The peripheral nervous system is divided into the  autonomic and somatic nervous systems. The auto-  nomic nervous system controls cardiac and smooth  muscle contraction, and glandular secretion. The  somatic nervous system supplies skeletal muscle  during voluntary movement and conducts sensory  information, such as pain and touch.   The autonomic nervous system is further divided  into the sympathetic and parasympathetic systems,  which generally oppose one another. For example, the  sympathetic system is generally catabolic, expending  energy (the "fight or flight system"). It increases heart  rate, dilates bronchi, and decreases secretions, whereas  the parasympathetic system is anabolic, conserving  energy, e.g., it decreases heart rate, stimulates gastro-  intestinal function (See Figs. 2.2 and 2.3 for a review of  functions). In the resting individual, the parasympa-  thetic system dominates in most organs, resulting in a  relatively slow heart beat, adequate secretions, and  appropriate bowel motility. In an individual under  stress, however, the sympathetic system dominates,  diverting energy to functions which make a person fit  to fight or flee (e.g., improved oxygenation of tissues by  bronchodilation and increased cardiac output).   Autonomic neurotransmission involves two neu-  rons, the presynaptic and the postsynaptic neurons  (Fig. 2.1). Presynaptic neurons extend from the brain to  autonomic ganglia where they transmit CNS signals to  postsynaptic neurons by releasing acetylcholine into    the synaptic cleft, which is the space between the two  neurons. Postsynaptic neurons subsequently transmit  impulses to end organs (e.g., heart, stomach) by  releasing norepinephrine (sympathetic neurons) or  acetylcholine (parasympathetic neurons).   The catecholamines norepinephrine and epineph-  rine transmit most impulses of the sympathetic system.  Upon release from presynaptic neurons, norepineph-  rine diffuses across the synaptic cleft and binds to  postsynaptic adrenergic (al, (X2, (3l or (32) receptors.  During times of stress, the adrenal gland releases  epinephrine (adrenaline) into the blood. Like norepi-  nephrine, circulating epinephrine is an agonist at  adrenergic (sympathetic) receptors. An exception to  catecholamine neurotransmission in the sympathetic  system is the sweat glands. Acetylcholine, which is  often considered a parasympathetic transmitter,  conveys sympathetic signals to sweat glands.   Acetylcholine transmits all parasympathetic signals  to end organs (heart, lungs, etc.) by binding to musca-  rinic (M) receptors. In addition, acetylcholine plays  three other important roles in neurotransmission.   • Ganglionic transmission: Acetylcholine transmits  both sympathetic and parasympathetic impulses  from the "preganglionic" neurons in the brain and  spinal cord to nicotinic ganglionic (N g ) receptors on  "postganglionic" neurons of the autonomic nervous  system. This occurs in sympathetic ganglia, which  are located along the spinal cord, and in parasympa-    Figure 2.1 Schematic of  autonomic and somatic motor  neurons. Presynaptic neurons  are depicted loith solid cell bodies.  Postsynpatic neurons are  speckled. The neurotransmitter  released by the presynaptic  neuron and the type of receptor it  activates are listed below each  synapse.   thetic ganglia, which lie near the end organs. Be-  cause all ganglionic transmission is cholinergic,  drugs which block ganglionic transmission (Table  2.8) inhibit either sympathetic or parasympathetic  signals, depending on which system is predominant  at the moment.   • Neuromuscular transmission: Acetylcholine, re-  leased from neurons, causes muscle contraction by  binding to nicotinic muscle (N m ) receptors on  muscle cells, causing calcium influx (Fig. 2.1).   • Central neurotransmission: Acetylcholine is a  neurotransmitter in the brain, acting predominantly  via muscarinic receptors.   Before learning about specific drugs which modify  neurotransmission, it is helpful to consider how  messages are transmitted from one neuron to another  and the strategies available for enhancing or suppress-  ing neurotransmission.   First, consider the processes involved in neurotrans-  mission (Fig. 2.4A and 2.4B): 1) the neurotransmitter is  synthesized from chemical precursors, 2) it is packaged  into vesicles in the presynaptic terminal, 3) the presyn-  aptic nerve is stimulated causing the synaptic vesicles  to fuse with the synaptic membrane and release the   Figure 2.2 The "Fight or Flight" response demonstrates the  ability of the sympathetic nervous system to provide energy for vital  functions. Decreased pulmonary secretions and bronchodilation  increase blood oxygenation. Increased heart rate and contractility  improve cardiac output. Arteriolar constriction shunts blood from  the skin and digestive tract, whereas arterioles in the heart and  skeletal muscle dilate to supply more blood to the latter organs.  Glycogen and lipids break down and glucose is synthesized for  energy. Gl motility and secretions decrease and urine is retained  (because you can '/ fight a bear when you 're urinating).    neurotransmitter, 4) the neurotransmitter diffuses  across the synaptic cleft and may bind to postsynaptic  receptors, 5) binding of neurotransmitter to receptor  results in either opening of an ion channel or activation  of a "second messenger" such as cAMP or inositol  phosphate, 6) the resulting ion influx or second mes-  senger activation causes an action (e.g., depolarization)  of the postsynaptic cell. Neurotransmitter molecules  which fail to bind to postsynaptic receptors are de-  stroyed by degradative enzymes, are taken up into the  presynaptic neuron to be recycled, or diffuse away  from the synaptic cleft.   Figure 2.3 The parasympathetic pig's heart beats sluggishly  while his digestive tract hogs the energy. He's drooling because of  increased secretions. He needs to breath oxygen because his  bronchioles are constricted. He is defecating and urinating and he  has an erection (you 'll have to picture this as none of these are  drawn, for modesty). (The sympathetic system, by the way,  controls ejaculation). Notice how tiny his pupils are compared to  the scared boy in figure 2.2.    Figure 2.4A Norepinephrine synthesis, release and  degradation. 1). Norephinephrine is synthesized from the amino  acid tyrosine. Tyrosine is hydroxylated to dopa which is then  carboxylated to dopamine. 2). Dopamine (empty squares) diffuses  into synaptic vesicles where the enzyme dopamine ff-hydroxylase  hydroxylates dopamine, forming norepinephrine (solid squares).   3). Upon nerve stimulation, calcium enters the presynaptic neuron  and causes the synaptic vesicles to fuse with the plasma membrane  and release norepinephrine into the synaptic cleft.   4, 5, 6). Norepinephrine diffuses throughout the synaptic space and  may bind to either al adrenergic receptors, ffl adrenergic receptors  or [)2 adrenergic receptors. Direct sympathomimetic drugs  (adrenergic agonists) bind to these receptors as ivell, without  interacting with the presynaptic neuron. 7). al adrenergic  receptors are located on the presynaptic neuron in some cases.  Stimulation of al presynaptic receptors by norepinephrine inhibits  subsequent release of norepinephrine from the terminal. 8). The  enzyme catechol-o-methyl transferase degrades catecholamines, such  as norepinephrine. 9). More commonly, excess norepinephrine is  transported back into the presynaptic neuron where it is (10)  repackaged in storage vesicles or (11) degraded by mitochondrial  monoamine oxidase. 12). Indirect sympathomimetics are drugs that  work by entering the presynaptic terminal and displacing norepi-  nephrine.   Figure 2.4B Synthesis, release and degradation of  acetylcholine. 1). The enzyme choline acetyltransferase catalyzes  the acetylation of choline by acetyl Co A to form acetylcholine.   2). Acetylcholine is stored in storage vesicles. 3). Upon nerve  stimulation, an action potential travels down the neuron and  causes calcium influx into the nerve terminal. Calcium influx  causes the vesicles to fuse with plasma membrane and release  acetylcholine. Acetylcholine diffuses through the synaptic cleft and  may bind to (4) Nm receptors (nicotinic receptors on muscle cells,  (5) Ng receptors (nicotinic receptors on ganglionic synapses of the  autonomic nervous system), (6) Ml muscarinic receptors, (7) M2  muscarinic receptors or (8) M3 muscarinic receptors. At least six  muscarinic receptors have now been identified, of which Ml, M2  and M3 receptors have been most carefully studied (Table 2.5).   9). Acetylcholine is cleared from the synaptic cleft by active re-  uptake and is hydrolyzed into choline and acetic acid. 10).  Acetylcholine breakdown products are recycled into acetylcholine.   Endogenous sympathetic agonists (norepinephrine,  epinephrine and dopamine) and other sympathomi-  metic drugs are presented in Tables 2.1A and 2.1 B.  Direct sympathetic agonists bind to a,, a,, P, or P 2  adrenergic receptors where they "turn on" second  messengers (Fig. 2.5). The second messenger associ-  ated with each receptor class mediates different effects.  Thus the actions of each agonist depend on the class or  classes of receptors to which it binds and the tissue  location of the receptors. The location of adrenergic    receptors and the consequences of their stimulation are  outlined in Table 2.2.   Catecholamines are chemicals which contain a  catechol group and an amine. Catechol-O-methyl  transferase (COMT) and monoamine oxidase (MAO)   Vasoconstriction (al).  Vasodilation (p2). Injected with  local anesthetics: al-mediated  vasoconstriction delays  distribution of anesthetic away  from the site of injection.   All cardiac effects mediated by pi  receptors: Increased heart rate;  contractility: conduction velocity; and  automaticity of A-V node, HIS-Purkinje  fibers and ventricles.   al: INTENSE vasoconstriction  leading to TT mean arterial  pressure, (vasoconstriction is  unopposed because drug fails to  bind to P2 receptors - which  cause vasodilation when  stimulated).   Intense vasoconstriction causes reflex  (parasympathetic-mediated) slowing of  the heart. This reflex bradycardia  overwhelms the weak pi  cardiostimulatory effects.   Intense vasodilation (P2)  reduces mean arterial pressure.  Doesn't bind to a 1 receptors.   Stimulates heart more than epinephrine  due to direct effects and response to  decreased mean arterial pressure.   Low doses: constricts arterioles  in sites other than the brain &  kidneys. Thus preserves flow to  these vital organs. At higher  doses, constricts all vessels.   Pi effects: T contractility, T systolic  pressure, less effect on rate than  isoproterenol. Causes indirect release  of norepinephrine which is offset by  inhibition of norepinephrine release via  presynaptic dopamine receptors.   4. heart rate (reflex to T mean arterial  pressure). Used clinically to treat  paroxysmal supraventricular  tachycardia.   Very few cardiac effects due to lack of  affinity for pi receptors.   are degradative enzymes which rapidly metabolize  catecholamines and consequently shorten the duration  of catecholamine effects. Despite their short duration  of action, catecholamines are used clinically to treat  anaphylaxis, cardiac arrest, heart failure and shock  (Table 4.2B and associated text).   Noncatecholamine adrenergic agonists (Table 2.1 A)  have longer serum half-lives than catecholamines,  because they are not metabolized by MAO or COMT.  Most noncatecholamine sympathomimetics are (3,-  preferring agents which are marketed as  bronchodilators (Table 5.1 A) or uterine relaxants (Table  10.3). Exceptions include phenylephrine and methox-   Indirect sympathomimetics cause norepinephrine  release from presynaptic terminals, but do not bind to  adrenergic receptors (Fig. 2.5, Table 2.1B). These drugs  enter the presynaptic terminal and displace stores of  norepinephrine from storage vesicles. Mixed sympa-  thomimetics displace norepinephrine from presynaptic  terminals and bind to adrenergic receptors. (Fig. 2.5,  Table 2.1 B).    Bronchodilation ((3),  vasoconstriction (a), and  decreased secretions (a).  Used therapeutically as  bronchodilator (Table 5.1).   Glycogenolysis and  gluconeogenesis (132). lipolysis  ((31), predominant i insulin  release (a2) but also t insulin  release ((32). T renin secretion   Gut relaxation (a, (32);  bladder sphincter contraction  (a); uterus contraction in  non-pregnant women (al),  uterus relaxation in near-term  women ((32).    No (32 effects. Thus it  cannot be used as a  bronchodilator.    Endogenous transmitter  of the peripheral nervous  system. Used only when  intense vasoconstriction  is necessary (septic  shock).   Metabolized by COMT, but  it is a poor substrate for  monoamine oxidase.   Synthetic derivative of  dopamine, but has no  effect at dopamine  receptors.    Included in cold remedies as  a nasal decongestant.  Decongestant effects due to  nasal vasoconstriction.   Used to treat paroxysmal  atrial tachycardia. Reflex  i heart rate is maintained  after drug is removed.    Figure 2.5 Direct, indirect and mixed actions of sympa-  thomimetic drugs. TOP: Direct agents (open triangles) mimic  norepinephrine as agonists at adrenergic receptors without  interacting with the presynaptic neuron. The chemical structure of  the drug determines its subclass specificity. MIDDLE: Indirect  sympathomimetics (striped) force epinephrine release from the  presynaptic terminal (solid triangles). Thus, these agents enhance  the actions of endogenous norepinephrine. Indirect agents do not  bind to adrenergic receptors. BOTTOM: Mixed sympathomimetics  (speckled) induce the release of norepinephrine and also bind to  adrenergic receptors. Sympathetic neurotransmission is also  enhanced by inhibition of the degradative enzyme, monoamine  oxidase. Monoamine oxidase inhibitors are used to treat depression  (Table 3.1 B).    1 Not yet determined which subclass of receptors is responsible for these actions.   2 Arterioles in skin and brain lack p 2 receptors. In other areas of the body, the degree of sympathomimetic-indeced vasoconstriction and/or  vasodilation depends on the drug's affinity for oci (vasoconstriction) or (5? (vasodilation) receptors (Table 2.1 A.).   Hypertension, cerebral  hemorrhage, convulsions,  coma, confusion, anxiety,  hallucinations, fever, tremor,  restlessness.   Treat toxicity by  acidification of urine (it is  a weak base) and  administration of a  blockers or nitroprusside  (for hypertension), and  antianxiety agents.   Adrenergic neurotransmission can be blocked either  by decreasing sympathetic outflow from the brain  (Table 2.3), suppressing norepinephrine release from  presynaptic neurons (Table 2.3) or blocking postsynap-  tic adrenergic receptors (Table 2.4).   Alpha-2 (a,) adrenergic receptors inhibit sympa-  thetic neurotransmission by two mechanisms.  Postsynaptic a 2 receptors inhibit sympathetic neurons  that exit the brain. Alpha-2 receptors are also found on  presynaptic nerve terminals where they inhibit norepi-  nephrine release.   Central anti-adrenergic drugs are commonly used to  treat hypertension (Table 4.3C). Clonidine and  guanabenz suppress sympathetic outflow from the    brain by binding to a, adrenergic receptors. In con-  trast, methyldopa is metabolized in the presynaptic  neuron to a-methyl norepinephrine. When released  from the presynaptic terminal, a-methyl-  norepinephrine acts as a potent a 2 agonist.   The extent to which clonidine, guanabenz and  methyldopa prevent norepinephrine release by binding  to presynaptic (X, receptors is not known.   Peripheral presynaptic anti-adrenergics inhibit  norepinephrine release from the presynaptic terminal.  Guanadrel and reserpine deplete norepinephrine from  presynaptic vesicles. As a result, guanadrel initially  releases norepinephrine from the terminal causing a  transient increase in adrenergic transmission.   Decarboxylated to a-methyl  dopamine then p-hydroxy-  lated to a-methylnorepineph-  rine, a potent a2 receptor  agonist. Results in 4  sympathetic outflow from   Sedation, mild orthostatic  hypotension, dry mouth, fever,  nasal stuffiness, Coombs  positive RBCs, salt and water  retention, rebound hypertension.   4 norepinephrine  concentration in nerve  terminals. Chronically,  sensitizes nerve to  sympathomimetics.   By rapid IV infusion: 4 blood  pressure, then transient  hypertension, then 4 arterial  pressure if patient is standing.   Depletes catecholamines and  serotonin in brain, adrenal,  and heart. Inhibits uptake of  norepinephrine into  presynaptic vesicles.  Chronically sensitizes patient  to sympathomimetics.   Nightmares, depression,  diarrhea, cramps, T risk of breast  cancer, peptic ulcers,  parasympathetic predominance.   Reserpine is long-acting, and the postsynaptic  neurons respond to the paucity of norepinephrine by  "upregulating" (increasing) the number of receptors on  the postsynaptic membrane. As a result, the postsyn-  aptic terminal is supersensitive to direct sympathomi-  metics. Consequently monoamine oxidase inhibitors  (which prevent destruction of endogenous cat-  echolamines such as norepinephrine and epinephrine)  and direct sympathomimetics (Table 2.1 A) should be  avoided in patients who have received reserpine.   Alpha blockers: Alpha adrenergic antagonists  compete with endogenous catecholamines for binding  at and a 2 receptors. Because norepinephrine and  epinephrine cannot bind to a receptor that is occupied  by an antagonist, the actions of catecholamines at    a adrenergic receptors (Table 2.2) are inhibited.  Adrenergic blockers used to treat hypertension are  presented in greater detail in Table 4.3C.   The vasodilation induced by alpha-blockers may  result in orthostatic hypotension (blood pools in legs  when the patient is upright) and tachycardia which is a  Pj-mediated sympathetic reflex to hypotension.  Because CX 2 receptors regulate norepinephrine release,  blockade of these receptors might result in hypersecre-  tion of norepinephrine.   Beta blockers: Nonspecific beta blockers (block  both Pj and P 2 receptors) have been used as first-step  antihypertensive agents. Because these agents block p,  receptors as well as P, receptors, bronchospasm may  occur. Newer agents are p,-specific and are not  contraindicated in asthmatic patients.   effects are long lasting.  Sometimes used for noncompliant  patients because of long half-life.   Vasodilation (a,). Blocks  sympathetic outflow from the  brain and feedback inhibition of  norepinephrine release at a ?  receptors. Increases insulin  release.    Compared to propranolol; less  bronchospasm in asthmatics,  less inhibition of vasodilation and  liver effects.   Postural hypotension (blood  pooling), intense reflex  tachycardia and force of  contraction (enhanced by block  of NE feedback control at a 2 ).  Arrhythmias, ischemia, sexual  dysfunction, nasal congestion.   Slow onset, but long lasting  due to irreversible binding to  receptor.   No large reflex tachycardia;  postural hypotension with first  dose; less sexual dysfunction.   Hypertension; benign  prostatic hyperplasia  (relaxes smooth muscles  produced by blockade of a,  in bladder neck and  prostate.   No large reflex tachycardia;  postural hypotension with first  dose; less sexual dysfunction.   No large reflex tachycardia;  postural hypotension with first  dose; less sexual dysfunction.   Further suppresses a failing  heart: fatigue, impotence,  diarrhea, numbness, orthostatic  hypotension.   Oral completely absorbed,  with peak levels in 1-2 hr and  steady state in 3 days.  Extensive 1" pass effect; IV  peak occurs in 5 min.   Well absorbed, extensive 1“  pass effect, terminal  elimination half-life 7-10 hrs,  extensively metabolized.   Hypertension, angina  pectoris, SVT, ventricular  arrhythmias, myocardial  infarction, migraine  prophylaxis, essential  tremors and other uniabeled  uses.   Low bioavailability due to  significant 1"pass effect:  Readily enters CNS; Haft-life  3-5 hours; Hepaticaily  metabolized.   Hypertension, myocardial  infarction, migraine  prophylaxis; Ophthamologic  agent used to i intraocular  pressure.   Lower toxicity than propranolol;  less likely to increase peripheral  resistance, cause broncho-  spasm, or inhibit liver metabolism.   Acetylcholine is the neurotransmitter of the para-  sympathetic nervous system, the neuromuscular  junction, and autonomic ganglia. In addition, acetyl-  choline in the brain plays a role in memory formation,  motor skills and other important tasks.   Muscarinic receptors (M) mediate postganglionic  parasympathetic and CNS functions of acetylcholine,  whereas nicotinic receptors are found in ganglia (N )    and at the neuromuscular junction (N m ). Table 2.5  outlines cholinergic actions at muscarinic receptors and  nicotinic receptors.   Choline esters are simply choline bound to an  acetyl derivative by an ester bond. The ester bond of  acetylcholine and related drugs is hydrolyzed by  enzymes known as cholinesterases (e.g., acetylcholines-  terase). Choline esters are more or less sensitive to  cholinesterase deactivation depending on their chemi-  cal structure.   Cholinomimetic alkaloids are derived from plants  by alkaline extraction. They are chemically distinct   See M, , M 2 , and M 3 rows above.   See M 1 , M 2 , and M 3 rows above.   Nicotine is among the most commonly used drug.  Smokers become tolerant to and dependent on its  effects. Nicotine stimulates the CNS, releases epineph-  rine from adrenal glands, stimulates and then blocks  receptors in ganglia and at the neuromuscular junction.  In the latter two cases, nicotine binds to the nicotinic  receptor, causing depolarization of the postsynaptic  neuron. In contrast to most agonists, however, nicotine  remains at the receptor, preventing further stimulation  of the occupied receptor. Like ganglion blockers, the    action of nicotine at each visceral organ depends on  whether the sympathetic or parasympathetic system is  predominant at the time.   Found in mushroom  Amanita muscaria. The  agent used to  characterize the  muscarinic receptor   The actions of acetylcholine are terminated in the  synaptic cleft primarily by acetylcholinesterase, which  cleaves the transmitter at the ester bond. The agents in  Table 2.6 inhibit acetylcholinesterase, thus preventing  transmitter (acetylcholine) degradation.   • The carbamyl ester inhibitors compete with acetyl-  choline for the active site of the enzyme. Acetylcho-  linesterase becomes carbamylated as it cleaves the  ester linkage. The carbamyl group prevents acetyl-  choline from binding to the active site of acetylcho-  linesterase for a period of minutes to hours. Upon  decarbamylation, the enzyme regains its ability to  cleave acetylcholine.   • Edrophonium, a competitive anticholinesterase,  contains a quaternary ammonium which is attracted  to an anionic pocket near the active site of acetylcho-    linesterase. Edrophonium does not act as long as  other agents because the binding is rapidly reversed.  • The organophosphorus inhibitors have very high  affinity for the active site of acetylcholinesterase.  Once bound, these agents inactivate the enzyme by  phosphorylation. Regeneration of the enzyme may  take over a week.   Cholinesterase inhibitors are used to treat glaucoma  and myasthenia gravis. In glaucoma, aqueous humor  production exceeds outflow, resulting in increased  intraocular pressure. In the presence of cholinesterase  inhibitor eye drops, acetylcholine causes constriction of  the sphincter muscle which surrounds the iris. The iris  is drawn away from the canal of Schlemm, enhancing  outflow of aqueous humor.   Myasthenia gravis is an autoimmune disease in  which antibodies bind to nicotinic receptors at the  neuromuscular junction. Cholinesterase inhibitors  prevent acetylcholine degradation, which increases the  probability that remaining receptors will bind acetyl-  choline.   Readily absorbed through Gl  tract. Hydrolyzed by  cholinesterases. Readily  absorbed IM or IV; peak effects  within minutes and persists -60  minutes.   Myasthenia gravis diagnosis and  treatment, paralytic ileus, atony  of detrusor of bladder, reversal of  neuromuscular blockade following  anesthesia.   Myasthenia gravis diagnosis,  treatment of excess tubocurarine  to reverse neuromuscular  blockade.   Absorbed parenterally, destroyed  in Gl tract. Short acting and  reversible. Not useful in  maintenance therapy.   Lipid soluble. Absorbed through  skin, mucosa, Gl tract. Enters  circulation and reaches all central  and peripheral cholinergic  synapses    Figure 2.6 Acetylcholinesterase inhibitors (ACHI) prevent  acetylcholine degradation by inhibiting the enzyme acetyl-  cholinesterase.   Cholinergic antagonists are classified as muscarinic  blockers (Table 2.7), ganglion blockers, and neuromus-  cular blockers (Table 2.8). At therapeutic doses,  muscarinic antagonists do not bind to nicotinic recep-  tors and neuromuscular blockers (Nm antagonists) do  not bind to muscarinic receptors. Most cholinergic  agonists, on the other hand, bind to both muscarinic  and nicotinic receptors.   Muscarinic antagonists, ganglion blockers and  neuromuscular blockers are all competitive antagonists  which can be overcome by adequate concentrations of  cholinergic agonists.   The prototype antimuscarinic agent is atropine, an  alkaloid isolated from Atropa belladona (deadly night-  shade) and many other plants. Atropine blocks the  muscarinic actions of cholinergic agonists (Table 2.5).  Its actions are dose dependent, occurring approxi-  mately in the following order as the dose of atropine is  increased :   • Inhibition of voiding (constriction of sphincter and  relaxation of detrusor)   Other muscarinic antagonists resemble atropine,  but differ slightly in potency and specificity for various  organs. These are noted in table 2.7.   In addition, some antipsychotics, antihistamines,  antidepressants, and opioids have anticholinergic  effects. Patients receiving these agents should be told  that dry mouth, tachycardia and constipation are  possible side effects.   Belladonna poisoning occurs with the ingestion of  anticholinergic drugs or plants such as nightshade,  thorn-apple, Jimson weed, stinkweed or devil’s apple.  Poisoning can also occur in children receiving  atropinic eye drops because of systemic absorption.   Symptoms include severe antimuscarinic effects  (Table 2.7), restlessness, headache, rapid and weak  pulse, blurred vision, hallucinations, ataxia, "burning"  skin and possibly coma. Children are more susceptible  to intoxication and death from belladonna poisoning.   Poisoning is treated with IV physostigmine (Table  2.6). CNS excitement or convulsions may be treated  with benzodiazepines.   Ganglion blockers (Ng antagonists) block nicotinic  receptors in both sympathetic and parasympathetic    ganglia. Because of the complex and unpredictable  actions of these agents, they are seldom used clinically  (Hexamethomium, mecamylamine). Trimethephan is,  however, occasionally used to treat hypertensive crisis.   Sympathetic and parasympathetic ganglia are  clusters of synapses between the spinal cord and   Preanesthetic to prevent respiratory secretions,  treatment of parkinsonism, severe bradycardia,  peptic ulcers, irritable bowel syndrome, mild  diarrhea, bladder spasms, enuresis,  bronchospasm   More potent at eye and glands than atropine, but less  potent at heart, lungs and Gl tract.   Prevention of motion sickness, nausea and  vomiting; Inhibits excessive motility ot the Gl  tract in irritable colon syndrome, mild  dysentery, diverticulitis   Mydriasis and cycloptegia for refraction and  treatment of uveal tract inflammation   Nonspecific direct relaxant effect on smooth muscle; No  antimuscamic activity and thus little effect on gastric  acid secretion   1/5 of the anticholinergic effect ot atropine with 4 to 10  times the antispasmodlc activity.   For relief of bladder spasms resulting in  urinary leakage and incontinence.   Relaxes smooth muscle of bladder and also has direct  effect on muscle   Symptomatic relief of dysuria. urgency,  noctuna. suprapubic pain, frequency and  incontinence that may occur with cystitis,  orostatitis. urethritis.   Centrally acting: reduces akinesia, tremor, and rigidity by  20%: may also reduce drooling   Adjunctive treatment of peptic ulcer,  antisecretory. an t is pas mot ic.    Treatment ot peptic ulcer; IV form used to  decrease salivary and tracheaobronchial  secretions and to block cardiac inhibitory  reflexes during Induction of anesthesia and  intubation.   Selective antimuscarinic activity for gastric acid secretory  cells: lesser effect on salivary secretion   visceral organs in which nerves from the brain connect  with nerves which innervate end organs. Acetylcholine  is the neurotransmitter in all sympathetic and parasym-  pathetic ganglia. Ganglion blockers therefore reduce  the effects of whichever system is predominant. In the  resting individual, parasympathetic control dominates   Thus, when ganglion blockers are administered to non-  stressed individuals, one would predict a shift from  parasympathetic predominance to sympathetic pre-  dominance.   Action potentials trigger calcium influx and the  subsequent release of acetylcholine (ACh) from presyn-  aptic motor neurons. ACh diffuses across the mem-  brane cleft and binds to nicotinic receptors on the  muscle end plate. Nicotinic receptors have five sub-  units, two of which bind ACh. When both are occu-  pied, the ion channel (the core of the ring formed by  the 5 subunits) opens, allowing Na* and Ca + * influx  and K' efflux. The simultaneous opening of many ion  channels leads to membrane depolarization and  propagation of an action potential in the muscle cell.  The action potential induces the excitation-contraction  coupling mechanism which causes muscle contraction.    • Nondepolarizing blockade occurs when pure  antagonists compete with agonists for nicotinic  receptors. Because antagonists lack activity, there is  no muscle contraction (fasciculations). Blockade is  overcome by high concentrations of agonist (ACh).   • Depolarizing blockade occurs when an agonist  binds to the receptor (causing fasciculations) fol-  lowed by slow dissociation of the agonist from the  receptor. During the time that the agonist remains  bound to the receptor, other agonist molecules  cannot stimulate the receptor.   Consequence of Blockade: Neuromuscular block-  ade causes paralysis of all muscles, including those of  respiration. Intubation and ventilation equipment  must be prepared prior to injecting neuromuscular  blockers. Reversing agents must be available.   Monitoring Neuromuscular Blockade: The periph-  eral nerve stimulator is a device which delivers electri-  cal impulses to nerves by way of electrodes placed on   Competes with ACh at  nicotinic receptors. Does not  activate receptor Blockade  can be overcome by high  concentration of agonists.   Adjunct to anesthesia: muscle  relaxant, eases intubation and  ventilation, eases orthopedic  manipulation, controls respiration  during chest surgery.    Ideal for patients with kidney and  liver failure (metabolized in  blood).   Used when elevated heart rate Is  desired; Adjunct to anesthesia, to  facilitate mechanical ventilation  and intubation   Initial fasculatlons  (depolarization), then Phase 1  block (4 min block of voltage  sensitive sodium channels).  Then. Phase II block (desen-  sitize receptor, lasts 20 min).  Parasympathetic stimulation  (therapeutic dose), sympa-  thetic stimulation (high dose).   Ideal for Intubation because of  rapid onset and short duration.  Adjunct to anesthesia and  mechanical ventilation.   the skin. The response to the stimulus (muscle twitch)  indicates the level of neuromuscular blockade.   In the operating room, the most useful stimulation  pattern is the train of four. Four impulses are deliv-  ered over two seconds:   Other patterns of stimulation include sustained  tetany and single stimulation. Patients who respond to  a sustained (5 second) 50 Hz stimulation are ready for  extubation (patient will be able to cough, inspire and  raise head). Failure to elicit > 5% of normal twitch to a  single 0.2 msec, 0.1 Hz stimulation indicates that the  blockade is sufficient for intubation.   Purpose & timing: Most patients are removed from  the ventilator before leaving the surgery suite. Rever-  sal of neuromuscular blockade allows the patient to  use the diaphragm and intercostal muscles to breathe.  It is essential that at least a single twitch is produced in  response to stimulation before an attempt is made to  discontinue artificial ventilation.   Pre-reversal: Atropine or glycopyrrolate (musca-  rinic antagonists (Table 2.7)) are often administered  prior to reversing agents to prevent bradycardia,  salivation and other muscarinic effects caused by the  administration of cholinesterase inhibitors.   Reversal: Cholinesterase inhibitors inhibit acetyl-  choline degradation (Table 2.6). The resulting in-  creased acetylcholine concentration competes with  neuromuscular blockers, reversing the blockade.   IV. Little dependence on  kidney (<20%) for  elimination; dosage  adjustment necessary in  liver impairment.   Usually cardiac stable, but  induces severe tachycardia,  bradycardia, A-V block or CHF  complications in 1% of patients.   IV. Depends on kidney  (60-80%) for elimination;  Renal and liver impairment  requires dosage  adjustments.   T intraocular pressure  (contraindicated: open eye  wounds) and gastric pressure  (caution: reflux during intubation),  dysrhythmias. Postoperative  muscle pain (myoglobin release  and hyperkalemia). May trigger  malignant hyperthermia.   Effects not reversed by  acetylcholinesterase  inhibitors. Numerous  contraindications (e.g.,  hyperkalemia, bums,  digoxin, myopathies,  pseudocholinesterase   Local anesthetics are used to block pain conduction  by nerves. They are used for infiltration anesthesia,  local nerve blocks, spinal nerve blocks and epidural  nerve blocks. The first local anesthetic was cocaine,  which has largely been replaced by synthetic agents.   Mechanism of Action: Local anesthetics inhibit  nerve conduction by reducing the permeability of the  neuronal membrane to sodium. This prevents sodium  influx which is required for propagation of action  potentials.   Chemistry: Lidocaine and procaine are the proto-  type local anesthetics (Table 2.9). All local anesthetics  are composed of a hydrophilic domain connected to a   hydrophobic domain by an alkyl chain. The drugs are  classified as amides or esters according to the type of  bond between the hydrophobic domain and the alkyl  chain.   Bicarbonate may be added to local anesthetic prepara-  tions to increase the percent of anesthetic in the  nonionized form. This accelerates penetration of the   Ionized form of drug  temporarily reduces the  permeability of neuronal  membranes to sodium. Thus,  action potentials cannot be  generated or propagated.   All types of Injection and topical  anesthesia, sedation,  arrhythmias (Table 4. 7A),  intracranial hypertension.    For production of local or regional  anesthesia for surgery, post-op  pain and obstetrical procedures.    Local infiltration, lumbar,  subarachnoid, caudal, peripheral  nerve, dental block. Long  duration increases utility for  epidural block during labor,    Peripheral, central nerve block;  lumbar peridural, caudal.  Intraabdominal surgery, maxillary  Infiltration.   PERMANENT neural damage may  result from use of this agent for  spinal anesthesia.   nerve sheath. Once internalized, the drug re-equili-  brates to the cationic (active) form.   Preferential blockade of small nerve fibers: Pain  and temperature fibers (A8 and C fibers) are more  easily penetrated by local anesthetics than larger  neurons. The order of loss of nerve function is pain,  temperature, touch, proprioception and skeletal  muscle tone.   Vasoconstriction response to epinephrine causes local  hemostasis, inhibiting distribution of local anesthetic  away from the site of injection, decreasing systemic  absorption and prolonging duration of action.   Consequences of IV injection: When injecting local  anesthetics subcutaneously or intramuscularly, aspi-  rate prior to injection to decrease the likelihood of  intravascular injection. Systemic absorption can affect  the cardiovascular system and the CNS. IV injection is  characterized by oral numbness, light headedness,  altered taste, or tinnitus. Epinephrine, if included in  the anesthetic preparation, will cause transient tachy-  cardia.   Metabolized by mixed  function oxidases in liver.  Some metabolites are active.  Excreted in the urine.   Thousands of neuronal signals race through our  brains each moment, controlling our breathing, move-  ments, thoughts and emotions with admirable preci-  sion. Neuronal circuits provide the basic "road map"  for brain signals, and chemical neurotransmitters carry  information from one neuron to another. Neurotrans-  mission in the brain parallels that in the autonomic  nervous system (Chapter 2), but utilizes several chemi-  cals and peptides in addition to acetylcholine and  norepinephrine. Neurotransmitters that have been  most carefully studied are introduced below.   Treatable neurotransmission diseases fall into two  categories: those caused by too much neurotransmis-  sion and those caused by too little neurotransmission.  "Too much" neurotransmission may be due to:   • a focus of hyperexcitable neurons that fire in the  absence of appropriate stimuli (e.g., seizure disor-  ders). Therapy is directed toward reducing the  automaticity of these cells.   • too many neurotransmitter molecules binding to  postsynaptic receptors (possible explanation for  psychoses). Therapy includes administration of  antagonists which block postsynaptic receptors.   • too few neurotransmitter molecules binding to  postsynaptic receptors (e.g., depression, Parkinson’s  disease). Several treatment strategies increase  neurotransmission, including 1) drugs that cause  release of neurotransmitter stores from the presynap-  tic terminal, 2) neurotransmitter precursors that are  taken-up into presynaptic neurons and metabolized  into active neurotransmitter molecules, 3) drugs  which inhibit the enzymes that degrade neurotrans-  mitters and 4) agonists that act at postsynaptic  receptors.   Because numerous pathways in the brain use the  same neurotransmitter, manipulating transmission in a  diseased pathway simultaneously affects synapses of  normal neurons. For this reason, CNS drugs are  notorious for causing a variety of side effects.   This chapter presents CNS agents according to  diseases that are treated by neurotransmission modula-  tors. General anesthetics are also included in this CNS    drug chapter, but their mechanism of action does not  appear to be mediated by neurotransmitter receptors.   The synthesis, release and degradation of norepi-  nephrine are presented in Figure 2.4A. Four classes of  adrenergic receptors (a,, a 2 , p, and P 2 ) are presented in  Table 2.2. Pathways in the brain that utilize norepi-  nephrine have not been clearly identified. Drugs that  mimic or modulate norepinephrine transmission are  presented in Tables 2.1 to 2.4.   A leading hypothesis suggests that depression is  caused by impaired monoamine (e.g., norepinephrine,  dopamine, serotonin) neurotransmission. Drugs which  induce monoamine release are indicated for attention  deficit disorder and narcolepsy. The biochemical distur-  bance responsible for these two diseases is unknown.   Dopamine is synthesized from Dopa, the hydroxy-  lated congener of the amino acid tyrosine (Fig. 2.4A). It  is degraded by monoamine oxidase A in the brain and  monoamine oxidase B outside the CNS and by cat-  echol-O-methyl transferase (COMT).   Dopamine receptors are classified as D, or D 2  receptors. Both subtypes reside in numerous regions of  the brain. No specific D, agonists have been identified.  Apomorphine is a D, agonist. Activation of either  subtype inhibits the rate of neuronal firing. Particularly  important dopaminergic pathways include 1) the  nigrostriatal pathway (from substantia nigra to stria-  tum), 2) neurons of the chemoreceptor trigger zone of  the medulla, which controls vomiting, and 3) projec-  tions from the hypothalamus to the intermediate lobe  of the pituitary, which are thought to regulate prolactin  release.   Antipsychotic drugs (Tables 3.3A and 3.3B) inhibit  dopamine-stimulated adenylate cyclase (usually  associated with D t receptor activation) and block D,  dopamine receptors, suggesting that psychoses may    result from overstimulation of dopamine receptors.  Another disorder, Parkinson 's Disease, is caused by too  little dopaminergic input from the substantia nigra into  the striatum. Loss of the nigrostriatal dopamine  neurons results in a relative decrease in dopamine  input (inhibitory) compared to acetylcholine input  (excitatory. Fig. 3.3).   As mentioned above, impaired monoamine neuro-  transmission has been implicated in causing depression,  attention deficit disorder and narcolepsy.   The amino acid tryptophan is hydroxylated and  then decarboxylated to form 5-HT. In neurons, 5-HT is  stored (in vesicles), released, taken up into presynaptic  neurons and either recycled or metabolized.   5-HT is released from inhibitory neurons originating  in the raphe nuclei of the pons and midbrain. 5-HT  stimulates either 5-HT, or 5-HT, receptors which are  distinguished by the specific antagonists methysergide  (5-HT, -specific) and ketanserin (5-HT,-specific). The  hallucinogenic drug, lysergic acid diethylamide (LSD)  is a potent agonist at both receptor subtypes. In  addition to its role as a neurotransmitter, 5-HT in-  creases small intestine motility and modulates vasodi-  lation. Ninety percent of the body's 5-HT is stored in  enterochromaffin cells of the small intestine.   Depression, attention deficit disorder and headaches  have been attributed to serotonergic imbalances. Many  serotonergic agents have been developed in the last few  years for the treatment of these diseases.   The synthesis, release and degradation of acetylcho-  line are presented in Figure 2.4B. Acetylcholine binds  to both muscarinic and nicotinic receptors throughout  the brain. Drugs which mimic or modify acetylcholine  neurotransmission are presented in Tables 2.5 to 2.9.   A cholinergic antagonist is used in the treatment of  Parkinson's disease to correct the imbalance of acetyl-  choline and dopamine neurotransmission created by  the degradation of dopaminergic nerves (Table 3.5).  Cholinergic or anti-cholinergic drugs are not otherwise  used to treat CNS disorders.   GABA is an inhibitory amino acid neurotransmitter  of brain intemeurons and other cerebral neurons. The  enzyme glutamic acid decarboxylase catalyzes the  synthesis of GABA from glutamate. GABA is stored in  presynaptic vesicles and binds to either GABA-A or  GABA-B receptors upon release.    GABA receptors reside on two subunits of a four-  subunit receptor complex that surrounds and regulates  a chloride ion channel. GABA activation of the recep-  tor induces chloride influx into the neuron. This  hyperpolarizes the neuron, making it more difficult to  fire when stimulated by excitatory neurotransmitters.  Benzodiazepines enhance the actions of GABA at  GABA-A receptors, but not GABA-B receptors.   Agents which enhance the actions of GABA such as  benzodiazepines and barbiturates are used to treat  anxiety and seizures and as sedatives or muscle relaxants.   Glutamate or a structuraily-similar chemical is an  excitatory neurotransmitter in many areas of the brain.  Stimulation of EAA receptors increases cation conduc-  tance, leading to depolarization, or stimulates phos-  phatidyl inositol turnover.   Excitatory amino acids such as glutamate are  thought to be important in learning, memory and other  brain functions. Glutamate-induced excitotoxicity is  implicated in the pathogenesis of Alzheimer's Disease,  Huntington's Disease, stroke, epilepsy and amyo-  trophic lateral sclerosis (ALS). Riluzole (Rilutek ),  protects neurons from glutamate toxicity in animals  and minimally slows progression of ALS.   Endorphins, enkephalins and dynorphins are opiate  receptor agonists that are cleaved from a protein called  pro-opiomelanocortin. Opiate receptors are located  along the periaqueductal gray matter. Morphine and  related drugs act at opiate receptors to relieve pain  (Table 3.7A, 3.7B). In times of stress or pain, endog-  enous peptides act at opiate receptors.   In addition to the endogenous opiate peptides,  several other peptides function as neu retransmitters  (e.g., substance P, vasoactive intestinal peptide). These  agents are generally cleaved from larger peptide  precursors. They can assume a variety of three dimen-  sional shapes, making it difficult to assess the chemis-  try of peptide-receptor interactions. For this reason, no  chemical agonists (other than morphine) or antagonists  have been identified for peptide receptors.   Major depression is characterized by intense  sadness or loss of interest in usual activities, ac-  companied by poor appetite, insomnia or hypersomnia,  psychomotor agitation or retardation, decrease in  sexual drive, fatigue, feelings of worthlessness, de-  creased concentration, or thoughts of death or suicide.   Mania, another affective disorder. Mania is charac-  terized by elevated, expansive, or irritable mood,  accompanied by increased activity, pressure of speech,  flight of ideas, grandiosity, decreased need for sleep,  distractibility, or involvement in activities that have  high potential for painful consequences. Patients that  cycle between depression and mania carry the diagno-  sis of bipolar affective disorder.    The biogenic amine hypothesis suggests that  depression is due to paucity of norepinephrine, do-  pamine, or serotonin neurotransmission in the brain  whereas mania is caused by excessive monoamine  neurotransmission. The observation that antidepres-  sants increase the synaptic concentration of the mono-  amines circumstantially supports the biogenic amine  hypothesis (Tables 3.1 A, 3.1B). Lack of correlation  between the onset of drug action (hours) and clinical  response (weeks) however, draws criticism to the  theory. The latency of antidepressant effects prompted  the suggestion that relief from depression may be due  to postsynaptic receptor downregulation (expression of  fewer receptors at the synaptic membrane) in response  to elevated concentrations of biogenic amines that  result during antidepressant therapy (Fig. 3.1).   Not yet clear. Most block  reuptake of monoamine  neurotransmitters, increasing  synaptic levels of the  transmitter. Subsequent  downregulation (reduction in  the number of receptors) of  postsynaptic receptors may  be the true mechanism of  action (Fig. 3.1).   First line of pharmacotherapeu-  tics to treat major depressive  episodes. Also enuresis,  agoraphobia (fear of open  spaces) with panic attacks,  obsessive compulsive neurosis,  chronic pain, neuralgia, migraine  headaches.   Anticholinergic effects,  cardiotoxicity, sedation,  orthostatic hypotension, mania,  hypomania, weight gain,  impotence, obstructive jaundice.   Original TCAD. Prescribed less  often because of side effects.  Enuresis in children.   Less sedation, fewer  anticholinergic effects. Sudden  death in children has occurred.   Use increasing because there is a  more clear relationship between  plasma levels and clinical  efficacy than other TCADs.   Depression may be due to a relative  decrease in monoaminergic neurotrans-  mission. In animal studies, tricyclic  antidepressants initially block re-uptake of  monoamines, resulting in higher neuro-  transmitter concentrations in the synaptic  cleft. Over a period of time, the postsyn-  aptic neuron responds to the chronic  elevation of monoamines by expressing  fewer receptors on the postsynaptic  membrane. If indeed clinical response is  due to receptor downregulation, then the  hypothesis that depression is due to  inadequate monoaminergic transmission  would be unsatisfactory. It is unclear  whether these mechanisms are responsible  for relief from depression in humans.   Well absorbed, widely  distributed, highly bound to  plasma proteins, half-lives  range from 8 hrs to 90 hrs,  metabolized more rapidly by  children and more slowly by  elderly patients.   Tolerance to anticholinergic side  effects may develop. Physical  and psychic dependence  develops occasionally. Sudden  withdrawal leads to malaise,  chills, coryza and muscle aches.   Do not administer to patients  with monoamine oxidase  inhibitors in their system  (potentiation may be lethal).  Other drugs which bind to  plasma proteins may  displace TCADs. May  potentiate effects of other   May shorten the cycle  length between mania and  depression in patients  with bipolar disease.   Patients coming out of  depression are at  increased risk of  committing suicide  because they regain the  energy to fulfill their  ideations.   PO. Longest half-life (75-90  hrs). Thus lower daily dose  than other tricyclics.   Blocks metabolism of  biogenic amines  (norepinephrine, serotonin,  dopamine) increasing the  synaptic concentration of  these transmitters.  Suppresses REM sleep.   Used to treat depression if tri-  cyclic antidepressants fail and  when electroconvulsive therapy  fails or is refused. Also used to  treat narcolepsy, phobic/anxiety  states and Parkinson's disease.   Hepatotoxicity, excessive CNS  stimulation, orthostatic hypoten-  sion. Overdose may cause  agitation, hallucinations,  hyperreflexia, hyperpyrexia,  convulsions, altered blood  pressure.   Drug discontinued in 1 5% of  patients due to nausea,  headache, nervousness,  isomnia, anxiety or diarrhea,  altered platelet function; rash.   Nausea, headache, diarrhea, dry  mouth, dizziness, insomnia,  fatigue, impotence, altered  platelet function.   Nausea, vomiting, somnolence,  insomnia, dizziness, agitation,  anxiety, weakness, headache,  abnormal ejaculation, altered  platelet function.    Depression. Used by some to  treat aggressive disorders and  cocaine withdrawal.   Rash, hypertension, tachycardia,  shortness of breath, many CNS  effects reported, i appetite,  priaprism.   Potentiate the effects of  sympathomimetics (including  tyramine present in dairy and  yeast products,  amphetamines in diet pills,  and sympathomimetics in  cold remedies).    Lit e-tnreaienmg react ion  possible with monoamine  oxidase inhibitors (MAOI)  and with cisapride. Do not  use within 2 weeks.    MAOI interaction. Similar to  fluoxetine. Does not affect  levels of other protein-bound  drugs.   PO. 70% protein bound,  half-life = 1 1 hrs. More rapid  onset than tricyclic  antidepressants.   Some argue that Alprazolam has  high dependency/abuse potential  and a severe withdrawal  syndrome.    Drugs which lower seizure  threshold. Bupropion  induces P450 enzymes,  altering drug metabolism.   Attention deficit disorder (ADD) in children is  characterized by short attention span, restlessness,  distractibility, impulsivity and emotional lability.  Hyperactivity is sometimes associated. Amphetamine-  like drugs reduce these symptoms in >80% of affected  children (Table 3.2). Many treatment plans also involve  family counseling and/or psychotherapy. Therapy is  usually tailored around the school schedule, the goal  being to enhance school performance and encourage  behavior which is suitable for the classroom. Drug  therapy is often discontinued during school vacations.   The anorectic property (appetite suppression) of  d-amphetamine may cause growth retardation. These  effects are less pronounced with other psychomotor  stimulants. Insomnia and nervousness are common  side effects of all psychomotor stimulants.    Amongst the methylated xanthines (Table 3.2),  caffeine is included in some analgesic preparations  because of its CNS-stimulating and cerebrovascular-  constricting effects. Many people consume coffee or  soft drinks, which contain caffeine, to maintain alert-  ness and to stay awake.   Caffeine is psychologically addicting and tolerance  develops to CNS and cardiovascular effects. With-  drawal often results in headaches.   Theophylline is a methylated xanthine which  exemplifies a clinically useful drug with a narrow  margin of safety. Theophylline is used to treat bron-  chial asthma as well as apnea and bradycardia in  premature infants. Serum concentrations must be  maintained between 10 and 20 pg/ml because it is  ineffective at lower concentrations and it produces  undesirable effects at higher concentrations.   Releases biogenic amines  (NE, dopamine, serotonin)  from storage vesicles. CNS  stimulant, decreases appetite,  improves ability of trained  athletes and coordination and  performance of fatigued  subjects, increases blood  pressure.   Narcolepsy, attention deficit  disorder in children. No longer  recommended for obesity.   CNS overstimulation,  restlessness, dizziness,  insomnia, increased blood  pressure, arrhythmia, anorexia,  psychotic episodes.   Adenosine receptor  antagonist. High dose: t Ca ++  permeability in sarcoplasmic  reticulum and T cAMP by  inhibiting phosphodiesterase.  Stimulates CNS, constricts  cerebral arterioles, induces  diuresis, stimulates heart,  bronchodilates.   Prolonged apnea in pre-term  infants (unlabeled use). Included  in some over-the counter  analgesic preps, particularly  headache remedies.    Figure 3.2 Why are CNS stimulants prescribed to  hyperkinetic children ? "Stimulant " is perhaps a misnomer for  the actions of amphetamine-like drugs. Although the drugs were  first characterized with regard for their ability to stimulate CNS  functions, the effects of these drugs are actually very complex. In  animal studies, amphetamines accelerate behavior ivhich is slow in  the absence of drug and suppress rapid behavior patterns. It has  been hypothesized that the sedative effects of amphetamines in  hyperkinetic children are due to inhibition of " fast-rate " behavior,  and that amphetamine-induced acceleration of"slow-rate" behavior  in children with attention deficit disorder may account for im-  proved learning and memory skills.    CNS, excreted without  undergoing metabolism,  half-life = 4-6 hrs.  Elimination is slowed by  alkalination of urine.    PO. half-life = 3. 5hrs in  children, 8.5 hrs in adults.   Psychotic Disorders are clinical syndromes charac-  terized by impaired sense of reality, disturbances of  thought & emotion, hallucinations (often auditory -  "the voice tells me..."), delusions ("1 possess the power  to..."), and confusion. The biochemical defects for these  diseases have not been clearly elucidated. The syn-  dromes listed may represent several discrete diseases  which have similar clinical presentation.   Schizophrenia is a psychotic disorder in which the  patient exhibits symptoms listed above for at least six  months leading to impaired ability to maintain inter-  personal relationships, a job, or daily living skills.  Active psychosis often occurs only during a small  portion of the patient's life. Between psychotic epi-   Widely accepted theories suggest that psychoses is  due, at least in part, to excessive dopamine neurotrans-  mission. This theory was originally based on the  observation that all antipsychotic drugs blocked D,  dopamine receptors. More recently, investigators  demonstrated that antipsychotic drugs inhibit dopam-  ine-stimulated cAMP production. This action cannot  easily be attributed to receptor blockade because  dopamine-stimulated cAMP production is linked to D,  rather than D, receptors and antipsychotic drugs have  low affinity for D, receptors.   As described in the chapter introduction, dopamine  is the neurotransmitter of numerous pathways in the   The actions of antipsychotic  drugs are complex . The ability  of antipsychotics to block D2  dopamine receptors correlates  with their clinical efficacy.  Animal studies have shown  that dopamine synthesis and  metabolism increase with  acute treatment and receptor  upregulation occurs after a  few weeks of antipsychotic  administration. It is likely that  these effects occur as a  regulatory response to the  drug-induced decrease in  dopaminergic transmission.   Psychoses, including mania,  acute idiopathic psychoses and  acute episodes of  schizophrenia; nausea and  vomiting; hiccoughs.   Acute dystonia (abnormal muscle  tone), Parkinsonism, malignant  syndrome, akathisia. tardive  dyskinesia, jaundice, sedation,  orthostatic hypotension,  anticholinergic effects,  adrenergic blocking effects and  allergic reactions to the drug.   Less sedative effects and  orthostatic hypotension, but more  extrapyramidal effects than  chlorpromazine    brain. Because antipsychotic drugs block all D 2 dopam-  ine receptors, they suppress all D, receptor-mediated  dopamine actions in the brain. Specific neurologic side  effects of antipsychotic drugs include:   • Acute dystonia: Patients may develop face, neck and  back spasms within a week of therapy initiation.  Antiparkinsonian drugs reduce symptoms (Table  3.5).   • Parkinsonism: Symptoms include "pill-rolling" with  fingers, limb rigidity, shuffling gait, bradykinesia,  and mask facies caused by dopamine receptor  antagonism in the nigrostriatal pathway. Symptoms  develop within one month of initiating therapy.  Parkinsonism is treated with drugs described in  Table 3.5.   • Malignant syndrome: This relatively rare, but  sometimes fatal syndrome is marked by catatonia.    rigidity, stupor, fluctuating blood pressure, fever  and dysarthria. Antipsychotic drug must be  discontinued promptly! Malignant syndrome is  treated with bromocriptine (dopamine agonist)  or dantrolene (mechanism of action associated  with reversing malignant syndrome is unknown),  but not antiparkinsonian agents.   • Akathisia: Motor restlessness occurring within  two months of antipsychotic drug initiation.  Decrease dose or discontinue drug. Treat with  benzodiazepines or low-dose propranolol.   • Tardive dyskinesia: Up to 20% of patients  treated with antipsychotics for months to years  (particularly phenothiazines and haloperidol)  develop involuntary movements of the face,  trunk, and extremities (dyskinesia & choreoathe-  tosis). Often non-reversible.   PO/I M/PR Absorption of  oral forms is erratic.  Distribute to tissues with  high blood supply and  cross placenta, half-life =  20-40 hrs. Metabolized by  liver to primarily inactive  forms. Elimination varies  with age of patient.   Tolerance develops to sedative  effects. Some cross tolerance,  but drugs are not easity  substituted for one another.  Choreoathetosis may develop  upon abrupt withdrawal.   Chlorpromazine enhances  the effects of central  depressants, sedatives,  analgesics, antihistamines,  alcohol and morphine.  Increases respiratory  depression caused by  meperidine. Inhibits actions  of levodopa and dopamine  agonists.   These drugs are  sometimes called  neuroleptics because  they reduce initiative and  interest in the  environment, alleviate  aggressive and impulsive  behavior, and reduce  spontaneous movement  and complex behavior in  animals. Generally  antipsychotic drugs with  more anticholinergic  effects produce fewer  extrapyramidal side  effects.   Dopamine stimulation of D, receptors in the chemo-  receptor trigger zone (CTZ) of the medulla mediates  some forms of nausea and vomiting. Several antipsy-  chotic agents antagonize D, receptors in the CTZ,  suppressing nausea and vomiting due to cancer  chemotherapy agents and other drugs and radiation  therapy (Table 3.4). Dopamine antagonists are not the  only class of drugs employed to prevent or treat nausea  and vomiting. Serotonin (5-1TT,) antagonists are potent  antiemetics, particularly useful for chemotherapy-  induced nausea. A few cholinergic antagonists and  histamine antagonists reduce emesis and control  motion sickness (Table 3.4). The neural pathways  influenced by these antagonists have not been clearly  identified.   Antipsychotic mechanism  unclear. Blocks dopamine  receptors as well as  cholinergic, adrenergic,  serotonergic & histaminergic  neurotransmission.   Schizophrenia in those whom  traditional antipsychotics have  failed or have produced  intolerable side effects.   Psychoses, Tourette's  syndrome, severe behavioral  problems in children, hyperactive  children (short term),   Less sedation, anticholinergic  effects, and alpha-adrenergic  blocking effects than  chlorpromazine. Rarely  hypotension. Extrapyramidal  side effects may be dramatic.   Mechanism unknown. Binds  as antagonist at serotonin,  dopamine, alpha adrenergic  and HI histamine receptors.   Prochlorperazine, triflupromazine. chlorpromazine and trifluoperazine are phenothiazine  antipsychotics which are described in Table 3.3. These agents control vomiting by blocking D2  dopamine receptors in the chemorecept or trigger zone (CTZ) of the brainstem.   Both a Dj dopamine antagonist and an Hi histamine antagonist which is used to control motion  sickness as well as nausea and vomiting. Particularly useful following surgery because it reduces  anesthesia-related nausea, Induces light sleep and reduces apprehension.   (Reglan) Also used clinically as a Gl stimulant to improve gastric emptying   This anticholinergic is available as a transdermal preparation to prevent motion sickness. Overdose  may cause confusion, memory alterations and other anticholinergic effects.   Diphenhydramine, dimenhydrinate and meclizine are antihistamines with anticholinergic effects.  Anticholinergic drugs reduce motion sickness as well as emesis.   Blocks serotonin (5-HT3) receptors, but not dopamine receptors Used to control chemotherapy-  induced nausea. Remarkably more effective than other agents in patients receiving chemotherapy,   Therapy is  withheld if  granulocyte  count is  < 1500/mm J .    PO/IIWIV. Begin treatment  at low dose, individualize  dose for each patient.   Enhances actions of CNS depressants,  alcohol. & anticonvulsants. Decreases  actions of amphetamines. Severe  hypotension with alcohol, epinephrine,  antihypertensives. Antimuscarinics:  Increase intraocular pressure and reduce  haloperidol effects. Lithium:  encephalopathic syndrome.   Lowers seizure threshold in patients  taking seizure medications. Potentiates  CNS depressants.   Metabolized by P450 enzyme that is  inhibited by many other drugs.   Parkinson's Disease affects a half million Americans.  Symptoms include tremor (pill-rolling) at rest, bradyki-  nesia (slow movements), and cogwheel rigidity.   The disease is caused by decreased dopamine  neurotransmission in the nigrostriatal pathway second-  ary to degradation of dopaminergic neurons that  project from the substantia nigra (black substance) to  the striatum (caudate and putamen). Figures 3.3 and  3.4 outline the neuropathology of Parkinson's Disease.  Treatment consists of either increasing dopamine  neurotransmission or blocking cholinergic neurotrans-  mission (Table 3.5, Fig. 3.4).   Figure 3.3 The symptoms of Parkinson's Disease are  caused by degeneration of dopaminergic neurons in the  nigrostriatal pathway. Inhibitor}/ dopaminergic neurons which  project from the substantia nigra to the caudate and putamen are  most affected. Cholinergic input (excitatory) to the caudate and  putamen appears to be unaffected; thus the balance is tipped toward  cholinergic input.   Decarboxylated to dopamine  (DA) in brain. Improves  neurological, motor, and  altered mood symptoms of  Parkinson’s Disease.   Nausea, vomiting due to  stimulation of emetic center  (tolerance develops to Gl  effects), modest orthostatic  hypotension, arrhythmias in older  patients, involuntary movements  (dose limiting), psychiatric  disturbances, T sexual activity  due to actions on hypothalamus.   Diminishes decarboxylation  of l-dopa in peripheral tissues.  Improve effect of l-dopa,  decrease required dose of  l-dopa by about 75%.   Reduces levodopa-induced  nausea and vomiting. Does not  alleviate most side effects  caused by levodopa. Has no  known toxicities when  administered alone.   Few side effects. At high doses  may induce hallucinations, confu-  sion & nightmares.   Parkinson's disease, particularly  when tolerance develops to  l-dopa or when symptom relief  "swings" between doses. Also  hyperprolactinemia, adjunct in  treatment of pituitary tumors.   Irreversibly inhibits mono-  amine oxidase type B (but not  type A). Inhibits intracerebral  metabolic degradation of DA.   Adjunct to levodopa/carbidopa in  cases when response to  levodopa/carbidopa is no longer  adequate.   Antagonists at cholinergic  receptors. Lessen ACh:DA  imbalance in striatum. Less  effective than l-dopa for  tremor and other symptoms.   Supplement to l-dopa for Parkin-  son's. Alone when l-dopa is con-  traindicated.   Figure 3.4 Synaptic view of Parkinson's Disease (PD) and therapy. Dopaminergic terminals decay in PD, leading to decreased  dopamine (DA, solid triangles). L-dopa, an amino acid precursor of DA crosses the blood brain barrier, enters surviving DA terminals and  is converted to DA. Increased DA neurotransmission partially restores the dopamine-acetylcholine neurotransmission balance.   PO. Rapidly absorbed, half-life = 1-3  hrs. Less than 1% of levodopa  penetrates CNS because of  peripheral decarboxylation. This is  circumvented by coadministration  of carbidopa, a dopa decarboxylase  inhibitor.   Pyridoxine: may reduce effects of levodopa by  stimulating decarboxylation. Antipsychotic  drugs: block DA receptors. MAO inhibitors:  cause buildup of sympathomimetic amines  (withdraw 2 weeks before administration of  levodopa). Anticholinergic drugs: synergism with  levodopa, may delay absorption by slowing  gastric emptying. Antidepressant drugs:   PO. 1 nitiate at low dose and  individualize. Rapid, partial  absorption, half-life = 1 .5-3 hrs.   Selegiline slows progression of  Parkinson’s when used in  conjunction with  levodopa/carbidopa.   Benztropine, procyclidine, and  biperiden, are other anti-  cholinergics used for Parkinson’s  disease.   Opium, derived from poppies, relieves pain and  induces euphoria by binding to "opiate receptors” in  the brain. These opioid drugs mimic the actions of  three peptide families in the brain known as the  endorphins, the enkephalins, and the dynorphins.  These peptides, along with several nonopioid peptides  (MSH, ACTH, & lipotropin) are cleaved from the  protein precursors proopiomelanocortin (POMC),  proenkephalin, and prodynorphin (Fig. 3.5).   Three subtypes of receptors, mu, kappa and delta,  mediate the effects of opioid drugs and peptides. The  prototype agonist is morphine, which is a potent  analgesic and sedative. Agonists with similar analgesic  effects (full agonists) are described in Table 3.6A and  partial agonists are described in Table 3.6B. Opioid    agonists also reduce intestinal motility (antidiarrheals),  reduce coughing (antitussives) and induce vomiting.  Nonanalgesic agonists used for these purposes are  listed in Table 3.6C.   Patients on morphine and related agonists must be  monitored for signs of CNS-mediated respiratory  depression, which is the dose-limiting side effect of  opioid agonists.   Principles that should be kept in mind when  prescribing pain relievers include:   • Narcotic analgesics should be employed only when  pain cannot be relieved by non-narcotic analgesics  (Chapter 9).   • Abuse and street-sales of narcotic agents are com-  mon. Monitor patients for drug-seeking behavior.   • Remind patients that constipation is a likely side  effect and that a stool softener may be necessary.   Induces analgesia, sedation,  respiratory depression,  nausea, vomiting, vertigo,  miosis, ADH release, Gl effects  (decreased propulsion and  secretions, tonic spasm).  Increases tone in bile duct,  bronchi, ureters, and bladder.   Severe pain which cannot be  alleviated by non-narcotic  analgesics or weaker narcotic  analgesics. Drug of choice for  treating severe pain of myocardial  infarction.   Respiratory depression,  constipation, CNS disturbances,  orthostatic hypotension,  cholestasis, nausea and vomiting  with initial doses.   Also used to treat rigors such as  those induced by amphotericin B.   Like morphine. Overdose causes  convulsions due to excitatory  actions of metabolite.    Figure 3.5 Cleavage of pro-opiomelanocortin (POMC) into p-endorphin and non-opioid peptides. POMC serves as a  precursor ( pro-) for the opiate peptide, /3- endorphin ( - opio -) ;for a-, fi- and y-melanoq/te-stimulating hormone (MSH, -melano-h for  adrenocorticotrophic hormone (ACTH, - cort -) : and for a- and p- lipotropin (-in). Notice that the peptides are not located end-to-end, but  that some of the smaller peptide sequences are embedded in larger sequences (e.g., a-lipotropin, p-MSH and fi-etidorphin are contained  within plipotropin). Two other protein precursors contain enkephalins and dy nor plans. Proenkephalin contains seven met -enkephalin  sequences (Tyr-Gly-Gly-Phe-Met). Prodynorphin contains three leu-enkephalin sequences ( Tyr-Gly-Gly-Phe-Leu ) and the sequences for  dynorphin A, Dynorphin B, a-neodynorphin and p-neoendorphin.    IM/PO/PR/SC/IV, epidural,  intrathecal. Poorly  absorbed, metabolized by  conjugation w/ glucuronic  acid. 4-6 hr duration.   Tolerance develops to analgesic  effects, but not to constipating  effects. High abuse potential.  Wthdrawal leads to insomnia,  pain, increased Gl activity,  restlessness.   Enhances actions of other  CNS depressants. Increases  neuromuscular blocker-  induced respiratory  depression. Additive with  drugs that cause  hypotension.   The analgesic actions of  opioids are threefold. The  perception of pain is  reduced (increased  threshold), the unpleasant  psychological response is  reduced, and sleep is  induced even in the  presence of pain.    Wth MAO inhibitors, causes  severe CNS excitation,  respiratory depression, or  hypotension.   IM/SC/PO. Excreted more  slowly than morphine (half-  life =25h). Withdrawal  symptoms are less  intense, but prolonged.    Detoxification replaces  heroin dependence with  methadone dependence.  Then slowly reducing  methadone dose to zero.   Similar to morphine, but less  intense at doses which relieve  moderate pain. At high doses,  toxicity is as severe as with  morphine.   Dizziness, sedation, nausea,  vomiting. Overdose causes  convulsions. CNS depression,  coma, death.   Similar to morphine, but less  potent. Antagonized by  naloxone, not by nalorphine.   Treatment of narcotic overdose.  Diagnostic agent (for evaluation  of addiction) in methadone  programs. To reduce  postoperative respiratory  depression.   Induces narcotic withdrawal  syndrome (appetite loss, muscle  contraction, fever/chills,  restlessness, cardiovascular and  respiratory symptoms,  nausea. vomiting, diarrhea.)   Diphenoxylate is used to treat diarrhea. It is too insoluble to escape the Gl tract. Like morphine,  it causes constipation, but diphenoxyjate fails to produce analgesia. Antidiarrheal effects can  be blocked by narcotic antagonists (Table 3.6).   Dextromethorphan is the dextro- isomer of codeine. It is included in cough medicine because of  its centrally acting antitussive effects. Dextromethorphan actions are unaffected by narcotic  antagonists. It causes little sedation or Gl disturbances.   Stimulates the chemoreceptor trigger zone, causing nausea and vomiting. These emetic effects  are blocked by narcotic antagonists. Apomorphine has few other narcotic-like effects.   Tramadol (Ultram®) is a non-opiate synthetic  analgesic that is indicated for moderate to severe pain.  Tramadol and its primary metabolite bind to g-opioid  receptors, but is only partially antagonized by nalox-  one. It also reduces uptake of norepinephrine and  serotonin.    Compared to other central analgesics, it produces  less respiratory depression and histamine release than  opiates and less platelet toxicity than nonsteroidals.  Toxicity includes constipation, dizziness, nausea/  vomiting, headache, pruritis. Tramadol-induce miosis  may limit the utility of pupil examination in head  trauma patients. Tolerance, dependence, abuse are less  likely to develop with Tramadol than with opioids.   1 0% demethy lated to form  morphine, the rest is  conjugated in liver and  excreted in urine.   Included in a number of  cough medicine prepara-  tions because of  antitussive effects.    Overdose often leads to  death, particularly in  patients with history of  psychiatric disorders.    IM/IV/SC. More rapid  onset, shorter duration  than morphine. Well  absorbed, highly  metabolized.   Lower risk of abuse than morphine.  Antagonist effects can induce  withdrawal in narcotic addicts.   Taken orally, only  pentazocine is absorbed.  By IV however, naloxone  blocks pentazocine.   30 mg. codeine phosphate, 325 mg. aspirin, 40 mg.  caffeine, 50 mg. butalbital   60 mg. powdered opium and 15 mg. powdered Used for control of   4.5 mg. oxycodone HCI, 0.38 mg. oxycodone  terephthalate and 325 mg. aspirin   Barbiturates and benzodiazepines enhance the  actions of the inhibitory neurotransmitter, gamma-  aminobutyric acid (Fig 3.6, Tables 3.8A, 3.8B and 3.8C).  Agents from both classes are effective sedative-  hypnotics (sleep-inducing agents), antianxiety agents,  and anticonvulsants (Table 3.9). Benzodiazepines are  prescribed more often than barbiturates because they  cause fewer side effects.   The non-barbiturate/non-benzodiazepine sedatives  are not listed in a table. Zolpidem (Ambien), Chloral  hydrate, paraldehyde, meprobamate and glutethimide  cause sedation, but are neither benzodiazepines or  barbiturates. Zolpidem acts through the GABA  receptor and its actions mimic benzodiazepines. It is  used for short-term treatment of insomnia. Chloral  hydrate is used for sedation in children. It is reduced  in the body to trichloroethanol, a potent ethanol. Like  ethyl alcohol, the side effects of chloral hydrate include  mucosal irritation, light-headedness, malaise and  ataxia. Paraldehyde, meprobamate and glutethimide  are seldom used.   Figure 3.6. Schematic model of the GABA/Benzodiaz-  epittel Barbiturate receptor complex. The receptor complex  surrounds a chloride ion channel. Gamma-amino butyric acid  (GABA) is an inhibitory neurotransmitter. GABA binds to the  receptor causing chloride influx. The movement ofcldoride into the  neuron hyperpolarizes the neuronal membrane, making it more  difficult for excitatory neurotransmitters to depolarize the cell.  Benzodiazepines and barbiturates enhance the actions of GABA,  but fail to open the chloride channel in the absence of GABA.   GABA receptor on chloride channels. Results in retention of  GABA at its receptor causing increased flux of chloride  through the channel. Induces sedation, euphoria, other  mood alterations, hypnosis, “barbiturate” fast waves in   EEG, respiratory depression. At high doses, may cause  cardiovascular depression or death.   Mechanism/ Actions : Bind to benzodiazepine site on  neuronal GABA receptor complex. Enhances GABA-  mediated chloride influx (neuronal inhibition). At  therapeutic doses may also inhibit neurons by unknown  mechanisms which are unrelated to either GABA or chloride  influx. Cause sedation, skeletal muscle relaxation, and  "barbiturate" fast waves on EEG. Also has anticonvulsant  effects.   1 ndications : Clinical uses include treatment of epileptic  seizures and as a component of anesthesia.   Benzodiazepines are usually preferred to barbiturates for  treatment of anxiety. Antipsychotics are preferred for  treatment of neurotic states.   Indications: Generally, benzodiazepines are used for  treatment of anxiety and neurotic states, nervous tension,  agitation, psychosomatic illness, delerium tremens. Also  used for skeletal muscle relaxant, anticonvulsant, and  sedative properties. Diazepam is the benzodiazepine of  choice for muscle relaxation and intractable seizures.   Undesirable effects: Drowsiness, clouding of  consciousness, dysarthria, ataxia, "paradoxical"  stimulation due to behavioral disinhibition, CNS depression  to the point of coma and respiratory arrest, laryngospasm.   Undesirable Effects: Drowsiness, clouding of  consciousness, dysarthria, ataxia, behavioral  disinhibition, dermatitis.   Pharmacokinetics: PO/PR/IM/IV. Well absorbed orally.  Give IMonly if patient can’t take orally. Give IV slowly  because of hypotension risk. Barbiturates vary markedly in  lipid solubility and plasma protein binding (Table 3.8B).  Barbiturates induce P450 enzymes in the liver which   Pharmacokinetics: Primary difference between  various benzodiazepine agonists are their pharmacokinetic  properties (Table 3.8C).   Tolerance/Dependence: Tolerance, metabolic  dependence, and psychologic dependence are likely.  Dependence presents much like chronic alcoholism. Upon  withdrawal, convulsions, hyperthermia, and delerium may be  severe enough to cause death.   Tolerance/Dependence: High dose, chronic therapy  may lead to dependence. Abrupt withdrawal may cause  syndrome that mimics alcohol withdrawal (convulsions, hy-  perthermia. delerium). Cross tolerance and dependence  occur.   Drug Interactions: Barbiturates as a class interact with  over 40 other drugs. These interactions are largely due to  alteration of metabolizing enzymes in the liver or  interference with the absorption of other drugs.   Duration: 10-12 hours. Barbital is excreted primarily by the kidneys. Phenobarbital is  metabolized by the P450 enzymes in the liver. Phenobarbital induces P450 enzymes, causing  increased metabolism of many drugs. Phenobarbital is used clinically as an anticonvulsant.   Duration: 3-6 hours. Metabolized by P450 enzymes in liver. Amobarbital is sometimes  administered by psychiatrists during analysis or therapy. Prior to some neurosurgical  procedures (e.g., temporal lobectomy for intractable seizures) amobarbital is injected unilaterally  into the carotid artery to determine the dominant hemisphere of the brain.   Duration: <3 hours. These drugs are deposited in fat, then secondarily metabolized by the liver.    ** Flumazenil (Romazicon) is a competitive antagonist at benzodiazepine receptors. Used clinically to reverse    benzodiazepine sedation or overdose and as part of the treatment for hepatic encephalopathy. Resedation occurs  in about 10% of reversals. Seizures infrequently occur with reversal, usually following multi-drug overdose.   Most rapidly absorbed. Metabolized  in liver to active metabolites which  prolong clinical duration of action.  Metabolized slowly by infants, elderly  and patients with hepatic disease.   Has antidepressant actions as well as anxiolytic  actions. Also used to treat panic attacks. Unlike  many benzodiazepines, alprazolam does not cause  daytime drowsiness.   Useful for achieving rapid sedation of agitated  patients. No daytime sedation.   Poorly absorbed, requres higher  doses than diazepam to achieve  same effects.   Useful for treating elderly patients and patients with  liver dysfunction because it does not rely on the  liver for metabolism.   Associated with decreased IQ in  children that have been treated  chronically.   Status epilepticus. Rapid onset  useful for stopping active  seizures. Not used for chronic  seizure control.   Reduces sodium, calcium and  potassium currents across  neuronal membranes. Unclear  which effects are responsible  for seizure prophylaxis.   Nystagmus, ataxia, other CNS  disturbances, bone marrow  suppression, gingival  hyperplasia, hepatotoxicity, Gl  disturbances. IV administration  may cause CNS depression,  severe hypotension, arrhythmias,  and hyperkinesis.   Similar to phenytoin. Also has  antidiuretic effect. Chemical  structure similar to tricyclic  antidepressants.   All types of seizures except  absence. Trigeminal neuralgia,  manic depression, schizophrenia  that fails to respond to  antipsychotics.   All seizure types, particularly  disorders of combined seizure  types. Manic episodes in bipolar  disorder.   Severe/fatal hepatotoxicity.  particularly in small children,  much less in adults. Thrombo-  cytopenia, hyperammonemia.   Mechanism unknown. Maybe  related to actions at the GABA  or NMDA (glutamate) receptor  channels.   No longer recommended because  of aplastic anemia and liver failure  risk.   Risk of aplastic anemia, hepatic  failure. Somnolence, headache,  fatigue, nausea, photosensitivity.   Headache, nausea, dizziness,  vomiting, fatigue, ataxia, blurred  vision, confusion, rashes,  hepatotoxicity, blood dyscrasias,  lupus-like syndrome (rare).   Mechanism unknown. Related  to GABA, but likely acts at  distinct receptor.   Dizziness, headache, nausea,  ataxia, somnolence, diplopia,  blurred vision. Life-threatening  rash in children (1 :50) and adults  (1:1000).   Mechanism unknown. May be  related to actions at GABA or  kainate/ AMP A receptors.   Seizures occur as a result of hyperactivity or  hypersynchronicity of neurons in the brain. Focal  seizures involve a cluster of neurons and present with  unilateral symptoms. They are often due to structural  abnormalities such as scars, tumors or inflammation.   Generalized seizures involve both hemispheres.  They occur either as a result of hyperexcitability  throughout the brain or because an epileptic focus  spreads to both sides of the brain. By the latter mecha-  nism, focal seizures may become generalized.   • Partial Seizures: Simple partial seizures consist of a  single detectable motor, sensory or psychological  dysfunction which does not change during an  episode. Consciousness is retained throughout.  Partial complex seizures begin in a focal area, usually  in the temporal lobe or limbic cortex, and spread.  Focal signs are often followed by automatisms (e.g.,  lip smacking, sweating) and dulled or lost conscious-  ness. Effective drugs include carbamazepine,  phenytoin, clonazepam and primidone. Valproic  acid is sometimes added.   • Absence Seizures (Petit mal): Generalized seizures  in children or teens which present as brief episodes  of blank staring but no convulsions. Effective drugs  include ethosuximide, valproate, clonazepam and  trimethadione.   • Generalized Tonic-Clonic Seizures (Grand mal):  Begin with prolonged contractions of muscles in  extension followed by cyanosis due to arrested  breathing. Patients then experience whole-body  clonic jerks. Treatment options include phenytoin,  diazepam carbamazepine, phenobarbital and  primidone.   • Status Epilepticus: Continuous series of seizures  without reawakening. May cause permanent brain  damage. Intravenous, diazepam, phenytoin or  phenobarbitol is recommended for treatment.   • Increase dose of suitable single agent until desired  effect is achieved or until toxicity prevents further  increase.   • A second drug may be added if maximal doses of the  initial drug fail. The initial drug should then be  tapered and discontinued.   • Abrupt discontinuance of an anticonvulsant may  induce status epilepticus. Always taper doses.   Inhalation anesthetics are inert vapors used during  surgery to achieve sedation, muscle relaxation and  analgesia. The first anesthetic, ether, was introduced in  1846 by a second-year medical student at Massachu-  setts General Hospital. Ether has since been replaced  by non-volatile agents.   Inhalation anesthetics do not appear to work  through a receptor mechanism and the mechanism of  action remains a mystery. Theories suggesting that  anesthetics work by altering the lipids in cell mem-  branes stem from the observation that the potency of  anesthetics correlates extremely closely with the  solubility of the drug in oil.    The measure of potency is the minimum alveolar  concentration (MAC). MAC is the concentration of  anesthetic that causes immobility in 50% of subjects  exposed to the agent at one atmosphere. The MACs of  commonly used anesthetics are:   Note that the MAC of nitrous oxide is greater than  100%. This means that less than 50% of exposed  subjects would be anesthetized even if 100% nitrous  oxide was administered. Thus nitrous oxide is a poor  anesthetic when used alone.   CNS: Sedation, hypnosis, CNS depression, decreased cerebral blood flow and metabolism (reduced  intracranial pressure). CV: 10-20% drop in blood pressure. Resp: Apnea, bronchoconstriction.   Onset 40 seconds, duration 30 minutes, drug released from fat stores may prolong anesthesia.   CNS: More potent than thiopental. CV: Bradycardia, hypotension, decreased myocardial perfusion.  Resp: Apnea. Tox: Pain on injection (use lidocaine first), CNS stimulation, severe cardiovascular  depression in elderly and hypovolemic patients. Kinetics: IV. Onset 1 min. Very rapidly cleared by  metabolism and tissue distribution. Constant infusion necessary to maintain anesthesia.   Myoclonus, vomiting, adrenal insufficiency from chronic use. Kin: IV. Onset 1 min, Duration 3-5 min.   CNS: Dissociative (disconnected from surroundings) anesthesia, analgesia, increased intracranial  pressure. CV: Increase or decrease in blood pressure, heart rate. Resp: Apnea, bronchodilation.   Tox: Hallucinations (Adults > children), nightmares, increased secretions. Kinetics: IV/IM. Onset   CNS: Anesthesia, skeletal muscle relaxation. CV: Myocardial depression (*E>H>I), decreased  vascular resistance, sensitize heart to catecholamines (*H>E>I). Resp: Respiratory depression,  bronchodilation (*H>E>I). Tox: Malignant hyperthermia possible with all. Halothane associated with  hepatotoxicity and infrequent liver failure. Enflurane: nephrotoxicity Kinetics: Isoflurane is least  metabolized, lack of metabolites credited for hepatic & renal safety. All stored in fat. Newer agents  include Desflurane and Sevoflurane.   CNS: 100% Nitrous oxide fails to induce anesthesia in >50% of people - usually used with other  agents. CV: When combined with halothane or enflurane, less hypotension at equivalent depth of  anesthesia. Resp: Little effect. Tox: Transient hypoxia following use. Kinetics: Least soluble in  blood. Thus, excreted rapidly by expiration of unmetabolized gas   1 The molecular mechanism of action is unknown for most anesthetics. Agents often used with an anxiolytic (Table 3.8)  and/or paralytic (Table 2.9). Drugs are rapidly distributed, metabolized in the liver and excreted by the kidney unless noted.   Sumatriptan (Imitrex*), naratriptan (Amerge),  rizatriptan (Maxalt), and zolmitriptan (Zomig) are  vascular 5HT, (serotonin) receptor agonists that causes  vasoconstriction of the basilar artery and dura mater  vessels. Pain relief occurs in 15 - 80% of patients.    Onset of relief is 10-120 minutes. Toxicity includes;  dizziness, tingling, flushing, chest discomfort, weak-  ness, neck pain.   Propranolol and timolol are used to prevent onset of  migraine headaches (Table 2.4).   • It pumps blood through a system of blood vessels that  has a limited volume capacity.   • Heart failure occurs when the heart can no longer pump  enough blood to meet the metabolic demands of the  body. The most common cause is myocardial injury  from ischemia, inflammation and chronic hypertension.   • Hypertension develops when blood volume is great  compared to the space available inside blood vessels.  Mean arterial pressure is equal to cardiac output times    peripheral resistance. Increased heart rate, de-  creased vascular resistance and myocardial contrac-  tility, enhance cardiac output. Vasoconstriction  elevates peripheral resistance.   • Angina (chest pain) is the heart's way of signalling  that some of its cells are not getting enough oxygen  (too little blood flow). Myocardial infarction occurs  when oxygen-starved areas of the heart begin  dying.   An understanding of the pathophysiology of each  disease and the therapeutic goals of each treatment  strategy will make learning the individual drugs much  easier. Table 4.1, which follows, describes the pharma-  cologic approach to treating heart malfunctions. Note  that some drugs are used to treat several malfunctions.   Diuretics decrease blood volume by increasing the volume  ol water excreted In the urine,   Clonldine is an agonist at a 2 receptors. Qomdine inhibits  further release ol the sympathetic agonist, norepinephrine,  and Inhibits sympathetic outflow from the brain.    Atenolol is a |5, adrenergic receptor antagonist that  reduces heart rate and myocardial work   Nifedipine blocks calcium entry into smooth muscle cells  of arterial walls, preventing contraction.   Streptokinase converts plasminogen toplasmin. Plasmin  digests fibrin and fibrinogen, thus dissolving clots.   Nitroglycerin reduces venous tone (It also dilates  coronary arteries, enhancing blood delivery to the heart).   Amrinone inhibits cAMP degradation (cAMP is a  biochemical messenger that stimulates the heart.   Destroy clots that have already formed Streptokinase converts plasminogen to plasmin.   Diuretics reduce blood pressure and edema by  increasing urine production. All diuretics enhance  water and sodium excretion, but the effect of diuretics  on other salts depends on the mechanism of action  (Table 4.2A, Fig. 4.1).   • Thiazide diuretics inhibit sodium and chloride  reabsorption in the distal tubule, resulting in mild    • Loop diuretics are more powerful than thiazides and  must be used cautiously to avoid dehydration. These  agents may cause hypokalemia, so potassium levels  should be followed closely.   • Potassium-sparing diuretics enhance sodium and  water excretion while retaining potassium. These  agents are marketed in combination with potassium-  wasting diuretics in order to minimize potassium  imbalances.   diuresis. Potassium supplements may be necessary interfering with ion secretion or absorption in the  because of potassium-wasting effects. kidney.   Inhibits sodium and chloride  reabsorpion in the distal  tubule. Loss of K + , Na+, and  CL causes increase in urine  output. Sodium loss results in   Hypokalemia, hyponatremia,  hyperglycemia, hyperuricemia,  hypercalcemia, oliguria, anuria,  weakness, decreased placental  flow, sulfonamide allergy, Gl  distress.   Inhibits chloride reabsorption  in thick ascending loop of  Henle. High loss of K+ in  urine.   Preferred diuretic in patients with  low GFR and in hypertensive  emergencies. Also, edema,  pulmonary edema, and to mobilize  large volumes of fluid.   Hyponatremia, hypokalemia,  dehydration, hypotension,  hyperglycemia, hyperuricemia,  hypocalcemia, ototoxicity,  sulfonamide allergy, hypomagne-  semia, hypochloremic alkalosis,  hypovolemia.   Blocks Na + , K + , Cl' carrier in  thick ascending loop.   Similar to furosemide. Ototoxicity  has not been reported. Large  doses may cause severe  myalgia.    Used with other diuretics because  K + -sparing effects lessen  hypokalemic effects. May  correct metabolic alkalosis.   HYPERkalemia, sodium or water  depletion. Patients with diabetes  mellitus may develop glucose  intolerance.   Antagonist of aldosterone  (aldosterone causes Na+  retention). Also has actions  similar to amiloride.   Used with thiazides for edema (in  congestive heart failure),  cirrhosis, and nephrotic  syndrome. Also to treat or  diagnose hyperaldosteronism.   As for amiloride. Also causes  endocrine imbalances (acne, oily  skin, hirsutism, gynecomastia)   Directly inhibits Na + reab-  sorption and secretion of K+  and H+ in collecting tubule.   Acute renal failure, acute closed  angle glaucoma, brain edema, to  remove overdoses of some  drugs.   Headache, nausea, vomiting,  chills, dizziness, polydipsia,  lethargy, confusion, and chest  pain.   Figure 4.1 Site of diuretic actions. Thiazide diuretics inhibit  sodium and chloride reabsorption in the distal tubule. Loop  diuretics inhibit chloride reabsorption in the thick ascending loop of  Hettle. Potassium sparing diuretics inhibit potassium secretion  and influence sodium excretion in the distal convoluted tubule.  Mannitol osmotically inhibits water and sodium reabsorption  throughout the nephron.   Increases toxicity of digitalis  or lithium; hypokalemia with  corticosteroids or ACTH;  orthostatic hypotension with  alcohol, barbiturates or  narcotics. Decreases  effects of vasopressors.   There are over a dozen  thiazide-like diuretics  which differ primarily in  dosage requirements and  duration. Consult a drug  index for these details.   Increases toxicity of ototoxic  and nephrotoxic drugs and  lithium. Probenecid and  indomethacin inhibit diuretic  effects of furosemide.  Enhances effect of  antihypertensive drugs.   Signs of hypochloremic  alkalosis include tetany;  increased bicarbonate,  heart rate BUN, and  hematocrit; decreased  blood pressure, sodium,  and skin turgor.   PO/IV. 95% absorbed, 95%  protein bound, half metab-  olized, half-life = 1 .5 hrs.   PO. Excreted unchanged in  kidney, 6 hr half-life. Can  be used in patients with  hepatic insufficiency.    Severe hyperkalemia with  potassium supplements.  Increased hyperkalemia with  other K+-sparing diuretics.   PO. Metabolized exten-  sively in liver to an active  metabolite. Metabolite is  98% protein bound, half-life  = 1-1.5 days.   As for amiloride. Also  increases risk of digoxin  toxicity and decreases  vasopressor action of  norepinephrine.   The metabolite canrenone  is primarily responsible for  the actions of this drug.   Heart failure, hypertension,  pulmonary edema because of  transient increase in blood  pressure.    Initially increases central  venous pressure,  therefore may induce  heart failure in  susceptible patients.   Adrenergic agonists increase blood pressure by  stimulating the heart (Pi receptors) and/or constricting  peripheral blood vessels (al receptors). In hyperten-  sive patients, adrenergic effects can be suppressed by  inhibiting release of adrenergic agonists or by antago-  nizing adrenergic receptors (Table 4.2B & C).   divided into "central" and "peripheral"  antiadrenergics (Table 4.2B). Central antiadrenergics  prevent sympathetic (adrenergic) outflow from the  brain by activating inhibitory (X2 receptors. By  reducing sympathetic outflow, these agents encour-  age "parasympathetic predominance". Thus, the list  of undesirable effects resembles the list of parasym-  pathetic actions (Fig 2.3). Peripheral antiadrenergics   in sympathetic nervous system activity  (decreased heart rate, cardiac ouput  and blood pressure). Exact mechanism  unknown.   Rash, Drowsiness, dry mouth, constipation,  headache, impaired ejaculation. Rebound  hypertension if withdrawn abruptly. To limit  toxicity, start with low dose and increase  slowly.   As for clonidine. Also, synthesized to  methylnorepinephrine which acts as a  weak sympathomimetic "false  neurotransmitter" which decreases  sympathetic outflow from the CNS.   Dry mouth, sedation, slight orthostatic  hypotension. Some patients experience  impotence, psychic disturbances,  nightmares, involuntary movements, or  hepatotoxicity.   As for clonidine. Also depletes  norepinephrine stores in peripheral  adrenergic nerve terminals.   Partially depletes catecholamine stores  in peripheral nervous system and  perhaps in the CNS. Decreases total  peripheral resistance, heart rate, and  cardiac output.   Parasympathetic predominence  (bradycardia, diarrhea,  bronchoconstriction, increased secretions),  decreased cardiac contractility and output,  postural hypotension (depletes  norepinephrine inhibiting vasoconstriction),  peptic ulcers, sedation and suicidal  depression, impaired ejaculation,  gynecomastia. Low risk of rebound  hypertension because of long duration of  action.   Sequestered into adrenergic nerve  endings. Initially releases  norepinephrine (increase BP and HR).  Then depletes norepinephrine from  terminal and interferes with release.  Reflex tachycardia is then impossible  because of depletion of norepinephrine.   Initial increase in heart rate and blood  pressure (due to release of norepinephrine).  Resting and orthostatic hypotension.  Bradycardia, decreased cardiac output,  dyspnea in COPD patients, severe nasal  congestion. No depression (poor CNS  penetration)   Like guanethidine, but works faster,  releases norepinephrine initially  (transient increase in blood pressure),  and has little CNS activity.   prevent norepinephrine release from peripheral  nerve terminals (e.g., those which terminate on the  heart). These agents deplete norepinephrine stores in  nerve terminals.   • Alpha and beta blockers compete with endogenous  agonists for adrenergic receptors. Antagonist occu-  pation of al receptors inhibits vasoconstriction and  occupation of (31 receptors prevents adrenergic  stimulation of the heart.    Selective al or (31 blockers are replacing nonspecific  (3 blockers, because they produce fewer undesirable  effects. Several (3 blockers have intrinsic sympathomi-  metic activity (act as weak agonists at some adrenergic  receptors). These drugs stimulate (32 receptors, which  reduces the likelihood that rebound hypertension  (sympathetic reflex to fall in blood pressure) will  develop. Activated 02 receptors dilate large central  arteries which provide a reservoir for blood.   Alcohol, barbiturates, and  sedatives increase CNS  depression. Concomitant  withdrawal of (3-blockers   If blood pressure drop  is too great, reflex  renin production may  cause sodium and  water retention.   PO/IV. Although 63% excreted  unchanged by kidneys, it can be  used in patients with renal  insufficiency.   If signs of heart failure (due  to fluid retention as a result  of decreased renal blood  flow) occur, discontinue  drug. Contraindicated in  those with liver dysfunction.   Antibodies to  methyldopa may  cause hemolytic  anemia (fairly rare, but  potentially lethal).   PO.Well absorbed, extensively  metabolized. Plasma half-life is  shorter than therapeutic half-  life, suggesting that drug may be  retained at its site of action.   Because of  “parasympathetic  predominance”,  contraindicated in patients  with congestive heart failure,  asthma, bronchitis, peptic  ulcer disease. Patients with  family history of depression.   Actions of direct-acting  catecholamines are sharply  increased. Reduces  effectiveness of mixed or  indirect sympathomimetics.  Causes severe hypertension  with MAO inhibitors. Causes  severe bradycardia, heart block  or failure with digitalis, quinidine,  or beta blockers. Potentiates  actions of antihypertensive  agents or CNS-depressants.   PO. Incompletely absorbed,  >30% bioavailability, half  eliminated unchanged, half as  metabolites. Because of very  long half-life (5 days), maximal  actions may not develop for   Tricyclic antidepressants inhibit  uptake into neuron decreasing  antihypertensive effects. Other  interactions similar to reserpine  (above).    PO. Incompletely absorbed,  excreted unchanged (50%) and  as metabolites (50%). Shorter  half-life (12 hrs) than  guanethidine.   Because of long half-  life, effects may  persist up to two  weeks after  discontinuation.   Hypotension (postural hypotension  on first dose is sudden and severe).  Sodium depletion (often caused by  diet or diuretic therapy in  hypertensive patients) worsens the  hypotensive episodes. Edema, dry  mouth, congestion, headache,  nightmares, sexual dysfunction and  lethargy may also be observed.   Blocks al, pi and p2. Achieves  lower blood pressure (al ) without  reflex tachycardia (Pi blockade).   Has some intrinsic sympathomimetic  activity as well as pi blocking  activity.   Blocks both pi and p2 adrenergic  receptors. Decreases heart rate and  output and 1 renin release.  Bronchoconstriction via antagonism  of P2 receptors.   Transient hypertension due to  antagonism of p2 receptors (which  dilate large arteries) and reflex  response to decreased cardiac  output, bronchospasm, otherwise  like atenolol.   Intrinsic sympathomimetic activity  decreases likelihood of rebound  hypertension (by dilating large  arteries via (52) or bronchospasm.    PO. 50% bioavailability, >90% plasma  protein bound, eliminated as unchanged  drug and as metabolites. Terazosin,  Doxazosin, and Tamsulosin have longer  half lives than Prazosin, which permits  once daily dosing.    Phenobarbital shortens its  half-life. Enhances actions  of other antihypertensives,  may produce severe  hypotension.   Because of severe ortho-  static hypotension,  patients should be lying  down and observed for at  least two hours after initial  doses.   Carvedilol: Increases effects/toxicity of calcium entry  blockers, clonidine, digoxin, insulin, antidiabetics.   Severe diabetes,  bradycardia, partial  heart block, severe  heart failure,  asthma,  emphysema.    1 V. Short duration (half-life = 9 min)  because it is metabolized by erythrocyte  esterase.   Abrupt discontinuation  may cause rebound  hypertension and  tachardia. Increases risk  of stroke, angina,  arrhythmias, infarction.   PO. Longer half-life than propranolol (it is  not metabolized). Enters CNS, but  causes fewer side effects that  propranolol.   The previous table presented drugs that caused  vasodilation by blocking al -mediated vasoconstriction.  Vasodilation can also be induced by inhibiting other  endogenous vasoconstrictors or by activating a vasodi-  lation pathway (Tables 4. 2D & 4.3). Examples of  vasodilators include:   suppress the synthesis of angiotensin 11, a potent  vasoconstrictor. In addition, ACE inhibitors may  induce production of vasodilators in the body.   • Calcium entry blockers prevent calcium influx into  the muscle cells of blood vessel walls. Smooth  muscle relies on the influx of extracellular calcium  for contraction. Blockade of the calcium influx  prevents contraction, causing vasodilation. Smooth   Captopril (Capoten)  Lislnopril (e g., Prinivil)  Enalapril (Vasotec)  Ramipril (Altase)  Benazepril (Lotensin)  Fosinopril (Monopril)  Quinapril (Accuprih  Moexipril (Univasc)  Trandolapril (Mavik)   Inhibits angiotensin convert-  ing enzyme (ACE) in the lung,  which reduces synthesis of  the vasoconstrictor,  angiotensin II. Suppresses  aldosterone, resulting in  natriuresis. Potentiates other  vasodilators (e.g.,  bradykinin, prostaglandins).   Hypertension. Particularly  useful for high-renin  hypertension. Preferred drug  for hypertensive patients with  diabetic nephropathy because  glucose levels are not  affected. Heart failure • used  with diuretics and digitalis.  Myocardial infarction - to  enhance heart reoerfusion.   All ACE inhibitors: First  dose hypotension,  dizziness, proteinuria,  rash, tachycardia,  headache.   Relaxes arterioles (not veins)  independent of sympathetic  interactions. Decreases  blood pressure leading to  reflex tachycardia and  increased cardiac output  Directly increases renal blood  flow.   Moderate hypertension. May  be used in pregnant women  who are hypertensive.   Reflex tachycardia,  palpitations, fluid retention,  systemic lupus  erythematosis-like  syndrome. Chronic therapy  may lead to peripheral  neuritis (due to interference  with vitamin B6 metabolism  in neural tissue).   Decreases peripheral  vascular resistance, possibly  by antagonizing calcium.  Suppresses insulin release  and increases hepatic  glucose release.   Short term control of severe  hypertension in hospital  setting. Hypoglycemia  secondary to hyperinsulinism  which is refractory to other  forms of treatment.   Converted to nitric oxide,  which induces cGMP. cGMP  stimulates a phosphorylation/  dephosphorylation cascade.  Relaxes smooth muscle by  dephosphorylating myosin.    muscle is also responsible for propulsion in the GI  tract. Inhibition of propulsion by calcium channel  blockers causes constipation, a prevalent side effect of  calcium channel blocker therapy. Cardiac muscle  and conducting tissue rely on rapid influx of sodium  and slow influx of calcium through separate channels  for contraction. The slow calcium channel is particu-  larly important in the S-A and A-V nodes. Blockade  of these channels slows the heart. Skeletal muscle    contraction is induced by rapid influx of sodium,  which triggers the release of calcium from the  sarcoplasmic reticulum. Because these cells do not  require extracellular calcium for contraction, calcium  channel blockers fail to affect skeletal muscle.   • Direct vasodilators relax smooth muscle cells which  surround blood vessels by a mechanism which is not  yet clear, but likely involves production of nitric  oxide by vascular endothelium.    PO. Prolonged duration in  patients with renal  dysfunction. Captopril  requires 2-3 doses per day,  others one.    Pregnancy . May cause fetal  death or injury during second or  third trimester. Bilateral renal  artery stenosis.    Increased antihypertensive  and hypotensive effects with  diuretics, sympathetic  blockers. Increased serum  potassium with potassium-  sparing diuretics. Decreased  antihypertensive effects with  indomethacin.    Often used in conjunction  with a thiazide diuretic.  Immediate cessation is  indicated upon signs of  potential anaioedema  (swelling of face, lips,  eyelids or difficulty  breathing or swallowing).    PO/IV/IM. Excreted  unchanged and as  acetylated metabolites.  Rapid acetylators have  lower plasma levels than  slow acetylators.    Beta-blockers are usually  used concomitantly to  reduce reflex tachycardia.  Diuretics are also used  adjunctively to reduce  sodium and water  retention.    IV/PO. Onset <5 min,  duration 3-12 hrs. with rapid  IV administration. High  plasma protein binding.  Crosses brain & placental  barriers.    Use with caution in patients with  carbohydrate metabolism  disorders (e.g., diabetes mellitus)  and patients with impaired cardiac  function.    Effects are enhanced by  other diuretics. Profound  hypotension occurs with  other antihypertensives.  Diazoxide displaces warfarin  and phenytoin from albumin.    Metabolized to cyanide and  cyanmethemoglobin inside  red blood cells. Full effect  within two minutes and rapid  loss of effect when infusion  is discontinued.    Dramatic changes in blood  pressure occur with small  infusion rate changes.    Aspirin reduces the rate of cardiovascular events by  1 /3 in patients with stable angina, and should be given  to all patients unless they have a clear contraindication.  Patients with aspirin allergy should be placed on either  ticlopidine or clopidogrel (Table 4.10). These drugs  have not been specifically studied in patients with  stable angina, but are effective antiplatelet agents.    Neutropenia is much less common in patients treated  with clopidogrel than patients treated with ticlopidine.   Beta-blockers (Table 4.2C) reduce the frequency of  angina and increase treadmill time in patients with  chronic angina. There is less evidence that beta-  blockers reduce death in this setting, unless the patient  has had a previous infarction.   Calcium channel blockers (Table 4.3) are equally  effective as beta-blockers in reducing anginal symp-  toms in stable patients. Some studies have suggested a  higher cardiovascular event rate with short acting  dihydropyridines (nifedipine) and these drugs should  not be used without a beta blocker. Calcium channel  blockers are recommended in patients with vasospastic  angina.   Similar to calcium channel blockers and beta  blockers, nitrates improve excercise tolerance, and time  to onset of angina in patients with exertional stable  angina (Table 4.4). Nitrates are contraindicated in   Drug of choice for acute  paroxysmal supraventricular  tachycardia. Slows  ventricular response to atrial  fibrillation. Hypertension.   Less pronounced heart rate reduction.  Reduces afterload by dilating peripheral  arteries. Increases oxygen supply to  myocardium by preventing sympathetic-  induced coronary artery spasm.   Reduces angina episodes.  Increases exercise tolerance  in stable angina. Also used as  an antihypertensive.   Little depression of nodes. Fails to  dilate coronary arteries. Causes reflex  increase in heart rate and output.   Myocardial infarction, periph-  eral edema, dizziness, nau-  sea, transient hypotension,  reflex tachycardia, pulmonary  edema.   Selectively inhibits vascular smooth  muscle contraction and S-A node  conduction with little effect on heart  contractility or A-V node conduction.   Little tachycardia because of  selective actions. Headache,  peripheral edema, and flushing.   Calcium entry blocker with the greatest  effect on cerebral artery vasodilation.   Carcinogenic and teratogenic in  animal experiments. Headache  and diarrhea are most common.   PO/IV. Well absorbed, 80%  metabolized in first pass. 90%  protein bound. Metabolites are  active. Half-life is 5 hrs but may  be up to 20 hrs in patients with  cirrhosis.   Patient on IV p-  blockers or digitalis.  A-V node block,  sick sinus  syndrome,  cardiogenic shock,  heart failure,  hypotension.   Beta blockers or digitalis: Increases  likelihood of bradycardia or A-V  blockade. Quinidine or prazosin:  Increases hypotension. Digoxin  levels are increased. Cimetidine  reduces verapamil clearance.   Depolarization (leading to  contraction) of vascular  smooth muscle is depen-  dent on calcium entry.   Vasodilation is induced by  calcium entry blockers  because they inhibit  calcium influx.   PO. 50% bioavailability after oral  dose. 75% protein bound, half-  life^ hrs, metabolites are active.  Reduce dose in patients with  renal dysfunction.   Beta-blockers and digoxin increase  A-V conduction time. Diltiazem  increases propranolol levels.  Cimetidine and drugs metabolized by  P-450 increase diltiazem levels.   Beta blockers increase risFof  severe hypotension, heart failure,  and angina. Nifedipine increases  effects of oral anticoagulants.    Initiate within three days  of hemorrhage and  continue for 3 weeks.   patients taking sildenafil (Viagra). Sildenafil potenti-  ates the hypotensive effects of nitrates and increasas  the risk of life threatening hypotension.   The drugs discussed above have been tested in  combination, and combination therapy is more effec-  tive than single drug therapy.   Rupture of an unstable plaque, and resulting  thrombus formation leads to unstable angina. Treat-  ment is targeted toward reducing myocardial demand,  improving oxygen delivery, reducing coronary spasm,  and halting thrombus formation. Heparin has been the  primary anticoagulant. Recent trials have revealed the  importance of antiplatelet therapy.   Oxygen therapy improves oxygen delivery in the  subset of patients who are hypoxemic from CHF or  underlying lung disease. Morphine reduces the pain  and anxiety that can worsen symptoms in many  patients. Treating these symptoms can reduce the  myocardial demand, reducing the total amount of  ischemia.   Medications that directly decrease cardiac  workload are effective in unstable angina. Beta  blockers reduce ischemic burden by decreasing heart  rate and blood pressure (Table 4.2C). This class of  medications may reduce further myocardial infarctions    by 10-20%. Nitrates are extremely effective in reducin  symptoms by decreasing blood pressure and inducinj  coronary vasodilation (Table 4.4). Although nitrates  clearly reduce symptoms, there is no convincing  evidence that they reduce mortality or the rate of  myocardial infarctions. Calcium channel blockers mu:  be considered as two classes: dihydropyridines (i.e.  nifedipine) and non-dihydropyridines (i.e. diltiazem,  Table 4.3). It is important to note that nifedipine can b  hazardous in this setting, leading to a higher rate of  myocardial infarction or recurrent angina if given  without a beta blocker. Non-dihydropyridine calcium  channel blockers (i.e. diltiazem) can be safely used ant  may reduce the rate of death or recurrent myocardial  infarction. This class of medicines is an excellent choic  in patients with absolute contraindications to beta  blockers.   Heparin has proven effective in the setting of  unstable angina in many studies, reducing the rate of  myocardial infarction or death by up to 35% when  used in addition to aspirin (Table 4.9). Weight based  protocols have become more popular in the wake of  studies that have demonstrated their superiority over  non weight based treatment. More recently, low  molecular weight heparin (i.e. enoxaparin) has prover  more effective than unfractionated heparin in the  setting of unstable angina. All low-molecular weight  heparins are not equal. Other LMWH's have not  proven superiority over heparin in the setting of  unstable angina.   Antiplatelet therapy has also been studied carefull)  Aspirin therapy has reduced the rate of recurrent  ischemia, infarctions and death by more than 50%.  Two newer antiplatelets, derivatives of  thienopyridines, have recently been added (Table 4.10  Ticlopidine (Ticlid) has been most extensively studied  in the field of ischemic cerebrovascular events, and    Agents that preferentially  block (31 adrenergic  receptors decrease heart  rate and output and  reduce renin release.    Reduces peripheral  arterial resistance in  hypertensive patients, by  inhibiting angiotensin  converting enzyme    Metaprolol is indicated for  congestive heart failure.  Metaprolol. atenolol,  propranolol and timolol are  indicated for post-  myocardial infarction  patients. Many are indicated   CNS sedation and  depression. Not indicated  for acute or severe heart  failure.   reduced the rate of vascular events compared to aspirin. It  does carry an increased risk of neutropenia and rarely can  cause thrombotic thrombocytopenic purpura. Clopidogrel  (Plavix) has been compared to aspirin and was more  effective in preventing recurrent ischemic events in  patients with vascular disease. Although neither  thienopyridine has been studied specifically in unstable  angina, they are accepted substitutes for those patients  that cannot take aspirin.   Thrombolytic therapy reduces the relative risk of death  by 20% if given within the first 12 hours of an acute  infarction. There are several types of thrombolytic agents  available (Table 4.10). Accelerated dose alteplase reduced  mortality further than streptokinase in a very large study  (GUSTO). Since then, other tissue plasminogen activators  have been developed that are easier to dose. These drugs  should only be used in the setting of ST elevation. Throm-  bolysis is not effective when the patient’s ECG shows only  ST depression or no diagnostic changes. In fact, there is  evidence that thrombolysis is dangerous in non-ST  elevation ischemic syndromes.   Aspirin by itself reduces the risk of death from an  infarction by 23%. It has an additive effect when used in  combination with a thrombolytic medication. Aspirin  should always be used in the setting of an infarction  unless the patient has evidence of an active gastrointes -  tinal bleed, or a true allergy to aspirin. In the setting of an  allergy, ticlopidine or clopidogrel can be substituted for  aspirin.   Beta blockers (Table 4.2C) reduce chest pain, myocar-  dial wall stress and infarct size in the setting of an infarct.  Over 50,000 patients have been enrolled in studies de-  signed to evaluate the effects of beta blockers during or    after an infarction. The evidence overwhelmingly  suggests that beta blockers reduce death after myocar-  dial infarction, and these drugs should be given in all  patients with acute myocardial infarction who do not  have clear contraindications such as pulmonary  edema, hypotension, bradycardia, advanced heart  block or asthma.   Angiotensin inhibitors (Table 4.2D) have been  convincingly shown to dramatically decrease death  rates in patients with reduced left ventricular dysfunc-  tion after an infarction. These drugs also reduce death  in all patients after myocardial infarction but the  relative risk reduction of death is much less powerful.  ACE inhibitors also reduce the rate of progression to  heart failure. ACE inhibitors should be given in all  patients presenting with an acute myocardial infarc-  tion, unless they have contraindications such as renal  failure, bilateral renal insufficiency, hypotension, or  angioedema due to previous ACE inhibitor use.   Nitrate therapy has not consistantly reduced death  or recurrent infarction in these patients (Table 4.4).   This class of medications does reduce ischemic chest  pain and should be used for symptomatic patients.   Calcium-channel blockers do not reduce mortality  during or after acute myocardial infarction. Diltiazem  may reduce the rate of recurrent infarction after a non  Q wave infarct, but any advantage over aspirin and  beta blockers is not known. There may be an adverse  effect of short acting dihydropyridines (nifedipine) and  these drugs should be avoided in this setting.   Antiarrhythmic drugs have been studied in the  setting of acute infarctions. Class 1 and Class in drugs  have increased the rate of death compared to placebo  when used to supress ventricular ectopy after myocar-  dial infarctions, especially in patients with reduced left  ventricular function.    PO. Metabolized  extensively in liver to active  metabolite. Metabolite is  98% protein bound,  therefore the halflife is 1 -  1 .5 days.   Acute pulmonary edema usually accompanies left  heart failure. Successful treatment of pulmonary  edema reduces the risk of secondary right heart failure.  Early interventions in patients with pulmonary edema  include (1) sitting the patient upright to decrease   Drug therapy consists of (1) furosemide or  bumetanide, potent diuretics which reduce vascular  volume, leading to a shift of fluid from the lungs into t  vasculature; and (2) morphine, a venodilator which  decreases preload and reduces anxiety through its actii  on opiate receptors in the brain (Tables 4.3A & 3.6A).  Nitrates and/or bronchodilators may be added to reck  ischemic damage and improve ventilation, respectivel)  (Tables 4.4 & 5.1).   Shock is a potentially fatal condition in which tissut  are poorly perfused and, consequently, become ischem   Inhibits Na + /K + -ATPase  (sodium pump) and t inward  current of Ca ++ . Contraction  enhanced by T intracellular  Ca ++ . T cardiac output and  i heart size, venous return,  and blood volume. Causes  diuresis by T renal perfusion  Slows ventricular rate in atrial  tibrillation or flutter by   Heart failure, atnal fibrillation,  atrial flutter, paroxysmal tachy-  cardia. Also Indicated for  hypoventilation, cardiogenic  shock and thyrotoxic shock.   Often a loading dose is  administered first to achieve  therapeutic concentrations more  rapidly.   Digitalis intoxication (See text),  bradycardia, AV or SA node  block, arrhythmias. Also  anorexia, nausea, vomiting,  diarrhea, headache, fatigue,  malaise, visual disturbances, and  gynecomastia. Increased  peripheral resistance may  increase the heart's workload,  worsening ischemic damage.    Seldom used because of long  half-life (if toxicity develops, it is  difficult to rid the body of active  drug). Useful In patients with  renal failure because they are  unable to excrete digoxin.   Inhibits phosphodiesterase  (the enzyme that breaks down  cAMP). cAMP Increases  calcium uptake Increases  contractility, stroke volume,  ejection fraction, and sinus  rate. Decreases peripheral  resistance.    Very few side effects. Headache  and worsening of angina have  been reported.   Betai receptor-preferring  adrenergic agonist. At  moderate dose. Increases  contractility without increasing  heart rate or blood pressure.  Minimal effect on blood  vessels.   To increase cardiac output in  chronic heart failure. May be  used with afterload reducing  agents. Also used for treatment  of shock.   Treatment consists of maintaining oxygenation, support-  ing blood pressure and treating the metabolic acidosis if it  is severe. The type of shock must be diagnosed so that the  underlying problem can be treated.   Vasopressors constrict blood vessels and improve  cardiac function by stimulating adrenergic receptors  (Table 2.1). They are employed when intravenous fluids  alone fail to increase central venous pressure. Peripheral  vasoconstriction shunts blood to the heart and lungs. It  may seem odd that vasoconstrictors are used to treat a  condition marked by poor tissue perfusion. Indeed,  improvement in central venous pressure is frequently at  the expense of ischemic damage to peripheral tissues.   Low-dose dopamine is the preferred agent for treating  shock. At "renal doses", dopamine dilates renal vessels    (dopamine receptor-mediated) while constricting  vessels in other tissues. Norepinephrine and high-  dose dopamine constrict all vessels including those of  the kidney and brain. In addition, both of these agents  improve cardiac function by stimulating (3, adrenergic  receptors. Dopamine is more potent than norepineph-  rine in this regard.   Dobutamine and isoproterenol are also used in  cardiogenic shock because they improve myocardial  contractility. These agents are contraindicated when  shock is due to hypovolemia rather than cardiac insuf-  ficiency, because they have no direct vasoconstrictor  effects (weak a, agonists). Dobutamine must be used  with caution in patients with systolic blood pressure  less than 100 because it can worsen hypotension.   PO/IV. 36 hr half-life, 75%  absorbed in Gl tract, slow  distribution due to large  apparent volume of distri-  bution (reduced in elderly),  excreted unchanged in  urine (but dose adjustment  unnecessary w/ renal  dysfunction). 25% protein  bound.   Increased risk of toxicity with  drugs that alter serum  electrolytes (potassium-  depleting diuretics,  corticosteroids, thiazide and  loop diuretics, amphotericin   B, quinidine, amiodarone).  Blockers of p adrenergic  receptors, calcium channels,  or acetylcholinesterase  increase risk of complete AV  block. Drugs which alter Gl  absorption may alter  bioavailability.   fcCG effects: T wave  diminished in amplitude or  inverted, P-R interval  prolonged, Q-T interval  shortened. Tests for  serum digoxin levels may  be altered by electrolyte  imbalance, renal  impairment, age, thyroid  disease, other drugs, or  substances In the body  which imitate digoxin in  radioimmunoassay.   PO/IM/IV., seven day half-  life, 100% Gl absorption,  97% protein bound,  distribution similar to  digoxin, liver metabolism,  bile excretion.   It takes several weeks to  reach steady state  kinetics when starting the  drug and several weeks to  clear the drug upon  discontinuation due to  long half-life.   IV. 6 hr half-life, partially  metabolized in liver, low  plasma protein binding.    Amrinone increases diuresis  in patients on diuretics.  Digitalis inotropy and risk of  toxicity increased (amrinone  causes hypokalemia).  Excessive hypotension with  disopyramide.   If cellular supplies of  cAMP are depleted,  amrinone will not be  effective. Capable of  increasing myocardial  contraction even in the  presence of p-adrenergic   IV. 2.4 min half-life.  Continuous infusion is  necessary to maintain  therapeutic effect.   Because of short half-life,  can only be used for  short-term therapy.   PO. All patients MUST start  with 1 mg dose before bed,  then increase dose slowly if  hypotension is not a  problem.   The following tables present arrhythmias based on  the anatomical site of the underlying abnormality -  atrial, ventricular or supraventricular  (A-V junction) accessory pathway. Arrhythmias occur  because one or more regions of the heart are 1) beating    too slowly (sinus bradycardia); 2) beating too fast  (sinus or ventricular tachycardia, atrial or ventricular  premature depolarization, atrial flutter); 3) beating  automatically without regard for impulses originating  from the SA node (multifocal atrial tachycardia, atrial  fibrillation, ventricular fibrillation), or 4) allowing  impulses to travel along an accessory pathway to areas  of the heart which should not be depolarized at that  particular moment (A-V reentry, Wolff-Parkinson-  White syndrome).   Increased parasympathetic  (vagal) tone causes heart to  beat at < 60 beats per  minute. Depolarization  originates from sinoatrial  node (hence the name  sinus).    Not treated if asymptomatic.  If patient develops angina,  hypotension, heart failure or  other symptoms, treat with   Increased sympathetic tone  causes heart to race (100-  1 60 beats per minute).  Depolarization originates  from sinoatrial node.   Depolarization originates  from several atrial foci at  irregular intervals. Rate is  rapid (100-200 beats per  minute) and irregular.   Heart beats prematurely  because a focus of atrial  cells fires spontaneously  before the SA node is ready  to fire.   Atrial Flutter: Atrial  impulse reenters and  depolarizes atrium.  Generates 250-350 impulses  per minute. The ventricle  responds to every 2nd or 3rd  impulse. Both atrial and  ventricular rhythm are  regular.    P waves are present, but are  morphologically different  from one another. P-R  interval varies.   Propranolol  (because it decreases  catecholamine-induced firing  rate of SA node and slows  conduction through A-V  node.)    Interruption of regular rhythm  by an early P wave. P wave  may be followed by a normal  QRS if the SA node and  ventricle have had time to  repolarize.    Series of 2-4 closely spaced  P waves followed by a normal  QRS complex.    Multiple ectopic foci of atrial  cells generate 350-450  impulses per minute. The  ventricle responds to an  occasional impulse. Both  atrial and ventricular rhythm  are irregular.   A strip of conducting tissue  (other than the A-V node)  connects the atrium and  ventricle. Irrpulses reaching  the ventricle via the A-V node  circle back to the atrium via  the accessory pathway.  Alternatively, the circuit may  be reversed.    Generally normal QRS  complexes following normal P  waves. The inverted P wave  (retrograde atrial contraction)  is buried in the QRS. Rate is  150-250/ minute.    Each P wave is followed  rapidly by a QRS. A “delta  wave" leads into the QRS.  Rate can exceed 300  beats/minute.    Carotid sinus massage may  suppress tachycardia by  increasing vagal tone.  Alternatively:    Ventricular  Tachycardia: Usually  secondary to reentry circuit.  Both A-V reentry and Wolff-  Parkinson-White may  progress to ventricular  tachycardia.   Erratic discharge from many  ectopic foci in the ventricle.  Rate is 350 - 450 beats/min.  Rhythm is irregular.   Wide, tall QRS complexes  which are not associated with  a P wave. A prominent  T wave often points in the  opposite direction as the  QRS complex. A a    Wide QRS complexes with  abnormal S-T segment and T  wave deflections (opposite in  direction to QRS). AV  dissociation and right bundle  branch block are often  associated.   IV Lidocaine  IV Procainamide  IV Bretyiium  Oral drugs are used for  chronic therapy  Amiodarone  Quinidine  Procainamide  Disopyramide  Flecanide, Encainide,  Tocainide, Mexiletine   Life threatening. If cardio-  version fails, Epinephrine  is given prior to defibrillation.  If this fails combine I V  lidocaine and defibrillation.  Either additional doses of  lidocaine or Bretyiium can  then be used with defibrilla-  tion. Amiodarone is also  effective.   The sinoatrial node paces the heart by spontane-  ously depolarizing and stimulating the conducting  nerves of the atrium. The impulse rapidly spreads  through the atrium, causing myocardial cells of the  atrium to contract in unison. The impulse reaches the  atrioventricular (A-V) node, which in turn transmits  the conduction signal to the His-Purkinje conduction  pathway. The His-Purkinje system carries the impulse  to ventricular myocardial cells, causing a powerful  contraction that propels blood throughout the body.   Interruption of this magnificent system, by the  mechanisms described in Table 4.6, jeopardizes tissue  oxygenation and may lead to death. Antiarrythmic    drugs influence cardiac conduction properties (usually  by modifying ion conductance) and may revert an  abnormal rhythm to sinus rhythm.   An understanding of the mechanism by which  action potentials are propagated through conducting  cells facilitates learning about the mechanism of  antiarrythmic action (Fig. 4.2).   Antiarrhythmic drugs have been divided into four  classes to facilitate comparison and discussion. Since  the time the drugs were classified, however, it has  become clear that drugs within each class may differ  significantly and cannot be substituted for one another.  The original classification scheme (bold-face print) and  other generalizations include:    Depresses automaticity of  ectopic foci. Slows  conduction velocity in atria &  His-Purkinje cells. Prolongs  refractory period throughout  heart (except nodes) and  accessory pathways. Has  anticholinergic effects which  may actually enhance A-V  conduction in patients with  rapid atrial depolarization.    Multifocal atrial tachycardia,  premature atrial depolarization,  premature ventricular  depolarization, atrial fibrillation  (these result from increased  automaticity of ectopic foci), and  ventricular tachycardia.    Torsades de pointes (recurrent,  temporary arrhythmia), increases  ventricle response to atrial  tachyarrhythmia, nausea,  vomiting, diarrhea,  hypersensitivity, cinchonism,  thrombocytopenic purpura.    Premature atrial depolarization,  atrial fibrillation,  Wolff-Parkinson-White,  ventricular tachycardia,  atrial flutter, premature  ventricular depolarization.   Fewer Gl effects and weaker  anticholinergic effects than  quinidine, but similar cardiac  toxicity. Lupus-like syndrome  and other hypersensitivity  reactions.   Depresses automaticity of  ectopic foci, increases  conduction velocity of A-V  node and His-Purkinje.   CNS: paresthesias, drowsiness,  confusion, restlessness (at low  doses). At high doses, seizures  or disorientation. Cardiac  depression (if given by rapid IV),  arrhythmias.   Shortens refractory period in  atrium, AV node, and  ventricle. Prolongs refractory  period in accessory pathway.   • Class I drugs are Na+ channel blockers. Class la  drugs have little effect on SA node automaticity,  while most other antiarrhythmics reduce SA node  automaticity. Class la drugs slow conduction  velocity and tend to be more effective than other  classes in prolonging the refractory period. No clear  generalizations can be made of Class lb agents.   • Automaticity is suppressed in ectopic foci by every  antiarrhythmic except bretylium.   Phase 0: Voltage-dependent  Mr channel opens and  rapid sodium influx  depolarizes cell. Phase 1:   Rapid phase of repolariza-  tion caused by inactivation  of Na' influx and the  activation of a transient  outward K* current. Phase  2: Plateau phase, characterized by low membrane conductance and  the activation of a slow imvard Ca ** current. Phase 3. Repolariza-  tion to resting potential results from outward K* current. Phase 4.  Outward K* current is deactivated and an inward Na+ current  reduces transmembrane potential.   Phenobarbetal and phenytoin  increase metabolism of  quinidine. Quinidine  increases plasma levels of  digoxin, enhances  vasodilator-induced  hypotension and potentiates  warfarin.    PO/IM/IV. Low protein binding,  otherwise like quinidine. The  metabolite, N-acetylprocainamide  (NAPA) is active and toxic. NAPA  levels should be monitored.   IV, rarely IM. Rapidly metabo-  lized by liver (2 metabolites are  active), excreted by kidney.   Serum level increased by  drugs which reduce blood  flow to liver (p blockers) and  by cimetidine.   PO. Maintain dose < 1 .2 g/day to  reduce risk of CNS toxicity.  Extensive metabolism in liver.   PO. Well absorbed (100%). Half  metabolized by liver, half  excreted unchanged by kidneys.   Additive toxicity without  therapeutic benefit when  combined with other  class lb antiarrhythmics.   Reduces 1) automaticity of SA  node & ectopic foci, 2) con-  duction velocity throughout.  Prolongs refractory period in  His-Purkinje, ventricle, and  accessory pathways.   Slows conduction throughout,  prolongs atrial and ventricular  refractory period, has weak   Nausea, dizziness, constipation,  altered taste sensation. May  worsen heart failure or  arrhythmias.   p adrenergic receptor  antagonist, i heart rate,  contractility and automaticity.  Prolongs A-V conduction time  and refractoriness.   Reduces potassium efflux.  Prolongs refractory period and  action potential in His-Purkinje  and ventricles.   Ventricular tachycardia, with  electric defibrillation as last resort  for ventricular fibrillation.   Hypotension, nausea & vomiting  (if infused too fast). Initial  release of norepinephrine may   Reduces potassium efflux.  Reduces automaticity of SA  node and ectopic foci,  reduces conduction velocity  and increases refractoriness.   Corneal deposits (reversible),  hypo- or hyper- thyroidism (T4-  like structure), photosensitivity,  pulmonary fibrosis, bradycardia  (rarely severe).   Sinus bradycardia, AV block,  hypotension, Gl upset,  constipation. If infused rapidly  into elderly patients, may cause  left ventricular failure.   Profongs refractory period,  decreases conduction in A-V  node and His-Purkinje system.   Only drug which increases  automaticity of ectopic  pacemakers. Slows  conduction velocity  throughout. Complex actions  on refractory period.   Decreases conduction  velocity, prolongs refractory  period and decreases  automaticity in A-V node.   Beta adrenergic blocker that  slows refractory period of  Purkinje fibers & heart muscle   widely between patients. 10% of  the population metabolizes the  drug slowly (4 times slower than  remaining 90% of population.)    Effects additive with other  drugs which affect heart  conduction. Cimetidine  increases half-life of  encainide.    PO. 1 0% of the population  metabolizes the drug slowly,  prolonging the half-life  substantially. Titrate doses  carefully.    Propafenone increases  plasma levels of propranolol,  digoxin and warfarin.  Cimetidine increases  propafenone levels.    Slow heart rate. Prolong PR PO/IV. 90% protein bound. Possibly fatal A-V node block   and QT interval. Metabolized by liver, excreted by when combined with digitalis.   IV. Serum levels do not correlate  w/ efficacy (binds tightly in heart).  Excreted unchanged by kidney.   Other antiaarhythmics  suppress actions of  bretylium. Bretylium  increases hypotensive  effects of vasodilators.   through liver. Half-life increases  up to fourfold in cirrhotic patients.  Metabolites are active.    Increases serum digoxin  levels. Enhances A-V node  suppression of digoxin or  propranolol - may progress to  A-V block.   Slows rate, prolongs PR  interval, shortens QT  interval, diminishes  amplitude of T wave.   PO/IV. 36 hour half-life, excreted  unchanged in urine, 25% protein  bound.   IV. Rapidly (<30 seconds)  deaminated in serum to active  agent, inosine.   Lipoproteins are serum transport vehicles for lipids  and triglycerides. There are six classes of lipoproteins,  which differ with respect to lipid and protein content,  transport function and mechanism of lipid delivery.  They are named according to their size and density.  Chylomicrons and chylomicron remnants carry lipids  that are absorbed through the intestine (exogenous  pathway). The other four lipoproteins form the endog-  enous transport pathway that delivers cholesterol and  triglycerides secreted by the liver. The four lipopro-  teins of the endogenous pathway are very low density  lipoprotein (VLDL), intermediate density lipoprotein  (IDL), low density lipoprotein (LDL) and high density  lipoprotein (HDL).   Elevated lipoprotein concentration contributes to  the formation of atherosclerotic plaques and in some  cases pancreatitis. Treatment strategies focus first on  diet and correction of underlying metabolic diseases.  Diets that are low in cholesterol and saturated animal  fats reduce lipoprotein levels. In addition, overweight  patients should reduce their total caloric intake.  Exercise increases serum concentrations of HDL, which  is associated with reduced risk of coronary artery    disease. Secondary hyperlipidemia frequently subsides  upon treatment of the underlying metabolic disease or  cessation of aggravating factors.   Drug therapy is generally reserved for patients who  fail to respond to diet or other measures described  above. Lipid-lowering agents are described in Table  4.8. Strategies for reducing lipid levels include:   1) reducing endogenous cholesterol synthesis, 2)  enhancing cholesterol excretion, 3) inhibiting synthesis  of lipoproteins, 4) enhancing degradation of lipopro-  teins. Drugs that work by different mechanisms are  sometimes combined to achieve a greater reduction in  lipoproteins than possible by monodrug therapy.   All drugs are administered orally. Side effects  include G1 distress and rash. Most agents potentiate  oral anticoagulants.   Anticoagulants inhibit blood coagulation,  antithrombotic agents prevent platelet aggregation,  and thrombolytic agents degrade clots that have  already formed.   Forms insoluble complex  with bile salts, excreted in  feces. Body compensates  by increasing LDL  receptors and oxidizing  cholesterol to bile acids.   LDL >190 mg/dl (160 with 2  risk factors) provided that 6  month trial of low lipid diet has  failed.   Lovastatin (Mevacor)  Pravastatin (Pravachol)  Simvastatin (Zocor)  Fluvastatin (Lescol)  Cerevastatin (Baycol)  Atorvastatin (Lipitor)   Inhibit HMG-CoA  reductase in liver. This  enzyme catalyzes the  rate-limiting step in  cholesterol synthesis.   Inhibits VLDL synthesis,  increases lipoprotein  lipase activity. Thus,  reduces triglyceride  levels.    All drugs are administered orally. Side effects include Gl distress and rash. Most agents potentiate oral anticoagulants.   Blood coagulation occurs as a "cascade" of pro-  teolytic factors are activated. Each factor is proteolyzed  into an active protease. The newly-formed protease in  turn proteolyzes the next factor into an active protease.  The cascade produces fibrin, which forms an insoluble  network that entangles blood cells and platelets.   Several clotting factors require vitamin K for activa-  tion. Inhibition of vitamin K is therefore a pharmaco-  logic strategy for preventing coagulation (Table 4.9).  The other clinically useful anticoagulation strategy  involves inactivating coagulation Factor III, which    prevents activation of the coagulation cascade from the  extrinsic pathway (Table 4.9).   Thromboxane and some prostaglandins serve as  mediators of platelet aggregation. Antithrombotic  agents inhibit prostaglandin and thromboxane synthe-  sis (Table 4.10). Alternatively, prostaglandins that  inhibit platelet aggregation may be used to prevent  thrombosis. Once a thrombus has formed, the only  clinically-useful pharmacologic strategy involves  degrading fibrin with thrombolytic agents (Table 4.10).   Binds to antithrombin III. This complex then  binds to and inhibits activated clotting factors  (factor Xa). Larger amounts inactivate  thrombin and clotting factors to prevent  conversion of fibrinogen to fibrin.   Antagonize vitamin K. Interfere with the  synthesis of vitamin K-dependent clotting factors  (11, VII, IX, X).   Preventing postoperative deep vein  thrombosis and pulmonary embolism.  Maintaining extracorporeal circulation during  open heart surgery and renal hemodialysis.  Achieving immediate anticoagulation.   Deep venous thrombosis, ischemic heart disease  (selected patients), rheumatic heart disease,  pulmonary embolism. Lifelong use in patients  with artificial heart valves.   PO. Well absorbed rapidly, 99% plasma protein  bound, half-life = 37 hrs, metabolized by liver.   Risk of bleeding or hemorrhage is increased  with concommitant administration of aspirin,  ibuprofen, anticoagulants/thrombolytics,  dextran, phenylbutazone, indomethacin,  dipyridamole, several penicillins and  cephalosporins, valproic acid, plicamycin,  methimazole, propylthiouracil, probenecid,  hydroxychloroquine, chloroquine.   Urokinase and streptokinase increase risk of  bleeding. Anticoagulation effects are increased  by aspirin, phenylbutazone, oxyphenbutazone,  dlsulfiram, cimetidine, sulfinpyrazone,  metronidazole, trimethoprim-sulfamethoxazole,  dextrothyroxine, anabolic steroids, heparin, and  many others. Anticoagulation effects are  decreased by drugs which induce P-450  enzymes, rifampin, cholestyramine, high dose  vitamin Cor K.   Because of hemorrhage risk, check  hematocrit and test for blood in stool.  Administer with caution to menstruating  women, or patients with subacute bacterial  endocarditis, severe hypotension, liver  disease, or blood dyscrasias. Protamine  sulfate inactivates heparin and can be used  as an antagonist if severe bleeding occurs.   Prothrombin time should be monitored carefully in  patients taking warfarin. However, ecchymoses,  hematuria, uterine and intestinal bleeding, and  other signs of hemorrhage may occur even when  prothrombin time is within normal range.   Low molecular weight heparins [Daltreparin (Fragmin), Ardeparin (Normiflo)] and  heparinoids [Enoxaparin (Lovenox)] are used for prophyloxis or treatment of deep venous  thrombosis and pulmonary emboli. Aldeparin and Enoxaparin also reduce risk of ischemia in  unstable angina or non-Q-wave myocardial infarction. These do not alter PT or PTT. Increase risk  of spinal/epidural hematoma following lumbar puncture. Lepirudin (Refludan) is a recombinant  hirudan (leech polypeptide) that is used for anticoagulation in patients with heparin-induced  thrombocytopenia.   prostaglandins (which induce myocardial infarction in patients  platelet aggregation). with unstable angina or prior   Reduces risk of stroke in  patients who are adversely  affected by aspirin.   Streptokinase Activates plasminogen to To lyse thrombi in ischemic, but Bleeding, bruising. Rarely   Well absorbed primarily in  upper small intestine.  Distributes to CNS. Me-  tabolized in liver, half-life =   Increased risk of bleeding with anticoagulants.  Increased risk of Gl ulceration with alcohol,  corticosteroids, phenylbutazone,  oxyphenbutazone. Decreases uricosurea  effects of probenecid and sulfinpyrazone and  diuretic effects of spironolactone. Decreases  absorption of tetracycline. Increases plasma  levels of methotrexate.   Potentiates aspirin efrfects on platelets (may be  harmful). Absorption is impaired by antacids.  Elimination is reduced by cimetidine.    In patients with antibodies  against streptokinase  (resulting from  streptococcal infections),  half-life is 1 2 min. In others,  half-life = 83 min.   Enhances risk of bleeding caused by aspirin,  heparin, or other anticoagulants.   The agents listed in Table 4.10 differ from all the  other drugs in this chapter. These are not chemicals,  isolated from plants or synthesized in a lab. They are  glycoproteins produced by cultured mammalian cells,  into which the gene for erythropoietin, G-CSF or GM-  CSF has been introduced. Because they are identical or  nearly identical to endogenous hematopoetic agents,  there are relatively few side effects.   These agents are extremely expensive to develop  and produce. The investment has led to exciting new    therapeutic interventions, however, which were  impossible with conventional drug development  techniques. Recombinant DNA technology is now  being applied to numerous medical problems, particu-  larly those due to paucity of an endogenous substance  (e.g., insulin in diabetes mellitus).   The agents listed below reduce the need for blood  transfusions in patients with chronic anemia, reduce  the incidence of life-threatening infections in patients  with low neutrophil counts, and improve the success of  autologous bone marrow transplantation in cancer  patients.   Epoetin alpha is recombinant human erythropoietin. Erythropoetin, which is synthesized in the kidney  in response to hypoxia or anemia, stimulates erythropoiesis. Epoetin alpha is indicated for anemia in  patients with chronic renal failure, because these patients are unable to synthesize erythropoetin to  correct the anemia. Additional uses include correcting zidovudine (AZT)-induced anemia in HIV-  infected patients and chemotherapy-induced anemia in cancer patients. Several weeks of therapy are  required before the hematocrit levels rise, therefore, this drug cannot replace transfusions for the  acute treatment of severe anemia. Epoetin alpha should not be used in patients with uncontrolled  hypertension because the elevation in hematocrit may exacerbate hypertension.   Filgrastim is human recombinant granulocyte colony stimulating factor (G-CSF), which induces  synthesis of neutrophils from progenitor cells. It is indicated for replenishment of neutrophils in cancer  patients treated with myelosuppressive anticancer agents. The goal is to prevent neutropenia, which  is associated with life-threatening bacterial infections. In the past, neutropenia-associated infection  was the dose-limiting toxicity of many chemotherapeutic agents. Now, filgrastim permits the  development of chemotherapy protocols that include higher doses of myelosuppressive drugs. This  will likely result in higher treatment success, but will also result in the development of toxicities that  were previously rarely seen, because the toxicities are produced only at high doses. Filgrastim should  not be used within 24 hours of the administration of anticancer drugs because the effect of cytotoxic  agents on rapidly dividing myeloid cells is not clear. The theoretical concern that filgrastim might act  as a growth factor for malignancies has not been substantiated clinically. Filgrastim is indicated for the  treatment of severe cyclic neutropenia and severe chronic neutropenia. The most frequent  undesirable effect is medullary bone pain, likely due to rapid cell proliferation within the marrow.   Sargramostim is human recombinant granulocyte-macrophage colony stimulating factor (GM-CSF). It  stimulates the proliferation of all lines of blood cells. It induces maturation of granulocytes and  macrophages, but not erythrocytes or megakaryocytes. Sargramostim also activates mature  granulocytes and macrophages. The principle indication is to accelerate bone marrow replenishment  following autologous bone marrow transplantation. It is under investigation for the treatment of several  other myelosuppresive disorders. As with G-CSF, the possibility that GM-CSF might act as a growth  factor for some types of cancer has not been ruled out.   Oprelvekin is a recombinant growth factor that stimulates platelet production. It is indicated for  maintaining platelet counts following chemotherapy. Clinical trials show limited efficacy. Toxicity  includes fluid retention, tachycardia and other cardiovascular reactions.   Bronchoconstriction, inflammation and loss of lung  elasticity are the three most common processes that  result in bronchial obstruction. Therapy for obstructive  lung disease is aimed at preventing or reversing these  processes.   Bronchoconstriction results from the effects of  acetylcholine, histamine, and inflammatory mediators  released within the bronchial walls. The vagus nerve  releases acetylcholine in response to stimulation of  upper airway mucosa by irritants. Acetylcholine also  triggers release of pulmonary secretions which further  reduce air flow by plugging airways. Sympathomimet-  ics (adrenergic agonists, cholinergic antagonists),  methylated xanthines and corticosteroids reverse or  reduce bronchoconstriction (Tables 5.1A and 5. IB).   Chronic Inflammation is caused by prolonged  exposure to airway irritants such as pollution and  cigarette smoke. Bronchiolar inflammation results in  narrowed airways, increased secretions, epithelial  proliferation, loss of ciliated epithelium and fibrosis.  Corticosteroids inhibit the inflammatory response, but    their use is at the expense of systemic side effects  (Table 5.1B).   Loss of lung elasticity results in terminal bronchi-  ole enlargement, changes in lung compliance and the  collapse of airways which are normally tethered open  by surrounding lung tissue. It has been suggested that  cigarette smoke stimulates proteases and inhibits  antiproteases. The relative abundance of proteases  degrade normal lung tissue leading to a loss of sup-  portive lung tissue. Specific therapy to reverse or  prevent proteolytic destruction of lungs is not readily  available.   For diagnostic and treatment purposes, obstructive  lung disease is subclassified as either reactive airway  disease or chronic obstructive lung disease (COPD).   trachea and bronchi of patients with reactive airway  disease are particularly sensitive to stimulants such as  cigarette smoke, dust, cold air and allergens. Patients  present with wheezing, coughing and chest tightness.  Decreased oxygenation of the lungs secondary to  tracheobronchial constriction, mucus production,  inflammation and edema cause these symptoms.    Therapeutic strategies are discussed below. Hospi-  talization, oxygen supplementation, nebulized bron-  chodilator therapy, corticosteroid therapy and occa-  sionally intubation are required for severe episodes.   Patients with chronic bronchitis and/or emphysema  experience chronic dyspnea as a result of airway  obstruction and inflammation. COPD patients com-  plain of persistent cough and dyspnea on exertion. On  physical examination, use of accessory respiratory  muscles and expiratory wheezing are commonly noted.  Expiratory wheezing is due in part to bronchiolar  collapse which traps air distal to the constricted site.   The method of treatment depends on the severity of  the episode and the patient's response to previous  therapy. Therapeutic options include:   • Beta-adrenergic agonists bind to P 2 receptors on  bronchial smooth muscle, causing an increase in the  biochemical messenger, cyclic AMP (cAMP). In-  creased levels of cAMP cause relaxation of bronchial  muscle cells, resulting in bronchodilation.   (3,-selective agents are preferred to nonselective  P-blockers because they are less likely to cause  tachycardia (mediated by (preceptors). These agents  are first line for prophylaxis and treatment of asthma.   Chronic treatment of asthma or  bronchospasm in adults. Not for  acute exacerbations.   receptors), vasoconstriction  (ai) and i secretions (ai).  More detail in Table 2. 1 .   (anaphylaxis). Less potent than  albuterol for maintainance, but  available without prescription.   effects because it is a quaternery  ammonium compound which  crosses into systemic circulation  poorly.   • Corticosteroids decrease peribronchial inflammation.  Inhaled steroids are recommended in conjunction  with beta agonists and cromolyn for asthma prophy-  laxis. Corticosteroid "bursts" (high doses for a few  days) are sometimes used when maintenance therapy  fails to control asthma.   • Cromolyn is a prophylactic agent. It inhibits the  release of mediators from inflammatory cells, such as  mast cells. It is used exclusively in asthma.   • Methylxanthines increase cAMP and inhibit ad-  enosine-induced bronchoconstriction. Oral theophyl-  line is used for outpatient management of asthma less  frequently than in the past. An intravenous bolus of    aminophylline, the water-soluble salt of theophyl-  line, produces therapeutic serum levels faster than  oral theophylline. Aminophyline is therefore used in  acute management.   • Cholinergic Antagonists reduce bronchoconstriction  and secretions caused by parasympathetic transmis-  sion. Ipratroprium bromide is preferred for the  treatment of non-asthmatic COPD in adults and is a  secondary drug in the treatment of asthma.   Most of these agents are administered by inhala-  tion. Consider improper administration of  bronchodilators as an explanation for therapeutic  failure.   a lnh: Ons < 1 5m, Dur 3-4h  PO: Ons < 30m, Dur 4-8h.  Time of onset and duration  are most important points of  distinction between these  drugs.    MAO inhibitors, tricyclic  antidepressants and other  sympathomimetics enhance  sympathomimetic effects,  may induce toxicity, (i-  blockers inhibit activity.   Physician should be  consulted if increased  frequency required for  symptomatic relief.   = subcutaneous, Ons = onset, Dur = duration, m = minutes, h = hours.   The mechanism by which  methylxanthines dilate  bronchioles is unknown. At  toxic doses, these agents  inhibit phosphodiesterase, the  enzyme which breaks down  cAMP (the second messenger  that mediates adrenergic-  induced bronchodilation).  Methylxanthines block  adenosine receptors which  may account for CNS and  cardiac stimulation.  Methylxanthines also induce  diuresis by an unknown  mechanism.   Used for maintainance therapy in  moderate to severe asthma. Slow  onset limits effectiveness in  acute situations. Theophylline is  being replaced by ipratroprium  bromide and/or sympathomimetic  agents for non-asthmatic COPD.   Nausea, vomiting, headache,  insomnia, tachycardia, dizziness,  neuromuscular irritability,  seizures. Side effects are dose  related (TT risk when serum  concentration >20 pg/ml). Serum  levels can be easily monitored.   Decrease inflammation and  edema in respiratory tract.  Enhance activity of  sympathomimetics in hypoxic  and acidotic states.   Prevents the release of  inflammatory mediators (e.g.,  histamine) from mast cells,  macrophages, neutrophils and  eosinophils.   Competitive antagonist of  leukotriene D4 and E4  receptors. Inhibits broncho-  constriction and inflammation.   PO/PR. Well absorbed,  liver metabolism, Kidney  excretion. Dozens of  standard and long-acting  preparations available.   Sympathomimetics T risk of  heart and CNS toxicity.  Cimetidine, oral  contraceptives and several  antibiotics T half-life of  theophylline -thus T toxicity.  Phenobarbital and phenytoin  induce metabolism of  theophylline, thus i half-life.  Dehdydration results from  t diuresis with concurrent  use of furosemide.   Warn patients: doubling a  dose, even if one is  missed, is very  dangerous. Intoxication  may cause seizures.   Aminophylline is the water  soluble salt of  theophylline. It is 79%  theophylline.   PO/IV/IM. Rapid urinary  excretion of unchanged  drug. Half-life prolonged by  probenecid (Fig. 7.13).   Steroids are adjunct  agents and should be  discontinued as soon as  possible.   Treatment of status asthmaticus  (drug does not adequately relieve  symptoms), patients w/ systemic  fungal infections.    Inhalation agents must  not be substituted for  systemic steroids without  first tapering systemic  steroids.    Inhalation. Slow onset of  action. Effective  prophylaxis may require  several weeks of therapy.   May allow patient to  reduce maintenance dose  of bronchodilators or  corticosteroids.   Infant respiratory distress syndrome (IRDS) is caused, in part, by surfactant deficiency. Surfactant  decreases surface tension in the lungs, permitting alveoli to open more readily. Exosurf and   Survanta are surfactant replacement products administered endotracheally to reduce the incidence  and severity of IRDS. Survanta is isolated from bovine lung and supplemented to resemble natural  surfactant. Exosurf is a synthetic surfactant analog. Toxicity includes desaturation and bradycardia  during administration and risk of pulmonary hemorrhage.   Recombinant human DNase cleaves DNA strands. It is administered by inhalation to patients with  cystic fibrosis to decrease the viscosity of bronchial secretions. The viscosity is due to strands of   DNA from lysed inflammatory cells. DNase treatment reduces the frequency of respiratory infections,  presumably by reducing barriers to bronchial clearance.   Mucolytic agent reduces viscosity of mucous by cleaving protein complexes. Used in patients with  chronic bronchopulmonary disease.   Patients with alphai antitrypsin deficiency develop pan acinar emphysema due to degradation of  elastin by neutrophil-produced elastase. Alphai -Proteinase Inhibitor is purified from pooled human  plasma and is administered intravenously each week. The primary toxicity is fever.   A humanized monoclonal antibody targeted against respiratory syncytial virus (RSV). It provides  passive immunity for high risk infants (prematurity, bronchopulmonary dysplasia) when given as  monthly IM injections during winter and early spring months when RSV infections are prevalent in the  community.   Inhibit inflammatory cells in nasal mucosa. Reduce symptoms of rhinitis. May increase risk of thrush  (oropharyngial Candida) and prevent healing of damaged nasal mucosa.   Helicobacter pylori is a bacterium that causes most  cases of gastritis and duodenal ulcer disease. H. pylori  ulcers are in some cases precancerous. Prior to the  identification of H. pylori as a causitive agent, peptic  ulcers were treated with agents that reduced or neutral-  ized gastric acid.   Current practice utilizes at least two antibiotics with  an antisecretory agent and/or bismuth. Although H.  pylori is readily suppressed by a single antibiotic,  monotherapy is suboptimal because it fails to eradicate  the organism and leads to selection of resistant organ-  isms. Antibiotics typically used for H. pylori disease  include amoxacillin, clarithromycin, metronidazole or  tetracycline. These are reviewed in Chapter 7.   Antisecretory agents include proton pump inhibi-  tors (e.g., omiprazole) and H2 histamine receptor  antagonists (e.g., ranitidine) which are described in  Table 6.1. These agents reduce gastric acid production  and promote mucosal healing. Bismuth reduces  bacterial adherence to mucosal cells and damages  bacterial cell walls. It is also the active ingredient in  Pepto-Bismol, an anti-diarrheal agent.    Gastroesophageal Reflux Disease (GERD) and  Dysmotility Reflux esophagitis is an inflammation of  esophageal mucosa caused by reflux of acidic stomach  contents into the esophagus. The underlying defect is  usually an incompetent lower esophageal sphincter.  The disease is exacerbated by obesity and smoking  (nicotine relaxes the lower esophageal sphincter).  Nonmedical treatment includes elevation of the head  of the bed, avoidance of eating before sleep, loose  fitting clothing and surgical procedures that restore the  competency of the lower esophageal sphincter.   H, histamine-receptor antagonists are effective for  short-term treatment of GERD (Table 6.1). Similarly,  agents that increase the rate of gastric emptying,  inhibit the proton pump of gastric parietal cells, form a  protective coat in the stomach or augment endogenous  prostaglandins to promote bicarbonate and mucin  release are are used for GERD, dysmotility, or stomach  mucosa protection (Table 6.1).   Antacid salts, available over the counter (e.g.,  TUMS), provide transient symptomatic relief of gastric  acid irritation. Drugs which alter stomach or duodenal  pH frequently alter absorption of other oral drugs.  Review potential drug interactions before prescribing.   Well tolerated. Diarrhea,  dizziness, rash, headache,  confusion, somnolence,  decreased libido, impotence,  gynecomastia. Rarely, blood  dyscrasias, hepatotoxicity and  renal toxicity .    Similar to cimetidine. Possibly  less CNS and sexual disturbance  than cimetidine.   Neutralize gastric acid. Thus,  mucosal irritation is reduced.  Pain relief precedes healing.   Constipation, hypercalcemia,  metabolic alkalosis, hemorrhoids,  bleeding anal fissures. Rarely,  milk-alkali syndrome (if taken  chronically with milk or  bicarbonate).   Horrible taste. Less likely than  others to cause aspiration  pneumonitis in sedated patients  because it is nonparticulate.   Sucrose and polyaluminum  hydroxide polymerize at low  pH to form protective coating.   Inhibits H + /K + ATPase (proton  pump) of parietal cell. Thus,  reduces acid secretion.   Effective therapy requires  at least two antibiotics  and an antisecretory  aqent or bismuth.    Use with caution in patients  over 50 years old with  kidney or liver failure.   Increases concentration of  anticoagulants, theophylline,  lidocaine, phenytoin,  benzodiazepines, nifedipine,  propranolol, others by  inhibiting liver P450  enzymes. Alters serum level  of many other drugs. Consult  Drug Index.   PO/IV. High first pass  metabolism, unchanged drug and  metabolites excreted in urine.   Binds and inactivates  tetracycline, reduces  absorption of warfarin,  digoxin, and other drugs.  Increases risk of quinidine  toxicity.   Decreases absorption of  drugs which are preferentially  absorbed at low pHs   PO. Acid labile capsule contains  enteric-coated granules, short  half-life (1-1.5 hr).   Diarrhea is usually caused by infection, toxins or  drugs. Antidiarrheal agents are described in Table 6.2.  Several of these drugs are sold over-the-counter and are  used more frequently than medically indicated.   Viral or bacterial-induced diarrhea is usually  transient and requires primarily a clear liquid diet and  increased fluid intake. Antimicrobial therapy may be  indicated by the presence of specific pathogens in the  stool or fecal leukocytes. Intravenous fluids may be  required if dehydration occurs.   Parasitic infections are treated with agents described  in Table 7.14. Antidiarrheal agents that decrease    intestinal motility are contraindicated in parasitic  infections and some bacterial infections (e.g., shigello-  sis) because they suppress expulsion of the organisms.   Drug or toxin-induced diarrhea is best treated by  discontinuing the causative agent when possible.   Chronic diarrhea may be due to laxative abuse,  lactose intolerance, inflammatory bowel disease,  malabsorption syndromes, endocrine disorders,  irritable bowel syndrome and other disorders. Treat-  ment with nonspecific antidiarrheal agents such as  those listed in Table 6.2 may mask an underlying  disorder. Treatment of chronic diarrhea should be  aimed at correcting the cause of diarrhea in addition to  than alleviating the symptoms.   Diphenoxylate is an agonist at  opiate receptors in Gl tract  and atropine blocks  muscarinic receptors. Both  actions inhibit peristalsis.   Few, minor side effects include  constipation, abdominal and  bowel distention, nausea.   Diarrhea. Prophylaxis for  traveler’s diarrhea. Large dose  requirements limit utility for long  trips.   May T K+ loss or interfere with  absorption of drugs and nutrients.   A variety of factors including low-fiber diets, drugs  (e.g., anticholinergics, antacids or narcotics), prolonged  immobilization and abdominal surgery cause constipa-  tion.   Constipation in most nonhospitalized patients can  be resolved by increasing the fiber content of their diet  or by supplementing the diet with bulk-forming  agents.    Rectal administration of laxatives is preferred to  oral if there is a question of intestinal obstruction.  Agents which stimulate peristalsis should be avoided  when obstruction is possible.   Laxative abuse is the most common complication of  laxative therapy. Chronic use of laxatives may lead to  dependence on such agents for normal bowel move-  ments. Senna, in particular, is dangerous when used  chronically because it may damage nerves, resulting in  intestinal atony.   Nondigested plant cell wall  absorbs water into feces, thus  softening the stool.   Metabolized in intestine to  ricinoleate. a surfactant which  decreases water and  electrolyte absorption and  increases motility.   Cramps, nausea. Chronic use  must be avoided. Dehydration,  electrolyte imbalances and nerve  damage may develop.   Mg ++ or Na + salts are poorly  absorbed and thus drawwater  into the lumen. High dose rids  bowel of parasites and  empties bowel preoperatively.   PO. Metabolized in intestine to  lactate which acts as a laxative  osmotically and by lowering pH.   Anal leakage and irritation,  reduces vitamin absorption.  Aspiration pneumonitis may  develop with oral administration.   Diarrhea, abdominal cramps.  Increases absorption of mineral  oil (do not use with mineral oil).   Co-authored by Kevin A. Cassady, M.D. and Helen Yun, Pharm. D., M.B.A.    An ongoing war rages between the medical commu-  nity and bacteria. Physicians utilize the latest antibac-  terial weaponry, while bacteria have only personal  protective gear and some basic strategies for intercept-  ing weapons. Nevertheless, because of their sheer  number, ability to adapt, and unembarassed penchant  for reproducing, bacteria often have the upper hand.   Effective antimicrobial therapy exploits the differ-  ences between microbial and eukaryotic cells. Organ-  isms that differ significantly from human cells are  easier to selectively kill than those which have few  unique properties.   When learning the anti-infective agents, it is useful  to group antimicrobials based on their mechanism of  action and their structure. The mechanism can provide  clues regarding a drug's spectrum and potential side  effects. For example, gentamicin, an aminoglycoside,  gains access to bacteria by an oxygen-dependent pump  and then binds to a ribosomal protein unique to  bacteria. Based on this one can predict the antibiotic  will fail to enter anaerobic bacteria. In addition, one  can see that by blocking the energy dependent trans-  port system or changing the ribosomal protein binding  site, the bacteria develops resistance to the drug.  Finally, when taught that renal tubule cells actively  endocytose the drug during excretion, one can predict  that gentamicin might be nephrotoxic.    In addition to the mechanism of action, key issues  to consider when learning about antibiotics are:   • Chemistry: Subtle differences in chemical structure  can alter spectrum of activity, distribution in the  body, toxicity and likelihood of resistance.   • Spectrum of activity: It is useful to generalize "Drug  A is generally effective against Gram-positives," but  important exceptions must also be learned "... but it  misses Enterococcus."   • Mechanisms of microbial resistance to antibiotics and  ways to circumvent resistance.   • Toxicity: Learn the most common side effects as well  as the uncommon but severe. Uncommon, mild  toxicities can be looked up in the future.   • Administration: Oral vs. parenteral, one vs. three  doses daily. These parameters affect patient compli-  ance, frequency of hospitalization and cost.   • Distribution: Drugs must reach microbes to be  effective. Know which drugs penetrate the blood  brain barrier, joint capsules, the eye, and abscess  walls. Know which drugs fail to leave the gastro-  intestinal system and those that concentrate in the  urinary tract.   Following an introduction to therapeutic strategies  and commonly encountered microbes, this chapter  discusses antibacterial, antiviral, antifungal, and  antiprotozoal drugs.   Figure 7.1 Selective toxicity of antibiotics. Bacterial cells  differ from normal human cells in that they have cell walls,  structurally-different ribosomes, and unique metabolic patlra>ays.  Antibiotics are designed to exploit these differences so that bacteria,  but not human cells, arc damaged.   Don't harm innocent bystanders: The primary goal  of antimicrobial therapy is to kill bacteria without  harming tissues of the host (Fig. 7.1). Antibiotics  exploit the unique features of microbes (cell walls,  different ribosomal structures, unique enzymes) absent  in eukaryotic cells. Drugs like penicillins have few side  effects because they attack bacterial structures that are  absent in human cells. These agents have high selec-  tive toxicity (i.e., good therapeutic index). In contrast,  drugs like amphotericin, which attack less unique  features in fimgi, are toxic to human cells at therapeutic  doses (poor selective toxicity).   identity and drug-sensitivity of the infecting organism  must be determined as rapidly as possible so that  rational therapy can be initiated. If the identity of the  pathogen is unknown, empiric therapy (best guess) is  initiated. The site of infection and Gram stain proper-  ties of the organism provide clues to its identity. Rapid  identification tests (e.g., latex agglutination) may  further confirm the identity. Local susceptibility  reports provide information on the susceptibility of  pathogens to antibiotics and allow a rational start to  antibiotic therapy.   Cultures are the gold standard for identification of  microbes. Unfortunately, several days may be required  for growth and identification of the organism. False  positive cultures occur when culture materials become  contaminated and when organisms are colonizing (but  not infecting) the host. False negative cultures occur  because of poor sampling technique, prior antibiotic  therapy, and inappropriate culture media or tech-  niques.    Empiric therapy should be changed to narrow-  spectrum, effective agent(s) when culture and sensitiv-  ity results are available.   Sensitivity Determination: The sensitivity of  bacteria to various antibiotics is determined by grow-  ing cultures in the presence of the antibiotics of inter-  est. The minimal inhibitory concentration (MIC) is  the concentration of antibiotic which prevents growth  of the culture. The minimal bactericidal concentration  (MBC) is the concentration that kills 99.9% of the  inoculum. The serum bactericidal titer is the dilution  of patient's serum (which contains antibiotic molecules  that haven’t been distributed to other sites, bound to  „ plasma proteins, metabolized, or excreted) that is   capable of killing the pathogen. This provides informa-  tion on whether the concentration of antibiotics in a  given patient is high enough to be effective in body  spaces (e.g., joints, meninges) characterized by poor  antibiotic permeability.   Keep your empiric therapy arsenal small: Antibi-  otic therapy often begins before the infectious agent is  identified. Each practitioner should thoroughly  understand a small number of antibiotics that are  frequently used for empiric therapy. The history,  infection location and rapid identification tests de-  scribed above provide clues to the identity of the  microbe. The following statements summarize key  points about drugs that are frequently used for empiric  therapy. If the presumed organisms are:   • Gram-positives: Nafcillin (TV) and dicloxacillin (PO)  provide excellent coverage of most Gram-positives  and are not destroyed by penicillinases. First genera-  tion cephalosporins (e.g., cephalexin, cefazolin) are  effective against most skin and skin structure infec-  tions.   • Gram-negatives: Third generation cephalosporins  are effective against many Gram-negatives and are  not destroyed by cephalosporinases. They penetrate  the brain well. Cephalosporins and penicillins may  enhance the activity of aminoglycosides against  Gram-negatives. The combination of “Amp & Gent"  (ampicillin and gentamicin) provides very good  coverage of both Gram-positives and Gram-nega-  tives. Trimethoprim-sulfamethoxazole (Bactrim/  Septra) is active against most urinary tract infections.  Amoxicillin is frequently used for otitis media and  other bacterial upper respiratory infections.   • Pseudomonas : Ticarcillin or ceftazidime cover most  Gram-negatives, including Pseudomonas, but fail to  treat some Gram-positives. Imipenem and  meropenem have good activity against Pseudomonas.    • Anaerobes: Metronidazole or clindamycin cover  most anaerobic bacteria. Mouth anaerobes are  adequately covered by penicillin.   • Mycoplasma: The macrolides (erythromycin,  clarithromycin, azithromycin) treat presumed  Mycoplasma pneumonia, along with most other  organisms that cause community-acquired  pneumonia.   • Systemic fungi: Amphotericin is the drug of choice  for presumed fungemia. Systemic fungal infections  occur most frequently in patients that have been on  broad spectrum antibiotics that have destroyed their  endogenous bacteria, allowing fungal overgrowth.    aminoglycosides. Aminoglycosides work intracellu-  larly, but may have difficulty entering the cell.  Penicillins and cephalosporins prevent repair of  holes in the bacterial cell wall, making it easier for  aminoglycosides to enter.    Figure 7.2 Under the right circumstances, it may be necessary  to initiate therapy with several antibiotic agents.   7.2): Quite often it is advantageous to use multiple  drugs to treat an infection. Examples include:   • Unknown microbe: If you haven't identified the  Gram stain properties of an infectious agent, it is  sometimes necessary to treat with antibiotics that  cover a broad spectrum of microbes. Often a drug  that covers most gram positive organisms and a drug  that covers gram negative bacteria are combined. An  agent that covers anaerobes or Pseudomonas may also  be desirable. Single drug therapy can then be insti-  tuted when the organism is identified.    Figure 7.3 Bacteriostatic drugs require an intact immune  system to eradicate an infection.   Know which drugs kill and which drugs maim  (Fig. 7.3): Bactericidal antibiotics kill bacteria (cidal).  Bacteriostatic agents only inhibit bacterial prolifera-  tion while the host's immune system does the killing.  Bactericidal agents are necessary for infections in  patients with defective immune systems (cancer, AIDS,  diabetes) and for overwhelming infections. Patients  MUST take their full course of medication. Patient  compliance is often poor because it appears that their  infection has subsided when in fact it is only sup-  pressed.   Get the drug to the site of infection: The brain,  joints, testes, and eye are "protected" sites in the body.  Few drugs penetrate the barriers that surround these  sites. When treating infections at these sites, one must  choose agents that penetrate the barriers and that are  active against the infecting organism. Similarly,  abscess walls form an effective barrier to antibiotics.  Abscesses must be incised and drained.    • To prevent resistance: It is more difficult for bacteria  to develop resistance to two drugs with different  mechanisms than to develop resistance to a single  agent.    • To achieve synergy: The actions of some drugs make  other drugs more effective. The classic example is the  combination of penicillins or cephalosporins with   Background: Before the advent of penicillin, Gram-  positive cocci were responsible for most known infec-  tions. Initially susceptible to basic penicillins. Gram-  positive bacteria have developed resistance to basic  penicillins and some strains may be resistant to special-  ized penicillins.   Appearance: Blue & round by microscopy. A  peptidoglycan (polypeptide + sugar) cell wall sur-  rounds the bacteria. The impermeability of this wall  (compared to Gram-negative bacteria) is responsible for  the retention of blue dye during Gram staining. Peni-  cillins, cephalosporins, bacitracin, vancomycin and  cycloserine inhibit the synthesis of the peptidoglycan  wall.   Common Sites of Invasion: Staph aureus & Staph  epidermidis inhabit most people's skin and are likely to  infect wounds, surgical sites and indwelling catheters  (may cause infective endocarditis). Strep pneumoniae  is often the cause of community-acquired pneumonia  and adult bacterial meningitis. "Strep throat" is an  infection caused by Group A beta-hemolytic Strepto-  coccus. If untreated, it may elicit an immunologic  reaction in the heart, joints and other tissues, known as  rheumatic fever.   Figure 7.4 Staph, anti Strep, are protected by a crosslinked  glycoprotein umll. Penicillin, cephalosporins, imipenem,  aztreonam and vancomycin prevent construction and repair of the  wall.   Figure 7.5 Anaerobic bacteria produce foul-smelling  infections that are typically encased in an abscess wall.  Metronidazole, chloramphenicol and clindamycin are used to treat  anaerobic infections, which are typically composed of mixed Gram-  positive and Gram-negative organisms.    Background: Common anaerobes include Bacteroi-  des fragilis, Clostridium difficile and Fusobacterium. C.  botulinum and C. tetani produce toxins responsible for  botulism and tetanus, respectively. Metronidazole,  chloramphenicol or clindamycin are effective against  anaerobic infections.   Appearance: Mixed Gram-positives and Gram-  negatives compose most anaerobic infections. Infec-  tions are frequently encased in an abcess wall. Anaer-  obes produce foul-smelling gas.   Common Sites of Invasion: Anaerobes colonize the  mouth, gastrointestinal tract and skin of all persons.  Infections develop when anaerobes penetrate poorly  oxygenated tissues (e.g., the diabetic foot) or tissues  that are normally sterile (e.g., peritoneum). When  broad spectrum antibiotics diminish normal bowel  flora, C. difficile proliferates and releases a toxin that  causes pseudomembranous colitis.    Figure 7.6 Gram negative bacteria. The glycoprotein wall of  Gram negatives resembles that of Gram positives. In addition,  Gram negatives wear a protective outer coat which is impermeable  to penicillin. Ampicillin and amoxicillin however, can penetrate  the outer coat and destroy the cell wall. Grant-negatives cause  meningitis, pneumonia, bladder infections, otitis media and sinus  infections.   Background: Common Gram-negative pathogens  can be divided into four groups: 1) Enterics, consisting  of those organisms that normally inhabit the GI tract  (Escherichia, Shigella, Salmonella, Klebsiella, Enterobacter,  Serratia, Proteus, and others), 2) Haemophilus influenzae,   3) Neisseria and 4) Pseudomonas. Although rarely a  cause of hospital acquired (nosocomial) infections prior  to the advent of antibiotics, the enterics are now  responsible for most nosocomial infections. Strains  resistant to many antibiotics have developed.   Appearance: Enterics and Haemophilus influenzae are  red and elongated by microscopy (Fig. 7.6). The  plasma membrane of Gram-negative bacteria is pro-  tected by an adjacent rigid peptidoglycan wall (site of  action for penicillins, cephalosporins, etc.) which is  encased by an outer membrane. Penicillins must cross  the outer membrane in order to act at the inner cell  wall. The outer membrane is made of lipopolysacchar-  ides interrupted by transmembrane protein pores  (which prohibit entry of most penicillins and cephalos-  porins). Broad spectrum penicillins and third genera-  tion cephalosporins are more hydrophilic than  previous drugs, allowing passage through the selective  pores. Even so, some Gram-negative strains are    resistant to penicillins because they produce B-  lactamases (penicillin-destroying enzymes) that are  concentrated in the space between the outer membrane  and the cell wall. Neisseria are paired red spheres.  Pseudomonas also has an extracellular polysaccharide  slime layer and unipolar flagella.    Figure 7.7 Neisseria meningitides and N. gonorrhea are the  only gram negatives that are susceptible to penicillin G and other  narrow spectrum penicillins. Ceftriaxone has now replaced  penicillin as the drug of choice for N. gonorrhea due to the  emergence of penicillin-resistant strains.   Common sites of invasion: The enterics are  responsible for many urinary tract infections and  aspiration pneumonia due to the proximity of the  gastrointestinal tract (their home) to the urethra and  the lungs. Neisseria gonorrhea is responsible for  sexually transmitted gonorrhea. N. meningitidis and  H. influenzae both cause meningitis. H. influenzae  more commonly causes pneumonia, particularly in the  elderly. Pseudomonas aeruginosa is sometimes  responsible for hospital acquired infections. Pseudo-  monal infections can occur at any site, particularly in  immunocompromised patients. If adequate moisture  is available, Pseudomonas may colonize any surface in  the hospital (including workers) and is resistant to  many disinfectants.   Figure 7.8 Stella Pseudomonas shoxvs off her slime coat and  flagella, which distinguish her from the other gram negatives. She  can infect any site in the body and is relatively resistant to most  antibacterial agents. Tobramycin or ceftazidime are preferred  agents for treating Pseudomonal infections.   The agents described in Table 7.1 kill bacteria by  preventing synthesis or repair of the cell wall. The cell  wall protects bacteria, which are hyperosmolar, and  prevents them from absorbing water and exploding.   The mechanism of cell wall synthesis is demon-  strated in Figure 7.9. In brief, peptidoglycan chains  synthesized in the cytoplasm of bacteria are transferred  across the plasma membrane and linked to other  peptidoglycan chains. The result is a "chain-link" wall  that sxirrounds the bacteria.   Because human cells lack cell wails, they are gener-  ally unaffected by inhibitors of cell wall synthesis. This  explains why penicillins and cephalosporins have few  side effects.   Penicillin was first isolated from the Penicillium  mold in 1949. It was effective against a variety of  bacteria including most Gram-positive organisms.  Excessive use of penicillin led to the development of  bacterial resistance (penicillinase production), render-  ing the drug useless against many strains of bacteria.    Nevertheless, it remains an inexpensive and well  tolerated drug of choice for several infections.   The pharmacokinetics, spectrum of activity and  clinical uses of penicillins are presented in Table 7.2.   Chemistry: Penicillins, cephalosporins,  monolactams (aztreonam) and carbapenems  (imipenem) all have a beta-lactam ring in the center.  Some of these are inactived if the ring is cleaved by 13-  lactamases (Fig. 7.10, 7.1 1). Others (e.g., aztreonam,  imipenem) are resistant to |3-lactamases.   Early penicillin was acid labile and could not be  administered orally. It was ineffective against many  Gram-negative bacteria and was destroyed by 13-  lactamases. Each of these limitations has been over-  come in newer penicillins due to alterations of the  chemical structure or the development of adjunct  agents such as probenicid and clavulanic acid. These  advances are diagrammed in figures 7.10, 7.11, and  7.12.   Clavulanic acid and probenicid potentiate the  actions of penicillins and cephalosporins. Clavulanic  acid potentiates penicillins by binding to and inhibiting  p-lactamase (Figure 7.11). Augmentin® is the trade  name for amoxicillin and clavulanic acid, and  Timentin® is the trade name for ticarcillin and  clavulanic acid. Probenicid acts by competing with    Table 7. 1 Bactericidal Drugs that Work at the Cell Wall   Prevents transfer of cell wall  precurser f rom plasma  membrane to cell wall.   DOC 1 : Penicillin or methicillin-  resistant Staph and Strep  infections. Bacteriostatic against  Enterococcus.   Syndrome" when administered by  rapid IV: tachycardia, flushing,  paresthesias, hypotension,  severe nephrotoxicity.   Inhibits recycling of the carrier  which transports cell wall  precursors across the plasma  membrane.   DOC: Acinetobacter. Excellent  coverage of most Gram-positives  and Gram-negatives (including  those which produce (3-  lactamases) and P. aeruginosa.  May find role in mixed infections.   Excellent coverage of Gram-  negatives including P.  aeruginosa. Not active against  Gram-positives.   Similar side effects as penicillins  (hypersensitivity, seizures,  hepatitis), Injection site pain, Gl  upset.   penicillin for the organic anion  transport system, which is the pri-  mary route of penicillin excretion (Fig  7.12). The result is higher serum  levels of penicillin.   Allergic Reactions: Penicillin  reactions range from skin rashes to  anaphylactic shock. The more severe  reactions are uncommon, but poten-  tially life-threatening. Some allergic  reactions are mediated by IgE anti-  bodies. Alternative antibiotics should  be used in patients with a history of  reactions even though penicillin  allergies are overreported. Skin tests  using penicilloylpolylysine and  penicillin degradation products  provide information about penicillin  sensitivity in patients with no history  of penicillin use. Virtually all patients  who are truly allergic to one form of  penicillin will be allergic to other  penicillins.    Marketed in combination  with polymyxin or  neomycin as a topical  agent.   IM/IV. Imipenemis  administered with cilastatin  (inactive), which inhibits  renal metabolism of  imipenem. Renal failure  requires dose reduction for  both.    IM/IV. Wide distribution  including joints, brain, and  urine. Decrease dose with  renal failure.    Figure 7.9 Bacterial cell wall synthesis. 1) Alanine molecules are added to  a carbohydrate tripeptide to form a "T" shaped cell wall precursor. This reaction is  inhibited by D-cycloserine. 2) The precursor is transported across the plasma  membrane by a carrier. Vancomycin inhibits the transport process. 3) The  transporter is recycled to the inside of the cell to carry other precursors. Bacitracin  inhibits this step. 4) The precursor is linked to the existing cell wall structure by  transpeptidase. Penicillins, cephalosporins, imipenem and aztreonam inhibit the  transpeptidase. Transpeptidase is one of several penicillin binding proteins and is  not the only site of penicillin action.    Figure 7.10. Penicillin Chemistry Penicillinases inactivate  penicillin by cleaving the fi-lactam ring. In penicillinase-resistant  penicillins, a bulky chemical groups prevents entry to the active site  of penicillinase, but does not interfere with binding to the bacteria.  Narrow spectrum penicillins are unable to pass through the outer  membrane of Gram-negative bacteria. Broad spectrum penicillins  are more hydrophilic and are thus able to penetrate the aqueous  pores of the outer membrane.   B-lactam binds penicillin  binding proteins (similar  structurally to pentapeptide's  alanine terminus) and inhibits  crosslinking of bacterial cell  wall components (Fig. 7.9)   Bulky side group protects the  p-lactam ring from  penicillinases. Hydrophobic  side group, however, inhibits  antibiotic s ability to penetrate  gram negative bacteria via  nydrophylic porins.   Amino side group makes these  agents hydrophilic enough to  penetrate the porins in gram  negative organisms.   Side chain makes it more  resistant to p-lactmases from  Gram-negative species  especially Pseudomonas  species.   Gram-negative infections  (especially Pseudomonas ) and  aminopenicillin-resitant Proteus  infections. Less effective  against Gram-positive  penicillinase-roducing organisms.   As above plus piperacillin-  resistant Gram-negative and  Gram-positive penicillinase-  producing organisms.    “Pen G IV/IM. Pen V PO (acid  stable). Procaine and benzathine  prolong half-life.   Eliminated by organic acid  transfer system in kidney.  Probenicid competes at this  transporter. Can be used to  increase penicillin half-life.  Distributes to eyes, joints and  brain if meninges are inflamed.    TVls preferred route because of  low absorption from PO/IM sites.  Excreted by liver - high  concentration in bile.    Hypersensitivity reactions  (anaphalaxis or hemolysis).  Rare neurologic toxicity  (seizures) due to inhibition  of GABA neurotransmission  (P-lactam is structurally  similar to GABA).  Neutropenia.    Figure 7.11. Penicillinases and penicillinase-resistant  penicillins. Top: Penicillins destroy bacteria after binding to  penicillin binding proteins (PBPs). Middle: Penicillinases are  enzymes produced by bacteria that destroy penicillins by cleaving  the beta-lactam ring of the drug. Penicillins are "lured" into the  active site because they are chemically similar to penicillin binding  proteins. Bottom: Clavulanic acid is a "decoy" drug that  enhances the activity of penicillins. Clavulanic acid binds to the  active sites of penicillinases rendering the enzyme inactive.   Figure 7.12 Probeniciil potentiates the action of penicil-  lins and cephalosporins by competing for excretion at the  organic anion transport system (OATS) in the kidney.   (5- lactam binds penicillin  binding proteins. Inhibits  cell wall synthesis and may  in turn activate autolysins.  Bacteria develop resitance  by reducing drug  permeability, mutating  penicillin binding proteins  and producing p-lactamase  and cephalasporinases  (clavulanate can circumvent  this problem)   Used for surgical prophylaxis  and for treating skin or soft  tissue infections caused by  Staph. or Strep.   Cefoxitin and Cefotetan  (cephamycins) and  Loracarbef (carbacephem)  are structurally and  pharmacologically related to  the cephalosporins.   Extended Gram-negative  activity (H. flu, Enterobacter,  Proteus. Neisseria species).  None are effective  against Pseudomonas.  Used for otitis media,  pharyngitis, and sinus, skin,  and respiratory infections.  Cefuroxime used as single  dose therapy for N. gonorrhea.  cefuroxime is more effective  than cefazolin in prophylaxis  against MRSA wound  infections.   Fail to penetrate CSF  cefuroxime achieves CSF  levels but third generation  agents preferred because of  greater penetration and more  rapid sterilization.   Similar mechanism to first  generation cephalosporins;  however more resistant to  Beta lactamase produced  by Gram negative bacteria.   Variable efficacy against  Pseudomonads (ceftazidime,  cetipime, and cetoperazone  have best coverage).   Cephalosporins share with penicillins a common  mechanism, susceptibility to B-lactamases (penicilli-  nases, cephalosporinases) and similar side effects.   Like penicillins, the original “generation" of cepha-  losporins was most effective against Gram-positive  organisms. Chemical modifications increased the  effectiveness of subsequent generations against Gram-  negatives and reduced their ability to fight Gram-  positive infections.   Perhaps the greatest problem with cephalosporins is  that their names sound alike. When learning the  cephalosporins, concentrate on the commonly used    (anaphalaxis, serum sickness), cephalosporin and penicillins  Gl disturbances. occurs in 1 0% to 1 5% of   Rare neurologic toxicity  (seizures, confusion)  especially with Cefazolin.  Hematologic abnormalities;  (neutropenia, thrombocyto-    Cefotetan (a cephamycin) and  Cefpodoxime (an ester  prodrug) have improved Gram-  negative coverage equivalent  to many of the third generation  cephalosporins. They are  sometimes grouped with the  third generation  cephalosporins. Cefotetan  cefmetazole, and cefoxitin  cover Bacleroides and  Clostridium spp.   Ceftriaxone associated with  acalculous cholestasis and  bilirubin displacement from  albumin. Use cautiously in  neonates and avoid in  jaundiced infants.    agents first. Each generation has only one preferred  oral preparation, usually referred to by the trade  names Keflex (cephalexin), Ceclor (cefaclor) and  Suprax (cefixime) for 1st, 2nd and 3rd generation,  respectively.   Up to this point, we have discussed antibiotics that  work outside of the bacteria or at its surface. Cell  wall inhibitors cannot kill all types of bacteria  because some lack cell walls. Other bacteria have  unique structures that resist the action or the accu-  mulation of the cell wall inhibitors. Antibiotics that  target other vital unique bacterial features are  effective in eliminating these infections.   These anti-microbials work within the bacteria  and affect the genetic code or protein synthesis. The  antibiotics target bacterial structures and enzymes  (bacterial ribosomes, bacterial RNA polymerase,   DNA gyrase, dyhydrofolate reductase) that although  unique to the bacteria, can share homology with host  structures. These drugs, therefore, often have poorer  selective toxicity than the cell wall inhibitors. The  intrabacterial antibiotics have mechanisms of action  similar to those used to combat viral, protozoal, and  some fungal infections.   The disruption of a microbe's genetic code and the  inhibition of DNA replication provide common  targets for anti-infectious agents. This can be done by  destroying the conformation of the DNA  (quinolones/ fluoroquinolones), by introducing  defective building blocks for DNA synthesis (ddl,  ddC, griseofulvin) or by inhibiting enzymes or  cofactors necessary for DNA synthesis (sulfonamids,  acyclovir, vidarabine). Drugs that target DNA  frequently arc mutagenic or carcinogenic because  they can damage eukaryotic DNA.   The fluoroquinolones are a growing class of  antimicrobial agents. The newer quinolones  ((al)trovafloxacin, sparfloxacin, and levofloxacin)  have improved activity against gram positive organ-  isms. This combined with their excellent gram  negative coverage and excellent tissue penetration,  has broadened their list of indications to include skin  and skin-structure, bone and joint, gastrointestinal,  and respiratory infections. Additionally, quinolones  can be used for sexually transmitted diseases (gonor-  rhea and Chlamydia).   Blocks a subunit of DNA  gyrase. Bactericidal -  prevents supercoiling  resulting in inhibition of DNA  synthesis. Effective against  enteric Gram-negative  bacteria, but not   Hypersensitivity reaction,  nausea, photosensitivity,  seizures, headache, dizziness,  skin tumors (in mice). Displaces  oral anticoagulants from plasma  proteins. Causes growth plate  arrest in animals - not  recommended for children.   PO. This pro-drug is  hydroxylated to a bactericidal  metabolite which is  concentrated in urine. Does not  penetrate prostate. >90%  plasma protein bound.   PO. Penetrates prostate (50%  serum level). Lower incidence  of resistance than nalidixic  acid.   Disrupts DNA gyrase and DNA  topoisomerase activity. Good  gram negative coverage.    PO. Ciprofloxacin and ofloxacin  are also available as IV. Good  tissue penetration except CSF.  However, ofloxacin has good   Disrupts DNA gyrase and DNA  topoisomerase activity.  Excellent gram negative  coverage and improved Staph  coverage. (Al)trovafloxacin is  the only one with anaerobic  activity. All treat Legionella  and Chlamydia atypical  pneumonia.   ""Trovafloxacin and  altrovafloxacin are associated  with higher incidence of liver-  toxicity.   PO/IV. Renal elimination,  except trovafloxacin (PO) and  altrovafloxacin (IV).  (Al)trovafloxacin do not require  dose adjustment for renal  failure. Sparfloxacin is PO only.  Good fissure penetration.   Enters bacteria or protozoan  and is activated by reduction  of the nitro group. Activated  intermediates bind DNA and  inhibit its synthesis. Cidal  against obligate anaerobes  (Bacteroides. Clostridium.  Peptococcus) and Protozoans  ( Entamoeba histolytica.  Trichomonas, Giardia )   Disulfiram-like reaction with  alcohol (flushing, vomiting,  headache). CNS disturbance  (seizures, ataxia, dizziness),  nausea, anorexia, bloating,  cramping.   Penetrates well into tissues and  abcesses, empyemas and CSF.  Metabolism is through  glucuronidation. Majority of drug  is eliminated unmetabolized in  the urine.   Mechanism unclear, may  damage DNA. Kills many  urinary pathogens, but not  Pseudomonas. Klebsiella,  Proteus, Serratia,  Acinetobacter.   Nausea, vomiting (less so with  macrocrystalline formulation),  hepatotoxicity, pulmonary  fibrosis, neuropathy.   PO. Reduced in liver, excreted  by kidney. Reduce dose if renal  compromised. Do not  administer if creatinine  clearance < 40 ml/ min.    The antimetabolites described in Table 7.5 inhibit  DNA, RNA and protein production by blocking the  folate pathway. Tetrahydrofolate donates single  carbon molecules to the synthesis of purines, pyrimi-  dines and some amino acids (methionine, formyl-  methionine and serine).   The sulfonamides are structurally similar to para-  amino benzoic acid (PABA). Sulfonamides compete  with PABA and prevent it from being incorporated into  folate (Fig. 7.13). Trimethoprim prevents reduction of  dihydrofolate (FAIT) to tetrahydrofolate (FAH  by  binding to and inhibiting dihydrofolate reductase (Fig.  7.13). Human cells are spared from this reaction  because trimethoprim has very low affinity for human  dihydrofolate reductase.   The ability to achieve therapeutic levels of most  sulfonamides is limited by precipitation in urine. This  problem is circumvented by combining agents. Thera-  peutic doses of the combination can be achieved with  nonprecipitating concentrations of individual drugs.   Used for treatment of  uncomplicated urinary tract  infections, nocardiasis,  chancroid, prophylaxis against  rheumatic fever. Combined with  pyrimethamine for treatment of  Toxoplasmosis. Suifapyridine  used for Dermatitis  herpetiformis.   Bone marrow depress ion, renal  toxicity, photosensitivity,  hemolysis, hepatotoxicity,  hypersensitivity (fever/rash)  Stevens-Johnson Syndrome  (serum sickness). Kernicterus -  sulfas compete with bilirubin for  albumin sites. Resulting  elevated free bilirubin is  deposited in brain nuclei.   Precipitates in acidic urine.  Encourage fluids to prevent renal  stone formation.   Enteric Gram-negatives  (Proteus, E. coli, Klebsiella,  Enterobacter), H influenzae,  Shigella, Serratia, Salmonella,  Pneumocystis carinii.  Inexpensive, effective choice  for urinary tract infections, acute  otitis media, traveller's diarrhea.  Used for Pneumocysitis carinii  prophylaxis/treatment in  immunocompromised hosts.   Inhibits Pneumocystis carinii  trophozoites. Alternative  treatment for severe P. carinii  pneumonia in cases refractory to  or patients intolerant to   Hematologic, hepatic, renal,  and Gl toxicities. Give with  leukovorin to minimize toxicity.  Leukovorin repletes folate in  mammalian cells. TMTX/LV had  lower incidence of side effects  than TMP/SMZ in one clinical  trial of patients with HIV  disease.   Synthetic inhibitor of protozoan,  bacterial, and mammalian  dihydrofolate reductase (not  selective). Selectivity derived  from leukovorin rescue of human  cells.   Binds at the 30s/50s subunit  interface results in abnormal  reading of mRNA and defective  bacterial proteins (Fig 7.14).  Concentrated in bacterial  cytoplasm by energy (oxygen)  dependent protein transport.   Mutation of binding sites  Inhibition of transport and  permeability of drug.   Anarobic bacteria are resistant  because transport into bacteria is  oxygen dependent.   Prevents translocation of  polypeptide chain by binding to  the P site of the ribosomal 50s  subunit (Fig. 7.14).   Binds to 50s ribosomal subunit  and prevents chain elongation  by blocking transpeptidation  (Fig. 7.14).   Binds to 30s subunit blocking  amino acid-linked tRNA from  binding to the A’ site of the  ribosome (Fig. 7.14).   lxjg: salmonella typnosa  (typhoid fever), H. flu  meningitis or epiglottitis.  Some physicians/  institutions hesitate to use  chloramphenicol due to risk  of aplastic anemia.)   Gray syndrome - toxic  levels of drug in newborns  unable to conjugate drug.  Symptoms: abdominal  distention, vomiting, pallid  cyanosis, hypothermia,  collapse, death (40%).   Administer with caution in  patients with liver disease  or on medication  metabolized by P-450  system.   Mycoplasma , Strep throat,  upper respiratory infections  due to susceptible bacteria,  Staph, skin infections.   PO/IV Take on empty  stomach. Long half-life  permits once daily dosing.  Unmetabolized, excreted in  bile.    reversible elevation of liver  enzymes and Gl upset.  Pseudomembranous colitis seen  with any antibiotic but classically  associated with clindamycin.    Used for acne and  chlamydial infections. Also  for Borrelia Burgdorferi  (Lyme Disease).    Gl distress, reversible  nephrotoxicity , hepatotoxicity,  photosensitivity, dental staining  (not used in pre-pubertal children)  increased intracranial pressure  (rare).    PO. Strong chelator - don't  give with milk, antacid, Ca ++  or Fe ++ . No CSF penetration.  Concentrated by liver,  enterohepatic circulation.  Excreted in urine and feces.   C. difficile is resistant and  overgrowth / toxin release  may follow, causing  pseudo-membranous  colitis    Figure 7.14 Sites of bacterial protein synthesis inhibition. Bacterial rilwsomes exhibit binding sites that are distinct front human  ribosomes. Gentamicin binds at the 30s/50s interface and interferes with mRNA reading. Chloramphenicol , erythromycin and  clindamycin bind to the 50s subunit to prevent peptide chain elongation. Tetracycline binds to the 30s subunit which prevents tRNA from  binding to the “A " site of the ribosome.   Bacteria, like eukaryotic cells, must synthesize  proteins in order to survive. These proteins provide  structural integrity and enable bacterial energy produc-  tion. Protein synthesis is critical to a micro-organism  during replication when new structural proteins and  enzymes are essential for progeny. Anti-microbials  target several steps in protein synthesis. Some of the  drugs can kill but more often they only inhibit repro-    duction and rely on the immune system to kill the  organism. The first step in protein synthesis consists of  copying the mRNA code from a DNA blueprint.  Rifampin inhibits RNA Polymerase and destroys the  code for protein synthesis while the sulfonamides and  anti-metabolites block cofactors necessary for RNA and  protein synthesis.   After the mRNA code is created it travels to the  cytoplasm where ribosomes translate the code into a  polypeptide. Other anti-microbials (aminoglycosides,   chloramphenicol, erythromycin, tetracycline) target the  actual factory (50s subunit of the 70s ribosome) that  synthesizes the protein from the mRNA (Fig.7.14). The  bacterial ribosomes differs from mammalian ribosomes  They have different molecular weight (70s vs. 80s), and  bind antibiotics preferentially. The mitochondria within  the eukaryotic cells contain similar ribosomes to the  bacteria.   High exposure to some of these drugs can damaged  mammalian tissue by inhibiting this energy producing  organelle. Similarly, some of the drugs are less selective  for the bacterial ribosomes and can bind to the 80s  eukaryotic ribosome and damage host tissue. Rapidly  dividing cells, (GI mucosa, skin, bone marrow) and  cells in tissues exposed to higher levels of the drug  (kidney, liver) manifest the greatest toxicities from  these agents.   Tuberculosis (TB) and leprosy are the best known  mycobacterial diseases. The development of antibiotics  changed tuberculosis from a debilitating/ fatal illness to  one that was readily controlled with oral medications.  The prevalence declined until the 1980s, but is now  rapidly increasing, particularly among immunodefi-  cient individuals. The organisms are increasingly  resistant to multiple antimicrobials.   Mycobacteria are rod-shaped bacilli that stain  weakly gram positive. They are called "acid fast"  bacilli because they retain dye even when washed with  acid alcohol.   Mycobacteria infect mononuclear phagocytes, where  they may live for years as intracellular parasites.  Fulminant mycobacterial infections develop when the   Blocks p unit of bacterial RNA  polymerase. Stops bacterial  RNA synthesis.   Secretions (urine, sweat) turn  red. Hepatitis (especially in  alcoholics), flu symptoms.   Induces P450 enzymes,  increasing the metabolism of oral  contraceptives and other drugs.   Synthetic rifamycin with  improved activity against  rifampin resistant strains of M.  avium, (in vitro & mouse data).   Hepatitis, Hyperuricemia with  gouty arthritis. Never used alone  because of rapid resistance.   Mono-like symptoms, severe GI  intolerance and Hypersensitivity  lead to poor compliance.   Inhibits mycolic acid  synthesis in bacterial cell wall  (mechanism not confirmed)  Bacteriostatic   Reversible retrobulbar neuritis.  Loss of central vision. Patients  must have baseline ophthalmogic  exam prior to treatment.    host’s immune response is compromised. Thus pa-  tients with AIDS and alcohol addiction are particularly  susceptible.   Tuberculosis often presents with pulmonary symp-  toms, but may involve lymph nodes, bones, skin,  genitourinary tract and meninges.   Treatment consists of several drugs because resis-  tance develops to single agent therapy. In addition to  the emergence of antibiotic resistance, treatment of  mycobacteria presents unique problems due to 1) slow  growth rate reduces efficacy of antibiotics that prevent  rapid synthesis of proteins and DNA, 2) the cell wall is  not susceptible to classic cell wall inhibitors, 3) infec-  tions may be walled off in tubercles which reduce  antibiotic penetration, 4) infections occur frequently in  immunocompromised hosts which reduces the utility   Treatment guidelines continue to be revised as  multi-drug resistance increases. Prophylactic treatment  is recommended for asymptomatic patients that  develop skin test positivity and for young (< 4 years) or  immunocompromised patients that are exposed to an  infectious case of tuberculosis.   M. avium-intracellulare infects patients with chronic  pulmonary disease and may become fulminant in AIDS  patients. Atypical mycobacteria are treated with combi-  nation chemotherapy or in some cases, surgery. Because  drug resistance is more common in nontuberculous  mycobacterial infections than in TB, the susceptibility of  the microbe must be determined early.   Metabolized by thymidine kinase and other enzymes to  triphosphate analog which inhibits DNA polymerase and  incorporates into viral DNA. Binds to viral thymidine kinase with  higher affinity than It binds to mammalian thymidine kinase.   Phosphorylated by viral thymidine kinase to penciclovir  triphosphate which inhibits DNA polymerase in HSV.   Metabolized by thymidine kinase and other enzymes to  triphosphate form which inhibits DNA polymerase and incorporates  into viral DNA. Preferentially phosphorylated to active drug in  CMV-infected mammalian cells.   Analog of pyrophosphate. Competes for pyrophosphate site in  viral, but not human. DNA polymerase and reverse transcriptase.   Treatment/prophylaxis of  influenza A in the elderly and  patients with cardiopulmonary  dysfunction.   Analog of amantadine uncertain mechanism but appears to inhibit  viral uncoating.   Hospitalized children with  respiratory syncytial virus (RSV)  who are at risk for  cardiopulmonary complications.   Viruses are obligate intracellular parasites com-  posed of either DNA or RNA wrapped in a protein  nucleocapsid. Some viruses produce a glycoprotein  envelope that surrounds the nucleocapsid. Viruses  shed their capsid after invading a host cell. The host  cell then synthesizes new viruses using the message  encoded by the viral DNA or RNA.   Viral infections are diagnosed by clinical criteria,  culture, fluorescent antibody testing, polymerase chain  reaction, or serology. Clinically important viral  infections include:   • Herpes Family Viruses cause genital and oral herpes.  Varicella (chicken pox), and uncommon but severe  infections like Herpes encephalitis. Acyclovir is  treatment of choice.    • Cytomegalovirus (CMV) is problematic in transplant  patients, AIDS patients and other immunosup-  pressed individuals. Intravenous ganciclovir therapy  for CMV infections careful monitoring for granulocy-  topenia and thrombocytopenia.   • Influenza virus infections may be fatal in the elderly  or immunocompromised. Amantadine prevents  influenza infections when used prophylactically and  reduces the severity of symptoms in infected indi-  viduals. Rimantidine is a related drug that has been  approved for use in children.   • Respiratory syncytial virus (RSV) causes bronchiolitis  in children. RSV usually resolves with supportive  treatment. Ribavirin is recommended in children  who are at risk for cardiopulmonary complications.   • Human immunodeficiency virus (HIV) is discussed  on the next page.   Skin irritation and burning.  Crystalline nephropathy if drug is  infused rapidly. Nausea,  headache.   CNS level = 50% of serum  level. Decrease dose with  kidney dysfunction.    Nephrotoxicity - ay be reduced by  hydration and coadministration of  probenecid. Neutropenia.    Because drug does not  require phosphorylation, it  is active against thymidine  kinase-deficient strains.   Renal toxicity (frequent),  seizures, hypocalcemia, fever,  anemia, diarrhea, nausea, many  others.   IV. >80% excreted  unchanged in urine. CSF  penetration variable. Reduce  dose with renal dysfunction.    The greatest barrier to effective anti-HIV therapy is  the emergence of drug resistant strains. Human  immunodeficiency virus develops drug resistance by  mutating the enzymes that are targeted by antiviral  agents. Retroviral reverse transcriptase has low  transcription fidelity, so basepair substitutions are  common. These mutations translate into amino acid  substitutions which, if located in the drug-binding  pocket, may reduce the affinity of the enzyme for the  drug without diminishing the enzyme activity.   Because of drug resistance, monotherapy is seldom  used for treating ArDS patients. More often, when  therapy is initiated, multiple agents with different viral  targets are used. These multidrug "cocktails" are  analagous to combination chemotherapy used for  cancer patients.   There are currently three categories of anti-HIV  drugs: nucleoside analogs, non-nucleoside reverse  transcriptase inhibitors and protease inhibitors (Table  7.8B). Because AIDS patients are frequently on numer-    ous medications and may have renal or hepatic dys-  function, it is important to review potential drug  interactions and dose-adjustment information provided  with each agent. Note that the protease inhibitors and  Delavirdine fail to achieve therapeutic levels in cere-  brospinal fluid.   A current exception to the polytherapy approach is  the use of Zidovudine as a single agent to reduce  maternal-fetal transmission of HTV. To reduce the risk  of transmission, HIV-positive pregnant women take  Zidovudine prena tally then infants are treated for  approximately six weeks postnatally.   Immunocompromized patients are treated with  trimethoprim-sulfamethoxazole (TMP-SMZ) to reduce  the risk of Pneumocystis carinii (PCP) infection. TMP-  SMZ is preferred for prophylaxis and treatment of PCP  in adults as well, though alternative agents are avail-  able (Table 7.9). Agents used for prophylaxis and  treatment of other opportunistic infections are pre-  sented elsewhere in this chapter.   Zidovudine is used in the  prevention of maternal-fetal  transmission of HIV.   Protease inhibitor. Protease is an enzyme necessary for cleaving  the gag-pol precursor. Results in immature virus formation.   Oral dose form is drug of  choice for PCP prophylaxis in  immunosuppressed patients.  IV form is drug of choice for  PCP infection.   Must be given with  leucovorin to reduce  myelosuppresion and liver  toxicity.   Nebulized form used as  alternative PCP prophylaxis.  IV form is an alternative for  PCP treatment.   Mutations in reverse  transcriptase (e.g.,  conversion of methionine at  codon 184 to either  isoleucine or valine.)   Peripheral neuropathy,  pancreatitis, diarrhea, headache,  insomnia, vomiting, nausea, rash,  abdominal pain. Zdovudine-  myelosuppression.   PO. Metabolized in liver,  excreted in urine. Toxicity  may be enhanced by renal or  hepatic dysfunction.   Gl distress, headache, other  neurologic symptoms (e.g.,  weakness, anorexia,  parasthesias). Indinavir  associated with increased risk of  kidney stones.   Potentially serious drug  interactions due P450  enzyme competition. See  package insert.   PO. Well absorbed.  Nevirapine crosses  placenta and has better CNS  penetration than   Disrupts the plasma  membrane of fungal cells.  Amphotericin has greater  affinity for ergosterol  (component of fungal plasma  membrane) than for  cholesterol (mammalian).   DOC: Systemic fungal infections,  fungal meningitis, and fungal  urinary tract infections.   Poor therapeutic index (toxic at  therapeutic dose). Fever/chills,  nephrotoxicity (reduce risk by  hydrating patient), hypokalemia,  nausea, headache,  thrombophlebitis, anemia.   Impairs synthesis of  ergosterol, the principle sterol  of the fungal plasma  membrane.   DOC: Paracoccidioides  brasiliensis , thrush (pharyngeal  Candida ). Also for treatment of  chronic mucocutaneous  candidiasis, dermatophytes  (including griseofulvin-resistant).   Nausea, diarrhea, headaches,  rash, dizziness, fatal hepatic  necrosis, gynecomastia/breast  pain (due to inhibition of  testosterone synthesis).   Inhibits fungal cytochrome  P-450 enzymes. Damages  plasma membrane by inhibiting  sterol demethylation (an  essential step in the synthesis  of plasma membrane sterols).   Systemic histoplasmosis,  blastomycosis, coccidiomycosis  (including meningitis), or  sporotrichosis. Opportunistic  cryptococcosis, candidiasis.  Candidal thrush, vaginitis,  esophagitis.   Deaminated to 5-fluoro-uracil  by the fungus. Incorporated  into FtNA. Metabolized to  5-fluorodeoxvuridine (5-  FdURD) which inhibits  thymidilate synthetase.   Dermatophytes of hair, skin, and  nails. Up to six months treatment  may be required.   Inhibits squalene epoxidase,  the critical enzyme that  converts squalene to  ergosterol in fungi.    Slow IV for systemic  infections, intrathecal for  meningitis, bladder irrigation  for cystitis. Metabolism  poorly understood, no need  to reduce dose with renal  dysfunction.   Blood count, urinalysis, liver  enzymes, blood urea-nitrogen,  creatinine, & electrolytes should  be checked before and during  treatment. Liposome-encased  amphotericin (Abelcet,    PO. Acid pH (stomach)  required for dissolution.  Absorption decreased by  food, antacids, cimetidine.  Highly plasma protein  bound, lowCNS levels.   PO/IV. Requires acidic  environment for absorption.  Accumulates overtime,  long half-life, poor CSF and  urine penetration, hepatic  metabolism.   Contraindicated for pregnant  women. Drug binds to keratin of  growing tissues.   Fungi exist in a yeast form and a mold form.  The yeast form reproduces by budding or spore  formation and the mold form grows by extending  hyphae (branches). A history of travel is particu-  larly important when fungal infection is sus-  pected because most types of fungi are endemic  to specific regions.   Fungi are larger than bacteria and can usually  be visualized microscopically without stain,  particularly if nonfungal cells have been de-  stroyed by 10% potassium hydroxide (KOH  prep). Fungi are resistant to KOH because of  their unique, rigid cell wall. Because human cells  lack cell walls, antifungal therapy is directed  primarily at destroying the fungal cell wall.  Despite this apparent "selective" difference  between human and fungal cells, antifungal  agents are generally very toxic to human cells and  should be used with caution.   • Candida most often infects the mouth (thrush)  or the vagina, particularly in persons with  impaired cell-mediated immunity. Thrush is  generally treated with nystatin "swish and  swallow," or clotrimazole troches and vaginitis is  usually treated with miconazole. Systemic  Candida infections occur in immunosuppressed  patients and requires intravenous amphotericin B.   • Histoplasma capsulation, Blastomyces dcrmatitidis,  Coccidioides immitis and Aspergillus infections  generally present as pneumonia which may  progress to systemic fungosis. Amphotericin B  has traditionally been the drug of choice for such  systemic infections. Fluconazole and itraconazole  are newer drugs that rival amphotericin B with  regard to efficacy for some systemic fungal  infections. Amphotericin B requires intravenous  infusion, but fluconazole and itraconazole are  available in oral forms.   • Cryptococcus neoformans may also present as  pneumonia, but more commonly presents as  meningitis in immunosuppressed individuals.  Fluconazole and flucytosine are the only antifun-  gal agents that reach therapeutic concentrations in  the brain. Of the two, fluconazole is more effec-  tive against Cryptococcus.   Table 7.10 presents agents used to treat parasites. cates therapy. The drug of choice for the treatment of   Oral metronidazole is widely used for parasitic malaria depends on the pattern of drug resistance in   infections (e.g., Giardia). The intravenous preparation the region where the patient was infected. Individuals  is indicated for anaerobic bacterial infections. Lindane travelling to endemic regions are encouraged to take  is used for head lice. prophylactic antimalarial drugs.   Scabies (Sarcoptes scabiei);  body, head, and pubic louse  ( Pediculus capitis, P. corporis,  Phthirus pubis).   Topical administration may lead to  seizures, CNS disturbances, risk  of arrhythmias. Skin irritant.   Increases cell membrane  permeability causing loss of  intracellular calcium. Results  in paralysis of worms and  release from host tissues.   Dizziness, headache,  irreversible retinal damage,  impaired accommodation,  bullseye retina, hemolysis in  G6PD-deficient patients.   Chloroquine resistant P.  falciparum. Little effect on  sporozoites or pre-erythrocytic  stages.   Cinchonism, curare-like effects,  shock. MOST TOXIC antimalarial  (should only be used when other  antimalarials fail).   Well tolerated, benign sinus  bradycardia. Single dose cures  multidrug resistant P. falciparum  malaria.   Less resistance when used in  combination with sulfonamides  (Combination marketed as  Fansidar®).   Malaria prophylaxis. Erythrocytic  form of P. falciparum. Used in  combination with sulfonamides or  sulfones for acute attacks.  Combined with Sulfadiazine for  treating Toxoplasmosis.   Mechanism unclear. Likely to  involve crosslinking of  glutathione. Little resistance  to drug by P. vivax  (8-aminoquinoline).    Tumor cells are derived from normal cells in which  proliferation is poorly controlled. Because tumor cells  are similar to normal cells, it has been difficult to  develop anticancer agents which selectively kill tumor  cells without harming normal tissues.   Most anticancer agents act by inhibiting cell prolif-  eration. Generally this is achieved by either damaging  DNA or preventing DNA repair. Essentially, there are  four ways in which most anticancer drugs inhibit  proliferation:   • Linking alkyl groups to DNA bases. Inhibits repair of  DNA.   • Mimicking DNA bases, resulting in 1) incorporation  of drug into DNA or RNA, where it prevents repair    or terminates the chain or 2) negative feedback on  enzymes that synthesize or recycle purines.   • Intercalating between base pairs of DNA, disrupting  the triplicate codons or producing oxygen free  radicals which damage DNA.   Hormonal anticancer drugs antagonize receptors,  preventing endogenous growth-promoting hormones  from binding (Table 8.5). Other hormonal agents are  agonists at receptors that, when activated, inhibit  tumor growth.   In caring for patients on chemotherapy, it is  essential to evaluate the patient for dose-limiting side  effects (some, such as permanent cardiomyopathy  from Adriamycin, are initially asymptomatic), to know  how to treat neutropenic fever, and to effectively  manage nausea and vomiting.   Figure 8.1 The cell cycle. Cells pass through four stages of  growth during each mitotic cycle. Cells that contain a double  complement of DNA (G 2 cells) divide during mitosis (M phase).  Following a “gap" (G t phase) cells may either differentiate and  remain out of the cycle for a long period of time (G n period) or begin  the process of DNA synthesis (S phase). Another gap ( GJ follows.   Tumor cells are remarkably similar to noncancerous  human cells. Thus, there are relatively few drug  strategies for destroying tumor cells while sparing non-  neoplastic cells. Newer agents selectively target cancer  cells by using monoclonal antibody technology.  Neoplastic and normal cells differ primarily with  regard to the number of cells undergoing cell division,  and most anticancer drugs act by killing cells that are  dividing. The drugs accomplish this by interfering  with DNA, RNA, or protein synthesis or by inhibiting  the formation of microtubules in mitosis. Such agents  are called cell cycle-specific agents because they exert  their actions during distinct phases of the cell cycle  (Fig. 8.1). In general, agents that interfere with DNA  synthesis are S-phase specific; those that interfere with  microtubules disrupt mitosis and are called M-phase  specific.   DNA alkylating agents damage tumor cells regard-  less of whether the cell is actively dividing. Because of  this property, these agents are called "cell cycle-  nonspecific" drugs.   If a tumor cell is to be killed by an anticancer drug,   1) the drug must reach the tumor cell, 2) the tumor cell   must enter the phase of the cell cycle that is targeted by    the drug, and 3) the cell must not be resistant to the  drug.   Cancer cells become resistant to anticancer agents  through a variety of mechanisms including 1) reduced  uptake of drug into cell, 2) enhanced production of  enzymes that repair damaged DNA, 3) production of  chemically altered enzymes which are no longer  recognized by drugs that inhibit unaltered enzymes, 4)  reduced transformation of prodrugs (inactive precur-  sors) into cytotoxic agents and 5) enhanced transforma-  tion of toxic agents into inactive metabolites.   Some tumors become resistant to several classes of  antitumor agents, even if they have never been exposed  to some of these agents. This is called multidrug  resistance. Affected drugs include antibiotics, colch-  icine, the vinca alkaloids (vincristine & vinblastine) and  epidophyllotoxins (VP-16). Cross-resistance among  these agents is striking because they do not share a  common mechanism of action.   Multidrug resistance is due to increased expression  of an energy-dependent membrane glycoprotein  "pump” which lowers the intracellular concentration of  chemotherapeutic agents. The multidrug resistance  gene is likely one of multiple genes that are induced to  protect cells from toxic insults.   Erythropoietic and leukopoietic cells, cells lining the  gastrointestinal tract, and hair follicle cells are replaced  at a much greater rate than most other noncancerous  cells in the normal human. Because of the rapid growth  rate of these cells, they are susceptible to damage by  anticancer drugs. Bone marrow supression, mucositis,  and alopecia are predictable side effects of most anti-  cancer agents. In addition, many drugs cause toxicity  that is unrelated to cell growth rate (Fig. 8.3).   Chemotherapeutic regimens often consist of several  agents which have different mechanisms of action and  minimize overlapping toxic effects. This affords  multiple points of attack on the tumor cell while  sparing normal organs from the toxicity produced by  higher doses of a single drug. Most anticancer drugs  cause bone marrow suppression. Bone marrow-  sparing drugs (e.g., vincristine) are frequently included  in combination regimens, if the tumor is sensitive.   Alkylating agents were the first anticancer agents  developed. They are chemically related to mustard  gas which was used in World War I.   Alkylating agents are generally more effective  against slow-growing tumors than other classes of  antineoplastics because they are cell-cycle nonspecific.  Relatively few cells in slow-growing tumors are  mitotically during a given course of chemotherapy. In  contrast to most other agents, alkylator-induced    damage to cancer cells accumulates even during  quiescent portions of the cell cycle.   All alkylating agents are toxic to hematologic cells.  Thus, myelosuppression is a predictable side effect.  Alkylating agents may cause secondary tumors, even  years after therapy. Important side effects are shown  in Table 8.1 and Figure 8.3. Note which drugs are used  to treat CNS tumors, not because they are better  agents, but because they cross the blood brain barrier.  Similarly, drugs that penetrate the blood-testis barrier  are used to treat testicular cancer.   Decreased cellular uptake of drug  and increased repair of drug-  induced DNA damage.   Figure 8.4 DNA alkylation. Normally, DNA strands are  joined by hydrogen bonds and other weak forces which allow  separation during cell division. Bifunctional alkylating agents  (alkylating group on both ends) covalently bind double stranded  DNA together, preventing DNA transcription. Bifunctional  alkylation is more toxic than single strand alkylation because it is  less easily repaired.   PO/IV. This prodrug is  hydroxylated by the P450 system  to a cytotoxic agent.   Breast, testicular and other  solid tumors. Leukemia,  lymphoma, neuroblastoma,  Also for immunosuppression   IV. Concentrated in kidneys, liver  and intestines. Penetrates testis  barrier, partial CNS penetration.  Renal elimination.   Amifostine (Ethyol) can be  used to bind to toxic  cisplatin metabolites  hence decreasing   Anti metabolites are cell-cycle specific agents which  prevent synthesis of nucleotides or inhibit enzymes by  mimicking nucleotides.   Methotrexate inhibits dihydrofolate reductase, an  enzyme which reduces dihydrofolate (FH,) to  tetrahydrofolate (FH 4 ). Normally, the coenzyme FH 4  transfers a methyl group to dUMP, forming  thymidylate, and is oxidized to FH, in the process.  Methotrexate prevents recycling of this cofactor.  Because thymidylate is necessary for DNA synthesis,  methotrexate is toxic in the S-phase (synthesis).    Methotrexate toxicity to normal cells is reduced by  supplying an alternative cofactor, leucovorin, or by  bypassing the folate pathway by adding thymidine.  Thymidine is converted directly to thymidylate by  thymidine kinase. Administration of these agents after  methotrexate is called leucovorin or thymidine "res-  cue." Leucovorin and thymidine do not "rescue"  tumor cells from methotrexate because they do not  reach adequate concentration in tumor cells.   Other antimetabolites used to treat cancer are either  purine or pyrimidine analogs. In some cases, the  analogs are phosphorylated to nucleotides, then   S-phase. Also arrests  some cells in G1 phase,  preventing them from  entering S phase.   Blocks folate reduction by  inhibiting dihydrofolate  reductase. Dihydrofolate  reductase (DHFR) reduces  dihydrofolate to   tetrahydrofolate, the coenzyme  which is essential for the  production of thymidylate.   Decreased uptake, increased  production of dihydrofolate reductase  by gene amplification, altered forms of  dihydrofolate, which are not  recognized by methotrexate.   Metabolized to 6-  mercaptopurine ribose  phosphate (6MPRP), a false  negative feedback inhibitor.  Thioguanine: Metabolized to  Thio-GTP or Thio-dGTP which  incorporates into DNA.   Increased alkaline phosphatase  (degrades 6MPRP), decreased  sensitivity to feedback inhibition,  decreased HGPRTase (the  metabolizing enzyme).   Inhibits both DNA repair  (non phase-specific)  and DNA synthesis (S-  phase).   Metabolized intracellularly to  2-CdATP, which inhibits repair of  single strand DNA.   High levels of deoxynucleotide  deaminase (diverts 2-CdATP  precursers into nontoxic pathway).   Inhibits adenosine deaminase  causing increased dATP, which  blocks ribonucleotide reductase  (essential for DNA synthesis).    Metabolized to 2-fluoro-ara-  ATP, which inhibits DNA  polymerase, DNA primase and  ribonucleotide reductase.   Also metabolized to fluoro-  dUMP which inhibits thymidylate  synthetase. Roxuridineand  capecitabine are prodrugs to  fluorouracil.   Decreased phosphorylation of  prodrug to active form, i ncreased  intracellular catabolism (e.g. ,  increased phosphatase activity),  increased or altered target enzyme.   Metabolized to ara-CTP, which  is incorporated into DNA. Acts  as a chain terminator and  inhibits DNA polymerase.   Phosphorylation to dFdCDP and  dFdCTP which inhibit  ribonucleotide reductase. Also  DNA strand terminator.    incorporated into DNA or RNA where they inhibit  enzymes or result in faulty transcription or translation.  Nucleotide analogs also inhibit essential enzymes such  as thymidylate synthetase.   Figure 8.5 Antimetabolites such as thioguanine are  incorporated into DNA where they inhibit repair or replica-  tion enzymes. Thioguanine is phosphorylaled to thio-GTP which  mimics GTP. The exact mechanism by which thio-GTP inhibits  enzymes is unknown. The other purine and pyrimidine analogs  work by similar mechanisms.   PO/IV/intrathecal/intra-arterial.  Long retention in tissue, excreted  unchanged in urine. Monitor  serum levels.   Acute lymphocytic leukemia,  osteogenic sarcoma,  lymphoma, breast, head,  neck, small cell lung,  choriocarcinoma, psoriasis,  rheumatoid arthritis.   Leucovorin (formyl folate)  can be administered after  methotrexate to “rescue"  noncancerous cells.   Selective toxicity due to  paucity of  deoxynucleotide  deaminase in monocytes  and lymphocytes.   IV/PO/intra-arterial. Short half-  life, extensive metabolism.  Floxuridine is administered  intra-arterially to tumor bed.   Many solid tumors. Topically  for solar keratosis and  superficial carcinomas of the  skin. Floxuridine: Gl  adenocarcinoma.  Capecitabine: breast  carcinoma.   The antibiotics are drugs isolated from the fungal  species Streptomyce s. They are classified together based  solely on their origin. These agents have different  mechanisms of action, toxicities, pharmacokinetics and  clinical indications. Therefore, it is not useful to simply  learn a prototype drug for this class. The most com-  monly used antibiotics are Adriamycin, Actinomycin D,  mitomycin C and bleomycin.   Adriamycin (doxorubicin) is effective against a  broad range of tumors, both solid and hematologic. It  acts by intercalating between DNA bases, which  inhibits DNA and RNA synthesis. Adriamycin also    inhibits topoisomerase II, an enzyme responsible for  breaking and splicing DNA as supertwists are induced  or removed from the DNA coil. Inhibition of  topoisomerase results in DNA strand breaks.  Adriamycin cannot be used at maximally effective  doses for prolonged periods of time because it causes  irreversible cardiomyopathy. It is contraindicated in  patients with low cardiac ejection fractions. Toxicity  increases dramatically after a cumulative dose exceeds  a threshold level.   Dactinomycin is extensively used for pediatric  sarcomas. Dactinomycin intercalates between DNA  bases where it inhibits DN A-dependent RNA poly-   Intercalates between guanine  bases of DNA. Also decreases  RNA synthesis by blocking DNA-  dependent RNA synthesis.    Anthracycline. DNA intercalation,  decreases DNA and RNA  synthesis, single and double DNA  strand breaks via action on  topoisomerase II.   Not clear. In vitro, inhibits RNA  and DNA synthesis, causes DNA  strand breaks, inhibits  topoisomerase II.   Bithiazole rings intercalate into  DNA strand. Drug oxidizes Fe ++ ,  yielding free radicals which dam-  age DNA.    merase. Dactinomycin potentiates the toxicity of  radiation therapy when the two are administered  during the same time period.   Mitomycin C is an effective alkylating agent only  after it has been metabolized intracellularly. The  metabolite, a bifunctional alkylating agent, binds to  guanine residues which crosslinks DNA strands.   Bleomycin causes DNA strand breaks by producing  toxic free radicals. It is often used in combination  therapy for lymphomas, head and neck and testicular  cancer because it produces little bone marrow toxicity.  It does however cause dose-dependent pulmonary  fibrosis, oral ulcers, fever and chills.   Nausea, vomiting, diarrhea,  hypersensitivity, bone  marrow suppression,  ulcers, acne, increased  radiation reactions,  injection site necrosis.   Rapid IV. Half-life is short in  plasma and long in tissues.    Irreversible cardiomyopathy  which leads to congestive  heart failure, benign ECG  changes, leukopenia,  nausea, vomiting, injection  site necrosis. Radiation  Recall.   IV. Patients with impaired liver  function risk severe toxicity.  Reduce dose with liver  dysfunction Metabolized by  glycosidases.   Doxorubicin: Sarcomas,  multiple myeloma, malignant  lymphomas, acute leukemias  and testicular, ovarian,  breast, gastric, bladder, and  throat cancer.  Daunorubicin/   Monitor patients cardiac  ejection fraction to  assess toxicity.  Dexrazoxone  (Znecard) is a chelating  agent that interferes with  iron free radicals,  reducing anthracycline-  associated  cardiomyopathy.    Nausea, vomiting, diarrhea,  anorexia, mucositis,  nephrotoxicity, hypocal-  cemia, hypokalemia, hep-  atotoxicity, hemorrhagic  diathesis.   Adenocarcinoma of stomach,  colon, pancreas and breast:  squamous cell carcinoma of  head and neck.    Pulmonary fibrosis,  pneumonitis, little  immunosuppression or bone  marrow suppression.  Erythema, increased skin  pigmentation, ulceration,  fever, chills.   Renal excretion. Administer two  test doses to assess likelihood of  anaphylactic reaction (more  common in lymphoma patients).   Testicular cancer;  lymphomas; squamous cell  carcinoma of head. neck,  skin and genitalia. Also used  as sclerosing agent for  malignant pleural effusion.   The vinca alkaloids, vincristine, vinblastine, and  vinorelbine inhibit tumor growth by destroying  microtubules which are essential for cell structure and    mitosis. They differ in that vinblastine and vinorelbine  "blasts" bone marrow while vincristine spares marrow.  Vincristine however, causes peripheral neuropathy  which is manifested by decreased reflexes, foot drop,  weak fingers and decreased autonomic function.   Hydrolyzes L-asparagine to  aspartate. Lack of asparagine  kills tumor cells, which lack  asparagine synthetase. Normal  cells synthesize asparagine.   Alkylation of DNA seems most  important. Also inhibits purine  synthesis and interacts with  sulfhydryl groups in proteins.   Binds CD20 antigen on B  lymphocytes round in B-cell  lymphomas where it exerts its   Etoposide (VP-16) is a synthetic derivative of Mitotane is remarkably simply because it preferen-   epipodophyllotoxins. It appears to act by inhibiting tially accumulates in adrenocortical cells. Although  topoisomerase, causing DNA strand breaks. VP-16 is treatment is not curative, mitotane is used to decrease    Autonomic, peripheral and  motor neuropathy, injection  site necrosis. Vincristine  does not cause bone  marrow suppression.    Bone marrow suppression,  nausea, vomiting, neuro-  toxicity, CNS depression,  dermatitis, mucositis.   PO. Well absorbed, rapidly me-  tabolized to active drug by liver  microsomes.   Potentiates sedatives,  weak MAO inhibitor, acts  like disulfiram in patients  consuming alcohol.   Most anticancer hormones act as agonists that  inhibit tumor cell growth or as antagonists that com-  pete with endogenous growth promoting hormones.  Adrenocorticosteroids inhibit multiple cell processes  necessary for division. Leuprolide and Goserelin act at  the pituitary to reduce LH and FSH secretion. LH and  FSH promote growth of prostate cancer cells.  Estramustine relies on the estrogen moeity simply to  target the other half of the drug, which is an alkylating   Leukemias and lymphomas are derived from  immune cells, so it makes sense that agents which  regulate division of immune cells might also affect  tumor cell growth. Interferons are protein products  that were isolated from immune cells and are now  produced using recombinant DNA technology.  Interferons induce a number of gene products in cells  that are interferon receptor-positive. In addition, they  stimulate activity of certain immune cells, some of  which may act against tumor cells.   Estrogen receptor agonist which counteracts endogenous testosterone (testosterone enhances  tumor growth) in patients with prostate cancer.   Progesterone receptor agonist used to treat endometrial carcinoma, metastatic renal carcinoma and  breast cancer. Mechanism of action unclear.   Estrogen receptor antagonist. Prevents endogenous estrogens from stimulating tumor growth. Used  to treat estrogen receptor-positive breast cancer in postmenopausal women. Increased risk of  uterine cancer observed in women treated with tamoxifen.   Non-steroidal aromatase inhibitor selectively reduces circulating estradiol levels for the treatment of  advanced breast cancer (anastrazole and letrozole).   Testosterone receptor antagonist which augments late effects of leuprolide and inhibits transient  side effects caused by initial leuprolide-induced LH and FSH secretion.   Inhibit DNA and protein synthesis as well as mitosis. Used for acute lymphocytic leukemia, chronic  lymphocytic leukemia, acute myelogenous leukemia, multiple myeloma, breast cancer, lymphoma.   Analog of gonadotropin releasing hormone (GNRH). Desensitizes GNRH receptors in pituitary,  causing decreased release of gonadotropin. Results in decreased sex hormone release and is used  for advanced prostate cancer. Initially stimulates transient release of sex hormones (LH and FSH).   Estrogen agonist linked to alkylating agent. Drug uptake is enhanced in estrogen receptor-positive  cells, causing selective accumulation of alkylating agent in tumor cells. Used for prostate carcinoma.   Enhance activity of cytotoxic-T, natural killer cells and macrophages. Inhibit proliferation of tumor  cells. Used for hairy cell leukemia, AIDS-related Kaposi’s sarcoma. Other uses under investigation.   Complex actions on immune system. Enhances depressed immune functions, including antibody  production; T cell, macrophage, and monocyte activation. Used in conjunction with fluorouracil for  advanced colon cancer following resection.   Analog of retinoic acid (vitamin A) that induces maturation in acute promyelocytic leukemia cells and  neuroblastoma. Toxicity includes the retinoic acid-syndrome (fever, dyspnea, pulmonary infiltrates  and effusions, fluid retention), transient leukocytosis, pseudotumor cerebri.   A photosensitizing porphyrin that is toxic to cancer cells exposed to 630 nm light. Preferentially  retained in cancer cells after clearance from most normal tissues. Light exposure induces a  porphyrin excited state, which spin transfers to oxygen to form toxic oxygen free radicals. Indicated  for palliation of esophageal cancers that occlude the airway.    Drugs presented in this chapter modulate inflamma-  tion or other immune responses. Most of these agents  influence other cellular functions as well, and are  discussed in other chapters. The reason for the multi-  tude of actions is that these agents generally interfere  with processes that are vital to multiple biochemical  pathways.   A beautiful example of a drug with such pleiotropic  effects is aspirin. Aspirin reduces inflammation,  lowers the temperature of febrile patients, relieves  moderate pain and prevents blood clots. The biochemi-  cal mechanism of these actions is inhibition of the  enzyme, cyclooxygenase. Cyclooxygenase catalyzes  the synthesis of potent chemical messengers called  prostaglandins, which regulate inflammation, body  temperature, analgesia, platelet aggregation and  numerous other processes.   In producing inflammation, the role of prostaglan-  dins is to "call in" the immune system. Local tissue  infiltration by immune cells and the release of chemical  mediators by such cells cause the symptoms of inflam-  mation (heat, redness, tenderness). Thus, a second  mechanism for reducing inflammation involves inhibit-    ing immune functions. In the past, this was accom-  plished using nonspecific immunosuppressants such  as corticosteroids (presented in Chapter 10, page 10-8).  Recent advances in immunology fueled the develop-  ment of more selective agents, capable of inhibiting or  stimulating specific immune pathways. Such agents  permit exciting new therapeutic approaches to organ  transplantation, hyper- and hypo-immune diseases  and cancer.   A third mechanism for treating inflammation  involves antagonizing the effects of chemicals released  by immune cells. Histamine, released by mast cells  and basophils in response to antigens, causes bronchial  constriction and inflammation by binding to histamine  receptors on bronchial cells. Antihistamines are  antagonists which compete with histamine for these  receptors.   Like prostaglandins, histamine regulates numerous  processes, including acid and pepsin secretion in the  stomach, heart rate and vasodilation. Histamine  antagonists which prevent acid and pepsin secretion  are clinically used to treat peptic ulcer disease (Table  6 . 1 ).   Until a few years ago, there were two ways to  pharmacologically reduce inflammation. One ap-  proach was corticosteroids. The other was the chemi-  cally-diverse agents known as "non-steroidal anti-  inflammatory drugs" or NSAIDs (Tables 9.1, 9.2 and  9.3).   NSAIDs were used before their mechanism of action  was understood. Ample evidence indicates that  NSAIDs act by preventing prostaglandin synthesis.  They will likely be referred to as prostaglandin synthe-  sis inhibitors in the future.   Prostaglandins are a family of potent arachidonic  acid metabolites, which modulate some components of  inflammation, body temperature, pain transmission,  platelet aggregation and a host of other actions. They  are not stored by cells, but are synthesized and released  on demand. Prostaglandins are rapidly degraded, so  their half-life is in the range of seconds to minutes.   Aspirin and other NSAIDs inhibit cyclooxygenase, a  critical enzyme in prostaglandin synthesis. Because  this enzyme plays a role in the synthesis of all members  of the prostaglandin family, NSAIDs tend to inhibit all  prostaglandin functions (Tables 9.1 and 9.2).    Acetaminophen (e.g., Tylenol” ) parallels aspirin  with regard to its antipyretic (fever reducing) and  analgesic effects, yet it lacks anti-inflammatory and  antithrombotic actions. Because it produces less GI  irritation than aspirin, it was introduced as an aspirin  substitute. Soon, acetaminophen was used in place of  aspirin for fevers, analgesia and inflammation, even  though acetaminophen is a poor anti-inflammatory  drug. This illustrates the hazard of equating similar  drugs with one another rather than learning important  differences.   The use of aspirin-like drugs for arthritis illustrates  one problem assodated with selective drug distribu-  tion. Many drugs fail to penetrate into joint spaces.  High doses of aspirin or other non-steroidal anti-  inflammatory agents (NSAIDS) are required to achieve  therapeutic levels in the joint space. Of course toxicity  to tissues other than joints is more likely at high drug  concentrations. Gastrointestinal irritation and ulcer-  ation are likely to develop when high-dose NSAIDs are  employed unless anti-ulcer drugs are concurrently  administered to prevent gastroduodenal mucosa  damage.   Weak inhibitor of prosta-  glandin synthesis. Analgesic  & antipyretic effects equal  those of aspirin. Anti-inflam-  matory effects much weaker.   Mild to moderate pain and fever.  Preferred over aspirin in children  because it is less likely to cause  Reye s Syndrome.   Does not cause GI upset or  bleeding. Rash, occasionally with  fever. Overdose may cause  severe hepatic necrosis leading  to coma and death.   Inhibits cyclooxygenase, an  enzyme required for the  synthesis of prostaglandins  (prostaglandins mediate  inflammation, fever & pain).   Symptomatic relief of minor pain,  inflammation, fever, or  rheumatoid arthritis. Reduction of  stroke risk.   GI upset & bleeding, allergic reac-  tions. Increased risk of Reye's   Syndrome in children. Overdose,  called salicylism, involves  tinnitis, dizziness, headache,  fever, mental status changes,  hyperventilation, and respiratory  alkalosis which leads to metabolic  acidosis.   Less likely to cause Gl bleeding and tinnitis, but may cause acute interstitial nephritis.   Pro-drug is metabolized to 5-aminosalicylic acid. It is retained in the colon, making it  effective against ulcerative colitis. Also see sulfasalizine (Table 7.6).   Better tolerated than aspirin by most patients. Reduces diuretic effects of furosemide  and may reduce effectiveness of several antihypertensive agents.   More effective than aspirin, acetaminophen, codeine and oxycodone in relieving acute   epilepsy or Parkinson's disease. Most likely to be nephrotoxic. Also indicated to close  patent ductus arteriosus in newborns.   The only parenteral nonsteroidal anti-inflammatory for pain relief. Initial clinical trials   indicate that it is equal to narcotic analgesics for controlling postoperative pain.  IV/IM/PO dosing forms available for short-term pain management. No other indications.    PO/PR Readily absorbed, little  plasma protein binding,  metabolized by liver, excreted in  urine.   PO/PR. Readily absorbed in small  intestine, enters brain, highly  metabolized, excreted in urine.  Elimination is dose dependent.  Alkalinization of urine speeds  elimination.   Increased risk of bleeding  with anticoagulants,  decreased effects of  antigout agents, increased  risk of methotrexate toxicity.  Displacement of antidiabetic  agents from plasma proteins  induces hypoglycemia.   Joint inflammation and tissue damage characterize  arthritis. Antiarthritic agents include prostaglandin  inhibitors (Table 9.2), corticosteroids (Table 10.6), other  immunosuppressants (Table 9.3), and other antiar-  thritic agents (Table 9.3). The efficacy of antiarthritic  agents depends on the type of arthritis being treated  (Table 9.5).   The most important characteristics of antiarthritis  drugs are 1) ability to reduce inflammation, 2) ability to  reach therapeutic concentrations in joint capsules    without reaching toxic levels in serum. Drugs in Tables  9.2 and 9.2 are the primary antiarthritic agents.   Nonsteroidal anti-inflammatory agents are used most  frequently for arthritis. The major toxicity of these drugs,  when used at doses large enough to penetrate joint  capsules, is GI irritation and breakdown. Celecoxib  (Celebrex®) and rofecoxib (Vioxx*) are selective  cyclooxygenase-2 inhibitors. Because they do not inhibit  cyclooxygenase- 1 , there are fewer GI side effects at doses  that are effective for arthritis. Antacids, H2 blockers, or  prostaglandin analogs are prescribed to prevent or  reverse NSAID damage to GI mucosa (Table 6.1).   Nonsteroidal Anti-inflammatory Agents (NSAIDS) and Immunosuppressants — Tables 9.1, 9.2, 9.5  Methotrexate — Table 8.2    i accommodation, bullseye  retina, dizziness, headache,  hemolysis in G6PD deficient  patients.   Recent studies suggest that  gold salts are ineffective for  treating arthritis. They are still  prescribed, however.   Decreases uric acid levels by  inhibiting xanthine oxidase,  the enzyme which converts  hypoxanthine to xanthine and  xanthine to uric acid.   PO. Rapid complete  absorption, highly plasma  protein bound, primarily  excreted unchanged.   Sodium urate crystallizes in joints, inciting an  inflammatory reaction called tophaceous gout.  Aspirin-like drugs may relieve the symptoms of gout,  but therapy is more often directed at lowering uric acid  levels. Uric acid is a product of purine metabolism.  Strategies for reducing uric acid levels include inhibit-  ing xanthine oxidase, the enzyme responsible of uric  acid synthesis, and preventing uric acid reabsorption  from the urine. Antigout drugs are described in  Table 9.4.   Immunosuppressants help prevent rejection of  transplanted organs and bone marrow, prevent eryth-    roblastosis fetalis (destruction of fetal blood cells by  maternal antibody-mediated immunity) and may  reverse autoimmune diseases such as aplastic anemia  They work by a variety of mechanisms (Table 9.6).   4 - production of interleukin-ll by  activated T-helper cells, 2) i the  number of interleukin receptors on  cytotoxic-T cells, 3) allowing  proliferation of T-suppressor cells.   Agent of choice for  preventing and treating  transplanted organ  rejection. Graft versus  host disease in bone  marrow transplant.   Nephrotoxicity (presentation is  similarto kidney rejection!),  thromboembolism, neurotoxicity,  seizures, reversible  hepatotoxicity, hypertension.   Converted to 6-mercaptopurine ribose  phosphate which inhibits purine  synthesis. Because DNA & RNA  synthesis requires proteins, all  proliferating cells are inhibited (B-cells,  T-cells, nonimmune cells).   PRODRUG is converted by liver to an  alkylating agent which crosslinks DNA.  Proliferation of B-cells is inhibited more  than T-cells. May also attack  immunocompetent lymphocytes to  inhibit established immune respones.   Drug of choice for  Wegener's granuloma-  tosis. Also used for  severe rheumatoid  arthritis & autoimmune  blood disorders.   Alopecia, Gl distress,  hemorrhagic cystitis of the  bladder, bone marrow depression.   Horse IgG antibodies which selectively  suppress T-lymphocytes (cell-mediated  immunity) and humoral immunity.   Less often: arthralgia, chest or  back pain, dyspnea, vomiting,  nausea, headache, night sweats.   Human immune globulin which prevents  sensitization of Rho negative recipients  to Rho(D) positive blood. Theoretically  binds to Rho(D) antigens, masking  them from antigen-sensitive immune  cells.   In Rho(D) negative  mother carrying Rho(D)  positive fetus or  planning abortion. Goal:  prevent erythroblastosis  fetalis in future infants.   Flu-like illness, fever, headache,  sweating, weakness, pain at  injection site, leukopenia.   Copolymer of L-alanine, L-glutamate, L-  lysine and L-tyrosine modifies immune  system by unknown mechanism.   Corticosteroids (Tables 10.5 & 10.6), Nonsteroidal Anti-inflammatory Agents (Tables 9.1 & 9.2),   Basiliximab, Daclizumab, Muromonab-CD3, and Mycophenolate Mofetil are also used to prevent graft rejection in transplant settings.   Enhance activity of cytotoxic-T, natural  killer cells, and macrophages. Inhibit  proliferation of tumor cells and  suppress graft-versus-host disease.   Enhances production of T-cells and  gamma interferon. Activates natural  killer and lymphokine activated killer  cells.   Some immunosuppressants are not drugs, but are time, may be employed in the future for the treatment   instead antibodies that are produced by non-human of AIDS, other immunosuppressed states, cancer, and  animals and are directed at human immune cells. viral diseases. Interferons and interleukins are pep-   Immunostimulants, primarily investigational at this tides released by immune cells in the body (Table 9.6).    Oral most common, but  absorption is erratic. IV for  acute organ rejection.  Metabolized by liver. No  dose adjustment necessary  with renal dysfunction.   Synergistic nephrotoxicity with  amphotericin B, aminoglycosides  & trimethoprim. Drugs which  induce liver metabolizing  enzymes may shorten half-life of  cyclosporine.   Cyclosporine does not inhibit antibody-mediated (B-cell)  immunity. Therefore, transplant patients are not at  significant risk for microbial infections during cyclosporin  therapy. Other drugs (corticosteroids), however, may  supress the patient's antimicrobial defenses.   Similar efficacy to cyclosporin. Occasionally effective in  patients that have failed a cyclosporin trial. Vice versa.   PO/IV. Prodrug is  metabolized to  6-mercaptopurine (6MP).  6MP is converted to  6-thiouric acid by xanthine  oxidase. Renal excretion.   PO. Must be hydroxylated  by the P450 system to the  active form of the drug.    Encourage patients taking cyclophosphamide to drink  plenty of fluids and void often to prevent hemorrhagic  cystitis.   IV. Must have filter in IV  line to prevent insoluble  material from entering the  bloodstream.    Anaphylaxis occurs in < 1% of patients. An airway and  appropriate drugs should be at the bedside during the  course of therapy. Often administered with steroids to  reduce risk of anaphylaxis.    Contraindicated in Rho(D) positive patients or in Rho(D)  negative patients who have already developed anti-  Rho(D) antibodies.    Efficacy and safety have not been established beyond  two years. Patients develop antibodies against drug -  unclear whether efficacy is reduced in these patients.    Induces IgG levels. Renal immune deposits noted in  treated animals. Long term immune effects of this  synthetic antigen are unknown.   INVESTIGATIONAL. May suppress immune sytem in  some cases. Clinical efficacy for treatment of various  cancers is being determined.   Ragweed pollen, bee stings and other antigens elicit  immune responses ranging from mild wheezing to  potentially-fatal anaphylactic shock in sensitive indi-  viduals. Histamine, a chemical produced in many  human tissues, mediates many of these responses.   Mast cells and basophils release histamine in response  to a variety of antigens.   Following release, histamine binds to either HI or  H2 histamine receptors causing a variety of effects  (listed in Table 9.8). In addition to allergens, several  other substances cause histamine release, including  radiodiagnostic dyes, some antibiotics, kinins (chemi-  cals released by immune cells) and some venoms.  Several synthetic histamine agonists are available for  laboratory studies of histamine functions, but there are  virtually no clinical indications for histamine receptor  agonists.    Histamine antagonists, on the other hand, are  among the most widely used drugs. The term "antihis-  tamines" generally refers to drugs which block HI  histamine receptors. These agents prevent bronchial  smooth muscle contraction and inhibit histamine-  induced vasodilation and increased capillary perme-  ability. Therefore, HI antihistamines are particularly  useful for treating allergies.   H2 antagonists inhibit acid and pepsin secretion in  the gastrointestinal tract and are used to treat peptic  ulcer disease (Table 6.1).   Both HI and H2 histamine receptor antagonists act  by competing with histamine that has been released. A  second strategy for reducing histamine-induced  symptoms involves preventing histamine release from  mast cells and basophils. Inhibitors of histamine  release are available for prophylaxis against allergy and  asthma symptoms (Table 9.7).   Type 1 allergies (allergic rhinitis &  conjunctivitis, simple urticaria,  pruritis, angioedema). To induce  sleep.    Type 1 allergies. Hydroxyzine is  also used for treatment of anxiety  and pruritis. Meclizine is used for  motion sickness and vertigo.    H2 Receptor Antagonists - Described in detail in Table 6. 1   Stimulate phosphatidyl inositol and T Na +  and Ca ++ permeability of membranes.    Use cimetidine with caution Little plasma protein binding, little Cimetidine T levels of many drugs (e.g. , oral  in >50 year olds w/kidney or metabolism. anticoagulants, theophylline, caffeine, phenytoin,    Endocrine glands release endogenous chemicals,  called hormones, into the bloodstream to regulate the  function of target tissues. This chapter addresses  endocrine functions which are modified by clinically  useful drugs.   The pituitary gland regulates virtually every  endocrine gland and is often called the "master gland."  It is divided anatomically and functionally into an  anterior and a posterior lobe.   The hypothalamus secretes releasing and inhibitory  substances into the anterior pituitary vasculature,  thereby regulating anterior pituitary function. Pituitary  secretions are also controlled by feedback control via  circulating hormones. Endocrine systems influenced  by the anterior pituitary are:   • Sex Hormones: The pituitary glycoprotein  hormones, luteinizing hormone (LH) and follicle  stimulating hormone (FSH), control sex steroid  synthesis, spermatogenesis, follicular development  and menstruation. The hypothalamic peptide,  gonadotropin-releasing hormone (GnRH), stimulates  the release of both LH and FSH from the pituitary.  Circulating sex steroids inhibit the release of LH and  FSH; inhibin, a peptide synthesized in the gonads,  selectively inhibits FSH. Synthetic GnRH agonists  initially stimulate LH and FSH secretion, then  desensitize the pituitary, resulting in decreased LH  and FSH secretion. Nafarelin acetate (Synarel®)  leuprolide (Lupron®) and goserelin (Zoladex*) are  indicated for endometriosis. Histrelin acetate  (Supprelin®) nafarulin acetate (Synarel®) and  leuprolide (Lupron Depot) are indicated for preco-  cious puberty. Gonadorelin (Lutrepulse®) is indi-  cated for primary hypothalamic amenorrhea.   • Adrenal steroids: Corticotropin-releasing factor  (CRF), a hypothalamic releasing factor, stimulates    release of corticotropin (ACTH) from the pituitary  gland. ACTH stimulates the adrenal gland to  produce corticosteroid hormones (Tables 10.5 - 10.7).  Cleavage of the precursor pro-opiomelanocortin  (POMC) yields ACTH and another glycoprotein, [}-  lipoprotein (Fig. 3.5). P-lipoprotein further converts  to the endogenous opioid peptide endorphin.  Likewise, melanocyte stimulating hormone (MSH)  results from the cleavage of ACTH.   • Thyroid hormones: Thyroid stimulating hormone  (TSH), released by the pituitary gland, facilitates  synthesis and release of thyroxine (T 4 ) and triiodo-  thyronine (T.,). TSH is a glycoprotein composed of  two chains, designated a and p. The a chain of TSH  is identical to the a chain of FSH, LH and human  chorionic gonadotropin (hCG). TSH release is  stimulated by thyrotropin-releasing factor (TRH), a  hypothalamic peptide. Serum T3 and T4 are feed-  back inhibitors of TSH synthesis. They also act as  TRH antagonists in the pituitary.   • Growth Hormone: Pituitary growth hormone (GH)  is released by growing children in discrete pulses,  late in the sleep cycle. Hypothalamic growth  hormone-releasing factor (GRF) stimulates GH and  the hormone somatostatin (SR1F) inhibits it.  Somatostatin is released from the hypothalamus, the  gastrointestinal tract and the pancreas. It acts as a  neurotransmitter. Inadequate secretion of growth  hormone results in dwarfism. Recombinant human  growth hormone is available by prescription  (Somatrem®, Somatropin®). Synthetic GH contains  the 191 amino acid sequence of pituitary-derived  GH. Both endogenous and synthetic GH induce  skeletal and organ growth and promote anabolic  metabolism. Octreotide (Sandostatin®) is an analog  of somatostatin, which inhibits growth hormone. It  is used clinically to treat acromegaly.   • Prolactin: Prolactin is an anterior pituitary hormone  which induces milk secretion from the breasts of  lactating women. Nipple stimulation promotes    prolactin release and dopamine inhibits prolactin  release. Cabergoline (Dostinex®) is indicated for  hyperprolactinemia   The posterior pituitary stores and releases two  octapeptides, vasopressin and oxytocin, which are  synthesized in the supraoptic and paraventricular  nuclei of the hypothalamus. Both polypeptides are  carried to hypothalamic nerve endings in the posterior  pituitary by the transport protein, neurophysin.   • Vasopressin: Arginine vasopressin peptide (AVP,  antidiuretic hormone) promotes reabsorption of  water in the distal tubules and collecting ducts of the  kidney and vasoconstricts blood vessels. It is re-  leased from pituitary nerve terminals in response to  hypotension. Vasopressin deficiency results in  diabetes insipidus, a disorder which is remarkable  for polyuria (excessive urine production) and poly-  dipsia (excessive thirst). Vasopressin (Pitressin*),  lypressin (Diapid®) and desmopressin (DDAVP,  Stimate®) are synthetic analogs of arginine vasopres-  sin used for treatment of diabetes insipidus (intrana-  sal or intravenous). They act rapidly and their  antidiuretic actions persist for 8-20 hours.   Desmopressin is indicated for acute epistaxis  (intranasal) and G1 hemorrhage (intravenous). It is also  used to maintain hemostasis during surgical proce-  dures in patients with hemophilia A and Von  Willebrand's disease. The mechanism of platelet  function enhancement is unknown.    oxytocin, an octapeptide that differs from vasopressin  by two amino acids. Oxytocin induces contractions  in the gravid uterus and promotes milk ejaculation  from the post-partum breast. Uterine relaxants and  contractants are discussed in Table 10.3.   The pituitary does not control the endocrine pan-  creas or the parathyroid glands. The endocrine pan-  creas produces insulin, which regulates serum glucose  levels. Pancreatic hormones are discussed on pages  154-155.   Parathyroid hormone (PTH), vitamin D and calcito-  nin work in synchrony to regulate calcium homeostasis  (not presented in tables). PTH is an 84 amino acid  chain secreted by the parathyroid glands in response to  low serum calcium. PTH induces bone resorption,  which liberates calcium into the bloodstream. These  actions are dependent on adequate serum concentra-  tions of 1,25-dihydroxy cholecalciferol (a derivative of  vitamin D). Bone resorption is counterregulated by  calcitonin, which inhibits osteoclasts (the cells which  degrade bone).   PTH increases serum calcium levels by two other  mechanisms. PTH increases the synthesis of the active  form of vitamin D, 1,25-dihyroxy cholecalciferol, in the  kidney, which in turn stimulates production of calcium  binding protein. Calcium binding protein enhances  calcium phosphate absorption from the gut lumen.   PTH also inhibits renal calcium excretion, while  promoting phosphate excretion, causing a small  increase in serum calcium levels.    Figure 10.1 Mechanism of  Steroid hormone action. Steroid  hormones (S) penetrate plasma  membranes and bind to cytoplasmic  receptors (R). The steroid-receptor  complex enters the nucleus and binds  to DNA, stimulating transcription of  target genes.   Leydig cells in the testes produce testosterone  (smaller amounts produced in ovaries of females) in  response to LH stimulation. Testosterone is responsible  for male secondary sex characteristics and reproductive  capability.   Actions: Enhances development and maintenance of  male sex organs, sperm production, muscle mass, libido,  and other secondary sex characteristics.   Indications: Androgen deficiency (growth deficits,  impotence), delayed puberty in males, palliation of  breast cancer, postpartum breast pain and engorgement.   Undesirable Effects: Women - virilism (hirsutism),  menstrual irregularities. Men - prostatic hyperplasia or  cancer, gynecomastia (high dose or with liver disease).    pattern baldness, reduced sperm count (negative  feedback). Both sexes - hypercalcemia,  coagulopathies, sodium and water retention, hyper-  lipidemia, atherosclerosis, cholestatic hepatitis, liver  cancer.   Anabolic steroids are testosterone derivatives  which have relatively more anabolic (building) effects  than androgenic (masculinizing) effects.   Indications: Refractory anemia, wasting diseases  (cancer, osteoporosis, bums, severe infections),  corticosteroid induced catabolism (from long term  therapy).   Abuse: The muscle building capacity of anabolic  steroids has led to widespread abuse among athletes.  Side effects among these users are worse than among  patients with appropriate indications, because  athletes often use higher doses for prolonged periods  of time.   Finasteride (Proscaf®, Propecia®), inhibits conver-  sion of testosterone to 5a-dihydrotestosterone (DHT).  It is indicated for benign prostatic hypertrophy and is  being tested for prostatic cancer. At lower doses, it is  indicated for male pattern baldness.   IM. Short acting. Useful for palliative treatment of breast cancer because therapy can be  discontinued rapidly if hypercalcemia develops.   Short acting oral preparation is more convenient, but less effective than above  preparations. Used to treat hypogonadism which develops in adulthood.   Mechanism: Induce transcription of target genes via  intracellular receptors (Fig. 10.1).   Indications: Contraception, atrophic vaginitis,  osteoporosis, cardiovascular disease associated with  menopause, hemorrhagic menstrual bleeding, failure of  ovarian development, hirsutism, prostatic cancer.   Undesirable Effects: Nausea (worse in morning,  tolerance develops), breast tenderness and edema, and  gynecomastia. Increased risk of endometrial cancer.   Contraindications: Pregnancy (teratogenic),  estrogen dependent neoplasm, vaginal bleeding, liver  impairment, thromboembolic disorders.   Pharmacokinetics: Most estrogens are well ab-  sorbed orally. They tend to be rapidly degraded by the  liver during their first pass from the gastrointestinal  tract. Metabolites include glucuronide and sulfide  conjugates of estradiol, estrone, and estriol.   Mechanism: Induce synthesis of specific proteins  via intracellular receptors (Fig. 10.1).   Indications: Contraception, irregular or hemor-  rhagic menstrual bleeding, endometrial carcinoma,  hypoventilation.   Undesirable Effects: Masculinization with pro-  longed use, otherwise minimal toxicity. Undesirable  effects of oral contraceptives described on next page.   Most potent endogenous estrogen secreted by the ovary. Transdermal/IM/PO.  Reduces osteoporosis in postmenopausal women Oral form metabolized to estrone  (less active).   High potency, not degraded during first pass metabolism fhepatic enzymes fail to  recognize this chemically altered estrogen). Used in combination with progestins for  contraception.   Sulfate esters of estrogenic substances. Less potent than estradiol. Oral, IV, or  vaginal preparations are effective.   PO/IM. Used for secondary amenorrhea and hormone-induced abnormal uterine  bleeding. Intramuscular depot may have prolonged actions. Should be avoided in  women who have potential to become pregnant in the near future.   Palliative chemotherapy for breast or endometrial cancer. Also used as an appetite  stimulant.   Binds to estrogen receptor and induces expression of genes that maintain bone  density. Indicated for osteoporosis prevention. Is not an estrogen. Does not mime  estrogens in breast or uterus.   Pharmacokinetics: Metabolized by liver to glucu-  ronide or sulfate conjugates. Most of initial dose is  rapidly degraded by first pass metabolism, thus  progesterone fails to reach target tissues when adminis-  tered orally. Synthetic progestins, in contrast, are not  susceptible to first pass metabolism and can thus be  administered orally.   Estrogen/Progestin Combinations: Oral contracep-  tives which contain both estrogen and progestins are  the most commonly used form of birth control. They  are more effective in preventing pregnancy than any  other form of contraception and are more convenient  than many other forms. Nevertheless, the rate of  pregnancy in women using oral contraceptives is  higher than would be expected based on careful  clinical trials. The most common reason for this is  patient failure to take the pill at recommended dosing  intervals.   Dosing Regimen: Pills containing active steroids are  taken for 21 days of the 28 day cycle. Placebos or iron  pills are taken the remaining 7 days to maintain a  regimen of one pill per day. During the 7 days of non-  steroid pills, patients experience withdrawal bleeding.   Mechanism of Action: Suppresses ovulation by  feedback inhibition at the hypothalamus and pituitary.  Estrogen suppresses FSH and progestin suppresses LH.  In addition, the steroids directly cause cervical mucosal  thickening and render the endometrium "inhospitable"  for ovum implantation.   Dosing Regimen: MONOPHASIC preparations -  progestin dose is fixed through the cycle. BIPHASIC  and TRIPHASIC contraceptives were created with the  intention of more closely mimicking physiologic  concentrations of progestins and to decrease side  effects by lowering the overall dose of progestins.    BIPHASIC pills have low dose progestin for 10 days,  followed by 1 1 days at a higher dose. The concentra-  tion of progestin begins low in TRIPHASIC pills, then  increases each 7 days through the 21 day cycle. Estro-  gen concentration is fixed and unchanging in all three  formulations. TRIPHASIC pills most closely resemble  normal physiology and appear to be as effective as  monophasic and biphasic formulations.   Side effects: Improved formulation has dramati-  cally lowered the risk of side effects from birth control  pills. Most common side effects are nausea, vomiting,  breast tenderness, water retention, and weight gain.  Less frequent but more serious side effects include  increased risk for thromboembolic episodes, hepatic  adenomas, hemorrhagic stroke, myocardial infarction  and endometrial cancer. Smoking potentiates risk of  myocardial infarction 5-fold in women over 30.   Contraindications: History of thromboembolic  disorders, deep venous thrombosis, cerebral vascular  disease, myocardial infarction, liver cancer, estrogen-  dependent cancer, breast cancer, undiagnosed abnor-  mal genital bleeding, or suspected pregnancy.   Drug Interactions: Contraceptive effects are  decreased when taken with ANTIBIOTICS (ampicillin,  isoniazid, neomycin, pen V, rifampin, sulfonamides,  tetracycline) or CNS AGENTS (barbiturates, benzodi-  azepines, phenytoin). Contraceptives increase the  effects of corticosteroids and worsen side effects of  tricyclic antidepressants. Oral contraceptives decrease  the effectiveness of oral anticoagulants,  anticonvulsants, and oral hypoglycemic agents.   The mechanism is unclear but they probably act by  altering the endometrium to prevent ovum implanta-  tion. Minipills are taken every day (there is no 7 day  break in the cycle). Missed doses are treated as de-  scribed for combination products above, except  alternate forms of contraception are encouraged for  two weeks after omission of two doses. Lack of  estrogen may decrease side effects. Continued use  may lead to amenorrhea and endometrial atrophy.   Levonorgestrel implants are synthetic polymer  capsules embedded with levonorgestrel, a progestin.  The capsules are implanted subcutaneously in women  who chose this form of birth control. The capsules  continuously release progestin to maintain low,  contraceptive serum progestin levels. Failure rates are  similar to those of oral contraceptives. The most  frequent side effects are prolonged, absent, or irregular  menstual bleeding.   The posterior pituitary releases two hormones,  oxytocin and vasopressin. Oxytocin induces contrac-  tions in the gravid uterus and is therefore used when  labor acceleration is desired. Because it is chemically  similar to vasopressin, oxytocin has antidiuretic effects  and can cause fluid retention. Oxytocin, other uterine  contractants, and uterine relaxants are listed in Table  10.3.   Obstetricians administer methyl-ergonovine after  delivery to reduce uterine hemorrhage. This drug  causes vasoconstriction, but more importantly causes  tonic uterine contraction. The force of the muscle  contraction impedes blood flow through the uterus  which significantly reduces bleeding. The other uterine    contractants listed in Table 10.3 are used primarily for  inducing abortion. Uterine relaxants known as  tocolytic agents are p2 adrenergic agonists which  reduce contractions in patients with premature onset of  labor (Table 10.3).   Three pharmacologic strategies for treating infertil-  ity are presented in Table 10.4. Gonadorelin is syn-  thetic GnRH which stimulates FSH and LH production  when administered in pulses. Clomiphene is an anti-  estrogen which causes FSH and LH release by reducing  feedback inhibition by estrogen on the pituitary gland.  Menotropins are FSH and LH purified from the urine  of postmenopausal women. All have greater than 50%  success rate in achieving ovulation and all carry the  risk of inducing multiple pregnancies.   T force and frequency of  uterine contractions. Most  pronounced in near-term  uterus.   Contraction of myoepithelium  surrounding alveoli of mammary  gland. Antidiuretic (vasopressin)  effects.   Drug of choice to induce or  accelerate labor, to decrease  postpartum uterine bleeding.   Blocks adrenergic receptors,  causes vasoconstriction,  interacts with other receptors  (dopamine and tryptamine). 4  lactation by 4 prolactin levels.   To 4 uterine bleeding after  abortion or parturition. NOT for  induction of labor.   [is adrenergic receptor  preferring agonist, 4 uterine  smooth muscle contraction in  near-term pregnant women.   T glycogenolysis, tachycardia,  gluconeogenesis, gut relaxation,  and vasodilation. I respiration of  mast cells and neutrophils.   Gonadrenalin is synthetic human gonadotropin-releasing hormone (GnRH). Gonadorelin is administered  intravenously in pulses spaced 90 minutes apart. Like endogenous GnRH, the pulses of gonadrenalin  stimulate FSH and LH release and result in ovulation in about 90% of women who have been treated. The  rate of multiple pregnancies wasl 2% in a small series. When administered continuously, rather than in  pulses, GnRH analogs (Lupron 1 "’) suppress FSH and LH production by acting as feedback inhibitors.  Administered in this fashion, GnRH analogs are approved for the treatment of prostate cancer and  endometriosis.   Clomiphene stimulates LH and FSH release by reducing negative-feedback by estrogen on the pituitary.  Increased LH and FSH levels induces ovulation and maintains functional corpus lutea. The rate of multiple  pregnancies is 8%. Abnormal ovarian enlargement occurs in 1 4% of patients and may cause pain.   Menotropins are LH and FSH (purified from urine of postmenopausal women) which are administered  intramuscularly for 9-12 days and followed by an injection of chorionic gonadotropin. Multiple births occur  in 20% of menotropin-induced pregnancies. Ovarian hyperstimulation, hemoperitoneum, febrile reactions  and arterial thromboembolism are the most frequent undesirable effects.   Potential for uterine tetany or  rupture, trauma to infant, post-  delivery uterine atony. Prolonged  infusion (>24h) may cause water  intoxication (antidiuretic activity).   Potentiates hypertensive  effects of other drugs. May  cause stroke/hemorrhage,  fetal distress.   Synthetic oxytocin mimics  the effects of endogenous  oxytocin which is released  from the hypothalamus.    Hypertension. May cause death  of infant if given prior to delivery.  Potentially fatal poisoning may  occur at normal doses in patients  sensitive to ergot alkaloids.   Incomplete abortion. Nausea,  vomiting, fever. Uterine rupture,  perforation, inflammation,  cramps, CNS, cardiovascular and  respiratory complications.   20% saline solution is  preferred for abortion.  Consider alternatives for  women with previous C-  sections.   Hypotension, tachycardia (reflex  and pi stimulated), arrhythmia,  pulmonary edema. Bradycardia,  w/ abrupt withdrawal. Nausea,  headache, muscle tremor.    1 M/I V. If IM, onset = 1 hr,  duration = 3.5 hrs. If IV,  onset = seconds, duration =  30 min.   > 8 mEq/L may cause depression  of CNS. heart and reflexes.  Rushing, sweating, hypotension  and flaccid paralysis may occur.   Excess Ca ++ antagonizes  Mg ++ and is used to  counteract CNS and PNS  depression.   Cortisol is a glucocorticoid released by the adrenal  gland which helps maintain homeostasis by regulating  numerous enzymes throughout the body. During  periods of stress, cortisol plays an important role in  increasing blood glucose levels and elevating blood  pressure. Clinically, cortisol and its derivatives are  often used for their immunosuppressive properties.  They are also important for patients with adrenal  deficiencies.   Synthesis: The limbic system ultimately controls  cortisone production by regulating release of corti-  cotropin releasing hormone (CRH) from the hypothala-  mus via serotoninergic, dopaminergic and cholinergic  neurons. CRH stimulates release of adrenocorticotro-  phic hormone (ACTH) from the anterior pituitary.  ACTH activates adenylate cyclase in the adrenal cortex.  The resulting cAMP activates protein kinase which  enhances cholesterol esterase activity. Cholesterol  esterase increases the amount of cholesterol available to  mitochondria, where cortisone is made from choles-  terol. ACTH also stimulates the conversion of choles-  terol to pregnenolone, the first step in steroid synthesis.   Transport to tissues: Cortisol is secreted into the  blood stream where it is 90% bound to cortisol-binding  globulin (CBG) and albumin. Active cortisol (remain-  ing 10%) freely diffuses into cells where it exerts its  actions via intracellular receptors. CBG plays an  important role in regulating cortisol delivery and  clearance. Dexamethasone has low affinity for CBG. It    is therefore more potent pharmacologically because a  greater fraction is free in the bloodstream.   Metabolism: In the liver, cortisol is converted to  dihydro- and tetrahydro- derivatives which are subse-  quently conjugated with glucuronic add of sulfates.  The conjugates are water soluble and are rapidly  excreted by the kidneys. Liver failure leads to de-  creased metabolism and decreased CBG synthesis.  Thus greater amounts of unbound (active) cortisol is  present in the blood. This leads to hypercortism.  Likewise, renal failure increases the half-life of cortisol.   Clinical Indications: Replacement therapy in  adrenocortical insufficiency, salt-losing forms of  congenital adrenal hyperplasia, autoimmune diseases,  arthritis (Table 10.5), asthma (Table 5.1), dermatitis,  cancer (Table 8.5) and sarcoidosis.   Undesirable Effects: Adrenal suppression (insuffi-  ciency upon withdrawal), Cushing's Syndrome (os-  teoporosis, skin atrophy, central fat distribution,  abnormal glucose tolerance, behavioral abnormalities),  suppression of somatic growth, osteopenia and bone  fractures.   (Generally: anabolic in liver (gluconeogenesis) and catabolic in muscle, skin, lymph, adipose, and connective tissue)   Cushing's Syndrome: State of excess glucocorti-  coids caused by 1) overmedication with drugs listed  above, 2) adrenal hypersecretion due to tumor, or 3)  excessive ACTH release (pituitary adenoma or meta-  static tumors). Results in osteoporosis, skin atrophy,  abnormal fat distribution, abnormal glucose tolerance,  behavioral abnormalities, euphoria. Primary Hyperal-  dosteronism: Caused by adrenal adenoma which  secretes aldosterone. Results in hypertension, hy-  pokalemia, metabolic alkalosis, suppressed renin.  Aminoglutethimide (Cytadren 1 ) reduces synthesis of  adrenal hormones by blocking conversion of choles-  terol to A 5 -pregnenalone.   The proceeding information focused primarily on  glucocorticoids. Two other important classes of  steroids, mineralocorticoids and androgens, are also  produced by the adrenal glands.   Aldosterone is the primary mineralocorticoid. It  retains sodium (and subsequently water) in the blood.  It is stimulated in the renin-angiotensin pathway.   Dehydroepiandrosterone and androstenedione are  the principal androgens. They have little masculiniz-  ing effects in men, but are metabolized to testosterone  in women, resulting in development of pubic hair and  libido.   PO/IV/IM/Top. Chemically identical to cortisol produced by adrenal glands. Preferred drug for  replacement therapy. Has weak mineralocorticoid effects. Short acting.   POT Intermediate duration ofactTon.Compared to hydrocortisone, glucocorticoid effects are four  times more potent and mineralocorticoid effects are half as potent. Drug of choice for  maintainance therapy of severe asthma. Important agent in leukemia therapy.   PO/IV/IM. Intermediate duration of action. Compared to hydrocortisone, glucocorticoid effects  are five times more potent and mineralocorticoid effects are half as potent. Drug of choice for  treatment of acute asthmatic attacks (administered intravenously for this indication).   PO/IV/Top/Inh. Intermediate duration of action. Compared to hydrocortisone, glucocorticoid  effects are thirty times more potent. No mineralocorticoid effects.   PO/IV/IM/lnh In addition to uses listed in text, it is used to reduce elevated intracranial pressure.  Few mineralocorticoid effects. Dexamethasone suppresion test examines whether the  hypothalamus/pituitary can be suppressed by glucocorticoids. If the plasma cortisol level is < 5  pg/dl eight hours after receiving Igmof dexamethasone, Cushing's syndrome is ruled out.   Blocks conversion of cholesterol to  A 5 -pregnenolone (the first step in  steroid synthesis).   Uses: Cushing's disease: adjunct to irradiation in  preparing patients for adrenalectomy; treatment of  adrenal, breast, and ACTH-producing tumors.   Serotonin and cholinergic antagonist  which may inhibit secretion of ACTH  from pituitary microadenoma cells.   The thyroid gland synthesizes and releases T 3  (3^3 -triiodothyronine) and T 4 (thyroxine) which  regulate protein synthesis, regulate membrane-bound  enzymes and stimulate mitochondrial oxidation. T,  and T 4 also regulate fetal and infant brain development  and childhood growth. T, is more potent than T 4 .   Tj and T 4 synthesis: The thyroid follicular cell traps  inorganic iodide and oxidizes it to iodine. Iodine binds  to tyrosine residues of thyroglobulin to form  monoiodotyrosine (MIT) and diiodotyrosine (DIT).  Then, either two DIT molecules couple to form T 4 or  MIT couples with DIT, forming T, (Fig. 10.2). T 4 pro-  duction exceeds T, production in the thyroid gland and  T 4 is converted to T, in the periphery.   T 3 and T 4 release and transport: Thyroglobulin is  proteolyzed from T 3 and T 4 and the hormones are    released into the circulation. Only 20% of circulating T.  is secreted by the thyroid. The remainder is derived  from degradation of T,. Thyroxine-binding globulin  (TBG) and prealbumin carry most T 3 and T 4 molecules  in the blood, protecting the hormones from degrada-  tion. Only free (unbound) T 3 and T 4 are physiologically  active. Feedback mechanisms at the hypothalamus,  pituitary gland and thyroid gland inhibit or stimulate  Tj and T 4 production when free thyroid hormone levels  are too high or too low, respectively.   Clinical Features: Nervousness, weakness, heat  intolerance, sweating, weight loss, warm thin skin,  exophthalmos, loose stool. Known as Grave's disease  when goiter and ocular signs are present.   Inhibits transformation of  inorganic iodine to organic  iodine. Thyroxine can't be  formed without organic iodine.  Also inhibits iodotyrosine  coupling. No clinical effects  observed for several days.   Control hyperthyroidism until  surgery or 131 1 therapy. Long  term drug treatment to avoid  surgery or 131 1 therapy. About  half of patients will remain  euthyroid if drug is withdrawn  after prolonged use.   Temporary hypothyroidism (treat  with thyroxine), agranulocytosis,  rash, hyperplastic thyroid. Not  given to women who are likely to  become pregnant within 3 years.   “ " Also, blocks conversion of  T4 to T3 in peripheral tissues.   Inhibits release of thyroxine  from thyroid gland. Effects  are faster (1-3 days) but  weaker than methimazole or  PTU. Useful for two weeks,  then gland adapts and  resumes thyroxine secretion.   Adjunctive therapy used in  conjunction with drugs listed  above. Provides more rapid relief  in severely ill patients. Used to  devascularize thyroid gland prior  to thyroidectomy.   Emergent preparation of  hyperthyroid patients for surgery.  Thyrotoxicosis in pregnancy.  Thyroid storm.   Replaces normal serum levels  of T4 and T3 (T4 is converted  into T3 by deiodination in the  periphery).   When conversion of T4 to T3 is  abnormally low (myxedema  coma), liotrix may be more useful  than levothyroxine.   Etiology: Thyroid-stimulating antibodies bind to  TSH receptors, causing release of thyroxin (current  theory).   Lab Findings: Increased serum T, and T 3 levels and  increased radioiodide uptake.   Therapeutic Strategy: Control hyperthyroidism  with drugs (propylthiouracil or methimazole) for one  year, then, partial resection of thyroid gland.   Thyroid Storm: Observed in hyperthyroid  patients at the time of thyroidectomy (surgical trauma  causes instantaneous release of thyroid hormones) or  in hyperthyroid patients in sepsis. Signs include high  fever, irritability, delerium, tachycardia, vomiting,  diarrhea and hypotension. Coma may develop.  Treatment includes IV glucose and saline, vitamin B,  glucocorticoids.   PO. Excreted in urine.  Adjust dose in patients with  renal insufficiency.   Therapy requires good  patient compliance and  careful monitoring by health  professionals.   PO/IV. 100% absorbed, Because of short half-life,  rapid onset of action, serum levels pulsate   Clinical Features: Fatigue, weakness, cold intoler-  ance, hoarseness, constipation, cold dough-like skin,  thick tongue, bradycardia, excessive menstrual bleed-  ing, anemia. Cretinism in childhood.   Etiology: 1) Primary hypothyroidism - surgery,  radioiodine ablation, thyroiditis. 2) Secondary hy-  pothyroidism - hypofunction of pituitary or hypothala-  mus.   Lab Findings: Hypothyroid patients have low  concentrations of T 4 in their serum. The uptake of  radioactive iodide is low because thyroid stores of  iodine are not being used to produce thyroid hor-  mones. The pituitary hormone, thyroid-stimulating  hormone (TSH), is high in primary hypothyroidism  and low in secondary hypothyroidism.   Therapeutic Strategy: Replacement therapy with  purified or synthetic thyroid hormones (Table 10.8).   Myxedema Coma: Chronic, severe hypothyroidism  results in respiratory depression, hypothermia and  stupor. It is frequently fatal.    Figure 10.2 Synthesis of T r Schematic drawing of T,  synthesis as described in the text on the previous page. T, is formed  by the coupling of one diiodinated and one monoiodinaled tyrosine  on thyroglobulin. T synthesis follows the same pathways shown in  the figure except that two diiodinated tyrosine molecules couple to  form T . Abbreviations: D1T - diiodinated tyrosine, MIT -  monoiodinaled tyrosine, T3 - 3,5,3' -triiodothyronine, TBG -  thyroxin-binding globulin.   Insulin is produced by pancreatic islet beta  ceils and is released in response to elevated  serum glucose concentrations. The principle  actions of insulin are presented in Table 10.9.  Each of these actions reduces the plasma glucose  concentration.   Type 1) is due to an absolute deficiency of insulin  which usually develops by age 15 and results in weight  loss, hyperglycemia, ketoacidosis, atherosclerosis,  retinal damage and kidney failure. Because the pancre-    atic islet beta cells (which produce insulin) are dam-  aged or destroyed, oral hypoglycemics cannot induce  insulin release. Thus, patients require insulin injec-  tions.   Noninsulin-dependent diabetes mellitus  (NIDDM: Type II) is due to decreased release of  insulin or decreased response of tissue to insulin (e.g.,  decreased number of insulin receptors) resulting in  hyperglycemia but not ketoacidosis. Treatment focuses  on diet and exercise, oral hypoglycemic drugs if diet  fails, and insulin when all else fails.   Patients with insulin-dependent diabetes receive  subcutaneous insulin injections daily. The goal of  insulin therapy is to provide adequate glucose control  through each 24 hour period while minimizing the  number of injections required to achieve that control.  Repeated injections at the same site may result in  atrophy or hyperplasia at the injection site. Insulin  preparations of short, intermediate and long duration  are available (Table 10.10).   Human insulin (humulin) is prepared by recombi-  nant DNA technology or is synthesized from porcine  insulin (enzymatic replacement of the terminal arginine  with threonine). Human insulin is preferred to insulin  prepared from animals because it is less antigenic.  Porcine insulin differs from human insulin by one  amino acid (terminal arginine). Bovine insulin is the  most immunogenic preparation. A typical dosing   Humulin L, Lente Insulin, Lente lletin 1 and II,  Novolin L.    regimen consists of regular humulin with either lente  or NPH two to three times per day before meals.   Insulin Toxicity: The most common undesirable  effects of insulin administration are hypoglycemia and  hypokalemia. Hypoglycemia is manifested by weak-  ness, hunger, sweating, dizziness, tachycardia, anxiety,  tremor, headaches, mental disturbances and visual  disturbances. Many of these symptoms are caused by  hypoglycemic release of epinephrine (epinephrine  causes glycogenolysis, gluconeogenesis and lipolysis  and inhibits insulin release). Remaining symptoms are  due to the brain being starved of its energy supply.   Hypokalemia develops because insulin drives  potassium from serum into cells. It is most often  encountered in patients with ketoacidosis when insulin  therapy is instituted. Severe hypokalemia causes  cardiac arrhythmias and neuromuscular disturbances.  Repeated injections at the same site may result in  atrophy or hyperplasia at the injection site.   Insulin-Drug Interactions: Many drugs alter blood  glucose levels. Increased glucose renders diabetes  control difficult, even with insulin. Decreased blood  glucose levels may precipitate hypoglycemic episodes.    • Agents which increase blood glucose levels include  antipsychotic drugs, diazoxide, adrenergic antago-  nists (also decrease insulin release) and thyroid  supplements.   • Agents which decrease blood glucose levels include  alcohol, weight-reducing agents and catecholamine-  depleting agents.   Patients with noninsulin-dependent diabetes  mellitus (Type 2) who fail dietary control require oral  hypoglycemic agents. The sulfonylureas described in  Table 10.11 stimulate insulin secretion by pancreatic  beta cells and increase the sensitivity of tissues to the  actions of insulin. Like insulin, the most frequent  complication is hypoglycemia. Newer generations of  oral hypoglycemics reduce post-prandial sugar levels  or increase the sensitivity of target tissues to insulin.  Nonsulfonylureas are less likely to cause hypoglyce-  mia. Because diabetes damages kidneys and levers,  dose adjustments may be necessary. Patients with  NTDDM who fail dietary control and oral hypoglyce-  mic agents progress to insulin-dependency.   To lb ut a mTde TOnnase)  Tolazamide (Tolinase)  Acetohexamide (Dymelor)  Chlorpropamide  (Diabinese)   ”” Stimulates Insulin secretion by pancreatic beta cells and increaseslhe sensitivityof  tissues to the actions of insulin. May cause hypoglycemia. Patients who develop  hypoglycemia while taking Chlorpropamide must be monitored carefully for 3-5 days  because of its long half-life (60-90 hours). Clinical trials revealed unexpected increased  risk of cardiotoxicity when Tolbutamide was used for more than five years.   The “second generation" agents, glipizide and glyburide, are more potent than  sulfonylureas. Therefore the required dose is lower. However, these agents are no  better than the others with regard to glucose control.   Reduces intestinal uptake and hepatic production of glucose. Increases sensitivity of  tissues to insulin. Generally does not cause hypoglycemia. May act synergistically with  sulfonylureas. Rarely causes lactic acidosis, which is potentially fatal. More commonly  causes gastrointestinal side effects.   Alpha glucoside inhibitor slows carbohydrate digestion resulting in lower serum glucose  levels after meals. May be used with sulfonylureas. Hypoglycemia unlikely when used as a  single agent. Flatulance, diarrhea and abdominal pain are the most frequent side effects.   Enhances response of target cells (e.g., liver, muscle) to endogenous insulin, perhaps by  activating nuclear receptors that increase transcription of glucose control genes. Because  these require endogenous insulin, they should not be used for Type 1 diabetes or diabetic  ketoacidosis. Monitor liver function tests (LFTs). Discontinue drug if LFTs are greater than  3-times normal.   Blocks potassium channels in pancreatic beta cells, causing depolarization, calcium influx,  and ultimately insulin secretion. Thus reduces glucose levels through mechanism that  requires intact beta cells. Used alone or with metformin for type 2 diabetes that is diet  refractory. 
PharmacologyByLipincott CLINICAL PHARMACOLOGY MADE RIDICULOUSLY SIMPLE_djvu.txt