The same mechanisms by which drugs and toxins act on particular steps in the formation, storage, release, uptake, catabolism, and resynthesis of neurotransmitters such as dopamine, serotonin, norepinephrine, acetylcholine, and other catecholamines cannot be separated from their toxic effects. Johnston and Gross have summarized views of how these transmitters and modulating agents, by attaching to receptors at neuronal synapses, are able to increase or decrease the permeability of ion channels and stimulate or inhibit second cytoplasmic messengers (cyclic adenosine monophosphate [cAMP] and G-proteins). For example, drugs such as l-dopa, tryptophan, and choline enhance the synthesis of dopamine, serotonin, and acetylcholine, respectively, and may impart toxic effects through these same mechanisms. Baclofen modulates the release of gamma-aminobutyric acid (GABA), the main inhibitory transmitter in the central nervous system. Botulinum toxin prevents the release of acetylcholine in the neuromuscular junction and tetanus toxin does the same on GABA in Renshaw cells of the spinal cord. Benzodiazepines, bromocriptine, and methylphenidate are viewed as receptor agonists; the phenothiazines and anticholinergics act as receptor antagonists. Certain drugs enhance the activity of neurotransmitters by inhibiting their reuptake as, for example, the class of antidepressant drugs that has a relatively selective influence on the reuptake of serotonin. Others deplete existing neurotransmitters, and another class of drugs promotes the release of preformed synaptic transmitters; amphetamines and modafinil are examples in this class. Amantadine, an antiviral agent, may promote the release of dopamine. One must not assume that these are the exclusive modes of action of each of these drugs; for example, cocaine acts as a direct stimulant and through the inhibition of reuptake of catecholamines.
A majority of drugs that act on the nervous system are ingested; factors that govern their intestinal absorption must therefore be taken into account. Small molecules usually enter the plasma by diffusion, larger ones by pinocytosis. The substances with which the drugs are mixed; the presence of food, other drugs, or intestinal diseases; and the age of the patient all influence the rate of absorption and blood concentrations. Different calculations are necessary for intramuscular, subcutaneous, and intrathecal routes of administration. To some extent, the solubilities of drugs (in lipid or water) determine the routes by which they can be given; some drugs, such as morphine, can be administered by numerous routes. Carried in the blood, the drug (or toxin) reaches many tissues, including the nervous system; protein binding in the plasma has an important influence on distribution. Many drugs and toxic substances bind to serum albumin and other serum proteins, limiting the availability of the ionized form. The common drug and toxin transformations involve hydroxylation, deamination, oxidation, and dealkylation, which enhance their solubility and elimination mainly by the kidneys. Most of these catalytic processes occur in liver cells and utilize multiple enzymes.
To enter the extracellular compartment of the nervous system, a drug or toxic agent must transgress the tight capillary–endothelial barrier (blood–brain barrier) and the barrier between the blood and cerebrospinal fluid (blood–CSF barrier). Intrathecal injection circumvents these barriers, but then the agent tends to concentrate in the immediate subpial and subependymal regions. The process of movement from plasma to brain is by diffusion through capillaries or by facilitated transport. The solubility characteristics of the drug determine its rate of diffusion.