Therapeutic and toxic effects of drugs result from their interactions with molecules in the patient. Most drugs act by associating with specific macromolecules in ways that alter the macromolecules’ biochemical or biophysical activities. This idea, more than a century old, is embodied in the term receptor: the component of a cell or organism that interacts with a drug and initiates the chain of events leading to the drug’s observed effects.
Receptors have become the central focus of investigation of drug effects and their mechanisms of action (pharmacodynamics). The receptor concept, extended to endocrinology, immunology, and molecular biology, has proved essential for explaining many aspects of biologic regulation. The receptor concept has important practical consequences for the development of drugs and for arriving at therapeutic decisions in clinical practice.
1. Receptors largely determine the quantitative relations between dose or concentration of drug and pharmacologic effects.
The receptor’s affinity for binding a drug determines the concentration of drug required to form a significant number of drug-receptor complexes, and the total number of receptors may lim it the maximal effect a drug may produce.
2. Receptors are responsible for selectivity of drug action.
The molecular size, shape, and electrical charge of a drug determine whether and with what affinity it will bind to a particular receptor among the vast array of chemically different binding sites available in a cell, tissue, or patient. Accordingly, changes in the chemical structure of a drug can dramatically increase or decrease a new drug’s affinities for different classes of receptors, with resulting alterations in therapeutic and toxic effects.
3. Receptors mediate the actions of pharmacologic agonists and antagonists.
Some drugs and many natural ligands, such as hormones and neurotransmitters, regulate the function of receptor macromolecules as agonists; this means that they activate the receptor to signal as a direct result of binding to it. Some agonists activate a single kind of receptor to produce all their biologic functions, whereas others selectively promote one receptor function more than another.
Other drugs act as pharmacologic antagonists; that is, they bind to receptors but do not activate generation of a signal; consequently, they interfere with the ability of an agonist to activate the receptor. The effect of a so-called “pure” antagonist on a cell or in a patient depends entirely on its preventing the binding of agonist molecules and blocking their biologic actions.
Other antagonists, in addition to preventing agonist binding, suppress the basal signaling (“constitutive”) activity of receptors. Some of the most useful drugs in clinical medicine are pharmacologic antagonists