Although there is no single uniform theory that can explain the activity of drugs, several theories have been advanced over the years in attempts to elucidate drug action.
In general we may consider pharmacological action to be of two types. One type is thought to be caused solely by the physicochemical properties of the compound without discernible relationship to chemical structure. These structurally nonspecific drugs are usually administered in relatively large doses. It is presumed that such agents form a monomolecular layer over the total area of certain cells in the organism. Examples of such drugs were believed to be general anesthetic gases, depressants such as alcohol and chloral hydrate and antiseptics such as phenol and iodine. Structurally specific drugs, on the other hand, have an activity that is believed to emanate primarily from chemical structure. The total cell surface of target tissues or organs is presumably not involved; rather, the interaction of drug molecules entails relatively small, highly specific areas of the cell called receptors. These receptors are thought to be localized on, or in, such cell components as enzymes, nucleic acids, and portions of cellular membranes. Since the whole cell surface need not be covered, fewer drug molecules are required to elicit an effect. Thus we would predict the need for much smaller doses. Indeed, in this category we find drugs that are effective in astoundingly small quantities. Even these doses are far in excess of what would be needed for pharmacological effects if the drugs administered, by whatever routes currently used, were not subject to poor absorption, chemical inactivation, dilution by total body distribution, and diversion by excretion, before ever reaching the site of action.
It has been shown in some instances that extremely small fractions of the cellular surfaces need to be affected to elicit a drug response. It can be calculated that the dose of acetylcholine needed to reduce the heartbeat of a toad by 50% would cover only 0.016% of the surface area of the cells in the ventricle of the heart.
High potency (i.e., a low dosage requirement) is not, however, a decisive criterion in categorizing a drug as structurally specific. Many low-potency agents fall into the structurally specific category because of various other factors. A drug may require a high dose due to rapid metabolism to inactive forms, fast excretion, or a high degree of binding to plasma proteins.
The pharmacological effects of structurally specific drugs result from an interaction with a tiny area of certain cells that have functional groups, areas of polarity, and a general topography complementary to those of the drug. It is not surprising that we often find that apparently small structural alterations bring about drastic qualitative changes in activity.
The occupancy theory of drug activity was first proposed by Clark (1926) and Gaddum (1926). It was actually an adaptation of the Langmuir isotherm dealing with the adsorption of gases onto metallic surfaces. The basis of their idea was that the law of mass action, operative in gas-solid interactions, could be applied to drug-receptor interactions: that one drug molecule occupies one receptor site, just as gas molecules are adsorbed on active sites of a solid surface. The drug-receptor relationships can be expressed as:
R represents receptor; D, drug; RD, receptor-drug complex; E, pharmacological effect; Ku K2, and K3 are rate constants. The dissociation constant, Kv, can be calculated at equilibrium as:
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