-veer] is given along with a low dose of ritonavir. High-fat meals  also enhance absorption. Elimination of saquinavir is primarily by metabolism, followed by biliary excretion. Its  half-life is 7 to 12 hours, requiring multiple daily doses. Drugs that enhance the metabolism of saquinavir, such as  rifampin, rifabutin, nevirapine, efavirenz, and other enzyme inducers, should be avoided if possible. The most  common adverse effects of saquinavir treatment include headache, fatigue, diarrhea, nausea, and other  gastrointestinal disturbances. Increased levels of hepatic aminotransferases have been noted, particularly in  patients with concurrent viral hepatitis B or C infections.   Indinavir [in-DIH-na-veer] is well absorbed orally and, of all the protease inhibitors, is the least protein-bound, at 60  percent. Acidic gastric conditions are necessary for absorption. Absorption is decreased when administered with  meals, although a light, low-fat snack is permissible. Ritonavir overcomes this problem and also permits twice-a-day  dosing. Metabolism and hepatic clearance account for elimination of indinavir. The dosage should therefore be  reduced in the presence of hepatic insufficiency. Indinavir has the shortest half-life of the protease inhibitors, at  1.8 hours. It is well tolerated, with the usual gastrointestinal symptoms and headache predominating. Indinavir   causes nephrolithiasis and hyperbilirubinemia. Adequate hydration is important to reduce the incidence of kidney  stone formation, and patients should drink at least 1. 5 L of water per day. Fat redistribution is particularly  troublesome with this drug.   Nelfinavir [nel-FIN-a-veer] is a non-peptide protease inhibitor. It is well absorbed and does not require strict food or  fluid conditions; however, it is usually given with food. Nelfinavir undergoes metabolism by several CYP isozymes.   The maj or metabolite of nelfinavir produced by isozyme CYP2C19 has an antiviral activity equal to that of the  parent compound, but it achieves plasma concentrations only 40 percent of those of the parent compound.   Nefinavir is the only protease inhibitor that cannot be boosted by ritonavir, because it is not extensively  metabolized by CYP3A. The half-life of nelfinavir is 5 hours. Diarrhea is the most common side effect and can be  controlled by loperamide. Like other members of the class, nelfinavir can inhibit the metabolism of other drugs,  resulting in required alterations of drug dosage or the prohibition of combined use.    Fosamprenavir [fos-am-PREN-a-veer] is a prodrug that is metabolized to amprenavir following oral absorption. Its  long plasma half-life permits twice-a-day dosing, and coadministration of ritonavir increases the plasma levels of  amprenavir and lowers the total daily dose. Fosamprenavir boosted with ritonavir is one of the preferred protease  inhibitors according to the DHHS treatment guidelines. Nausea, vomiting, diarrhea, fatigue, paresthesias, and  headache are common adverse effects. Like other members of the class, fosamprenavir can inhibit the metabolism  of other drugs, resulting in required alterations of drug dosage or the prohibition of combined use.   Lopinavir [loe-PIN-a-veer] is a peptidomimetic protease inhibitor. It is one of the preferred protease inhibitors  according to the DHHS treatment guidelines. Lopinavir has very poor intrinsic bioavailability, which is substantially  enhanced by including a low dose of ritonavir in the formulation. [Note: Only the coformulation known as lopinavir  is available in the United States. ] Gastrointestinal adverse effects and hypertriglyceridemia are the most common  side effects for lopinavir, in addition to the other protease inhibitor class side effects. Like other members of the  class, lopinavir can inhibit the metabolism of other drugs, resulting in required alterations of drug dosage or the  prohibition of combined use. Enzyme inducers as well as St. J ohn's wort should be avoided, because they lower the  plasma concentrations of lopinavir. The oral solution contains alcohol; thus, disulfiram or metronidazole  administration can cause unpleasant reactions.   Atazanavir [ah-ta-ZA-na-veer] inhibits HIV protease and is structurally unrelated to other HIV protease inhibitors.  Atazanavir in combination with ritonavir are the only once-daily preferred protease inhibitors. Atazanavir is well  absorbed orally. Food increases absorption and bioavailability. The drug is highly protein bound (86 percent) and  undergoes extensive CYP3A4-catalyzed biotransformation. It is excreted primarily in the bile. Its half-life is about 7  hours, but it only needs to be administered once a day. Atazanavir is a competitive inhibitor of   glucuronyl transferase, and benign hyperbilirubinemia and jaundice are known side effects. In the heart,  atazanavir prolongs the PR interval and slows the heart rate. Atazanavir exhibits a decreased risk of  hyperlipidemia, but it is not known if atazanavir is less likely to cause insulin resistance and lipodystrophy, as seen  with other protease inhibitors. Like the other protease inhibitors, atazanavir is a potent inhibitor of CYP3A4 and has  the potential for many drug interactions. Atazanavir is contraindicated with use of prescription doeses of  proton-pump inhibitors, and administration must be spaced 12 hours apart from H 2 -blockers and antacids.   Tipranavir [ti-PRA-na-veer] inhibits HIV protease in viruses that are resistant to the other protease inhibitors.   Tipranavir is well absorbed when taken with food. The half-life is 6 hours, and it must be administered twice daily  in combination with ritonavir. Tipranvir has a unique action as a cytochrome P 450 inducer in addition to a  substrate that is different from the other protease inhibitors. Side effects are similar to those of the other protease  inhibitors with the exception of two a€oeblack boxa€^ warnings for severe and fatal hepatitis and rare cases of fatal  and nonfatal intracranial hemorrhages. Most patients had underlying comorbidities. Tipranavir is useful in  a€oesalvagea€§ regimens in patients with multidrug resistance.   Darunavir [da-RU-na-veer] is the most recently approved protease inhibitor and is also active against HIV protease  that is resistant to other protease inhibitors. Darunavir is well absorbed when given with food, and the terminal  elimination half-life is 15 hours when combined with ritonavir. Darunavir is extensively metabolized by the CYP3A  enzymes and is an inhibitor as well. The side effects are similar to those of the other protease inhibitors with the  addition of possible rash. Early reports demonstrate a decreased risk of hyperlipidemia, but it is not known if  darunavir is less likely to cause insulin resistance and lipodystrophy, as seen with other protease inhibitors.   Darunavir is useful in a€oesalvagea€^ regimens in patients with multidrug resistance, and studies are underway in  naA've patients.   Enfuvirtide [en-FU-veer-tide] is the first of new class of antiretroviral drugs known as entry inhibitors. Enfuvirtide  is a fusion inhibitor. For HIV to gain entry into the host cell, it must fuse its membrane with that of the host cell.   This is accomplished by changes in the conformation of the viral transmembrane glycoprotein gp41, which occurs  when HIV binds to the host cell surface. Enfuvirtide is a 36-amino-acid peptide that binds to gp41, preventing the  conformational change. Enfuvirtide, in combination with other antiretrovirals, is approved for therapy of  treatment-experienced patients with evidence of viral replication despite ongoing antiretroviral drug therapy. As a  peptide, it must be given subcutaneously. Most of the adverse effects are related to the injection, including   pain, erythema, induration, and nodules, which occur in almost all patients. Flowever, only 3 percent discontinue  treatment because of them. Enfuvirtide must be reconstituted prior to administration. It is an expensive  medication.   Maraviroc [ma-RA-vi-roc] is the second entry inhibitor. Because it is well absorbed orally, it is formulated as an oral  tablet. Maraviroc blocks the CCR5 coreceptor that works together with gp41 to facilitate HIV entry through the  membrane into the cell. H IV may express either the CCR5 coreceptor or the CXCR4 coreceptor, or both. A test to  determine tropism is required to distinguish the CCR5 from the CXCR4 coreceptor as well as mixed and dual tropic  virus. Only the CCR5-expressing virus can be treated with maraviroc. Maraviroc is metabolized by cytochromeP450  liver enzymes, and the dose must be reduced when given with the protease inhibitors. Maraviroc is generally well  tolerated.   Benign hyperbilirubinemia,  nephrolithiasis; take 1 hour  before or 2 hours after food;  may take with skim milk or a  low-fat meal; drink >1.5 L of  liquid daily   Diarrhea, nausea, taste  perversion, vomiting, anemia,  increased hepatic enzymes,  increased triglycerides. Requires  refrigeration; take with meals;  chocolate milk improves the  taste   Diarrhea, nausea, abdominal  discomfort, elevated trans-  aminase levels. Take with  high-fat meal or within 2  hours of a full meal    Figure 38.32 Summary of protease inhibitors. [Note: Lopinavir isco formulated with ritonavir ; ritonavir  inhibits the metabolism of lopinavir, thereby increasing its level in the plasma.]   Raltegravir [ral TEG ra veer] is the first of new class of antiretroviral drugs known as integrase inhibitors.  Ragtegravir specifically inhibits the final step in integration of stand transfer of the viral DNA into our own host cell  DNA. Raltegravir has a half-life of approximately 9 hours and is therefore dosed twice daily. The route of   metabolism is UGTIAl-mediated glucuronidation, therefore drug interactions with CYP450 inducers, inhibitors or  substrates do not occur. Raltegravir is well-tolerated with nausea, headache and diarrhea as the most common side  effects. Raltegravir, in combination with other antiretrovirals, is approved for therapy of treatment-experienced  patients with evidence of viral replication despite ongoing antiretroviral drug therapy.   Note added in proof: Etravirine [et-ra-VYE-rine] is the first second generation NNRTI. It is active against many of  the strains of HIV that are resistant to the first generation NNRTI. HIV strains with the commonn K103N resistance  mutation to the first generation of NNRTI 's are fully susceptible to entravirine. Following oral administration,  etravirine is well distributed and bioavailability is enhance when taken with a high-fat meal. Although it has a  half-life of approximately 40 hours, it is indicated for twice daily dosing. Etravirine is extensively metabolized to  inactive products. Etravirine is a potent inducer of cytochrome P450; therefore, the doses of cytochrome P450  substrates may need to be increased when given with etravirine. Rash is the most common side effect. Etravirine is  otherwsie well tolerated and does not have the CNS side effects that are seen with efavirenz and etravirine is  pregnany category B. Etravirine is indicaated for HIV treatment-experienced, multi-drug resistant adult patients  who have evidence of ongoing viral replication.   38.1 A 30-year-old male patient with an HIV infection is being treated with a HAART regimen. Four weeks after  initiating therapy, he comes to the emergency department complaining of fever, rash, and grastointestinal  upset. Which one of the following drugs is most likely the cause of his symptoms?    38.2 Chills, fever, and muscle aches are common reactions to which one of the following antiviral drugs?   38.3 An HIV-positive woman is diagnosed with CMV retinitis. She has been on a HAART regimen containing  zidovudine. Which of the following anti-CMV drugs is likely to cause additive myelosuppression with  zidovudine?   38. 4 A 25-year-old man is diagnosed with HIV, and therapy is initiated. After the first week of therapy, the  patient complains of headaches, irritability, and nightmares. Which one of the following antiretroviral drugs is  most likely to be causing these symptoms?   >Table of Contents > Unit VII - Chemotherapeutic Drugs >Chapter 39 - Anticancer Drugs   It is estimated that 25 percent of the population of the United States will face a diagnosis of cancer during their  lifetime, with 1.3 million new cancer patients diagnosed each year. Less than a quarter of these patients will be  cured solely by surgery and/or local radiation. Most of the remainder will receive systemic chemotherapy at some  time during their illness. In a small fraction (approximately 10 percent) of patients with cancer representing  selected neoplasms, the chemotherapy will result in a cure or a prolonged remission. However, in most cases, the  drug therapy will produce only a regression of the disease, and complications and/or relapse may eventually lead to  death. Thus, the overall 5-year survival rate for cancer patients is about 65 percent, ranking cancer second only to  cardiovascular disease as a cause of mortality. (See Figure 39. 1 for a list of the anticancer agents discussed in this  chapter.)   Cancer chemotherapy strives to cause a lethal cytotoxic event or apoptosis in the cancer cell that can arrest a  tumor's progression. The attack is generally directed toward DNA or against metabolic sites essential to cell  re p I i c at i o n a€" f o r example, the availability of purines and pyrimidines that are the building blocks for DNA or RNA  synthesis (Figure 39.2). Ideally, these anticancer drugs should interfere only with cellular processes that are unique  to malignant cells. Unfortunately, most currently available anticancer drugs do not specifically recognize neoplastic  cells but, rather, affect all kinds of proliferating cellsa€"both normal and abnormal. Therefore, almost all antitumor  agents have a steep dose-response curve for both toxic and therapeutic effects.   1. Goal of treatment: The ultimate goal of chemotherapy is a cure (that is, long-term, disease-free survival). A  true cure requires the eradication of every neoplastic cell. If a cure is not attainable, then the goal becomes  control of the disease (stop the cancer from enlarging and spreading) to extend survival and maintain the best  quality of life. This allows the individual to maintain a a€oenormala€^ : existence, with the cancer thus being  treated as a chronic disease. In either case, the neoplastic cell burden is initially reduced (debulked), either by  surgery and/or by radiation, followed by chemotherapy, immunotherapy, or a combination of these treatment   modalities (Figure 39.3). In advanced stages of cancer, the likelihood of controlling the cancer is far from reality  and the goal is palliation (that is, alleviation of symptoms and avoidance of life-threatening toxicity). This means  that chemotherapeutic drugs may be used to relieve symptoms caused by the cancer and improve the quality of  life, even though the drugs may not lengthen life.    2. Indications for treatment: Chemotherapy is indicated when neoplasms are disseminated and are not amenable  to surgery. Chemotherapy is also used as a supplemental treatment, to attack micrometastases following surgery  and radiation treatment in which case it is called adj uvant chemotherapy. Chemotherapy given prior to the  surgical procedure in an attempt to shrink the cancer is referred as neoadj uvant chemotherapy, and  chemotherapy given in lower doses to assist in prolonging a remission is known as maintenance chemotherapy.   3. Tumor susceptibility and the growth cycle: The fraction of tumor cells that are in the replicative cycle  (a€oegrowth fractiona€§) influences their susceptibility to most cancer chemotherapeutic agents. Rapidly  dividing cells are generally more sensitive to anticancer drugs, whereas slowly proliferating cells are less  sensitive to chemotherapy. In general, nonproliferating cells (those in the Go phase; Figure 39.4) usually survive  the toxic effects of many of these agents.   a. Cell-cycle specificity of drugs: Both normal cells and tumor cells go through growth cycles (see Figure 39.4).  Flowever, the number of cells that are in various stages of the cycle may differ in normal and neoplastic  tissues. Chemotherapeutic agents that are effective only against replicating cellsa€"that is, those cells that  are cyclinga€"are said to be cell-cycle specific (see Figure 39.4), whereas other agents are said to be  cell-cycle nonspecific. The nonspecific drugs, although having generally more toxicity in cycling cells, are  also useful against tumors that have a low percentage of replicating cells.   b. Tumor growth rate: The growth rate of most solid tumors in vivo is initially rapid, but growth rate usually  decreases as the tumor size increases (see Figure 39. 3). This is due to the unavailability of nutrients and  oxygen caused by inadequate vascularization and lack of blood circulation. Reducing the tumor burden  through surgery or radiation often promotes the recruitment of the remaining cells into active proliferation  and increases their susceptibility to chemotherapeutic agents.   Inhibition of dihydrofolate  reductase leads to an  inhibition of purine ring  and dTMP biosynthesis.   Incorporated into DNA  and RNA results in  altered functioning of  nucleic acids.    Figure 39.2 Examples of chemotherapeutic agents affecting the availability of RNA and DNA  precursors. dTMP =deoxythymidine monophosphate.   Drugs are usually administered on the basis of body surface area, with an effort being made to tailor the  medications to each patient.   1. Log kill: Destruction of cancer cells by chemotherapeutic agents follows first-order kinetics; that is, a given  dose of drug destroys a constant fraction of cells. The term log kill is used to describe this phenomenon. For  example, a diagnosis of leukemia is generally made when there are about 10 9 (total) leukemic cells.   Consequently, if treatment leads to a 99. 999- percent kill, then 0.001 percent of 10 9 cells (or 10 4 cells) would  remain. This is defined as a five-log kill (reduction of 10 5 cells). At this point, the patient will become  asymptomatic;   that is, the patient is in remission (see Figure 39.3). For most bacterial infections, a five-log (100,000-fold)  reduction in the number of microorganisms results in a cure, because the immune system can destroy the  remaining bacterial cells. Flowever, tumor cells are not as readily eliminated, and additional treatment is  required to totally eradicate the leukemic cell population.   0 A total of 10 9 cells Is the smallest tumor burden that is  physically detectable.    0 These 1 billion cells represent a tumor weighing  about 1 g or about the size of a small grape.    • Survival is extended, but the patient  eventually dies of the disease.   0 Treatment of occult micromotastases is continued  after clinical signs of cancer have disappeared.   0 Each drug Is chosen to have a different cellular  site of action or different cell-cycle specificity.   0 Each drug Is chosen to have a different  organ toxicity.   Figure 39.3 Effects of various treatments on the cancer cell burden in a hypothetical patient.    2. Pharmacologic sanctuaries: Leukemic or other tumor cells find sanctuary in tissues such as the central nervous  system (CNS), where transport constraints prevent certain chemotherapeutic agents from entering. Therefore, a  patient may require irradiation of the craniospinal axis or intrathecal administration of drugs to eliminate the  leukemic cells at that site. Similarly, drugs may be unable to penetrate certain areas of solid tumors.   3. Treatment protocols: Combination-drug chemotherapy is more successful than single-drug treatment in most of  the cancers for which chemotherapy is effective.   a. Combinations of drugs: Cytotoxic agents with qualitatively different toxicities, and with different molecular  sites and mechanisms of action, are usually combined at full doses.   This results in higher response rates, due to additive and/ or potentiated cytotoxic effects, and  nonoverlapping host toxicities. In contrast, agents with similar dose-limiting toxicities, such as  myelosuppression, nephrotoxicity, or cardiotoxicity can be combined safely only by reducing the doses of  each.   b. Advantages of drug combinations: The advantages of such drug combinations are that they 1) provide  maximal cell killing within the range of tolerated toxicity, 2) are effective against a broader range of cell  lines in the heterogeneous tumor population, and 3) may delay or prevent the development of resistant cell  lines.   c. Treatment protocols: Many cancer treatment protocols have been developed, and each one is applicable to  a particular neoplastic state. They are usually identified by an acronym; for example, a common regimen  called POMPa€"used for the treatment of acute lymphocytic leukemiaa€"consists of prednisone, oncovin  (vincristine), methotrexate, and purinethol (mercaptopurine). Therapy is scheduled intermittently  (approximately 21 days apart) to allow recovery of the patient's immune system, which is also affected by  the chemotherapeutic agent, thus reducing the risk of serious infection.   Cancer drugs are toxins that present a lethal threat to the cells. It is therefore not surprising that cells have evolved   elaborate defense mechanisms to protect themselves from chemical toxins, including chemotherapeutic agents.   1. Resistance: Some neoplastic cells (for example, melanoma) are inherently resistant to most anticancer drugs.  Other tumor types may acquire resistance to the cytotoxic effects of a medication by mutating, particularly  after prolonged administration of suboptimal drug doses. The development of drug resistance is minimized by  short-term, intensive, intermittent therapy with combinations of drugs. Drug combinations are also effective  against a broader range of resistant cells in the tumor population. A variety of mechanisms are responsible for  drug resistance, each of which is considered separately in the discussion of a particular drug.   2. Multidrug resistance: Stepwise selection of an amplified gene that codes for a transmembrane protein  (P-glycoprotein for aCoepermeabilityaC^ glycoprotein; Figure 39. 5) is responsible for multidrug resistance. This  resistance is due to adenosine triphosphatea€"dependent pumping of drugs out of the cell in the presence of  P-glycoprotein. Cross- resistance following the use of structurally unrelated agents also occurs. For example,  cells that are resistant to the cytotoxic effects of the vinca alkaloids are also resistant to dactinomycin, to the  anthracycline antibiotics, as well as to colchicine, and vice versa. These drugs are all naturally occurring  substances, each of which has a hydrophobic aromatic ring and a positive charge at neutral pH. [Note:  P-glycoprotein is normally expressed at low levels in most cell types, but higher levels are found in the kidney,  liver, pancreas, small intestine, colon, and adrenal gland. It has been suggested that the presence of  P-glycoprotein may account for the intrinsic resistance to chemotherapy observed with adenocarcinomas.]    verapamil ) can inhibit the pump and, thus, interfere with the efflux of the anticancer agent. However, these  drugs are undesirable because of adverse pharmacologic actions of their own. Pharmacologically inert pump  blockers are being sought.   Effective for both low-  growth-fraction  malignancies, such as  solid tumors, as well  as high-growth-fraction  malignancies   Figure 39.4 Effects of chemotherapeutic agents on the growth cycle of mammalian cells.    3. Toxicity: Therapy aimed at killing rapidly dividing cancer cells also affects normal cells undergoing rapid  proliferation (for example, cells of the buccal mucosa, bone marrow, gastrointestinal (Gl) mucosa, and hair),  contributing to the toxic manifestations of chemotherapy.   a. Common adverse effects: Most chemotherapeutic agents have a narrow therapeutic index. Severe  vomiting, stomatitis, bone marrow suppression, and alopecia occur to a lesser or greater extent during  therapy with all antineoplastic agents. Vomiting is often controlled by administration of antiemetic drugs.  Some toxicities, such as myelosuppression that predisposes to infection, are common to many  chemotherapeutic agents (Figure 39. 6), whereas other adverse reactions are confined to specific agents,  such as, cardiotoxicity with doxorubicin and pulmonary fibrosis with bleomycin. The duration of the side  effects varies widely. For example, alopecia is transient, but the cardiac, pulmonary, and bladder toxicities  are irreversible.   b. Minimizing adverse effects: Some toxic reactions may be ameliorated by interventions, such as the use of  cytoprotectant drugs, perfusing the tumor locally (for example, a sarcoma of the arm), removing some of  the patient's marrow prior to intensive treatment and then reimplanting it, or promoting intensive diuresis to  prevent bladder toxicities. The megaloblastic anemia that occurs with methotrexate can be effectively  counteracted by administering folinic acid (leucovorin, 5-formyltetrahydrofolic acid; see below). With the  availability of human granulocyte colony-stimulating factor ( filgrastim ), the neutropenia associated with  treatment of cancer by many drugs can be partially reversed.   4. Treatment-induced tumors: Because most antineoplastic agents are mutagens, neoplasms (for example, acute  nonlymphocytic leukemia) may arise 10 or more years after the original cancer was cured. [Note: Treatment-  induced neoplasms are especially a problem after therapy with alkylating agents.]   Antimetabolites are structurally related to normal compounds that exist within the cell. They generally interfere  with the availability of normal purine or pyrimidine nucleotide precursors, either by inhibiting their synthesis or by  competing with them in DNA or RNA synthesis. Their maximal cytotoxic effects are in S-phase (and, therefore,  cell-cycle) specific.   The vitamin folic acid plays a central role in a variety of metabolic reactions involving the transfer of one-carbon  units 1 and is essential for   cell replication. Methotrexate [meth-oh-TREK-sate] (MTX) is structurally related to folic acid and acts as an  antagonist of that vitamin by inhibiting dihydrofolate reductase 2 (DHFR)a€"the enzyme that converts folic acid to its  active, coenzyme form, tetrahydrofolic acid (FH 4 ).    1. Mechanism of action: Folic acid is obtained from dietary sources or from that produced by intestinal flora. It  undergoes reduction to the tetrahydrofolate form (FH 4 ) via a reaction catalyzed by intracellular nicotinamide-  adenine dinucleotide phosphatea€"dependent DH FR (Figure 39. 7). MTX enters the cell by active-transport  processes that normally mediate the entry of N * 1 2 * * 5 -methyl-FFl 4 . At high concentrations, the drug can also diffuse  into the cell. MTX has an unusually strong affinity for DFHFR and effectively inhibits the enzyme. Like  tetrahydrofolate itself, MTX becomes polyglutamated within the cella€"a process that favors intracellular  retention of the compound due to increased negative charge. MTX polyglutamates also potently inhibit DFHFR.  This inhibition deprives the cell of folate coenzymes and leads to decreased production of compounds that  depend on these coenzymes for their biosynthesis. Although these molecules include the nucleotides adenine,  guanine and thymidine and the amino acids methionine and serine, depletion of thymidine is the most prominent  effect. This leads to depressed DNA, RNA, and protein synthesis and, ultimately, to cell death (see Figure 39.7).  The inhibition of DFH FR can only be reversed by a 1000-fold excess of the natural substrate, dihydrofolate (FFI 2 ;  see Figure 39.7), or by administration of leucovorin, which bypasses the blocked enzyme and replenishes the  folate pool. [Note: Leucovorin, or folinic acid, is the N 5 -formyl groupa€"carrying form of FH 4 . ] MTX is specific  for the S phase of the cell cycle.   2. Resistance: Nonproliferating cells are resistant to MTX, probably because of a relative lack of DH FR,   thymidylate synthase, and/or the glutamylating enzyme. Decreased levels of the MTX polyglutamate have been   reported in resistant cells and may be due to its decreased formation or increased breakdown. Resistance in  neoplastic cells can be due to amplification (production of additional copies) of the gene that codes for DH FR,  resulting in increased levels of this enzyme. The enzyme affinity for MTX may also be diminished. Resistance can   also occur from a reduced influx of MTX, apparently caused by a change in the carrier-mediated transport  responsible for pumping the drug into the cell.   Administer N s -formyl-FH 4  [leucovorin or folinic acid)  which is converted to  N s , N 10 -methylene-FH 4  and, therefore, bypasses  the inhibited reductase.    Figure 39.7 Mechanism of action of methotrexate and the effect of administration of leucovorin. FH2 =  dihydrofolate; FH4 =tetrahydrofolate; dTMP =deoxythymidine monophosphate; dUMP =deoxyuridine  mono phosphate.    3 . Therapeutic uses: MTX, usually in combination with other drugs, is effective against acute lymphocytic  leukemia, choriocarcinoma, Burkitt's lymphoma in children, breast cancer, and head and neck carcinomas. In  addition, low-dose MTX is effective as a single agent against certain inflammatory diseases, such as severe    psoriasis and rheumatoid arthritis as well as Crohn's disease. All patients receiving MTX require close monitoring  for possible toxic effects.    a. Administration and distribution: MTX is variably absorbed at low doses from the Gl tract, but it can also be  administered by intramuscular, intravenous (IV), and intrathecal routes (Figure 39.8). [Note: Because MTX  does not penetrate the blood-brain barrier, it is administered intrathecally to destroy neoplastic cells that  are thriving in the central sanctuary sites.] High concentrations of the drug are found in the intestinal  epithelium, liver, and kidney as well as in ascites and pleural effusions. MTX is also distributed to the skin.   b. Fate: As previously mentioned, MTX is metabolized to polyglutamate derivatives. This property is important,  because the polyglutamates, which also inhibit DHFR, remain within the cell even in the absence of  extracellular drug. This is in contrast to MTX per se, which rapidly leaves the cell as the extracellular drug  levels fall. High doses of MTX undergo hydroxylation at the 7-position and becomes 7-hyroxymethotrexate.  This derivative is much less active as an antimetabolite. It is less water soluble than MTX and may lead to  crystalluria. Therefore, it is important to keep the urine alkaline and the patient well hydrated to avoid  renal toxicity. Excretion of the parent drug and the 7-OH metabolite occurs primarily via the urine, although  some of the drug and its metabolite appear in the feces due to enterohepatic excretion.   Unchanged  drug appears  in urine; at high  doses, 7-OH  metabolite is  also excreted   a. Commonly observed toxicities: In addition to nausea, vomiting, and diarrhea, the most frequent toxicities  occur in tissues that are constantly renewing. Thus, MTX causes stomatitis, myelosuppression, erythema,  rash, urticaria, and alopecia. Some of these adverse effects can be prevented or reversed by administering  leucovorin (see Figure 39. 7), which is taken up more readily by normal cells than by tumor cells. Doses of  leucovorin must be kept minimal to avoid possible interference with the antitumor action of MTX.    b. Renal damage: Although uncommon during conventional therapy, renal damage is a complication of  high-dose MTX and its 7-OH metabolite, which can precipitate in the tubules. Alkalinization of the urine and  hydration help to prevent this problem.   c. Hepatic function: Hepatic function should be monitored. Long-term use of MTX may lead to cirrhosis.   d. Pulmonary toxicity: This is a rare complication. Children who are being maintained on MTX may develop  cough, dyspnea, fever, and cyanosis. Infiltrates are seen on radiographs. This toxicity is reversible on  suspension of the drug.   e. Neurologic toxicities: These are associated with intrathecal administration of MTX and include subacute  meningeal irritation, stiff neck, headache, and fever. Rarely, seizures, encephalopathy, or paraplegia  occur. Long-lasting effects, such as learning   disabilities, have been seen in children who received the drug by this route.   f. Contraindications: Because MTX is teratogenic in experimental animals and is an abortifacient, it should be  avoided in pregnancy. [Note: MTX is used with misoprostol to induce abortion.]   The drug 6-mercaptopurine [mer-kap-toe-PYOOR-een] (6-MP) is the thiol analog of hypoxanthine. 6-MP and  6-thioguanine were the first purine analogs to prove beneficial for treating neoplastic disease. [Note:   Azathioprine, an immunosuppressant, exerts its cytotoxic effects after conversion to 6-MP. ] 6-MP is used  principally in the maintenance of remission in acute lymphoblastic leukemia. 6-MP and its analog, azathioprine, are  also beneficial in the treatment of Crohn's disease.   a. Nucleotide formation: To exert its antileukemic effect, 6-MP must penetrate target cells and be converted  to the nucleotide analog, 6-MP-ribose phosphate (better known as 6-thioinosinic acid, or TIMP; Figure 39.9).  The addition of the ribose phosphate is catalyzed by the salvage pathway enzyme, hypoxanthine-guanine  phosphoribosyl transferase (HGPRT). 3   b. Inhibition of purine synthesis: A number of metabolic processes involving purine biosynthesis and  interconversions are affected by the nucleotide analog, TIMP. Like adenosine monophosphate (AMP),  guanosine monophosphate (GMP), and inosine monophosphate (IMP), TIMP can inhibit the first step of de  novo purine-ring biosynthesis (catalyzed by glutamine phosphoribosyl pyrophosphate amidotransferase).  TIMP also blocks the formation of AMP and xanthinuric acid from inosinic acid. 4   c. Incorporation into nucleic acids: TIMP is converted to thioguanine monophosphate (TGMP), which after  phosphorylation to di- and triphosphates can be incorporated into RNA. The deoxyribonucleotide analogs  that are also formed are incorporated into DNA. This results in nonfunctional RNA and DNA.   2. Resistance: Resistance is associated with 1) an inability to biotransform 6-MP to the corresponding nucleotide  because of decreased levels of HGPRT (for example, in Lesch-Nyhan syndrome, in which patients lack this  enzyme), 2) increased dephosphorylation, or 3) increased metabolism of the drug to thiouric acid or other  metabolites.   3. Pharmacokinetics: Absorption by the oral route is erratic and incomplete. Once it enters the blood circulation,   the drug is widely distributed throughout the body, except for the cerebrospinal fluid (CSF; Figure 39. 10). The  bioavailability of 6-MP can be reduced by the first-pass    metabolism in the liver; while undergoing metabolism in the liver, 6-MP is converted to to the  6-methylmercaptopurine derivative or to thiouric acid (an inactive metabolite). [Note: The latter reaction is    catalyzed by xanthine oxidase. 4 5 ] Because the xanthine oxidase inhibitor, allopurinol, is frequently used to    reduce hyperuricemia in cancer patients receiving chemotherapy, it is important to decrease the dose of 6-MP  by 75 percent in these individuals to avoid accumulation of the drug and exacerbation of toxicities (Figure  39. 11). The parent drug and its metabolites are excreted by the kidney.    4. Adverse effects; Bone marrow depression is the principal toxicity. Side effects also include anorexia, nausea,   vomiting, and diarrhea. Occurrance of hepatotoxicity in the form of jaundice has been reported in about  one-third of adult patients.   6-Thioguanine [thye-oh-GWAH-neen] (6-TG), a purine analog, is primarily used in the treatment of acute  nonlymphocytic leukemia in combination with daunorubicin and cytarabine. Like 6-MP, 6-TG is converted  intracel lullarly to TGMP (also called 6-th i oguanyl ic acid) by the enzyme HGPRT. TGMP is further converted to the di-  and triphosphates, thioguanosine diphosphate and thioguanosine triphosphate, which then inhibit the biosynthesis  of purines and also the phosphorylation of GMP to guanosine diphosphate. The nucleotide form of 6-TG is  incorporated into DNA that leads to cell-cycle arrest.   1. Pharmacokinetics: Similar to 6-MP, the absorption of oral 6-TG is also incomplete and erratic. The peak  concentration in the plasma is reached in 2 to 4 hours after ingestion. When 6-TG is administered, it is converted  the S-methylation product, 2-amino-6-methylthiopurine bythiopurine methyltransferase (TPMT), which appears  in the urine. Patients with low or intermediate TPMT activity accumulate higher concentrations of thioguanine  cytotoxic metabolites compared to patients with normal TPMT activity. This results in unexpectedly high  myelosuppression and has also been associated with the occurrence of secondary malignancies. Approximately  three percent of whites and blacks express either a homozygous deletion or mutation of the TPMT gene. An  estimated 10 percent of patients may be at increased risk for toxicity because of a heterozygous deletion or  mutation of TPMT; therefore, TPMT genotyping is recommended before therapy. To a lesser extent,  6-thioxanthine and 6-thiouric acid are also formed by the action of guanase. Because the deamination product  6-thioanthine is an inactive metabolite, 6-TG may be administered along with allopurinol without any dose  reduction.   2. Adverse effects: Bone marrow depression is the dose-related adverse effect. 6-TG is not recommended for  maintenance therapy or continuous long-term treatments due to the risk of liver toxicity.   Fludarabine [floo-DARE-a-been] is the 5'-phosphate of 2-fluoroadenine arabinosidea€"a purine nucleotide analog. It  is useful in the treatment of chronic lymphocytic leukemia and may replace chlorambucil , the present drug of  choice. Fludarabine is also effective against hairy-cell leukemia and indolent non-Hodgkin's lymphoma. Fludarabine  is a prodrug, the phosphate being removed in the plasma to form 2-F-araA, which is taken up into cells and again  phosphorylated (initially by deoxycytidine kinase). Although the exact cytotoxic mechanism is uncertain, the  triphosphate is incorporated into both DNA and RNA. This decreases their synthesis in the S phase and affects their  function. Resistance is associated with reduced uptake into cells, lack of deoxycytidine kinase, and decreased  affinity for DNA polymerase plus other mechanisms. Fludarabine is administered IV rather than orally, because  intestinal bacteria split off the sugar to yield the very toxic metabolite, fluoroadenine. Urinary excretion accounts  for partial elimination. In addition to nausea, vomiting, and diarrhea, myelosuppression is the dose-limiting toxicity.  Fever, edema, and severe neurologic toxicity also occur. At high doses, progressive encephalopathy, blindness, and  death have been reported.   Another purine analog, 2-chlorodeoxyadenosine, or cladribine [KLA-dri-been], undergoes reactions similar to those  of fludarabine; that is, it must be converted to a nucleotide to be cytotoxic. It becomes incorporated at the  3'-terminus of DNA and, thus, hinders elongation. It also affects DNA repair and is a potent inhibitor of  ribonucleotide reductase. 6 Resistance may be due to mechanisms analogous to those that affect fludarabine,    although cross- resistance is not a problem. Cladribine is effective against hairy-cell leukemia, chronic lymphocytic  leukemia, and non-Hodgkin's lymphoma. It also has some activity versus multiple sclerosis. The drug is given as a  single, continuous infusion. Cladribine distributes throughout the body, including into the CSF. Severe bone  marrow suppression is a common adverse effect, as is fever. Peripheral neuropathy has also been reported. The  drug is teratogenic.   5-Fluorouracil [flure-oh-YOOR-ah-sil] (5-FU), a pyrimidine analog, has a stable fluorine atom in place of a hydrogen  atom at position 5 of the uracil ring. The fluorine interferes with the conversion of deoxyuridylic acid to thymidylic  acid, thus depriving the cell of thymidine, one of the essential precursors for DNA synthesis. 5-FU is employed  primarily in the treatment of slowly growing solid tumors (for example, colorectal, breast, ovarian, pancreatic, and  gastric carcinomas). Adj uvant therapy with levamisolea€"a veterinary anthelmintic agenta€"improves the survival  of some patients with colon cancer. When applied topically, 5-FU is also effective for the treatment of superficial  basal cell carcinomas.   Figure 39.12 Mechanism of the cytotoxic action of 5-FU. 5-FU is converted to 5-FdUMP, which competes  with deoxyuridine monophosphate (dUMP) for the enzyme thymidylate synthetase. 5-FU =5-fluorouracil;  5-FUR = 5-f luorouridi ne; 5-FUMP =5-fluorouridine monophosphate; 5-FUDP =5-fluorouridine diphosphate;  5-FUTP =5-fluorouridine triphosphate; dUMP =deoxyuridine monophosphate; dTMP =deoxythymidine  monophosphate. 5-FdUMP =5-fluorodeoxyuridine monophosphate.    1. Mechanism of action: 5-FU per se is devoid of antineoplastic activity. It enters the cell through a carrier-  mediated transport system and is converted to the corresponding deoxynucleotide ( 5-f lurodeoxyuridi ne    monophosphate (5-FdUMP); Figure 39. 12), which competes with deoxyuridine monophosphate for thymidylate  synthase. 7   5-FdUMP acts as a pseudosubstrate and is trapped with the enzyme and its coenzyme N 5 , N 10 -methylene  tetrahydrofolic acid (leucovorin), in a ternary complex that cannot proceed to release products. DNA synthesis  decreases due to lack of thymidine, leading to imbalanced cell growth and a€oethymidine-less deatha€ <;: of  rapidly dividing cells. [Note: Leucovorin is administered with 5-FU, because the reduced folate coenzyme is  required in the thymidylate synthase inhibition. Addition of the coenzyme increases the effectiveness of the  5-FU to form a ternary complex and produce an antipyrimidine effect. For example, the standard regimen for  advanced colorectal cancer today is irinotecan plus 5-FU/ leucovorin.] 5-FU is also incorporated into RNA, and  low levels have been detected in DNA. In the latter case, a glycosylase excises the 5-FU, damaging the DNA.   5-FU produces the anticancer effect in the S phase of the cell cycle.    2. Resistance: Resistance is encountered when the cells have lost their ability to convert 5-FU into its active form  (5-FdUMP) or when they have altered or increased thymidylate synthase levels.   3. Pharmacokinetics: Because of its severe toxicity to the Gl tract, 5-FU is given IV or, in the case of skin cancer,  topically (Figure 39.13). The drug penetrates well into all tissues, including the CNS. 5-FU is rapidly metabolized  in the liver, lung, and kidney. It is eventually converted to fluoro-i 2 -alanine, which is removed in the urine, and  to CO 2 , which is exhaled. The dose of 5-FU must be adj usted in the case of impaired hepatic function. Increased  rate of 5-FU catabolism through elevated levels of dihydropyrimidine dehydrogenase (DPD) can decrease the  bioavailability of 5-FU. The DPD level varies from individual to individual, that may differ by as much as six-fold  in the general population. Knowledge about an individual's DPD activity should allow more appropriate dosing of  5-FU.   4. Adverse effects: In addition to nausea, vomiting, diarrhea, and alopecia, severe ulceration of the oral and Gl  mucosa, bone marrow depression (with bolus injection), and anorexia are frequently encountered. An  allopurinol mouthwash has been shown to reduce oral toxicity. A dermopathy (erythematous desquamation of    the palms and soles) called the a€oehand-foot syndromeaCS is seen after extended infusions.   Capecitabine [cape-SITE-a-been] is a novel, oral fluoropyrimidine carbamate. It is approved for the treatment of  metastatic breast cancer that is resistant to first-line drugs (for example, paclitaxel and anthracyclines) and is  currently also used for treatment of colorectal cancer.   1. Mechanism of action: After being absorbed, capecitabine, which is itself nontoxic, undergoes a series of  enzymatic reactions, the last of which is hydrolysis to 5-FU. This step is catalyzed by thymidine  phosphorylasea€"an enzyme that is concentrated primarily in tumors (Figure 39. 14). Thus, the cytotoxic activity  of capecitabine is the same as that of 5-FU and is tumor specific. The most important enzyme inhibited by 5-FU  (and, thus, capecitabine ) is thymidylate synthase.   Figure 39.14 Metabolic pathway of capecitabine to 5-fluorouracil (5-FU). 5'-dFCR =5'-deoxy-  5-FLuorocytidine; 5'-dFUR =5'-deoxy-5-fluorouridine.   2. Pharmacokinetics: Capecitabine has the advantage of being well absorbed following oral administration. It is  extensively metabolized to 5-FU (as described above) and is eventually biotransformed into fluoro-i * 2 3 -alanine  and CO 2 . Metabolites are primarily eliminated in the urine or, in the case of CO 2 , it is exhaled.   3. Adverse effects: These are similar to those with 5-FU, with the toxicity occurring primarily in the Gl tract.  Capecitabine should be used cautiously in patients with hepatic or renal impairment. The drug is  contraindicated in individuals who are pregnant or are lactating. Patients taking coumarin anticoagulants or  phenytoin should be monitored for coagulation parameters and drug levels, respectively.   Floxuridine [floks-YOOR-ih-deen] is an analog (floxuridine is 2'-deoxy-5-f I uorouridine) of 5-FU. When given by rapid  intra-arterial injection, floxuridine is rapidly catabolized in the liver to 5-FU and produces antimetabolite effects.  The primary effect is to interfere with the synthesis of DNA and to a lesser extent inhibit the formation of RNA. The  drug is excreted intact and as fluorouracil, urea, and i±-fluoro-i 2 -alanine in the urine. Floxuridine is effective in the  palliative management of Gl adenocarcinoma that has metastasized to the liver. The common adverse effects are  nausea, vomiting, diarrhea, enteritis, stomatitis, and localized erythema.   Cytarabine [sye-TARE-ah-been] (cytosine arabi noside, or ara-C ) is an analog of 2'-deoxycytidine in which the  natural ribose residue is replaced by D-arabinose. Ara-C acts as a pyrimidine antagonist. The major clinical use of  ara-C is in acute nonlymphocytic (myelogenous) leukemia in combination with 6-TG and daunorubicin.   1. Mechanism of action: Ara-C enters the cell by a carrier-mediated process and, like the other purine and  pyrimidine antagonists, must be sequentially phosphorylated by deoxycytidine kinase and other nucleotide  kinases to the nucleotide form (cytosine arabinoside triphosphate, or ara-CTP) to be cytotoxic. Ara-CTP is an  effective inhibitor of DNA polymerase. The nucleotide is also incorporated into nuclear DNA and can retard  chain elongation. It is therefore S-phase (and, hence, cell-cycle) specific.   2. Resistance: Resistance to ara-C may result from a defect in the transport process, a change in phosphorylating  enzymes activity (especially deoxycytidine kinase), or an increased pool of the natural dCTP nucleotide.  Increased deamination of the drug to ara-U can also cause resistance.   3. Pharmacokinetics: Ara-C is not effective when given orally, because of its deamination to the noncytotoxic  uracil arabinoside (ara-U) by cytidine deaminase in the intestinal mucosa and liver. Given IV, it distributes    throughout the body but does not penetrate the CNS in sufficient amounts to be effective against meningeal  leukemia (Figure 39. 15). However, it may be inj ected intrathecally. A new preparation that provides slow  release into the CSF is also available. Ara-C undergoes extensive oxidative deamination in the body to ara-Ua€"a  pharmacologically inactive metabolite. Both ara-C and ara-U are excreted in the urine.   4. Adverse effects: Nausea, vomiting, diarrhea, and severe myelosuppression (primarily granulocytopenia) are the  maj or toxicities associated with ara-C. Hepatic dysfunction is also occasionally encountered. At high doses or  with intrathecal inj ection, ara-C may cause leukoencephalopathy or paralysis.   Gemcitabine [j em-SITE-ah-been] is an analog of the nucleoside deoxycytidine. It is used for the first-line treatment  of locally advanced or metastatic adenocarcinoma of the pancreas. It also is effective against nona€" small cell lung  cancer and several other tumors.   1. Mechanism of action: Gemcitabine is a substrate for deoxycytidine kinase, which phosphorylates the drug to  2', 2'-dif luorodeoxycytidine triphosphate (Figure 39. 16). The latter compound inhibits DNA synthesis by being  incorporated into sites in the growing strand that ordinarily would contain cytosine. Evidence suggests that DNA  repair does not readily occur. Levels of the natural nucleotide, dCTP, are lowered, because gemcitabine  competes with the normal nucleoside substrate for deoxycytidine kinase. Gemcitabine diphosphate inhibits  ribonucleotide reductase, which is responsible for the generation of deoxynucleoside triphosphates required for  DNA synthesis.   2. Resistance: Resistance to the drug is probably due to its inability to be converted to a nucleotide, caused by an  alteration in deoxycytidine kinase. In addition, the tumor cell can produce increased levels of endogenous  deoxycytidine that compete for the kinase, thus overcoming the inhibition.   3. Pharmacokinetics: Gemcitabine is infused IV. It is deaminated to difluorodeoxyuridine, which is not cytotoxic,  and is excreted in the urine.   4. Adverse effects: Myelosuppression is the dose-limiting toxicity of gemcitabine. Other toxicities include nausea,  vomiting, alopecia, rash, and a flu-like syndrome. Transient elevations of serum transaminases, proteinuria, and  hematuria are common.   The antitumor antibiotics owe their cytotoxic action primarily to their interactions with DNA, leading to disruption  of DNA function. In addition to intercalation, their abilities to inhibit topoisomerases (I and II) and produce free  radicals also play a maj or role in their cytotoxic effect. They are cell-cycle nonspecific.   Dactinomycin [dak-ti-noe-MYE-sin], known to biochemists as actinomycin D, was the first antibiotic to find  therapeutic application in tumor chemotherapy. Dactinomycin is used in combination with surgery and vincristine  for the treatment of Wilms' tumor. In combination with MTX, dactinomycin is effective in the treatment of  gestational choriocarcinoma. Some soft-tissue sarcomas also respond.   1. Mechanism of action: The drug intercalates into the minor groove of the double helix between guanine-  cytosine base pairs of DNA, 8 forming a stable dactinomycin- DNA complex. The complex interferes primarily with  DNA-dependent RNA polymerase, although at high doses, dactinomycin also hinders DNA synthesis. The drug also  causes single-strand breaks, possibly due to action on topoisomerase II or by generation of free radicals.   2. Resistance: Resistance is due to an increased efflux of the antibiotic from the cell via P-glycoprotein. DNA  repair may also play a role.   3. Pharmacokinetics: The drug, administered IV, distributes to many tissues but does not enter the CSF (Figure  39. 17). The drug is minimally metabolized in the liver. Most of the parent drug and its metabolites are excreted  via the bile, and the remainder are excreted via the urine.   4. Adverse effects: The major dose-limiting toxicity is bone marrow depression. The drug is immunosuppressive.   Other adverse reactions include nausea, vomiting, diarrhea, stomatitis, and alopecia. Extravasation during   inj ection produces serious problems. Dactinomycin sensitizes to radiation, and inflammation at sites of prior  radiation therapy may occur.   Doxorubicin [dox-oh-ROO-bi-sin] and daunorubicin [daw-noe-ROO-bi-sin] are classified as anthracycline antibiotics.  Doxorubicin is the hydroxylated analog of daunorubicin. Idarubicin [eye-da-RUE-bi-sin], the 4-demethoxy analog of    daunorubicin, and epirubicin [eh-pee-ROO bih-sin] are also available. Applications for these agents differ despite  their structural similarity and their apparently similar mechanisms of action. Doxorubicin is one of the most  important and widely used anticancer drugs. It is used in combination with other agents for treatment of sarcomas  and a variety of carcinomas, including breast and lung, as well as for treatment of acute lymphocytic leukemia and  lymphomas. Daunorubicin and idarubicin are used in the treatment of acute leukemias.   1. Mechanism of action: The anthracyclines have three major activities that may vary with the type of cell. All  three are effective in the S and G 2 phases.   a. Intercalation in the DNA: The drugs insert nonspecif ical ly between adj acent base pairs and bind to the  sugar-phosphate backbone of DNA. This causes local uncoiling and, thus, blocks DNA and RNA synthesis.  Intercalation can interfere with the topoisomerase lla€" catalyzed breakage/ reunion reaction of supercoiled  DNA strands, causing irreparable breaks.   b. Binding to cell membranes: This action alters the function of transport processes coupled to  phosphatidylinositol activation. 9    c. Generation of oxygen radicals: Cytochrome P450 reductase (present in cell nuclear membranes) catalyzes  reduction of the anthracyclines to semiquinone free radicals. These in turn reduce molecular O 2 , producing  superoxide ions and hydrogen peroxide, which mediate single-strand scission of DNA (Figure 39.18). Tissues    with ample superoxide dismutase or glutathione peroxidase activity are protected. 10 Tumors and heart tissue    are generally low in SOD. In addition, cardiac tissue lacks catalase and, thus, cannot effectively scavenge  hydrogen peroxide. Lipid peroxidation therefore may explain the cardiotoxicity of anthracyclines.   2. Pharmacokinetics: All these drugs must be administered IV, because they are inactivated in the Gl tract.  Extravasation is a serious problem that can lead to tissue necrosis. The anthracycline antibiotics bind to plasma  proteins as well as to other tissue components, where they are widely distributed. They do not penetrate the  blood-brain barrier or the testes. All these drugs undergo extensive hepatic metabolism. The bile is the major  route of excretion, and the drug dose must be modified in patients with impaired hepatic function (Figure  39. 19). Some renal excretion also occurs, but the dose generally need not be adj usted in patients with renal  failure. Because of the dark red color of the anthracycline drugs, the veins may become visible surrounding the  site of infusion, and the drugs also impart a red color to the urine.   Figure 39.18 Doxorubicin interacts with molecular oxygen, producing superoxide ions and hydrogen  peroxide, which cause single-strand breaks in DNA.    3. Adverse effects: Irreversible, dose-dependent cardiotoxicity, apparently a result of the generation of free  radicals and lipid peroxidation, is the most serious adverse reaction and is more common with daunorubicin and  doxorubicin than with idarubicin or epirubicin. Irradiation of the thorax increases the risk of cardiotoxicity.  Addition of trastuzumab to protocols with doxorubicin or epirubicin increases congestive heart failure. There  has been some success with the iron-chelator dexrazone in protecting against the cardiotoxicity of doxorubicin.  [Note: A new liposomal-encapsulated doxorubicin has been reported to be less cardiotoxic than the usual  formulation.] As with dactinomycin, both doxorubicin and daunorubicin also cause transient bone marrow  suppression, stomatitis, and Gl tract disturbances. Increased skin pigmentation is also seen. Alopecia is usually  severe. Occurrence of multidrug resistance is common; however, it is less frequent than with plant alkaloids.   Bleomycin [blee-oh-MYE-sin] is a mixture of different copper-chelating glycopeptides that, like the anthracycline  antibiotics, cause scission of DNA by an oxidative process. Bleomycin is cell-cycle specific and causes cells to  accumulate in the G 2 phase. It is primarily employed in the treatment of testicular cancers in combination with  vinblastine or etoposide. Response rates are close to 100 percent if cisplatin is added to the regimen. Bleomycin is  also effective, although not curative, for squamous cell carcinomas and lymphomas.    1. Mechanism of action: A DNA-Weomyc/n-Fe 2+ complex appears to undergo oxidation to bleomycin- Fe 3+ . The    liberated electrons react with oxygen to form superoxide or hydroxyl radicals, which in turn attack the  phosphodiester bonds of DNA, resulting in strand breakage and chromosomal aberrations (Figure 39.20).   2. Resistance: Although the mechanisms of resistance have not been elucidated, experimental systems have  implicated increased levels of bleomycin hydrolase (or deamidase), glutathione-S-transferase, and possibly,  increased efflux of the drug. DNA repair also may contribute.   3. Pharmacokinetics: Bleomycin is administered by a number of routes, including subcutaneous, intramuscular,  IV, and intracavitary. The b/eomyc/n-inactivating enzyme (a hydrolase) is high in a number of tissues (for  example, liver and spleen) but is low in lung and is absent in skin (accounting for the drug's toxicity in those  tissues). Most of the parent drug is excreted unchanged into the urine by glomerular filtration, necessitating  dose adj ustment in patients with renal failure.    Figure 39.20 Bleomycin causes breaks in DNA by an oxidative process.    4. Adverse effects: Pulmonary toxicity is the most serious adverse effect, progressing from rales, cough, and  infiltrate to potentially fatal fibrosis. The pulmonary fibrosis that is caused by bleomycin is often referred as  aicebleomycin lung.a€§ Mucocutaneous reactions and alopecia are common. Hypertrophic skin changes and  hyperpigmentation of the hands are prevalent. There is a high incidence of fever and chills and a low incidence  of serious anaphylactoid reactions. Bleomycin is unusual in that myelosuppression is rare.   Alkylating agents exert their cytotoxic effects by covalently binding to nucleophilic groups on various cell  constituents. Alkylation of DNA is probably the crucial cytotoxic reaction that is lethal to the tumor cells. Alkylating  agents do not discriminate between cycling and resting cells, but they are most toxic for rapidly dividing cells. They  are used in combination with other agents to treat a wide variety of lymphatic and solid cancers. In addition to  being cytotoxic, all are mutagenic and carcinogenic and can lead to second malignancies, such as acute leukemia.   Mechlorethamine [mek-lor-ETH-ah-meen] was developed as a vesicant (nitrogen mustard) during World War I. Its  ability to cause lymphocytopenia led to its use in lymphatic cancers. Because it can covalently attach to two  separate nucleotides, such as guanine on the DNA molecules, it is called a a€oebifunctional agent. a€ <;   Mechlorethamine was used primarily in the treatment of Hodgkin's disease and may find use in the treatment of  some solid tumors.   1. Mechanism of action: Mechlorethamine is transported into the cell, where the drug forms a reactive  intermediate that alkylates the N 7 nitrogen of a guanine residue in one or both strands of a DNA molecule  (Figure 39.21). This alkylation leads to cross-linkages between guanine residues in the DNA chains and/or  depurination, thus facilitating DNA strand breakage. Alkylation can also cause miscoding mutations. Although  alkylation can occur in both cycling and resting   cells (and, therefore, is cell-cycle nonspecific), proliferating cells are more sensitive to the drug, especially  those in the Gi and S phases.   Figure 39.21 Alkylation of guanine bases in DNA is responsible for the cytotoxic effect of  mechlorethamine.    2. Resistance: Resistance has been ascribed to decreased permeability of the drug, increased conj ugation with   3. Pharmacokinetics: Mechlorethami ne is very unstable, and solutions must be made up j ust prior to  administration. Mechlorethamine is also a powerful vesicant (blistering agent) and is only administered IV.  Because of its reactivity, scarcely any drug is excreted.   4. Adverse effects: The adverse effects caused by mechlorethami ne include severe nausea and vomiting  (centrally mediated). [Note: These effects can be diminished by pretreatment with ondansetron, granisetron,  or palonosetron with dexamethasone. ] Severe bone marrow depression limits extensive use. Latent viral  infections (for example, herpes zoster) may appear because of immunosuppression. Extravasation is a serious  problem. If it occurs, the area should be infiltrated with isotonic sodium thiosulfite to inactivate the drug.    Figure 39.22 Activation of cyclophosphamide and ifosfamide by hepatic cytochrome P450.   These drugs are very closely related mustard agents that share most of the same primary mechanisms and toxicities.  They are unique in that they can be taken orally and are cytotoxic only after generation of their alkylating species,  which are produced through hydroxylation by cytochrome P450. These agents have a broad clinical spectrum, being  used either singly or as part of a regimen in the treatment of a wide variety of neoplastic diseases, such as Burkitt's  lymphoma and breast cancer. Non-neoplastic disease entities, such as nephrotic syndrome and intractable  rheumatoid arthritis, are also effectively treated with low doses of cyclophosphamide.   1. Mechanism of action: Cyclophosphamide [sye-kloe-FOSS-fah-mide] is the most commonly used alkylating agent.  Both cyclophosphamide and ifosfamide [eye-FOSS-fah-mide] are first biotransformed to hydroxylated  intermediates primarily in the liver by the cytochrome P450 system (Figure 39.22). The hydroxylated  intermediates then undergo breakdown to form the active compounds, phosphoramide mustard and acrolein.  Reaction of the phosphoramide mustard with DNA is considered to be the cytotoxic step.   2. Resistance: Resistance results from increased DNA repair, decreased drug permeability, and reaction of the  drug with thiols (for example, glutathione). Cross-resistance does not always occur.   3. Pharmacokinetics: Unlike most of the alkylating agents, cyclophosphamide and ifosfamide can be administered  by the oral route (Figure 39.23). After oral administration, minimal amounts of the parent drug are excreted into    the feces (after biliary transport) or into the urine by glomerular filtration.   4. Adverse effects: The most prominent toxicities of both drugs (after alopecia, nausea, vomiting, and diarrhea)  are bone marrow depression, especially leukocytosis, and hemorrhagic cystitis, which can lead to fibrosis of the  bladder. The latter toxicity has been attributed to acrolein in the urine in the case of cyclophosphamide and to  toxic   metabolites of ifosfamide. [Note: Adequate hydration as well as IV inj ection of MESNA (sodium  2-mercaptoethane sulfonate), which neutralizes the toxic metabolites, minimizes this problem. ] Other toxicities  include effects on the germ cells, resulting in amenorrhea, testicular atrophy, aspermia, and sterility.   Veno-occlusive disease of the liver is seen in about 25 percent of the patients. A fairly high incidence of  neurotoxicity has been reported in patients on high-dose ifosfamide, probably due to the metabolite,  chloroacetaldehyde. Secondary malignancies may appear years after therapy.   Carmustine [KAR-mus-teen] and lomustine [LOE-mus-teen] are closely related nitrosoureas. Because of their ability  to penetrate into the CNS, the nitrosoureas are primarily employed in the treatment of brain tumors. They find  limited use in the treatment of other cancers. [Note: Streptozocin [STREP-toe-zoe-sin] is another nitrosourea that  is specifically toxic to the I 2 cells of the islets of Langerhans, hence its use in the treatment of insulinomas. ]    1. Mechanism of action: The nitrosoureas exert cytotoxic effects by an alkylation that inhibits replication and,  eventually, RNA and protein synthesis. Although they alkylate DNA in resting cells, cytotoxicity is expressed  primarily on cells that are actively dividing. Therefore, nondividing cells can escape death if DNA repair occurs.  Nitrosoureas also inhibit several key enzymatic processes by carbamoylation of amino acids in proteins in the  targeted cells.   2. Resistance: Although the true nature of resistance to nitrosoureas is unknown, it probably results from DNA  repair and reaction of the drugs with thiols.   3. Pharmacokinetics: In spite of the similarities in their structures, carmustine is administered IV, whereas  lomustine is given orally. Because of their lipophilicity, they distribute widely in the body to many tissues, but  their most striking property is their ability to readily penetrate into the CNS. The drugs undergo extensive  metabolism. Lomustine is metabolized to active products. The kidney is the major excretory route for the  nitrosoureas (Figure 39.24).   4. Adverse effects: These include delayed hematopoietic depression, which may be due to metabolic products. An  aplastic marrow may develop on prolonged use. Renal toxicity and pulmonary fibrosis related to duration of  therapy is also encountered. [Note: Streptozotocin is also diabetogenic. ]   Dacarbazine [dah-KAR-bah-zeen]a€"an agent that has found use in the treatment of melanoma, is an alkylating  agent that must undergo biotransformation to an active metabolite, methyltriazenoimidazole carboxamide (MTIC),  This metabolite is responsible for the drug's activity as an alkylating agent by forming methylcarbonium ions that can  attack the nucleophilic groups in the DNA molecule. Thus, similar to other alkylating agents, the cytotoxic action of  dacarbazine has been attributed to the ability of its metabolite to methylate DNA on the O 6 position of guanine.  Dacarbazine is administered by IV. Its maj or adverse effects are nausea and vomiting. Myelosuppression  (thrombocytopenia    and neutropenia) occur later in the treatment cycle. Hepatotoxicity with hepatic vascular occlusion may also occur  in long-term treatments.   The treatment of tumors in the brain is particularly difficult. Recently, temozolomide [te-moe-ZOE-loe-mide], a  triazene agent, has been approved for use against treatment-resistant gliomas and anaplastic astrocytomas.  Temozolomide is related to dacarbazine, because both must undergo biotransformation to an active metabolite,  MTIC, which probably is responsible for the methylation of DNA on the 6 position of guanine. Unlike dacarbazine,  tomozolomide does not require cytochrome P450 system for metabolic transformation; it undergoes chemical  transformation under normal physiological pH. Temozolomide also has the property of inhibiting the repair enzyme,  0 6 -guanine-DNA-alkyltransferase. A property that distinguishes temozolomide from dacarbazine is the former's  ability to cross the blood-brain barrier. Temozolomide is taken orally and has excellent oral bioavailability. The  parent drug and metabolites are excreted in the urine (Figure 39.25). Temozolomide is taken for five consecutive  days and repeated every 28 days. Similar to dacarbazine, its maj or initial toxicities are nausea and vomiting.  Myelosuppression (thrombocytopenia and neutropenia) occur later in the treatment cycle.   Melphalan [ MEL-fah- Ian], a phenylalanine derivative of nitrogen mustard, is used in the treatment of multiple  myeloma. This is a bifunctional alkylating agent that can be given orally. Although melphalan can be given orally,  the plasma concentration differs from patient to patient due to variation in intestinal absorbtion and metabolism.  The dose of melphalan is carefully adj usted by monitoring the platelet and white blood cell counts. Chlorambucil  [ clor- AM- byoo- si I ] is another bifunctional alkylating agent that is used in the treatment of chronic lymphocytic  leukemia. Both melphalan and chlorombucil have moderate hematologic toxicities and upset the Gl tract. Busulfan  [byoo-SUL-fan] is another oral agent that is effective against chronic granulocytic leukemia. Busulfan is also a    bifunctional alkylating agent that can cause myelosuppression. In aged patients, busulfan can cause pulmonary  fibrosis. Like other alkylating agents, all these agents are leukemogenic.   The mitotic spindle is part of a larger, intracellular skeleton (cytoskeleton) that is essential for the movements of  structures occurring in the cytoplasm of all eukaryotic cells. The mitotic spindle consists of chromatin plus a system  of microtubules composed of the protein tubulin. The mitotic spindle is essential for the equal partitioning of DNA  into the two daughter cells that are formed when a eukaryotic cell divides. Several plant-derived substances used as  anticancer drugs disrupt this process by affecting the equilibrium between the polymerized and depolymerized  forms of the microtubules, thereby causing cytotoxicity.   Vincristine [vin-KRIS-teen] [VX) and vinblastine [vin-BLAS-teen] (VBL) are structurally related compounds derived  from the periwinkle plant, Vinca rosea. They are therefore referred to as the vinca alkaloids. A structurally   related, new (and less toxic) agent is vinorelbine [vye-NOR-el-been] (VRB). Although the vinca alkaloids are  structurally very similar to each other, their therapeutic indications are different. They are generally administered  in combination with other drugs. VX is used in the treatment of acute lymphoblastic leukemia in children, Wilms'  tumor, Ewing's soft-tissue sarcoma, Hodgkin's and non-Hodgkin's lymphomas, as well as some other rapidly  proliferating neoplasms. [Note: VX (trade name, Oncovin) is the a€oeOa€§ in the POMP regimen for leukemia and  the MOPP regimen for Hodgkin's lymphoma. Due to relatively milder bone-suppressing ability, VX is used in a number  of other protocols.] VBL is administered with bleomycin and cisplatin for the treatment of metastatic testicular  carcinoma. It is also used in the treatment of systemic Hodgkin's and non-Hodgkin's lymphomas. VRB is beneficial in  the treatment of advanced nona€"small cell lung cancer, either as a single agent or with cisplatin.   1. Mechanism of action: VX and VBL are both cell-cycle specific and phase specific, because they block mitosis in  metaphase (M phase). Their binding to the microtubular protein, tubulin, is GTP dependent and blocks the  ability of tubulin to polymerize to form microtubules. Instead, paracrystalline aggregates consisting of tubulin  dimers and the alkaloid drug are formed. The resulting dysfunctional spindle apparatus, frozen in metaphase,  prevents chromosomal segregation and cell proliferation (Figure 39.26).   2. Resistance: Resistant cells have been shown to have an enhanced efflux of VX, VBL, and VRB via P-glycoprotein  in the cell membrane. Alterations in tubulin structure may also affect binding of the vinca alkaloids.   3. Pharmacokinetics: Intravenous injection of these agents leads to rapid cytotoxic effects and cell destruction.   This in turn can cause hyperuricemia due to the oxidation of purines that are released from fragmenting DNA  molecules, producing uric acid. The hyperuricemia is ameliorated by administration of the xanthine  oxidaseaC" i nhi bitor allopurinol. The vinca alkaloids are concentrated and metabolized in the liver by the  cytochrome P450 pathway. They are excreted into bile and feces. Doses must be modified in patients with  impaired hepatic function or biliary obstruction.   4. Adverse effects: Both VX and VBL have certain toxicities in common. These include phlebitis or cellulitis, if the  drugs extravasate during inj ection, as well as nausea, vomiting, diarrhea, and alopecia. However, the adverse  effects of VX and VBL are not identical. VBL is a more potent myelosuppressant than VX, whereas peripheral  neuropathy (paresthesias, loss of reflexes, foot drop, and ataxia) is associated with VX. Constipation is more  frequently encountered with VX, which can also cause inappropriate antidiuretic hormone secretion. The  anticonvulsants phenytoin, phenobarbital , and carbamazepine can accelerate the metabolism of VX, whereas  the azole antifungal drugs can slow its metabolism. Granulocytopenia is dose limiting for VRB.   Better known as Taxol, paclitaxel [PAK-li-tax-el] is the first member of the taxane family to be used in cancer  chemotherapy. A semisynthetic paclitaxel is now available through chemical modification of a precursor found in  the needles of Pacific yew species. Substitution of a side chain   has resulted in docetaxel [doe-see-TAX-el], which is the more potent of the two drugs. Paclitaxel has shown good  activity against advanced ovarian cancer and metastatic breast cancer. Favorable results have been obtained in  nona€" small cell lung cancer when administered with cisplatin. Docetaxel is showing impressive benefits, with  fewer side effects, in these conditions.   1. Mechanism of action: Both drugs are active in the G 2 /M phase of the cell cycle. They bind reversibly to the  i * 1 2 -tubulin subunit, but unlike the vinca alkaloids, they promote polymerization and stabilization of the polymer  rather than disassembly (Figure 39.27). Thus, they shift the depolymerization-polymerization process to  accumulation of microtubules. The overly stable microtubules formed are nonfunctional, and chromosome  desegregation does not occur. This results in death of the cell.   2. Resistance: Like the vinca alkaloids, resistance has been associated with the presence of amplified  P-glycoprotein or a mutation in the tubulin structure.   3. Pharmacokinetics: These agents are infused and have similar pharmacokinetics. Both have a large volume of  distribution, but neither enters the CNS. Hepati c metabolism by the cytochrome P450 system and biliary  excretion are responsible for their elimination into the stool. Thus, dose modification is not required in patients  with renal impairment, but doses should be reduced in patients with hepatic dysfunction.   4. Adverse effects: The dose-limiting toxicity of paclitaxel and docetaxel is neutropenia. [Note: Patients with  fewer than 1500 neutrophils/ mm 3 4 should not be given these agents.] Treatment with granulocyte colony-  stimulating factor ( Filgrastim ) can help to reverse neutropenia and prevent the problems associated with this  condition. Peripheral neuropathy can develop with either of these drugs. A transient, asymptomatic bradycardia  is sometimes observed with paclitaxel, and fluid retention is seen with docetaxel. The latter drug is  contraindicated in patients with cardiac disease. Alopecia occurs, but vomiting and diarrhea are uncommon.   Because of serious hypersensitivity reactions (including dyspnea, urticaria, and hypotension), a patient who is to  be treated with paclitaxel is premedicated with dexamethasone and diphenhydramine as well as with an PI 2  blocker.   Tumors that are steroid hormoneaC" sensitive may be either 1) hormone responsive, in which the tumor regresses  following treatment with a specific hormone; 2) hormone dependent, in which removal of a hormonal stimulus  causes tumor regression; or 3) both. Hormone treatment of responsive tumors usually is only palliative, except in  the case of the cytotoxic effect of glucocorticoids at higher doses (for example, prednisone ) on lymphomas.  Removal of hormonal stimuli from hormone-dependent tumors can be accomplished by surgery (for example, in the  case of orchiectomy for patients with advanced prostate cancer) or by drugs (for example, in breast cancer, for  which treatment with the antiestrogen tamoxifen is used to prevent estrogen stimulation of breast cancer cells).   For a steroid hormone to influence a cell, that cell must have intracellular (cytosolic) receptors that are specific for  that hormone (Figure 39.28A).   Prednisone [PRED-ni-sone] is a potent, synthetic, anti-inflammatory corticosteroid with less mineralocorticoid  activity than cortisol. The use of this compound in the treatment of lymphomas arose when it was observed that  patients with Cushing's syndrome, which is associated with hypersecretion of cortisol, have lymphocytopenia and  decreased lymphoid mass. [Note: At high doses, cortisol is also lymphocytolytic and leads to hyperuricemia due to  the breakdown of lymphocytes. ] Prednisone is primarily employed to induce remission in patients with acute  lymphocytic leukemia and in the treatment of both Hodgkin's and non-Hodgkin's lymphomas.   1. Mechanism of action: Prednisone itself is inactive and must first be reduced to prednisolone by  ll-P-hydroxysteroid dehydrogenase. 11 This steroid then binds to a receptor that triggers the production of  specific proteins (see Figure 39.28A).   2. Resistance: Resistance is associated with an absence of the receptor protein or a mutation that lowers receptor  affinity for the hormone. However, in some resistant cells, a receptor-hormone complex is formed, although a  stage of gene expression is apparently affected.   3. Pharmacokinetics: Prednisone is readily absorbed orally. Like other glucocorticoids, it is bound to plasma  albumin and transcortin. It undergoes ll-P-hydroxylation to prednisolone in the liver. Prednisolone is the  active drug. The latter is glucuronidated and excreted into the urine along with the parent compound.   4. Adverse effects: Prednisone has many of the adverse effects associated with glucocorticoids. It can predispose  to infection (due to its immunosuppressant action) and to ulcers and pancreatitis. Other effects include  hyperglycemia, cataract formation, glaucoma, osteoporosis, and change in mood (euphoria or psychosis).   Tamoxifen [tah-MOX- ih-fen] is an estrogen antagonist. It is structurally related to the synthetic estrogen  diethylstilbestrol and is used for first-line therapy in the treatment of estrogen receptora€"positive breast cancer.  Tamoxifen has weak estrogenic activity, and it is classified as a selective estrogen-receptor modulator (SERM).   Another SERM that has been approved for advanced breast cancer in postmenopausal women is toremifene [tore-  EM-ih-feen], It also finds use prophylactically in reducing breast cancer occurrence in women who are at high risk.  However, because of possible effects stimulating premalignant lesions due to its estrogenic properties, tamoxifen is  presently approved only for 5 years of use.   1. Mechanism of action: Tamoxifen binds to the estrogen receptor, but the complex is transcriptionally not  productive. That is, the complex fails to induce estrogen-responsive genes, and RNA synthesis does not ensue  (Figure 39.28B). The result is a depletion (down-regulation) of estrogen receptors, and the growth-promoting  effects of the   natural hormone and other growth factors are suppressed. [Note: Estrogen competes with tamoxifen.   Therefore, in premenopausal women, the drug is used with a gonadotropin-releasing hormone (GnRH) analog  such as leuprolide, which lowers estrogen levels.] The action of tamoxifen is not related to any specific phase  of the cell cycle.    2. Resistance: Resistance is associated with a decreased affinity for the receptor or the presence of a  dysfunctional receptor.   3. Pharmacokinetics: Tamoxifen is effective on oral administration. It is partially metabolized by the liver. Some  metabolites possess antagonist activity, whereas others have agonist activity. Unchanged drug and its  metabolites are excreted predominantly through the bile into the feces (Figure 39.29).    Unchanged  drug and/ /  metabolites  are excreted  via the bile  into the feces    4. Adverse effects: Side effects caused by tamoxifen are similar to the effects of natural estrogen, including hot  flashes, nausea, vomiting, skin rash, vaginal bleeding, and discharge (due to some slight estrogenic activity of  the drug and some of its metabolites). Hypercalcemia requiring cessation of the drug may occur. Tamoxifen can  also lead to increased pain if the tumor has metastasized to bone. Tamoxifen has the potential to cause  endometrial cancer. Other toxicities include thromboembolism and effects on vision. [Note: Because of a more  favorable adverse effect profile, aromatase inhibitors are making an impact in the treatment of breast cancer. ]   The aromatase reaction is responsible for the extra-adrenal synthesis of estrogen from androstenedione, which  takes place in liver, fat, muscle, skin, and breast tissue, including breast malignancies. Peripheral aromatization is  an important source of estrogen in postmenopausal women. Aromatase inhibitors decrease the production of  estrogen in these women.   1. Aminoglutethimide: Aminoglutethimide [ah-mee-noe-glue-TETH-ih-mide] was the first aromatase inhibitor to  be identified for the treatment of metastatic breast cancer in postmenopausal women. Aminoglutethimide was  shown to inhibit both the adrenal synthesis of pregnenolone (a precursor of estrogen) from cholesterol as well    as the extra-adrenal synthesis. Because the drug also inhibits hydrocortisone synthesis, which evokes a  compensatory rise in adrenocorticotropic hormone secretion sufficient to overwhelm the blockade of the  adrenal, the drug is usually taken with hydrocortisone. Due to its nonselective properties and unfavorable side  effects, as well as the need to concomitantly administer hydrocortisone (cortisol), newer aromatase inhibitors  (described below) have been developed.   2. Anastrozole and letrozole: The imidazole aromatase inhibitors, such as anastrozole [an-AS-troe-zole] and  letrozole [LE-troe-zole], are nonsteroidal. They have gained favor in the treatment of breast cancer because 1)  they are more potent (they inhibit aromatization by greater than 96 percent, compared to less than 90 percent  with aminoglutethimide), 2) they are more selective than aminoglutethimide, 3) they do not need to be  supplemented with hydrocortisone, 4) they do not predispose to endometrial cancer, and 5) they are devoid of  the androgenic side effects that occur with the steroidal   aromatase inhibitors. Although anastrozole and letrozole are considered to be second-line therapy after  tamoxifen for hormone-dependent breast cancer in the United States, they have become first-line drugs in  other countries for the treatment of breast cancer in postmenopausal women. They are orally active and cause  almost a total suppression of estrogen synthesis. They are cleared primarily by liver metabolism.   3. Exemestane: A steroidal, irreversible inhibitor of aromatase, exemestanei [ex-uh-MES-tane], is orally well  absorbed and widely distributed. Hepatic metabolism is by the CYP3A4 isozyme, but to date, no interactions  have been reported. Because the metabolites are excreted into the urine, doses of the drug must be adj usted in  patients with renal failure. Its maj or toxicities are nausea, fatigue, and hot flashes. Acne and hair changes also  occur.   Megestrol [me-J ESS-trole] acetate was formerly the progestin used most widely in treating metastatic hormone-  responsive breast and endometrial neoplasms. It is orally effective. Other agents are usually compared to it in  clinical trials. However, the aromatase inhibitors are replacing it in therapy.   Gonadotropin-releasing hormone is normally secreted by the hypothalamus and stimulates the anterior pituitary to  secrete the gonadotropic hormones, luteinizing hormone (LH; the primary stimulus for the secretion of testosterone  by the testes), and follicle-stimulating hormone (FSH; which stimulates the secretion of estrogen). The synthetic  nonapeptides, leuprolide [loo-PROE-lide] and goserelin [GOE-se-rel-in], are analogs of GnRH. As GnRH agonists,  they occupy the GnRH receptor in the pituitary, which leads to its desensitization and, consequently, inhibition of  release of FSH and LH. Thus, both androgen and estrogen syntheses are reduced (Figure 39.30). Response to  leuprolide in prostatic cancer is equivalent to that of orchiectomy (surgical removal of one or both testes), with  regression of tumor and relief of bone pain. These drugs have some benefit in premenopausal women with advanced  breast cancer and have largely replaced estrogens in therapy for prostate cancer. Leuprolide is available 1) as a  sustained-release preparation, 2) subcutaneous, or 3) as a depot intramuscular inj ection to treat metastatic  carcinoma of the prostate. Goserelin acetate is implanted intramuscularly. Levels of androgen may initially rise but  then fall to castration levels. The adverse effects of these drugs, including impotence, hot flashes, and tumor flare,  are minimal compared to those experienced with estrogen treatment.   Figure 39.30 Effects of some anticancer drugs on the endocrine system. A. In therapy for prostatic cancer.  B. In therapy of postmenopausal breast cancer. FSH =f ol licle-stimulating hormone; GnRH (LHRH) =  gonadotropin- releasing hormone (leuteinizing hormone-releasing hormone).   Estrogens, such as ethinyl estradiol or diethylstilbestrol , had been used in the treatment of prostatic cancer.   However, they have been largely replaced by the GnRH analogs because of fewer adverse effects. Estrogens inhibit  the growth of prostatic tissue by blocking the production of LH, thereby decreasing the synthesis of androgens in  the testis. Thus, tumors that are dependent on androgens are affected. Estrogen treatment can cause serious  complications, such as thromboemboli, myocardial infarction, strokes, and hypercalcemia. Men who are taking  estrogens may experience gynecomastia and impotence.   Flutamide [FLOO-tah-mide], nilutamide [nye-LOO-ta-mide], and bicalutamide [bye-ka-LOO-ta-mide] are  synthetic, nonsteroidal antiandrogens used in the treatment of prostate cancer. They compete with the natural  hormone for binding to the androgen receptor and prevent its translocation into the nucleus (see Figure 39.30).  Flutamide is metabolized to an active hydroxy derivative that binds to the androgen receptor. Flutamide blocks the  inhibitory effects of testosterone on gonadotropin secretion, causing an increase in serum LH and testosterone  levels. Therefore, flutamide is always administered in combination with leuprolide or goserelin which can  desensitize the hypothalamus-pituitary axis. These antiandrogens are taken orally. [Note: Flutamide requires dosing  three times a day and the others once a day. ] These agents are cleared through the kidney. Side effects include  gynecomastia and Gl distress and, in the case of flutamide, liver failure could occur. Nilutamide can cause visual  problems.   Monoclonal antibodies have become an active area of drug development for anticancer therapy and other  nonneoplastic diseases, because they are directed at specific targets and often have fewer adverse effects. They  are created from B lymphocytes (from immunized mice or hamsters) fused with aCoeimmortalaCS B-lymphocyte  tumor cells. The resulting hybrid cells can be individually cloned, and each clone will produce antibodies directed  against a single antigen type. Recombinant technology has led to the creation of a€oehumanizeda€' antibodies that  overcome the immunologic problems previously observed following administration of mouse (murine) antibodies.  Currently, several monoclonal antibodies are available in the United States for the treatment of cancer.  Trastuzumab, rituximab, bevacizumab, and cetuximab are described below. Others include gemtuzumab  ozogamicin, which is a monoclonal antibody conj ugated with a plant toxin that binds to CD33a€"a cell-surface  receptor that is present on the leukemia cells of 80 percent of patients with acute myelocytic leukemia;  alemtuzumab, which is effective in treatment of B-cell chronic lymphocytic leukemia that no longer responds to  other agents; and 1 131 -tositumomab, which is used in relapsed non-Hodgkin's lymphoma.   In patients with metastatic breast cancer, overexpression of transmembrane human epidermal growth  factoraC" receptor protein 2 (HER2) is seen in 25 to 30 percent of patients. Trastuzumab [tra-STEW-zoo-mab], a  recombinant DNAa€"produced, humanized monoclonal antibody, specifically targets the extracellular domain of the  HER2 growth receptor that has intrinsic tyrosine kinase activity. The drug, usually administered with paclitaxel, can  cause regression of breast cancer and metastases in a small percentage of these individuals. [Note: At least 50  tyrosine kinases mediate cell growth or division by phosphorylating signaling proteins. They have been implicated in    the development of many neoplasms by an unknown mechanism. ] Trastuzumab binds to HER2 sites in breast cancer  tissue and inhibits the proliferation of cells that overexpress the HER2 protein, thereby decreasing the number of  cells in the S phase.   1. Mechanism of action: How the antibody causes its anticancer effect remains to be elucidated. Several  mechanisms have been proposeda€"for example, down-regulation of HER2-receptor expression, an induction of  antibody-dependent cytotoxicity, or a decrease in angiogenesis due to an effect on vascular endothelial growth  factor. Efforts are being directed toward identifying those patients with tumors that are sensitive to the drug.   2. Pharmacokinetics: Trastuzumab is administered IV. Trastuzumab does not penetrate the blood-brain barrier.   3. Adverse effects: The most serious toxicity associated with the use of trastuzumab is congestive heart failure.   The toxicity is worsened if given in combination with anthracydine. Extreme caution should be exercised when  giving the drugs to patients with preexisting cardiac dysfunction. Other adverse effects include infusion-related  fever and chills, headache, dizziness, nausea, vomiting, abdominal pain, and back pain, but these effects are  well tolerated. Cautious use of the drug is recommended in patients who are hypersensitive to the Chinese  hamster ovary (CHO) cell components of the proteins or to benzyl alcohol (in which case sterile water can be  used in place of the bacteriostatic solution provided for preparation of the injection).   Rituximab (ri-TUCX-ih-mab) was the first monoclonal antibody to be approved for the treatment of cancer. It is a  genetically engineered, chimeric monoclonal antibody directed against the CD20 antigen that is found on the  surfaces of normal and malignant B lymphocytes. CD20 plays a role in the activation process for cell-cycle initiation  and differentiation. The CD20 antigen is expressed on nearly all B-cell non-Hodgkin's lymphomas, but not in other  bone marrow cells. Rituximab has proven to be effective in the treatment of posttransplant lymphoma and in  chronic lymphocytic leukemia.   1. Mechanism of action: The Fab domain of rituximab binds to the CD20 antigen on the B lymphocytes, and its Fc  domain recruits immune effector functions, inducing complement and antibody-dependent, cell-mediated  cytotoxicity of the B cells. The antibody is commonly used with other combinations of anticancer agents, such as  cyclophosphamide, doxorubicin, vincristine (Oncovin), and prednisone (CHOP).   2. Pharmacokinetics: Rituximab is infused IV and causes a rapid depletion of B cells (both normal and malignant).   3. Adverse effects: Severe adverse reactions have been fatal. It is important to infuse rituximab slowly.   Hypotension, bronchospasm, and angioedema may occur. Chills and fever frequently accompany the first  infusion, especially in patients with high circulating levels of neoplastic cells, because of rapid activation of  complement, which results in the release of tumor necrosis factor i±and interleukins. Pretreatment with  diphenhydramine, acetaminophen, and bronchodilators can ameliorate these problems. Cardiac arrhythmias  can also occur. Tumor lysis syndrome has been reported within 24 hours of the first dose of rituximab. This  syndrome consists of acute renal   failure that may require dialysis, hyperkalemia, hypocalcemia, hyperuricemia, and hyperphosphatasemia (an  abnormally high content of alkaline phosphatase in the blood). Leukopenia, thrombocytopenia, and neutropenia  have been reported in less than 10 percent of patients.   The monoclonal antibody, bevacizumab [be-vah-SEE-zoo-mab] is the first in a new class of anticancer drugs called  antiangiogenesis agents. Bevacizumab is approved for use as a first-line drug against metastatic colorectal cancer  and is given with 5-FU based chemotherapy. Bevacizumab is infused IV. It attaches to and stops vascular endothelial  growth factor from stimulating the formation of new blood vessels. Without new blood vessels, tumors do not    receive oxygen and essential nutrients necessary for growth and proliferation. The most common adverse effects of  this treatment are hypertension, stomatitis, and diarrhea. Less common are bleeding in the intestines, protein in  the urine, and heart failure. Among the rare serious side effects are bowel perforation, opening of healed wounds,  and stroke.   Cetuximab [see-TUX-i-mab] is another chimeric monoclonal antibody that has recently been approved to treat  colorectal cancer. It is believed to exert its antineoplastic effect by targeting the epidermal growth factor receptor  on the surface of cancer cells and interfering with their growth. It is usually combined with irinotecan during  treatment. Like other antibodies, it is administered IV. Cetuximab has caused difficulty breathing and low blood  pressure during the first treatment, and interstitial lung disease has been reported. Other side effects include rash,  fever, constipation, and abdominal pain.   Cisplatin [SIS-pla-tin] was the first member of the platinum coordination complex class of anticancer drugs, but  because of its severe toxicity, carboplatin [KAR-boe-pla-tin] was developed. The mechanisms of action of the two  drugs are similar, but their potency, pharmacokinetics, patterns of distribution, and dose-limiting toxicities differ  significantly. Cisplatin has synergistic cytotoxicity with radiation and other chemotherapeutic agents. Oxaliplatin  [ox-AL-ih-pla-tin], a new member of this class of drugs, is a closely related analog of carboplatin. Cisplatin has  found wide application in the treatment of solid tumors, such as metastatic testicular carcinoma in combination with  VBL and bleomycin, ovarian carcinoma in combination with cyclophosphamide, or alone for bladder carcinoma.  Carboplatin is employed when patients cannot be vigorously hydrated, as is required for cisplatin treatment, or if  they suffer from kidney dysfunction or are prone to neuro- or ototoxicity. Oxaliplatin is showing excellent activity  against advanced colorectal cancer.   1. Mechanism of action: The mechanism of action for this class of drugs is similar to that of the alkylating agents.   In the high-chloride milieu of the plasma, cisplatin persists as the neutral species, which enters the cell and  loses its chlorides in the low-chloride milieu. It then binds to the N * 2 3 * * * 7 of guanine in DNA, forming inter- and  intrastrand   cross-links. The resulting cytotoxic lesion inhibits both DNA replication and RNA synthesis. Similarly, the  chemical moieties that replace the chlorides in the carboplatin structure are removed hydrolytically to form the  active drug. Cytotoxicity can occur at any stage of the cell cycle, but cells are most vulnerable to the actions of  these drugs in the Gi and S phases. Both drugs can also bind proteins and other compounds containing thiol  (a€"SH) groups.   2. Resistance: Sensitivity to these agents is decreased if cells have elevated glutathione levels or increased DNA  repair or if metallothionein (a protein rich in a€"SH groups) is induced. Decreased cellular uptake has also been  implicated. Cross- resistance between cisplatin and carboplatin is not invariable. However, there is none with  oxaliplatin.   3. Pharmacokinetics: These agents are administered IV in saline solution. They can also be given intraperitoneally   for ovarian cancer and intra-arterially to perfuse other organs. More than 90 percent of cisplatin is covalently   bound to plasma proteins, but the binding of carboplatin to plasma proteins is very low. The highest   concentrations of the drugs are found in the liver, kidney, and intestinal, testicular, and ovarian cells, but little   penetrates into the CSF. The renal route is the main avenue for excretion (Figure 39.31).    4. Adverse effects: Severe, persistent vomiting occurs for at least 1 hour after administration of cisplatin and may  continue for as long as 5 days. Premedication with antiemetic agents is usually helpful. The major limiting  toxicity is dose-related nephrotoxicity, involving the distal convoluted tubule and collecting ducts. This can be  ameliorated by aggressive hydration and diuresis. Hypomagnesemia and hypocalcemia usually occur  concurrently. [Note: It is important to correct calcium levels before correcting magnesium levels. ] Other  toxicities include ototoxicity with high-frequency hearing loss and tinnitus, mild bone marrow suppression, some  neurotoxicity characterized by paresthesia and loss of proprioception, and hypersensitivity reactions ranging  from skin rashes to anaphylaxis. Patients concomitantly receiving aminoglycosides are at greater risk for  nephrotoxicity and ototoxicity. Unlike cisplatin, carbopiatin causes only mild nausea and vomiting, and it is not  nephro-, neuro-, or ototoxic. Its dose-limiting toxicity is myelosuppression.   Irinotecan [eye-rin-oh-TEE-kan] and topotecan [toe-poe-TEE-kan] are semisynthetic derivatives of an earlier, more  toxic drug, camptothecin [camp-toe-THEE-sin], They have a complicated multiring structure containing a lactone  ring that is essential for activity. Topotecan is employed in metastatic ovarian cancer when primary therapy has  failed and also in the treatment of small-cell lung cancer. Irinotecan is used as a first-line drug together with 5-FU  and leucovorin for the treatment of colon or rectal carcinoma.    1. Mechanism of action: These drugs are S-phase specific. They inhibit topoisomerase I, which is essential for the  replication of DNA in human cells (Figure 39.32). Unlike etoposide, which inhibits the related enzyme  topoisomerase II (see below), topotecan was the first clinically useful topoisomerase I inhibitor. SN-38 (the  active metabolite of irinotecan) is formed from irinotecan by carboxylesterase-mediated   cleavage of the carbamate bond between the camptothecin moiety and the dipiperidino side chain. SN-38 is  approximately 1000 times as potent as irinotecan as an inhibitor of topoisomerase I. The topoisomerases relieve  torsional strain in DNA by causing reversible, single-strand breaks. By binding to the enzyme-DNA complex,  topotecan or SN-38 prevent religation of the single-strand breaks.   2. Resistance: Several mechanisms may explain resistance. Among them are the ability to transport the drugs out  of the cell, decreased ability to convert irinotecan to the active SN-38 metabolite, or a down-regulation or  mutation in topoisomerase I.   3. Pharmacokinetics: Topotecan and irinotecan are infused IV. Hydrolysis of the lactone ring destroys the activity   of these drugs. Both the drugs and their metabolites are eliminated in the urine. Therefore, the dose may have  to be modified in patients with impaired kidney function.   4. Adverse effects: Bone marrow suppressiona€"particularly neutropeniaa€"is the dose-limiting toxicity for  topotecan. Frequent peripheral blood counts should be performed on patients taking this drug. [Note:  Topotecan should not be used in patients with a baseline neutrophil count of less than 1500 cells/ mm 3 . Doing so  could result in infection and death. ] Other hematologic complications, including thrombocytopenia and anemia,  may also occur. Nonhematologic effects include diarrhea, nausea, vomiting, alopecia, and headache.  Myelosuppression is also seen with irinotecan, and delayed diarrhea may be severe and require treatment with  loperamide.   Etoposide [e-toe-POE-side] and its analog, teniposide [ten-i-POE-side], are semisynthetic derivatives of the plant  alkaloid, podophyl lotoxi n. They block cells in the late S to G 2 phase of the cell cycle. Their major target is  topoisomerase II. Binding of the drugs to the enzyme-DNA complex results in persistence of the transient, deavable  form of the complex and, thus, renders it susceptible to irreversible double-strand breaks (Figure 39.33). Resistance   to topoisomerase inhibitors is conferred either by presence of the multidrug-resistant P-glycoprotein or by mutation  of the enzyme. Etoposide finds its major clinical use in the treatment of oat-cell carcinoma of the lung and in  combination with bleomycin and cisplatin for testicular carcinoma. Teniposide is used as a second-line agent in the  treatment of acute lymphocytic leukemia. Etoposide may be administered either IV or orally, whereas teniposide is  only administered IV. They are highly bound to plasma proteins and distribute throughout the body, but they enter  the CSF poorly. Despite this, teniposide has shown effectiveness against gliomas and neuroblastomas. Metabolites  are converted to glucuronide and sulfate conj ugates and are excreted in the urine. Drugs that induce the  cytochrome P450 system lead to an acceleration of teniposide metabolism. Dose-limiting myelosuppression  (primarily leukopenia) is the maj or toxicity for both drugs. Leukemia may develop in patients who were treated with  etoposide. Other toxicities are alopecia, anaphylactic reactions, nausea, and vomiting.   Imatinib [i-MAT-in-ib] mesylate is used for the treatment of chronic myeloid leukemia in blast crisis, as well as Gl  stromal tumor. It acts as a signal   transduction inhibitor, used specifically to inhibit tumor tyrosine kinase activity. A deregulated BCR-ABL kinase is  present in the leukemia cells of almost every patient with chronic myeloid leukemia. In the case of Gl stromal  tumor, an unregulated expression of tyrosine kinase is associated with a growth factor. The ability of imatinib to  occupy the a€oekinase pocketa€§ prevents the phosphorylation of tyrosine on the substrate molecule and, hence,  inhibits subsequent steps that lead to cell proliferation. Imatinib has the advantage over interferon-i± in that it can  be given orally. It also has a more rapid hematologic response than interferon-i± plus cytarabine. Studies of cell  lines indicate that resistance may occur by amplification of the BCR-ABL gene and/or by increased efflux due to  increased multidrug-resistance protein. The drug is very well absorbed orally. It undergoes metabolism by the  cytochrome P450 system to several compounds, of which the N-demethyl derivative is active. Excretion is  predominantly through the feces. Adverse effects include fluid retention and edema, hepatotoxicity,  thrombocytopenia or neutropenia, as well as nausea and vomiting.   Gefitinib [ge-FIN-ih-tib] targets the epidermal growth factor receptor. It is approved for the treatment of  nona€" small cell lung cancer that has failed to respond to other therapy, and it is effective in 10 to 20 percent of  patients with this cancer. Gefitinib is usually used as a single agent. Gefitinib is absorbed after oral administration  and undergoes extensive metabolism in the liver by the cytochrome P450 enzyme CYP3A4. At least five metabolites  have been identified, only one of which has significant antitumor activity. The major route of excretion of the drug  and its metabolites is the feces. The most common adverse effects are diarrhea, nausea, and acne-like skin rashes.   A rare but potentially fatal adverse effect is interstitial lung disease, which presents as acute dyspnea with cough.   Procarbazine [proe-KAR-ba-zeen] is used in the treatment of Hodgkin's disease and other cancers. Procarbazine  rapidly equilibrates between the plasma and the CSF after oral or parenteral administration. It must undergo a series  of oxidative reactions to exert its cytotoxic action that causes inhibition of DNA, RNA, and protein synthesis.   Metabolites and the parent drug are excreted via the kidney. Bone marrow depression is the maj or toxicity, and  nausea, vomiting, and diarrhea are common. The drug is also neurotoxic, causing symptoms ranging from drowsiness  to hallucinations to paresthesias. Because it inhibits monoamine oxidase, patients should be warned against  ingesting foods that contain tyramine (for example, aged cheeses, beer, and wine). Ingestion of alcohol leads to a  disulfiram-type reaction). Procarbazine is both mutagenic and teratogenic. Nonlymphocytic leukemia has  developed in patients treated with the drug.   L- Asparaginase [ah-SPAR-a-gi-nase] catalyzes the deamination of asparagine to aspartic acid and ammonia. The  form of the enzyme used chemotherapeutically is derived from bacteria. L-Asparaginase is used to treat childhood   and prednisone. Its mechanism of action is based on the fact that some neoplastic cells require an external source  of asparagine because of their limited capacity to synthesize sufficient amounts of that amino acid to support  growth and function. L-Asparaginase hydrolyzes blood asparagine and, thus, deprives the tumor cells of this amino  acid, which is needed for protein synthesis (Figure 39.34). Resistance to the drug is due to increased capacity of  tumor cells to synthesize asparagine. The enzyme must be administered either IV or intramuscularly, because it is  destroyed by gastric enzymes. Toxicities include a range of hypersensitivity reactions (because it is a foreign  protein), a decrease in clotting factors, liver abnormalities, pancreatitis, seizures, and coma due to ammonia  toxicity.   Human interferons have been classified into three typesa€"i+ i 2 , and l 3 a€"on the basis of their antigenicity. The i±  interferons are primarily leukocytic, whereas the I 2 and i 3 interferons are produced by connective tissue fibroblasts  and T lymphocytes, respectively. Recombinant DNA techniques in bacteria have made it possible to produce large  quantities of pure interferons, including two species designated interferon-\±-2a and -2b that are employed in  treating neoplastic diseases. lnterferon-\±-2a is presently approved for the management of hairy-cell leukemia,  chronic myeloid leukemia, and acquired immunodeficiency syndrome (AIDS) a€" related Kaposi sarcoma.  lnterferon-l±-2b is approved for the treatment of hairy-cell leukemia, melanoma, AIDS-related Kaposi's sarcoma,  and follicular lymphoma.   I. Mechanism of action: Interferons secreted from producing cells interact with surface receptors on other cells,  at which site they exert their effects. Bound interferons are neither internalized nor degraded. The i±and i 2  interferons compete with each other for binding and, therefore, presumably bind at the same receptor or in  close proximity; the I 3 interferons bind at different receptors. As a consequence of the binding of interferon, a  series of complex intracellular reactions take place. These include synthesis of enzymes, suppression of cell  proliferation, activation of macrophages, and increased cytotoxicity of lymphocytes. However, the exact  mechanism by which the interferons are cytotoxic is unknown   2. Pharmacokinetics: Interferons are well absorbed after intramuscular or subcutaneous inj ections. An IV form of   interferon-l±-2b is also available. Interferons undergo glomerular filtration and are degraded during  reabsorption, but liver metabolism is minimal.    Normal cells have high  levels of asparagine  synthetase and are able  to make sufficient  asparagine for protein  synthesis and cell growth.    Neoplastic cells have low  levels of asparagine syn-  thetase and are unable  to make sufficient aspar-  agine for protein syn-  thesis and cell growth.    Figure 39.34 Activity of asparagine synthetase in normal and neoplastic cells.   39.1 A patient with colonic cancer is being treated with 5-FU as well as leucovorin (N 5 ,N 10 -methylene  tetrahydrofolate). The rationale for administering the coenzyme depends on it being essential for:   39. 2 Neutropenia develops in a patient undergoing cancer chemotherapy. Administration of which one of the  following agents would accelerate recovery of neutrophil counts?   39.3 Hydration and/or diuresis can prevent the renal toxicity associated with:   39.4 A patient is being treated with allopurinol to control hyperuricemia resulting from chemotherapy. Which  of the following would have to have its dose reduced to prevent toxicity?   >Table of Contents > Unit VII - Chemotherapeutic Drugs >Chapter 40 - Immunosuppressants   The importance of the immune system in protecting the body against harmful foreign molecules is well recognized.  However, in some instances, this protection can result in serious problems. For example, the introduction of an  allograft (that is, the graft of an organ or tissue from one individual to another who is not genetically identical) can  elicit a damaging immune response, causing rej ection of the transplanted tissue. Transplantation of organs and  tissues (for example, kidney, heart, or bone marrow) has become routine due to improved surgical techniques and  better tissue typing. Also, drugs are now available that more selectively inhibit rejection of transplanted tissues  while preventing the patient from becoming immunologically compromised (Figure 40.1). Earlier drugs were  nonselective, and patients frequently succumbed to infection due to suppression of both the antibody-mediated  (humoral) and cell-mediated arms of the immune system. Today, the principal approach to immunosuppressive  therapy is to alter lymphocyte function using drugs or antibodies against immune proteins. Because of their severe  toxicities when used as monotherapy, a combination of immunosuppressive agents, usually at lower doses, is  generally employed. [Note: Immunosuppressive therapy is also used in the treatment of autoimmune diseases; for  example, corticosteroids can control acute glomerulonephritis. ] Immunosuppressive drug regimens usually consist of  anywhere from two to four agents with different mechanisms of action that disrupt various levels of T-cell  activation. The immune activation cascade can be described as a three-signal model. Signal 1 constitutes T-cell  triggering at the CD3 receptor complex by an antigen on the surface of an antigen-presenting cell (APC), Signal 2,  also referred to as costimulation, occurs when CD80 and CD86 on the surface of APCs engage CD28 on T cells. Both  Signals 1 and 2 activate several intracellular signal transduction pathways, one of which is the calcium-calcineurin  pathway, which is targeted by cyclosporine and tacrolimus. These pathways trigger the production of cytokines  such as interleukin ( I L) -2, IL- 15, CD154, and CD25. IL-2 then binds to CD25 (also known as the IL-2 receptor) on the  surface of other T cells to activate mammalian target of rapamycin (mTOR), providing Signal 3, the stimulus for  T-cell proliferation. Immunosuppressive drugs can be categorized according to their mechanisms of action: 1) Some  agents interfere with cytokine production or action; 2) others disrupt cell metabolism, preventing lymphocyte  proliferation; and 3) mono- and polyclonal antibodies block T-cell surface molecules.   Cytokines are soluble, antigen-nonspecific, signaling proteins that bind to cell surface receptors on a variety of  cells. The term cytokine includes the molecules known as ILs, interferons (IFNs), tumor necrosis factors (TNFs),  transforming growth factors, and colony-stimulating factors. Of particular interest when discussing  immunosuppressive drugs is IL-2a€"a growth factor that stimulates the proliferation of antigen-primed (helper) T  cells, which subsequently produce more IL-2, IFN-i 3 , and TNF-i 2 (Figure 40.2). These cytokines collectively activate  natural killer cells, macrophages, and cytotoxic T lymphocytes. Clearly, drugs that interfere with the production or  activity of IL-2, such as cyclosporine, will significantly dampen the immune response and, thereby, decrease graft  rejection.   Cyclosporine [sye-kloe-SPOR-een] ( CsA ) is a lipophillic cyclic polypeptide composed of 11 amino acids (several are  methylated on the peptidyl nitrogen). The drug is extracted from a soil fungus. Cs4 is used to prevent rej ection of  kidney, liver, and cardiac allogeneic transplants. CsA is most effective in preventing acute rejection of transplanted  organs when combined in a double-drug or triple-drug regimen with corticosteroids and an antimetabolite such as  mycophenolate mofetil. CsA is an alternative to methotrexate for the treatment of severe, active rheumatoid  arthritis. It can also be used for patients with recalcitrant psoriasis that does not respond to other therapies.   1. Mechanism of action: Cyclosporine preferentially suppresses cell-mediated immune reactions, whereas humoral  immunity is affected to a far lesser extent. After diffusing into the T cell, CsA binds to a cyclophilin (more  generally called an immunophilin) to form a complex that binds to calcineurin (Figure 40.3). The latter is  responsible for dephosphorylating NFATc (cytosolic Nuclear Factor of Activated T cells). The CsA-calcineurin  complex cannot perform this reaction; thus, NFATc cannot enter the nucleus to promote the reactions that are  required for the synthesis of a number of cytokines, including IL-2. The end result is a decrease in IL-2a€"the  primary chemical stimulus for increasing the number of T lymphocytes.   2. Pharmacokinetics: Cyclosporine may be given either orally or by intravenous infusion. Oral absorption is  variable. Interpatient variability may be due to metabolism by a cytochrome P450 (CYP3A4) in the    gastrointestinal tract, where the drug is metabolized. About 50 percent of the drug is associated with the blood  fraction. Half of this is in the erythrocytes, and less than one-tenth is bound to the lymphocytes. CsA is  extensively metabolized, primarily by hepatic CYP3A4. [Note: When other drug substrates for this enzyme are  given concomitantly, many drug interactions have been reported.] It is not clear whether any of the 25 or more  metabolites have any activity. Excretion of the metabolites is through the biliary route, with only a small  fraction of the parent drug appearing in the urine.   3. Adverse effects: Many of the adverse effects caused by CsA are dose dependent; therefore, it is important to  monitor blood levels of the drug. Nephrotoxicity is the most common and important adverse effect of CsA. It is  therefore critical to monitor kidney function. Reduction of   the CsA dosage can result in reversal of nephrotoxicity in most cases, although nephrotoxicity may be  irreversible in 15% of patients. [Note: Coadministration of drugs that also can cause kidney dysfunction (for  example, the aminoglycoside antibiotics) and anti-inflammatories, such as diclofenac, naproxen, or sulindac,  can potentiate the nephrotoxicity of CsA.] Hepatotoxicity can also occur; therefore, liver function should be  periodically assessed.] Infections in patients taking CsA are common and may be life-threatening. Viral  infections due to herpes group and cytomegalovirus (CMV) are prevalent. Lymphoma may occur in all  transplanted patients due to the net level of immunosuppression and has not been linked to any one particular  agent. Anaphylactic reactions can occur on parenteral administration. Other toxicities include hypertension,  hyperlipidemia, hyperkalemia (it is important not to use K + -sparing diuretics in these patients), tremor,  hirsutism, glucose intolerance, and gum hyperplasia.    At a result of  dephosphorylation  by caldneurin,  NFATc moves from  the cytoplasm to  the nucleus    NFATc associates  with other nuclear  components, leading  to activation of genes  encoding cytokines    Figure 40.3 Mechanism of action of cyclosporine and tacrolimus. 11-2 = interleukin-2; mTOR = mammalian  target of rapamycin; NFATc = cytosol ic nuclear factor of activated T cells.   Tacrolimus [ta-CRAW-lih-mus] (TAC, originally called FK506 ) is a macrolide that is isolated from a soil fungus. TAC is  approved for the prevention of rej ection of liver and kidney transplants and is given with a corticosteroids and/or  an antimetabolite. This drug has found favor over   CsA, not only because of its potency and decreased episodes of rej ection (Figure 40. 4) but also because lower doses  of corticosteroids can be used, thus reducing the likelihood of steroid-associated adverse effects. An ointment  preparation has been approved for moderate to severe atopic dermatitis that does not respond to conventional  therapies.    Figure 40.4 Five-year renal allograft survival in patients treated with cyclosporine or tacrolimus.    1. Mechanism of action: TAC exerts its immunosuppressive effect in the same manner as CsA, except that it binds  to a different immunophilin, FKBP-12 (FK-binding protein; Figure 40.5).   2. Pharmacokinetics: TAC may be administered orally or intravenously. The oral route is preferable, but as with  CsA, oral absorption of TAC is incomplete and variable, requiring tailoring of doses. Absorption is decreased if  the drug is taken with high-fat or high-carbohydrate meals. TAC is from 10- to 100-fold more potent than CsA. It  is highly bound to serum proteins and is also concentrated in erythrocytes. Like CsA, TAC undergoes hepatic  metabolism by the CYP3A4 isozyme; thus, the same drug interactions occur. At least one metabolite of TAC has  been shown to have immunosuppressive activity. Renal excretion is very low, and most of the drug and its  metabolites are found in the feces.   3. Adverse effects: Nephrotoxicity and neurotoxicity (tremor, seizures, and hallucinations) tend to be more  severe in patients who are treated with TAC than in patients treated with CsA, but careful dose adj ustment can  minimize this problem. Development of posttransplant, insulin-dependent diabetes mellitus is a problem,  especially in black and Hispanic patients. Other toxicities are the same as those for CsA, except that TAC does  not cause hirsutism or gingival hyperplasia. Compared with CsA, TAC has also been found to have a lower    incidence of cardiovascular toxicities such as hypertension and hyperlipidemia, both of which are common  disease states found in kidney transplant recipients. Anaphylactoid reactions to the injection vehicle have been  reported. The drug interactions are the same as those described for CsA.   Sirolimus [si h-ROW-lih-mus] (SRL) is a recently approved macrolide obtained from fermentations of a soil mold. The  earlier namea€"and one that is sometimes still useda€"is rapamycin. SRL is approved for use in renal  transplantation, to be used together with CsA and corticosteroids, thereby allowing lower doses of those  medications to be employed and, thus, lowering their toxic potential. The combination of SRL and CsA is apparently  synergistic because SRL works later in the immune activation cascade. To limit the long-term side effects of the  calcineurin inhibitor, SRL is often utilized in calcineurin inhibitor withdrawal protocols in patients who remain  rej ection free during the first 3 months posttransplant. The antiproliferative action of SRL has found use in  cardiology. SRL-c oated stents inserted into the cardiac vasculature inhibit restenosis of the blood vessels by  reducing proliferation of the endothelial cells. In addition to its immunosuppressive effects, SRL also inhibits  proliferation of cells in the graft intimal areas and, thus, is effective in halting graft vascular disease.    selected mRNAs  that promote  transition from  Gi to S phase  of the cell cycle.    Figure 40.5 Mechanism of action of sirolimus. mTOR =molecular target of rapamycin (sirolimus).    1. Mechanism of action: SRL and TAC bind to the same cytoplasmic FK-binding protein, but instead of forming a  complex with calcineurin, SRL binds to mTOR interfering with Signal 3). The latter is a serine-threonine   kinase. [Note: TOR proteins are essential for many cellular functions, such as cell-cycle progression, DNA repair,  and as regulators involved in protein translation. ] Binding of SRL to mTOR blocks the progression of activated T  cells from the Gi to the S phase of the cell cycle and, consequently, the proliferation of these cells (see Figure  40. 5). Unlike CsA and TAC, SRL does not owe its effect to lowering IL-2 production but, rather, to inhibiting the  cellular responses to IL-2.   2. Pharmacokinetics: The drug is available only as oral preparations. Although it is readily absorbed, high-fat  meals can decrease the druga€"s absorption. SRL has a long half-life compared to those of CsA and TAC, and a  loading dose is required at the time of initiation of therapy. Like both CsA and TAC, SRL is metabolized by the  CYP3A4 isozyme and interacts with the same drugs as do CsA and TAC. SRL also increases the drug  concentrations of CsA, and careful blood level monitoring of both agents must be employed to avoid harmful  drug toxicities. The parent drug and its metabolites are predominantly eliminated in the feces.   3. Adverse effects: A frequent side effect of SRL is hyperlipidemia (elevated cholesterol and triglycerides), which  can require treatment. The combination of CsA and SRL is more nephrotoxic than Cs4 alone due to the drug  interaction between the two; therefore, lower doses are initiated. Although the administration of SRL and TAC  appears to be less nephrotoxic, SRL can still potentiate the nephrotoxicity of TAC, and drug levels of both must  be monitored closely. Other untoward problems are headache, nausea and diarrhea, leukopenia, and  thrombocytopenia. Impaired wound healing has been noted with SRL in obese patients and those with diabetes;  this can be especially problematic immediately following the transplant surgery and in patients receiving  corticosteroids.   Immunosuppressive antimetabolite agents are generally used in combination with corticosteroids, and the  calcineurin inhibitors, CsA and TAC.   Azathioprine [ay-za-TFIYE-oh-preen] was the first agent to achieve widespread use in organ transplantation. It is a  prodrug that is converted first to 6-mercaptopurine ( 6-MP ) and then to the corresponding nucleotide, thioinosinic  acid. The immunosuppressive effects of azathioprine are due to this nucleotide analog. Because of their rapid  proliferation in the immune response and their dependence on the de novo synthesis of purines required for cell  division, lymphocytes are predominantly affected by the cytotoxic effects of azathioprine. [Note: The drug has  little effect on suppressing a chronic immune response.] Its major nonimmune toxicity is bone marrow suppression.  Concomitant use with angiotensin-converting enzyme inhibitors or cotrimoxazole in renal transplant patients can  lead to an exaggerated leukopenic response. Allopurinol, an agent used to treat gout, significantly inhibits the  metabolism of azatihioprine-, therefore, the dose of azathioprine must be reduced by 60 to 75 percent. Nausea and  vomiting are also encountered. (See p. 464 for a discussion of the mechanism of action, resistance, and  pharmacokinetics of 6-MP.)   Azathioprine has for the most part been replaced by mycophenolate mofetil [mye-koe-FEN-oh-late MAW-feh-til]  (MMF) because of the lattera€"s safety and efficacy in prolonging graft survival. It has been successfully used in    heart, kidney, and liver transplants. As an ester, it is rapidly hydrolyzed in the gastrointestinal tract to  mycophenolic acid (MPA), which is a potent, reversible, uncompetitive inhibitor of inosine monophosphate  dehydrogenase, blocking the de novo formation of guanosine phosphate. Thus, like 6-MP, it deprives the rapidly  proliferating T and B cells of a key component of nucleic acids (Figure 40.6). [Note: Lymphocytes lack the salvage  pathway for purine synthesis and, therefore, are dependent on de novo purine production. ] MPA is quickly and  almost completely absorbed after oral administration. Both MPA and its glucuronidated metabolite are highly bound  (greater than 90 percent) to plasma albumin, but no displacement-type interactions have been reported. The  glucuronide is excreted predominantly in the urine. The most common adverse effects include diarrhea, nausea,  vomiting, abdominal pain, leukopenia, and anemia. Higher doses of MMF (3 g/ day) were associated with a higher  risk of CMV infection. [Note: MPA is less mutagenic or carcinogenic than azathioprine. ] Concomitant administration  with antacids containing magnesium or aluminum, or with cholestyramine, can decrease absorption of the drug.   In an effort to minimize the gastrointestinal effects associated with MMF, enteric-coated mycophenolate sodium  (EC -MPS) was developed. The active drug (MPA) is contained within a delayed-release formulation designed to  release in the neutral pH of the small intestine. EC-MPS at 720 mg and MMF at 1000 mg contain equivalent amounts  of MPA. In Phase III studies, the new formulation was found to be equivalent to MMF in the prevention of acute  rejection episodes in kidney transplant recipients. However, the rate of gastrointestinal adverse events was similar  to that with MMF.   The use of antibodies plays a central role in prolonging allograft survival. They are prepared either by immunization  of rabbits or horses with human lymphoid cells (producing a mixture of polyclonal antibodies directed against a  number of lymphocyte antigens), or by hybridoma technology (producing antigen-specific, monoclonal antibodies).   [Note: Hybridomas are produced by fusing mouse antibody-producing cells with immortal, malignant plasma cells  (Figure 40. 7). Hybrid cells are selected and cloned, and the antibody specificity of the clones is determined. Clones  of interest can be cultured in large quantities to produce clinically useful amounts of the desired antibody.   Recombinant DNA technology can also be used to replace part of the mouse gene sequence with human genetic  material, thus a€oehumanizinga€§ the antibodies produced, making them less antigenic. ] The names of monoclonal  antibodies conventionally contain a€oemuroa€^ if they are from a murine (mouse) source and a€oexia€§ or  a€oeiza€^ if they are humanized (see Figure 40.7). The suffix a€oemaba€§ (monoclonal antibody) identifies the  category of drug. The polyclonal antibodies, although relatively inexpensive to produce, are variable and less  specific, which is in contrast to monoclonal antibodies, which are homogeneous and specific.   Thymocytes are cells that develop in the thymus and serve asT-cell precursors. The antibodies developed against  them are prepared by immunization of large rabbits or horses with human lymphoid cells and, thus, are polyclonal.  They are primarily employed, together with other immunosuppressive agents, at the time of transplantation to  prevent early allograft rej ection, or they may be used to treat severe rej ection episodes or corticosteroid-resistant  acute rej ection. Rabbit formulations of polyclonal antithymocyte globulin are more commonly used over the horse  preparation due to greater potency. The antibodies bind to the surface of circulating T lymphocytes, which then  undergo various reactions, such as complement-mediated destruction, antibody-dependent cytotoxicity, apoptosis,  and opsonization. The antibody-bound cells are phagocytosed in the liver and spleen, resulting in lymphopenia and  impaired T-cell responses. The antibodies are slowly infused intravenously, and their half-life extends from 3 to 9  days. Because the humoral antibody mechanism remains active, antibodies can be formed against these foreign  proteins. [Note: This is less of a problem with the humanized antibodies. ] Other adverse effects include chills and  fever, leukopenia and thrombocytopenia, infections due to CMV or other viruses, and skin rashes.    Figure 40.7 Conventions for naming monoclonal antibodies. [Note: Muromonati was named before the  convention was adopted to make the last three letters in their names mab . ]   Muromonab-CD3 [myoo-roe-MOE-nab] is a murine monoclonal antibody that is synthesized by hybridoma technology  and directed against the glycoprotein CD3 antigen of human T cells. Muromonab-CD3 is used for treatment of acute  rejection of renal allografts as well as for corticosteroid-resistant acute allograft rejection in cardiac and hepatic  transplant patients. It is also used to deplete T cells from donor bone marrow prior to transplantation.   1. Mechanism of action: Binding to the CD3 protein results in a disruption of T-lymphocyte function, because  access of antigen to the recognition site is blocked. Circulating T cells are depleted; thus, their participation in  the immune response is decreased. Because muromonab-CD3 recognizes only one antigenic site, the  immunosuppression is less broad than that seen with the polyclonal antibodies. T cells usually return to normal  within 48 hours of discontinuation of therapy.   2. Pharmacokinetics: The antibody is administered intravenously. Initial binding of muromonab-CD3 to the  antigen transiently activates the T cell and results in cytokine release (cytokine storm). It is therefore customary  to premedicate the patient with methyl prednisolone, diphenhydramine, and acetaminophen to alleviate the  cytokine release syndrome.   3. Adverse effects: Anaphylactoid reactions may occur. Cytokine release syndrome may follow the first dose. The  symptoms can range from a mild, flu-like illness to a life-threatening, shock-like reaction. High fever is common.  Central nervous system effects, such as seizures, encephalopathy, cerebral edema, aseptic meningitis, and  headache, may occur. Infections can increase, including some due to CMV. Muromonab-CD3 is contraindicated  in patients with a history of seizures, in those with uncompensated heart failure, in pregnant women, and in    those who are breast-feeding. Because of these adverse effects and the improved tolerability of thymoglobulin  and the IL-2 receptor antagonists, muromonab-CD3 is rarely used today.   The antigenicity and short serum half-life of the murine monoclonal antibody have been averted by replacing most  of the murine amino acid sequences with human ones by genetic engineering. Basiliximab [bah-si-LIK-si-mab] is said  to be a€oechimerizeda€§] because it consists of 25 percent murine and 75 percent human protein. Daclizumab  [dah-KLIZ-yoo-mab] is 90 percent human protein, and is designated a€oehumanized.a€§ Both agents have been  approved for prophylaxis of acute rejection in renal transplantation in combination with CsA and corticosteroids.  They are not used for the treatment of ongoing rejection.   1. Mechanism of action: Both compounds are anti-CD25 antibodies and bind to the T± chain of the IL-2 receptor on  activated T cells. They thus interfere with the proliferation of these cells. Basiliximab is about 10-fold more  potent than daclizumab as a blocker of IL-2 stimulated T-cell replication. Blockade of this receptor foils the  ability of any antigenic stimulus to activate the T cella€"response system.   2. Pharmacokinetics: Both antibodies are given intravenously. The serum half-life of daclizumab is about 20 days,  and the blockade of the receptor is 120 days. Five doses of daclizumab are usually administereda€"the first at 24  hours before transplantation, and the next four doses at 14-day intervals. The serum half-life of basiliximab is  about 7 days. Usually, two doses of this drug are administereda€"the first at 2 hours prior to transplantation, and  the second at 4 days after the surgery.   3. Adverse effects: Both daclizumab and basiliximab are well tolerated. Their maj or toxicity is gastrointestinal.   No clinically relevant antibodies to the drugs have been detected, and malignancy does not appear to be a  problem.   Alemtuzumab [al-em-TOOZ-oo-mab], a humanized monoclonal antibody directed against CD52, exerts its effects by  causing profound depletion of T cells from the peripheral circulation. This effect may last for up to 1 year.   Alemtuzumab is currently approved for the treatment of refractory B-cell chronic lymphocytic leukemia. Although  it is not currently approved for use in organ transplantation, it is being utilized in combination with SRL and  low-dose calcineurin inhibitors in corticosteroid avoidance protocols at many transplant centers. Preliminary results  are promising, with low rates of rej ection with a prednisone- free regimen. Side effects include first-dose cytokine-  release syndrome, requiring premedication with acetaminophen, diphenhydramine, and corticosteroids. Adverse  effects include neutropenia, anemia, and rarely, pancytopenia. Early results have not shown an increase in  opportunistic infections or lymphomas with alemtuzumab despite its potent immunosuppressive activity. A summary  of the major immunosuppressive drugs is presented in Figure 40.8   The corticosteroids were the first pharmacologic agents to be used as immunosuppressives both in transplantation  and in various autoimmune disorders. They are still one of the mainstays for attenuating rejection episodes. For  transplantation, the most common agents are prednisone or   methyl prednisolone, whereas prednisone or prednisolone are employed for autoimmune conditions. [Note: In  transplantation, they are used in combination with agents described previously in this chapter. ] The steroids are  used to suppress acute rejection of solid organ allografts and in chronic graft-versus-host disease. In addition, they  are effective against a wide variety of autoimmune conditions, including refractory rheumatoid arthritis, systemic  lupus erythematosus, temporal arthritis, and asthma. The exact mechanism responsible for the immunosuppressive  action of the corticosteroids is unclear. The T lymphocytes are affected most. The steroids are able to rapidly  reduce lymphocyte populations by lysis or redistribution. On entering cells, they bind to the glucocorticoid    receptor. The complex passes into the nucleus and regulates the translation of DNA. Among the genes affected are  those involved in inflammatory responses. The use of these agents is associated with numerous adverse effects.  For example, they are diabetogenic, and they can cause hypercholesterolemia, cataracts, osteoporosis, and  hypertension on prolonged use. Consequently, efforts are being directed toward reducing or eliminating the  use of steroids in the maintenance of allografts.    Figure 40.8 Sites of action of immunosuppressants. 11-2 = interleukin-2. NFATc = cytosol i c nuclear factor of  activated T cells.   40. 1 A 45-year-old male who received a renal transplant 3 months previously and is being maintained on  methylprednisolone, cyclosporine, and mycophenolate mofetil is found to have increased creatinine levels,  indicating possible rejection. Which of the following courses of therapy would be appropriate?   40. 2 A 23-year-old female suffering from grand mal epilepsy is being controlled with phenytoin. She is a  candidate for a renal transplant. Which agent might exacerbate the seizures in this patient?   40.3 Which of the following drugs used to prevent allograft rejection can cause hyperlipidemia?   40.4 Which of the following drugs specifically inhibit calcineurin in the activated T lymphocytes?   >Table of Contents > Unit VIII - Anti-inflammatory Drugs and Autacoids >Chapter 41 - Anti-inflammatory Drugs   Inflammation is a normal, protective response to tissue inj ury caused by physical trauma, noxious chemicals, or  microbiologic agents. Inflammation is the body's effort to inactivate or destroy invading organisms, remove irritants,  and set the stage for tissue repair. When healing is complete, the inflammatory process usually subsides. However,  inappropriate activation of our immune system can result in inflammation leading to rheumatoid arthritis (RA).  Normally, our immune system can differentiate between self and nonself. In RA, white blood cells (WBC) view the  synovium (tissue that nourishes cartilage and bone) as nonself and initiates an inflammatory attack. WBC activation  leads to activation of T lymphocytes (the cell-mediated part of our immune system), which will recruit and activate  monocytes and macrophages. These will secrete proinflammatory cytokines, including tumor necrosis factor (TNF)-i±  and interleukin (IL)-l into the synovial cavity. These cytokines will then cause 1) increased cellular infiltration into  the endothelium due to release of histamines, kinins, and vasodilatory prostaglandins; 2) increased production of  C-reactive protein by hepatocytes (a marker for inflammation); 3) increased production and release of proteolytic  enzymes (collagenases and metalloproteinases) by chondrocytes (cells that maintain cartilage), leading to  degradation of cartilage and j oint space narrowing; 4) increased osteoclast activity (osteoclasts regulate bone  breakdown), resulting in focal bone erosions and bone demineralization around joints; and 5) systemic  manifestations in which organs such as the heart, lungs, and liver are adversely affected. In addition to  T-lymphocyte activation, B lymphocytes are also involved and will produce rheumatoid factor (inflammatory marker)  and other autoantibodies with the purpose of maintaining inflammation. These defensive reactions will cause  progressive tissue inj ury, resulting in joint damage and erosions, functional disability, and significant pain and  reduction in quality of life. Pharmacotherapy in the management of RA includes anti-inflammatory and/or  immunosuppressive agents that will modulate/ reduce the inflammatory process with the goals of reducing  inflammation and pain and halting (or at least slowing) the progression of the disease. The agents to be discussed  include nonsteroidal anti-inflammatory drugs (NSAIDs) and celecoxib (cyclooxygenase-2 inhibitor), acetaminophen,  and disease-modifying antirheumatic drugs. Additionally, agents used for the treatment of gout will be reviewed  (Figure 41.1).   _ Indomethacin  _ Ketorolac  _ Ketoprofen  _ Meloxicam  _ Methyl sal icy la te  _ Nabumetone  _ Naproxen  _ Oxaprozin  _ Piroxicam    Figure 41.1 Summary of anti-inflammatory drugs. NSAIDs =nonsteroidal antiinflammatory drugs; COX =  cyclooxygenase.   All of the NSAIDs act by inhibiting the synthesis of prostaglandins. Thus, an understanding of NSAIDs requires  comprehension of the actions and biosynthesis of prostaglandinsa€"unsaturated fatty acid derivatives containing 20  carbons that include a cyclic ring structure. [Note: These compounds are sometimes referred to as eicosanoids;  a€oeeicosaa€i refers to the 20 carbon atoms. ]   Prostaglandins and related compounds are produced in minute quantities by virtually all tissues. They generally act  locally on the tissues in which they are synthesized, and they are rapidly metabolized to inactive products at their  sites of action. Therefore, the prostaglandins do not circulate in the blood in significant concentrations.  Thromboxanes, leukotrienes, and the hydroperoxyeicosatetraenoic and hydroxyeicosatetraenoic acids (HPETEs and  HETEs, respectively) are related lipids, synthesized from the same precursors as the prostaglandins, and use  interrelated pathways.   Arachidonic acid, a 20-carbon fatty acid, is the primary precursor of the prostaglandins and related compounds.  Arachidonic acid is present as a component of the phospholipids of cell membranesa€"primarily phosphatidylinositol  and other complex lipids. 1 Free arachidonic acid is released from tissue phospholipids by the action of phospholipase  A 2 and other acyl hydrolases via a process controlled by hormones and other stimuli. There are two maj or pathways  in the synthesis of the eicosanoids from arachidonic acid.   1. Cyclooxygenase pathway; All eicosanoids with ring structuresa€"that is, the prostaglandins, thromboxanes, and  prostacyclinsa€"are synthesized via the cyclooxygenase pathway. Two related isoforms of the cyclooxygenase  enzymes have been described. Cyclooxygenase-1 (COX-1) is responsible for the physiologic production of  prostanoids, whereas cyclooxygenase-2 (COX-2) causes the elevated production of prostanoids that occurs in  sites of disease and inflammation. COX-1 is described as a a€oe housekeeping enzymea€' that regulates normal  cellular processes, such as gastric cytoprotection, vascular homeostasis, platelet aggregation, and kidney  function. COX-2 is constitutively expressed in tissues such as the brain, kidney, and bone. Its expression at other  sites is increased during states of inflammation. The two enzymes share 60 percent homology in amino acid  sequence. However, the conformation for the substrate-binding sites and catalytic regions are slightly different.  For example, COX-2 has a larger and more flexible substrate channel than COX-1 has, and COX-2 has a large  space at the site where inhibitors bind (Figure 41.2). [Note: The structural differences between COX-1 and  COX-2 permitted the development of COX-2 selective inhibitors.] Another distinguishing characteristic of COX-2  is that its expression is inhibited by glucocorticoids (Figure 41.3), which may contribute to the significant  anti-inflammatory effects of these drugs.    COX-2 has a larger and more flexible  substrate channel than COX-1, and  COX-2 has a larger space at the site where  inhibitors bind.    Figure 41.2 Structural differences in active sites of cyclooxygenase (COX)-l and COX-2.   2. Lipoxygenase pathway: Alternatively, several lipoxygenases can act on arachidonic acid to form 5-HPETE,   12-HPETE, and 15-HPETE, which are unstable peroxidated derivatives that are converted to the corresponding  hydroxylated derivatives (the HETEs) or to leukotrienes or lipoxins, depending on the tissue (see Figure 41. 3). 2  Antileukotriene drugs, such as zi teuton, zafirlukast, and montelukast, are useful for the treatment of  moderate to severe allergic asthma (see p. 324).   Many of the actions of prostaglandins are mediated by their binding to a wide variety of distinct cell membrane  receptors that operate via G proteins, which subsequently activate or inhibit adenylyl cyclase or stimulate  phospholipase C. 3 This causes an enhanced formation of diacylglycerol and inositol 1,4, 5-trisphosphate.  Prostaglandin F 2 i±(PGF 2 i±), the leukotrienes, and thromboxane A 2 (TXA 2 ) mediate certain actions by activating  phosphatidyl inositol metabolism, causing an increase of intracellular Ca 2+ .   Prostaglandins and their metabolites produced endogenously in tissues act as local signals that fine-tune the    response of a specific cell type. Their functions vary widely, depending on the tissue. For example, the release of  TXA2 from platelets triggers the recruitment of new platelets for aggregation (the first step in clot formation).  However, in other tissues, elevated levels of TXA2 convey a different signal; for example, in certain smooth  muscles, this compound induces contraction. Prostaglandins are also among the chemical mediators that are  released in allergic and inflammatory processes.   The NSAIDs are a group of chemically dissimilar agents that differ in their antipyretic, analgesic, and  anti-inflammatory activities. They act primarily by inhibiting the cyclooxygenase enzymes that catalyze the first  step in prostanoid biosynthesis. This leads to decreased prostaglandin synthesis with both beneficial and unwanted  effects. Detection of serious cardiovascular events associated with COX-2 inhibitors have led to withdrawal of  rofecoxib and valdecoxib from the market (celecoxib is still available for use in patients with RA). Additionally, the  U.S. Food and Drug Administration (FDA) has required that the labeling of the traditional NSAIDs and celecoxib be  updated to include the following: 1) a warning of the potential risks of serious cardiovascular thrombotic events,  myocardial infarction, and stroke, which can be fatal; additionally, a warning that the risk may increase with  duration of use and that patients with cardiovascular disease or risk factors may be at greater risk; 2) a warning that  use is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft surgery;  and 3) a notice that there is increased risk of serious gastrointestinal (Gl) adverse events, including bleeding,  ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time  during use and without warning symptoms. Elderly patients are at greater risk for serious   Gl events. Aspirin, however, has proven to be beneficial in patients for the primary and secondary prevention of  cardiovascular events and is most commonly used for this purpose rather than for pain control.   Aspirin [AS-pir-in] is the prototype of traditional NSAIDs and was officially approved by the FDA in 1939. It is the  most commonly used and is the drug to which all other anti-inflammatory agents are compared.   1. Mechanism of action: Aspirin is a weak organic acid that is unique among the NSAIDs in that it irreversibly  acetylates (and, thus, inactivates) cyclooxygenase (Figure 41.4). The other NSAIDs, including salicylate, are all  reversible inhibitors of cyclooxygenase. Aspirin is rapidly deacetylated by esterases in the body producing  salicylate, which has anti-inflammatory, antipyretic, and analgesic effects. The antipyretic and  anti-inflammatory effects of salicylate are due primarily to the blockade of prostaglandin synthesis at the  thermoregulatory centers in the hypothalamus and at peripheral target sites. Furthermore, by decreasing  prostaglandin synthesis, salicylate also prevents the sensitization of pain receptors to both mechanical and  chemical stimuli. Aspirin may also depress pain stimuli at subcortical sites (that is, the thalamus and  hypothalamus).   2. Actions: The NSAIDs, including aspirin, have three maj or therapeutic actionsaC" namely, they reduce  inflammation (anti-inflammation), pain (analgesia), and fever (antipyrexia; Figure 41.5). Flowever, as described  later in this section, not all NSAIDs are equally potent in each of these actions.   Figure 41.4 Metabolism of aspirin and acetylation of cyclooxygenase by aspirin.    a. Anti-inflammatory actions: Because aspirin inhibits cyclooxygenase activity, it diminishes the formation of  prostaglandins and, thus, modulates those aspects of inflammation in which prostaglandins act as mediators.  Aspirin inhibits inflammation in arthritis, but it neither arrests the progress of the disease nor induces  remission.   b. Analgesic action: Prostaglandin E2 (PGE2) is thought to sensitize nerve endings to the action of bradykinin,  histamine, and other chemical mediators released locally by the inflammatory process. Thus, by decreasing  PGE2 synthesis, aspirin and other NSAIDs repress the sensation of pain. The salicylates are used mainly for    the management of pain of low to moderate intensity arising from musculoskeletal disorders rather than that  arising from the viscera. Combinations of opioids and NSAIDs are effective in treating pain caused by  malignancy. Diflunisal [dre-f lu-NI-sal] is three- to four-fold more potent than aspirin as an analgesic and an  anti-inflammatory agent, but it has no antipyretic properties.   c. Antipyretic action: Fever occurs when the set-point of the anterior hypothalamic thermoregulatory center  is elevated. This can be caused by PGE 2 synthesis, which is stimulated when an endogenous fever-producing  agent (pyrogen), such as a cytokine, is released from white cells that are activated by infection,  hypersensitivity, malignancy, or inflammation. The salicylates lower body temperature in patients with fever  by impeding PGE 2 synthesis and release. Aspirin resets the a€oethermostata€l? toward normal, and it rapidly  lowers the body temperature of febrile   patients by increasing heat dissipation as a result of peripheral vasodilation and sweating. Aspirin has no  effect on normal body temperature. Diflunisal does not reduce fever, because it does not cross the  blood-brain barrier.   d. Respiratory actions: At therapeutic doses, aspirin increases alveolar ventilation. [Note: Salicylates  uncouple oxidative phosphorylation, which leads to elevated CO 2 and increased respiration. ] Higher doses  work directly on the respiratory center in the medulla, resulting in hyperventilation and respiratory alkalosis  that usually is adequately compensated for by the kidney. At toxic levels, central respiratory paralysis  occurs, and respiratory acidosis ensues due to continued production of CO 2 .   e. Gastrointestinal effects: Normally, prostacyclin (PGI 2 ) inhibits gastric acid secretion, whereas PGE 2 and  PGF 2 i±stimulate synthesis of protective mucus in both the stomach and small intestine. In the presence of  aspirin, these prostanoids are not formed, resulting in increased gastric acid secretion and diminished mucus  protection. This may cause epigastric distress, ulceration, hemorrhage, and iron-deficiency anemia. Aspirin  doses of 1 to 4. 5 g/ day can produce loss of 2 to 8 mL of blood in the feces per day. Buffered and enteric-  coated preparations are only marginally helpful in dealing with this problem. Agents used for the prevention  of gastric and/or duodenal ulcers include the PGEi-derivative misoprostol and the proton-pump inhibitors  (PPIs); esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole)-, PPIscan also be used  for the treatment of an NSAID-induced ulcer and are especially appropriate if the patient will need to  continue NSAID treatment, ^-antihistamines (cimetidine, famotidine, nizatidine, and ranitidine ) relieve  dyspepsia due to NSAIDS, but they may mask serious Gl complaints and may not be as effective as PPIs for  healing and preventing ulcer formation.    Figure 41.5 Actions of nonsteroidal antiin flammatory drugs (NSAIDs) and acetaminophen.    f. Effect on platelets: TXA 2 enhances platelet aggregation, whereas PGI 2 decreases it. Low doses ( 60a€" 81 mg  daily) of aspirin can irreversibly inhibit thromboxane production in platelets via acetylation of  cyclooxygenase. Because platelets lack nuclei, they cannot synthesize new enzyme, and the lack of  thromboxane persists for the lifetime of the platelet (3a€"7 days). As a result of the decrease in TXA 2 ,  platelet aggregation (the first step in thrombus formation) is reduced, producing an anticoagulant effect  with a prolonged bleeding time. Finally, aspirin also inhibits cyclooxygenase in endothelial cells, resulting in  reduced PGI 2 formation; however, endothelial cells possess nuclei able to re-synthesize new  cyclooxygenase. Therefore, PGI 2 is available for antiplatelet action.    g. Actions on the kidney: Cyclooxygenase inhibitors prevent the synthesis of PGE 2 and PGl 2 a€”prostaglandins  that are responsible for maintaining renal blood flow, particularly in the presence of circulating  vasoconstrictors (Figure 41.6). Decreased synthesis of prostaglandins can result in retention of sodium and  water and may cause edema and hyperkalemia in some patients. Interstitial nephritis can also occur with all  NSAIDs except aspirin.    Figure 41.6 Renal effect of aspirin inhibition of prostaglandin synthesis. NSAIDs =nonsteroidal  anti-inflammatory drugs.    a. Anti-inflammatory, antipyretic, and analgesic uses: The salicylic acid derivatives are used in the  treatment of gout, rheumatic fever, osteoarthritis, and RA. Commonly treated conditions requiring analgesia  include headache, arthralgia, and myalgia.   b. External applications: Salicylic acid is used topically to treat corns, calluses, and warts. Methyl salicylate  ( a€oe o i I of wintergreena€§ ) is used externally as a cutaneous counterirritant in liniments.   c. Cardiovascular applications: Aspirin is used to inhibit platelet aggregation. Low doses are used  prophylactically to 1) reduce the risk of recurring transient ischemic attacks (TIAs) and stroke or death in  those who have had single or multiple episodes of TIA or stroke; 2) reduce the risk of death in those having  an acute myocardial infarction; 3) reduce the risk of recurrent nonfatal myocardial infarction and/or death  in patients with previous myocardial infarction or unstable angina pectoris; 4) reduce the risk of myocardial  infarction and sudden death in patients with chronic stable angina pectoris; 5) reduce the cardiovascular risk  in patients undergoing certain revascularization procedures.    a. Administration and distribution: After oral administration, the un-ionized salicylates are passively absorbed  from the stomach and the small intestine (dissolution of the tablets is favored at the higher pH of the gut).   Rectal absorption of the salicylates is slow and unreliable, but it is a useful route for administration to  vomiting children. Salicylates must be avoided in children and teenagers (<L5 years old) with varicella  (chickenpox) or influenza to prevent Reye's syndrome. Salicylates (except for diflunisal ) cross both the  blood-brain barrier and the placenta and are absorbed through intact skin (especially methyl salicylate).   b. Dosage: The salicylates exhibit analgesic activity at low doses; only at higher doses do these drugs show  anti-inflammatory activity (Figure 41.7). For example, two 325-mg aspirin tablets   administered four times daily produce analgesia, whereas 12 to 20 tablets per day produce both analgesic  and anti-inflammatory activity. For long-term myocardial infarction prophylaxis, the dose is 81 to 162  mg/ day; for those with RA or osteoarthritis, the initial dose is 3 grams/ day; for stroke prophylaxis, the dose  is 50 to 325 mg/ day; in a patient having an acute mycardial infarction, the dose is 162 to 325 mg of  nonenteric coated aspirin chewed and swallowed immediately.   c. Fate: At dosages of 650 mg/ day, aspirin is hydrolyzed to salicylate and acetic acid by esterases in tissues and  blood (see Figure 41.4). Salicylate is converted by the liver to water-soluble conj ugates that are rapidly  cleared by the kidney, resulting in elimination with first-order kinetics and a serum half-life of 3. 5 hours. At  anti-inflammatory dosages (>4 g/day), the hepatic metabolic pathway becomes saturated, and zero-order  kinetics are observed, with the drug having a half-life of 15 hours or more (Figure 41.8). Saturation of the  hepatic enzymes requires treatment for several days to 1 week. Being an organic acid, salicylate is secreted  into the urine and can affect uric acid excretiona€"namely, at low doses of aspirin, uric acid secretion is  decreased, whereas at high doses, uric acid secretion is increased. Both hepatic and renal function should  be monitored periodically in those receiving long-term, high-dose aspirin therapy, and aspirin should be  avoided in patients with a creatinine clearance of less than 10 mL/min.   a. Gastrointestinal: The most common Gl effects of the salicylates are epigastric distress, nausea, and   vomiting. Microscopic Gl bleeding is almost universal in patients treated with salicylates. [Note: Aspirin is an  acid. At stomach pH, aspirin is uncharged; consequently, it readily crosses into mucosal cells, where it  ionizes (becomes negatively charged) and becomes trapped, thus potentially causing direct damage to the  cells. Aspirin should be taken with food and large volumes of fluids to diminish dyspepsia. Additionally,  misoprostol or a PPI may be taken concurrently, ]   b. Blood: The irreversible acetylation of platelet cyclooxygenase reduces the level of platelet TXA 2 , resulting  in inhibition of platelet aggregation and a prolonged bleeding time. For this reason, aspirin should not be  taken for at least 1 week prior to surgery. When salicylates are administered, anticoagulants may have to be  given in reduced dosage, and careful monitoring and counseling of patients are necessary.   c. Respiration: In toxic doses, salicylates cause respiratory depression and a combination of uncompensated  respiratory and metabolic acidosis.   d. Metabolic processes: Large doses of salicylates uncouple oxidative phosphorylation. 4 The energy normally  used for the production of adenosine triphosphate is dissipated as heat, which explains the hyperthermia  caused by salicylates when taken in toxic quantities.   e. Hypersensitivity: Approximately 15 percent of patients taking aspirin experience hypersensitivity reactions.  Symptoms of true allergy include urticaria, bronchoconstriction, or angioedema. Fatal anaphylactic shock is  rare.   f. Reye's syndrome: Aspirin and other salicylates given during viral infections has been associated with an  increased incidence of Reye's syndrome, which is an often fatal, fulminating hepatitis with cerebral edema.   This is especially encountered in children, who therefore should be given acetaminophen instead of aspirin  when such medication is required to reduce fever, ibuprofen is also appropriate.   g. Drug interactions: Concomitant administration of salicylates with many classes of drugs may produce  undesirable side effects. Because aspirin is found in many over-the-counter agents, patients should be  counseled to read labels to verify aspirin content to avoid overdose. Salicylate is 90 to 95 percent protein  bound and can be displaced from its protein-binding sites, resulting in increased concentration of free  salicylate; alternatively, aspirin could displace other highly protein-bound drugs, such as warfarin,  phenytoin, or valproic acid, resulting in higher free concentrations of the other agent (Figure 41.9).   Chronic aspirin use should be avoided in patients receiving probenecid or sulfinpyrazone, because these  agents cause increased renal excretion of uric acid whereas aspirin (<2 g/day) cause reduced clearance of  uric acid. Concomitant use of ketorolac and aspirin is contraindicated because of increased risk of Gl  bleeding and platelet aggregation inhibition. Children who have received live varicella virus vaccine should  avoid aspirin for at least 6 weeks after vaccination to prevent Reye's syndrome.   h. In pregnancy: Aspirin is classified as FDA pregnancy category C risk during Trimesters 1 and 2 and category D  during Trimester 3. Because salicylates are excreted in breast milk, aspirin should be avoided during  pregnancy and while breast-feeding.    Drug-drug interactions  with salicylates leading to  altered effects of drugs or  metabolites are shown in    Increased plasma concentration,  leading to prolonged half-lives,  therapeutic effects, and toxicity    6. Toxicity: Salicylate intoxication may be mild or severe. The mild form is called salicylism and is characterized by  nausea, vomiting, marked hyperventilation, headache, mental confusion, dizziness, and tinnitus (ringing or  roaring in the ears). When large doses of salicylate are administered, severe salicylate intoxication may result    (see Figure 41. 7). The symptoms listed above are followed by restlessness, delirium, hallucinations, convulsions,  coma, respiratory and metabolic acidosis, and death from respiratory failure. Children are particularly prone to  salicylate intoxication. Ingestion of as little as 10 g of aspirin (or 5 ml of methyl salicylate, with the latter being  used as a counterirritant in liniments) can cause death in children. Treatment of salicylism should include  measurement of serum salicylate concentrations and of pH to determine the best form of therapy. In mild cases,  symptomatic treatment is usually sufficient. Increasing the urinary pH enhances the elimination of salicylate. In  serious cases, mandatory measures include the intravenous administration of fluid, dialysis (hemodialysis or  peritoneal dialysis), and the frequent assessment and correction of acid-base and electrolyte balances. [Note:  Diflunisal does not cause salicylism.]   Ibuprofen [eye-byoo-PROE-fen] was the first in this class of agents to become available in the United States. It has  been joined by naproxen [nah-PROX-en], fenoprofen [fen-oh-PROE-fen], ketoprofen [key-toe-PROE-fen],  flurbiprofen [flur-bye-PROE-fen], and oxaprozin [ox-ah-PROE-zin], All these drugs possess anti-inflammatory,  analgesic, and antipyretic activity; additionally, they can can alter platelet function and prolong bleeding time.   They have gained wide acceptance in the chronic treatment of RA and osteoarthritis, because their Gl effects are  generally less intense than those of aspirin. These drugs are reversible inhibitors of the cyclooxygenases and, thus,  like aspirin, inhibit the synthesis of prostaglandins but not of leukotrienes. All are well absorbed on oral  administration and are almost totally bound to serum albumin. [Note: Oxaprozin has the longest half-life and is  administered once daily. ] They undergo hepatic metabolism and are excreted by the kidney. The most common  adverse effects are Gl, ranging from dyspepsia to bleeding. Side effects involving the central nervous system (CNS),  such as headache, tinnitus, and dizziness, have also been reported.   This group of drugs includes indomethacin [in-doe-METH-a-sin], sulindac [sul-IN-dak], and etodolac [eh-TOE-  doh-lak]. All have anti-inflammatory, analgesic, and antipyretic activity. They act by reversibly inhibiting  cyclooxygenase. They are generally not used to lower fever. Despite its potency as an anti-inflammatory agent, the  toxicity of indomethacin limits its use to the treatment of acute gouty arthritis, ankylosing spondylitis, and  osteoarthritis of the hip. Sulindac is an inactive prodrug that is closely related to indomethacin. Although the drug  is less potent than indomethacin, it is useful in the treatment of RA, ankylosing spondylitis, osteoarthritis, and  acute gout. The adverse reactions caused by sulindac are similar to, but less severe than, those of the other NSAIDs,  including indomethacin. Etodolac has effects similar to those of the other NSAIDs. Gl problems are less common.   Piroxicam [peer-OX-i-kam] and meloxlcam [mel-OX-i-kam] are used to treat RA, ankylosing spondylitis, and  osteoarthritis. They have long half-lives, which permit once-daily administration, and the parent drug as well as its  metabolites are renal ly excreted in the urine. Gl disturbances are encountered in approximately 20 percent of  patients treated with piroxicam. Meloxicam inhibits both COX-1 and COX-2, with preferential binding for COX-2,  and at low to moderate doses shows less Gl irritation than piroxicam. However, at high doses, meloxicam is a  nonselective NSAID, inhibiting both COX-1 and COX-2. Meloxicam excretion is predominantly in the form of  metabolites and occurs equally in the urine and feces.   Mefenamic [meh-FEN-a-mick] acid and meclofenamate [meh-KLO-fen-a-mate] have no advantages over other  NSAIDs as anti-inflammatory agents. Their side effects, such as diarrhea, can be severe, and they are associated  with inflammation of the bowel. Cases of hemolytic anemia have been reported.   Diclofenac [dye-KLO-feh-nak] and tolmetin [tole-MEN-tin] are approved for long-term use in the treatment of RA,  osteoarthritis, and ankylosing spondylitis. Diclofenac is more potent than indomethacin or naproxen. An ophthalmic  preparation is also available. Diclofenac accumulates in synovial fluid, and the primary route of excretion for the  drug and its metabolites is the kidney. Tolmetin is an effective anti-inflammatory, antipyretic, and analgesic agent  with a half-life of 5 hours. It is 99 percent bound to plasma proteins, and metabolites can be found in the urine.  Toxicities of these two agents are similar to those of the other NSAIDs. Ketorolac [key-toe-ROLE-ak] is a potent  analgesic but has moderate anti-inflammatory effects. It is available for oral administration, for intramuscular use in  the treatment of postoperative pain, and for topical use for allergic conj unctivitis. Ketorolac undergoes hepatic  metabolism, and the drug and its metabolites are eliminated via the urine. Ketorolac is indicated for short-term  relief of moderate to severe pain for up to 5 days after the first dose is administered via IV or intramuscular dosing  at the doctor's office or in a hospital. This agent is to be avoided in pediatric patients; patients with mild pain, and  those with chronic conditions, the dose should not exceed 40 mg/ day. Ketorolac can cause fatal peptic ulcers as  well as Gl bleeding and/or perforation of the stomach or intestines.    Figure 41.10 Relative selectivity of some commonly used NASAIDs. Data shown as the logarithm of their ratio  of ICso (drug concentration to achieve 80 percent inhibition of cyclooxygenase).   Nabumetone [na-BYOO-meh-tone] is indicated for the treatment of RA and osteoarthritis and is associated with a  low incidence of adverse effects. Nabumetone is hepatically metabolized by the liver to the active metabolite,  which displays the anti-inflammatory, antipyretic, and analgesic activity. The active metabolite is then hepatically    metabolized to inactive metabolites with subsequent renal elimination. Therefore, cautious use of this agent in  patients with hepatic impairment is warranted; additionally, the dose should be adjusted in those with creatinine  clearance of less than 50 mL/ min.   Celecoxib [sel-eh-COCKS-ib] is significantly more selective for inhibition of COX-2 than of COX-1 (Figure 41.10). In  fact, at concentrations achieved in vivo, celecoxib does not block COX-1. Unlike the inhibition of COX-1 by aspirin  (which is rapid and irreversible), the inhibition of COX-2 is time dependent and reversible. Celecoxib is approved  for treatment of RA, osteoarthritis, and pain. Unlike aspirin, celecoxib does not inhibit platelet aggregation and  does not increase bleeding time. Celecoxib has similar efficacy to NSAIDs in the treatment of pain and the risk for  cardiovascular events. Celecoxib, when used without concomitant aspirin therapy, has been shown to be associated  with less Gl bleeding and dyspepsia; however, this benefit is lost when aspirin is added to celecoxib therapy. In  patients at high risk for ulcers (that is, history of peptic ulcer disease), use of PPIs with celecoxib and aspirin may  be necessary to avoid gastric ulcers.   I. Pharmacokinetics; Celecoxib is readily absorbed, reaching a peak concentration in about 3 hours. It is  extensively metabolized in the liver by cytochrome P450 (CYP2C9) and is excreted in the feces and urine. Its  half-life is about 11 hours; thus, the drug is usually taken once a day but can be administered as divided doses  twice daily. The daily recommended dose should be reduced by 50 percent in those with moderate hepatic  impairment, and celecoxib should be avoided in patients with severe hepatic and renal disease.   2. Adverse effects: Headache, dyspepsia, diarrhea, and abdominal pain are the most common adverse effects.   Celecoxib is contraindicated in patients who are allergic to sulfonamides. [Note: If there is a history of  sulfonamide drug allergy, then use of a nonselective NSAID along with a PPI is recommended.] As with other  NSAIDs, kidney toxicity may occur. Celecoxib should be avoided in patients with chronic renal insufficiency,  severe heart disease, volume depletion, and/or hepatic failure. Patients who have had anaphylactoid reactions  to aspirin or nonselective NSAIDs may be at risk for similar effects when challenged with celecoxib. Inhibitors of  CYP2C9, such as fluconazole, fluvastatin, and zafirlukast, may increase serum levels of celecoxib. Celecoxib  has the ability to inhibit CYP2D6 and, thus, could lead to elevated levels of some i 2 -blockers, antidepressants,  and antipsychotic drugs.   Figure 41. 11 summarizes some of the therapeutic advantages and disadvantages of members of the NSAID family.   Acetaminophen [a-SEAT-a-MIN-oh-fen] inhibits prostaglandin synthesis in the CNS. This explains its antipyretic and  analgesic properties. Acetaminophen has less effect on cyclooxygenase in peripheral tissues, which accounts for its  weak anti-inflammatory activity. Acetaminophen does not affect platelet function or increase blood clotting time.   Very potent; should be  used only after less  toxic agents have  proven ineffective   Lower toxicity and belter  acceptance in some  patients. Naproxen is  considered by some experts  as one of the safest NSAIDs    Figure 41.11 Summary of nonsteroidal anti-inflammatory agents (NSAIDs). *As a group, with the exception of  aspirin, these drugs may have the potential to increase myocardial infarctions and strokes.   Acetaminophen is a suitable substitute for the analgesic and antipyretic effects of aspirin for those patients with  gastric complaints, those in whom prolongation of bleeding time would be a disadvantage, or those who do not  require the anti-inflammatory action of aspirin. Acetaminophen is the analgesic/ antipyretic of choice for children  with viral infections or chickenpox (recall that aspirin increases the risk of Reye's syndrome). Acetaminophen does  not antagonize the uricosuric agents probenecid or sulfinpyrazone and, therefore, may be used in patients with  gout who are taking these drugs.   Acetaminophen is rapidly absorbed from the Gl tract. A significant first-pass metabolism occurs in the luminal cells  of the intestine and in the hepatocytes. Under normal circumstances, acetaminophen is conj ugated in the liver to  form inactive glucuronidated or sulfated metabolites. A portion of acetaminophen is hydroxylated to form  N-acetylbenzoiminoquinonea€"a highly reactive and potentially dangerous metabolite that reacts with sulfhydryl  groups. At normal doses of acetaminophen, the N-acetylbenzoiminoquinone reacts with the sulfhydryl group of  glutathione, forming a nontoxic substance (Figure 41. 12). Acetaminophen and its metabolites are excreted in the  urine.   With normal therapeutic doses, acetaminophen is virtually free of any significant adverse effects. Skin rash and  minor allergic reactions occur infrequently. There may be minor alterations in the leukocyte count, but these are  generally transient. Renal tubular necrosis and hypoglycemic coma are rare complications of prolonged, large-dose   therapy. With large doses of acetaminophen, the available glutathione in the liver becomes depleted, and  N-acetylbenzoiminoquinone reacts with the sulfhydryl groups of hepatic proteins, forming covalent bonds (see  Figure 41.12). Hepatic necrosis, a very serious and potentially life-threatening condition, can result. Renal tubular  necrosis may also occur. [Note: Administration of N-acetylcysteine, which contains sulfhydryl groups to which the  toxic metabolite can bind, can be lifesaving if administered within 10 hours of the overdose. ] This agent should be  avoided in patients with severe hepatic impairment. Periodic monitoring of liver enzymes tests is recommended for  those on high-dose acetaminophen.   Disease-modifying antirheumatic drugs (DMARDs) are used in the treatment of RA and have been shown to slow the  course of the disease, induce remission, and prevent further destruction of the j oints and involved tissues. When a  patient is diagnosed with RA, the American College of Rheumatology recommends initiation of therapy with DMARDs  within 3 months of diagnosis (in addition to NSAIDs, low-dose corticosteroids, physical therapy, and occupational  therapy). Therapy with DMARDs is initiated rapidly to help stop the progression of the disease at the earlier stages.   No one DMARD is efficacious and safe in every patient, and trials of several different drugs may be necessary. Most  experts begin DMARD therapy with one of the traditional drugs, such as methotrexate or hydroxychloroquine.   These agents are efficacious and are generally well tolerated, with well-known side-effect profiles. Inadequate  response to the traditional agents may be followed by use of newer DMARDs, such as leflunomide, anakinra, and  TNF-inhibitors (adalimumab, etanercept,   and infliximab). Combination therapies are both safe and efficacious. In most cases, methotrexate is combined  with one of the other DMARDs. In patients who do not respond to combination therapy with methotrexate plusTNF  inhibitors, or other combinations, treatment with rituximab or abatacept may be tried. Most of these agents are  contraindicated for use in pregnant women.   Methotrexate [meth-oh-TREX-ate], used alone or in combination therapy, has become the mainstay of treatment in  patients with rheumatoid or psoriatic arthritis. Methotrexate slows the appearance of new erosions within involved  j oints on radiographs. Response to methotrexate occurs within 3 to 6 weeks of starting treatment. It is an  immunosuppressant, and this may account for its effectiveness in an autoimmune disease. The other DMARDs can be  added to methotrexate therapy if there is partial or no response to maximum doses of methotrexate. Doses of  methotrexate required for this treatment are much lower than those needed in cancer chemotherapy and are given  once a week; therefore, the adverse effects are minimized. The most common side effects observed after  methotrexate treatment of RA are mucosal ulceration and nausea. Cytopenias (particularly depression of the WBC  count), cirrhosis of the liver, and an acute pneumonia-like syndrome may occur on chronic administration. [Note:  Taking leucovorin once daily after methotrexate reduces the severity of the adverse effects.] Contrary to early  concerns, there have been minimal unexpected side effects after more than 20 years of surveillance, but periodic  monitoring for signs of infections, complete blood counts, and liver enzymes tests are recommended.   Leflunomide (le-FLOO-no-mide) is an immunomodulatory agent that preferentially causes cell arrest of the  autoimmune lymphocytes through its action on dihydroorotate dehydrogenase (DHODH) . Activated proliferating  lymphocytes require constant DNA synthesis to proliferate. Pyrimidines and purines are the building blocks of DNA,  and DHODH is necessary for pyrimidine synthesis. After biotransformation, leflunomide becomes a reversible  inhibitor of DHODH (Figure 41. 13). Leflunomide has been approved for the treatment of RA. It not only reduces  pain and inflammation associated with the disease but also appears to slow the progression of structural damage.  Leflunomide can be used in monotherapy as an alternative to methotrexate or as an addition to methotrexate in  combination therapy.   1. Pharmacokinetics; Leflunomide is well absorbed after oral administration. It is extensively bound to albumin  ( >90 percent) and has a half-life of 14 to 18 days. [Note: Because of its long half-life, loading doses are    necessary. ] Leflunomide is rapidly converted to the active metabolite. The metabolites are excreted in the  urine and the feces. The active metabolite undergoes biliary recycling.   2. Adverse effects: The most common of these are headache, diarrhea, and nausea. Other untoward effects are   weight loss, allergic reactions including a flu-like syndrome, skin rash, alopecia, and hypokalemia. Leflunomide  is teratogenic in experimental animals and, therefore, is contraindicated in pregnancy and in women of child-  bearing potential. It should be used with caution in patients who have liver disease, because it is cleared by  both biliary and renal   excretion. Monitoring parameters include signs of infections, complete blood counts, and liver enzymes tests.   This agent is also used in the treatment of malaria. It is used for early, mild RA and has relatively few side effects.   When used alone, it does not slow j oint damage, therefore, it is often used in combination with methotrexate. Its  mechanism of action may include inhibition of phospholipase A 2 and platelet aggregation, membrane stabilization,  effects on the immune system, and antioxidant activity. It may cause renal toxicity   Sulfasalazine [sul l-fa-SAH- la-zeen] is also used for early, mild RA in combination with hydroxycholoroquine and  methotrexate. Onset of activity is 1 to 3 months, and it is associated with leukopenia.   D-Penicillamine [pen-ih-SILL-a-meen], an analog of the amino acid cysteine, slows the progression of bone  destruction and RA. This agent is used as add-on therapy to existing NSAID/ glucocorticoid therapy, but use in  patients on DMARD therapy is avoided due to serious adverse events (for example, blood dyscrasias or renal  impairment). Prolonged treatment with penicillamine has serious side effects, ranging from dermatologic problems  to nephritis and aplastic anemia. [Note: D-Penicillamine is used as a chelating agent in the treatment of poisoning  by heavy metals. It is also of benefit in treating cystinuria. ]   Gold compounds, like the other drugs in this group, cannot repair existing damage. They can only prevent further  inj ury. The currently available gold preparation is auranofin for oral administration. This agent is taken up by  macrophages and will suppress phagocytosis and lysosomal enzyme activity. This mechanism retards the progression  of bone and articular destruction, and beneficial effects may be seen in 3 to 6 months. The gold compounds are  being used infrequently by rheumatologists because of the need for meticulous monitoring for serious toxicity (for  example, myelosuppression) and the costs of monitoring.   Interleukin-lb and TNF-i±are proinflammatory cytokines involved in the pathogenesis of RA. When secreted by  synovial macrophages, IL-lb and TNF-i±stimulate synovial cells to proliferate and synthesize collagenase, thereby  degrading cartilage, stimulating bone resorption, and inhibiting proteoglycan synthesis. The TNF inhibitors  (etanercept, adalimumab, and infliximab) have been shown to decrease signs and symptoms of RA, reduce  progression of structural damage, and improve physical function; clinical response can be seen within 2 weeks of  therapy. If a patient has failed therapy with one TNF inhibitor, a trial with a different TNF inhibitor is appropriate.   Many experts propose that a TNF inhibitor plus methotrexate be considered as standard therapy for patients with  rheumatoid and psoriatic arthritis. Indeed, TNF inhibitors can be administered with any of the other DMARDs, except  for anakinra, an IL-1 receptor antagonist. Patients receiving TNF inhibitors are at increased risk for infections  (tuberculosis, and sepsis), fungal opportunistic infections, and pancytopenia. Live vaccinations should   not be administered while on TNF-inhibitor therapy. These agents should be used very cautiously in those with heart  failure, because these agents can cause and worsen preexisting heart failure.    Etanercept [ee-TAN-er-cept] is a genetically engineered fusion protein that binds to TNF-I+ thereby blocking its  interaction with cell surface TNF receptors. This agent is approved for use in patients with moderate to severe RA,  either alone or in combination with methotrexate. It is also approved for use in patients with polyarticular-course  j uvenile RA, psoriatic arthritis, ankylosing spondylitis, and psoriasis. The combination of etanercept and  methotrexate is more effective than methotrexate or etanercept alone in retarding the disease process,  improving function, and achieving remission (Figure 41. 14). Upon discontinuation of etanercept, the symptoms of  arthritis generally return within a month.   1. Pharmacokinetics: Etanercept is given subcutaneously twice a week. The time to maximum serum  concentration after a single inj ection is about 72 hours. Its median half-life is 115 hours.   2. Adverse effects: Etanercept is well tolerated. No toxicities or antibodies have been reported. Flowever, it can  produce local inflammation at the site of injection.    The incidence of remission in patients  receiving entanercept plus methotrexate  was greater than that found in patients  taking entanercept or methotrexate  alone.    Figure 41.14 Incidence of remission from the symptoms of rheumatoid arthritis after 1 year of therapy.   Infliximab (in-FLIX-i-mab) is a chimeric IgGi 2 monoclonal antibody composed of human and murine regions. The  antibody binds specifically to human TNF-I+ thereby neutralizing that cytokine. Infliximab is approved for use in  combination with methotrexate in patients with RA who have had inadequate response to methotrexate  monotherapy. This agent is not indicated for use alone, because monotherapy allows the body to develop  anti -infliximab antibodies, with a reduction in efficacy. Additional indications include plaque psoriasis, psoriatic  arthritis, ulcerative colitis, ankylosing spondylitis, and Crohn's disease for both fistulizing and nonfistulizing disease.  [Note: Increased levels of TNF-I±are found in fecal samples of patients with Crohn's disease].    1. Pharmacokinetics: Infliximab is infused IV over at least 2 hours. It distributes in the vascular compartment and  has a half-life of 9. 5 days. Its metabolism and elimination have not been described.   2. Adverse effects: Infusion reactions, such as fever, chills, pruritus, or urticaria, have occurred. Infections  leading to pneumonia, cellulitis, and other conditions have also been reported. Leukopenia, neutropenia,  thrombocytopenia, and pancytopenia have occurred. Whether treatment with infliximab predisposes to  lymphoma, a condition that occurs with immunosuppressive or immune-altering drugs, remains to be  established. [Note: Infliximab treatment does predispose to infections, which may be life-threatening. ]   Adalimumab [a-dal-AYE-mu-mab] is a recombinant monoclonal antibody that binds to human TNF-i± receptor sites,  thereby interfering with endogenous TNF-T± activity. This agent is indicated for treatment of moderate to severe  RA, either as monotherapy or in combination with methotrexate. It is also indicated for psoriatic arthritis,  ankylosing   spondylitis, and Crohn's disease. Adalimumab is administered subcutaneously weekly or every other week. It may  cause headache, nausea, rash, reaction at the inj ection site or increased risk of infection.   lnterleukin-1 is induced by inflammatory stimuli and mediates a variety of immunologic responses, including  degradation of cartilage and stimulation of bone resorption. Anakinra [an-a-KIN-ra] is an IL-1 receptor antagonist  because it binds to the IL-1 receptor, thus preventing actions of IL-1. Anakinra treatment leads to a modest  reduction in the signs and symptoms of moderately to severely active RA in adult patients who have failed one or  more DMARDs. The drug may be used alone or in combination with DMARDs (other than TNF inhibitors). Patients  should be monitored for signs of infection (tuberculosis and opportunistic infections have not been reported with  this agent) and undergo absolute neutrophil counts, because this agent is associated with neutropenia. This agent is  administered subcutaneously once a day if renal function is normal, and every other day in those with moderate to  severe renal impairment.   T lymphocytes need two interactions to become activated: 1) the antigen-presenting cell (that is, macrophages or B  cells) must interact with the receptor on the T cell, and 2) the CD80/CD86 protein on the antigen-presenting cell  must interact with the CD28 protein on the T cell. The result is activated T lymphocytes responsible for the release  of proinflammatory cytokines and maintenance of inflammation in RA. Flowever, T lymphocytes contain another  protein, CTLA4, which can bind to the CD80/ 86 protein found on the antigen-presenting cell; in fact, CTLA4 has  higher binding affinity for CD80/ 86 than does CD28. Binding of CTLA4 to CD80/ 86 results in deactivation of the T  lymphocyte. Abatacept [a-BAT-ah-cept] (CTLA-4lg) is a soluble recombinant fusion protein made up of the  extracellular domain of human CTLA4, and it competes with CD28 for binding on CD80/CD86 protein, thereby  preventing full T-cell activation. This agent is indicated for reducing signs and symptoms, inducing maj or clinical  response, slowing the progression of structural damage, and improving physical function in adult patients with  moderate to severe RA who have had an inadequate response to DMARDs such as methotrexate or TNF inhibitors.  Abatacept can be used alone or with DMARDs other than TNF inhibitors or anakinra.   1. Pharmacokinetics: The recommended dose is based upon weight and is administered as an IV infusion over 30  minutes at Weeks 2 and 4 after the first infusion and every 4 weeks thereafter with monitoring for infusion  reactions. The terminal half-life in RA patients administered multiple doses of 10 mg/ kg is 13 days (range, 8a€"25  days).   2. Adverse effects: The most commonly reported adverse effects include headache, upper respiratory infections,  nasopharyngitis, and nausea. Concurrent use with TNF inhibitors and anakinra is not recommended due to  increased risk of serious infections.   B lymphocytes are derived from the bone marrow and are necessary for efficient immune response; however, in RA,   inflammatory process in the synovium by 1) activating T lymphocytes, 2) producing autoantibodies such as anti-CCP  ( anti a€" cyclic citrull inated peptide antibody) and rheumatoid factor, and 3) producing pro-inflammatory cytokines  such asTNF-i±and IL-1. Rituximab [ ri-TUK-si- mab]is a genetically engineered chimeric murine/ human monoclonal  antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes, resulting  in B-cell depletion. This agent is indicated for use in combination with methotrexate to reduce signs and symptoms  in adult patients with moderate to severe RA who have had an inadequate response to one or more TNF-inhibitors.  Rituximab has been shown to reduce j oint erosion and j oint space narrowing in these patients.   1. Pharmacokinetics; Rituximab is administered as two 1000-mg IV infusions separated by 2 weeks. To reduce the  severity of infusion reactions, methyl prednisolone at 100 mg IV or its equivalent is administered 30 minutes  prior to each infusion. The mean terminal elimination half-life after the second dose is 19 days.   2. Adverse effects: Infusion reactions (that is, urticaria, hypotension, or angioedema) are the most common  complaints with this agent and typically occur during the first infusion. The infusion may be interrupted and the  patient treated with vasopressors, antihistamines, and fluids. If the infusion is to be continued, then the rate of  infusion should be reduced by 50 percent after symptoms have completely resolved.   Gout is a metabolic disorder characterized by high levels of uric acid in the blood. Flyperuricemia can lead to  deposition of sodium urate crystals in tissues, especially the joints and kidney. Flyperuricemia does not always lead  to gout, but gout is always preceded by hyperuricemia. In humans, sodium urate is the end product of purine  metabolism. 5 The deposition of urate crystals initiates an inflammatory process involving the infiltration of  granulocytes that phagocytize the urate crystals (Figure 41. 15). This process generates oxygen metabolites, which  damage tissues, resulting in the release of lysosomal enzymes that evoke an inflammatory response. In addition,  there is increased production of lactate in the synovial tissues. The resulting local decrease in pH fosters further  deposition of urate crystals. The cause of hyperuricemia is an overproduction of uric acid relative to the patient's  ability to excrete it. Most therapeutic strategies for gout involve lowering the uric acid level below the saturation  point (<6 mg/ dL), thus preventing the deposition of urate crystals. This can be accomplished by 1) interfering with  uric acid synthesis with allopurinol, 2) increasing uric acid excretion with probenecid or sulfinpyrazone, 3)  inhibiting leukocyte entry into the affected joint with colchicine, or 4) administration of NSAIDs.   Figure 41.15 Role of uric acid in the inflammation of gout. 
PharmacologyByLipincott Pharmacology by Lipincott_djvu.txt