Thomas F. Murray
Creighton University, Omaha, NE, USA
Pharmacology is the science of drug action, and a drug is defined as any agent (chemical, hormone, peptide, antibody, etc.) that, because of its chemical properties, alters the structure and/or function of a biological system. Psychopharmacology is a sub‐discipline of pharmacology focused on the study of the use of drugs (medications) in treating mental disorders. Most drugs used in animals are relatively selective. However, selectivity of drugs is not absolute inasmuch as they may be highly selective but never completely specific. Thus, most drugs exert a multiplicity of effects.
Drug action is typically defined as the initial change in a biological system that results from interaction with a drug molecule. This change occurs at the molecular level through drug interaction with molecular target in the biologic system (e.g. tissue, organ). The molecular target for a drug typically is a macromolecular component of a cell (e.g. protein, DNA). These cellular macromolecules that serve as drug targets are often described as drug receptors, and drug binding to these receptors mediates the initial cellular response. Drug binding to receptors either enhances or inhibits a biological process or signaling system. Of relevance to the field of psychopharmacology, the largest group of receptors are proteins. These include receptors for endogenous hormones, growth factors, and neurotransmitters; metabolic enzymes or signaling pathways; transporters and pumps; and structural proteins. Usually the drug effect is measured at a much more complex level than a cellular response, such as the organism level (e.g. sedation or change in behavior).
Drugs often act at receptors for endogenous (physiologic) hormones and neurotransmitters, and these receptors have evolved to recognize their cognate signaling molecules. Drugs that mimic physiologic signaling molecules at receptors are agonists, that is, they activate these receptors. Partial agonist drugs produce less than maximal activation of activation of receptors, while a drug that binds to the receptor without the capacity to activate the receptor may function as a receptor antagonist. Antagonists that bind to the receptor at the same site as agonists are able to reduce the ability of agonists to activate the receptor. This mutually exclusive binding of agonists and antagonists at a receptor is the basis for competitive antagonism as a mechanism of drug action. One additional class of drugs acting at physiologic receptors are inverse agonists. At physiologic receptors that exhibit constitutive activity in the absence of activation by an endogenous agonist, inverse agonists stabilize an inactive conformation and therefore reduce the activation of the receptor. Thus, inverse agonists produce responses that are the inverse of the response to an agonist at a given receptor. Theoretical log concentration‐response curves for these four classes of drugs are depicted in Figure 1.1.
Dose Dependence of Drug Interaction with Receptors
Receptor occupancy theory assumes that drug action is dependent on concentration (dose) and the attendant quantitative relationships are plotted as dose‐ or concentration‐response curves. Dose–response analysis is typically reserved to describe whole animal drug effects, whereas concentration‐response curves describe in vitro drug action where the actual concentration of the drug interacting with a receptor is known. Inspection of dose–response relationships reveals that for any drug, there is a threshold dose below which no effect is observed, and at the opposite end of the curve there is typically a ceiling response beyond which higher doses do not further increase the response. As shown in Figure 1.2, these dose‐ or concentration‐response curves are typically plotted as a function of the log of the drug dose or concentration. This produces an S‐shaped curve that pulls the curve away from the ordinate and allows comparison of drugs over a wide range of doses or concentrations.
A drug‐receptor interaction is typically reversible and governed by the affinity of the drug for the receptor. The affinity essentially describes the tightness of the binding of the drug to the receptor. The position of the theoretical S‐shaped concentration‐response curves depicted in Figure 1.2 reveals the potency of these drugs. The potency of a drug is a function of its affinity for a receptor, the number of receptors, and the fraction of receptors that must be occupied to produce a maximum response in a given tissue. In Figure 1.2, Drug A is the most potent and Drug C is least potent. The efficacy of all three drugs in Figure 1.2