Pharmacodynamic mechanisms regulate the effects of drugs on the human body.8 As noted earlier, drug-receptor binding results in multiple, complex chemical interactions. The site on the receptor at which a drug binds is called its binding site. The reactivity of a drug and that of a binding site determines how tightly two molecules will bind to each other. The favorability of a drug-receptor interaction is referred to as the affinity of the drug for its binding site on the receptor.
Affinity, predicated on the intrinsic properties of any given drug-receptor pair, is expressed by the dissociation constant (Kd). Kd is defined as that concentration of a drug at which 50% of the available receptors are occupied. When a sufficient number of receptors are occupied on or in a cell, the cumulative effect of receptor occupancy may become apparent in that cell. It follows that the drug-receptor binding relationship is closely related to the dose-response relationship.
There are two major types of dose-response relationships: graded and quantal. The graded dose-response curve (Figure 3) demonstrates the effect (E) of various doses or concentrations ([L]) of a drug on an individual from which two important parameters can be deduced: potency and efficacy. Potency (EC50) of a drug is defined as the [L] at which the drug elicits 50% of its maximal response. Efficacy (Emax) is the maximal effect of a drug when all available rectors are occupied.
The quantal dose-response curve (Figure 4) demonstrates the average effect of a drug, as a function of its dose, in a population of individuals from which three important parameters can be deduced: effectiveness, toxicity, and lethality. Responses are qualified as either present or absent. The doses that produce these responses in 50% of a population are defined as the median effective dose (ED50), median toxic dose (TD50), or medial lethal dose (LD50), respectively.
The therapeutic window is a range of doses of a drug that elicits a therapeutic response in a population of individuals without unacceptable toxic (adverse) effects. The therapeutic window can be quantified by the therapeutic index (TI): TI = TD50/ED50. A large TI represents a wide therapeutic window, e.g., a hundred-fold difference between TD50 and ED50. A small TI represents a narrow therapeutic window, e.g., a two-fold difference between TD50 and ED50.
Drug receptors exist in two conformational states in equilibrium with one another: an active state and an inactive state. The pharmacological properties of drugs can be based on their effects on the state of their receptors. A drug that favors binding to its active receptor, stabilizes its active conformation, and produces a pharmacological effect is called an agonist. A drug that causes an intrinsically active receptor to become inactive is called an inverse agonist.
A drug that binds to a receptor at its active site and produces maximal response when all receptors are occupied is called a full agonist. A drug that binds to a receptor at its active site, but produces only a partial response, even when all receptors are occupied is called a partial agonist. A drug that can inhibit the action of an agonist, but has no effect in the absence of that agonist, is called an antagonist. Antagonists can be divided into two classes: receptor and nonreceptor antagonists.
A receptor antagonist can bind the agonist binding site or an allosteric site, i.e., a site different from the agonist site, on a receptor. Binding of an antagonist to the active site prevents the binding of the agonist to the receptor. Binging of an antagonist to an allosteric site either alters the agonist’s affinity for its binding site or prevents the conformational change required for receptor activation. Antagonism at an agonist and an allosteric binding site may be competitive or noncompetitive.
An antagonist that competes with an agonist for the agonist binding site is referred to as a competitive antagonist. High concentrations of the agonist can overcome competitive antagonism, which is therefore, reversible. A noncompetitive antagonist binds covalently or with very high affinity to the agonist binding site. Consequently, high concentrations of the agonist are unable to overcome noncompetitive antagonism, which is therefore, irreversible.
A nonreceptor antagonist inhibits the ability of an agonist to initiate a response by chemical or physiological means. A chemical antagonist inactivates an agonist by modifying or sequestering it before it has the opportunity to act. For example, protamine binds to heparin, an anticoagulant, and inactivates it. A physiologic antagonist causes an effect opposite to that of an agonist. For example, β1-adrenoceptor antagonists counter tachycardia caused by excess thyroid hormone.