Publisher Summary

This chapter describes various characteristics of drug action. There are two important features concerning the biological action of drugs: one is that most drugs produce their effects in very small doses—that is, in very low concentrations in the tissues, and the other is that the majority of drugs are highly specific in terms of their chemical structure. The high potency of drugs can, therefore, be explained in terms of an interaction between the molecules of the drug and a specialized region of the cell membrane, the receptor, which mediates the response of the cell. The chemical specificity of drugs is explained in terms of a chemical relationship between the drug molecule and the receptor. The biological action of a drug is, therefore, explained in terms of an interaction with specific receptors for that drug. A drug that produces a response is known as an agonist, and agonists possess all three of the properties—namely, selectivity, affinity, and intrinsic activity.

Selectivity

This relates to the specificity of a drug for a particular receptor. A drug which is selective, and not all drugs are, will interact only with its own receptors and not those for other drugs or other types of drug. In this way a drug will produce effects in tissues or organs where its receptors are present and not where they are absent, and we can explain why drugs act only at certain sites in terms of the presence of its specific receptors and the selectivity of the drug for those receptors. A very simple analogy for this is that of the lock (receptor) and key (drug), but a better analogy is illustrated diagrammatically in Figure 1.1a, where the drug is seen to have the correct ‘shape’ to fit the receptor.

Affinity

Apart from the drug having the right shape or chemical structure to fit the receptor, there must also be some force or forces attracting the molecules of the drug to the surface of the receptor in order to form a drug-receptor complex, which initiates the biological response. This attraction of the drug for the receptor is known as the ‘affinity’ of the drug and, because most drug-receptor interactions are reversible, the forces involved are normally weak chemical bonds, of which there are three main types, as follows:

It is probable that all three types of reversible bond, i.e. ionic, hydrogen and van der Waals’, have a role in drug-receptor interactions. Thus, ionic bonding may be important initially in attracting the molecules of the drug to the surface of the receptor, but as the two come closer together, hydrogen and van der Waals’ forces may come into play. The affinity of a drug for its receptor may therefore depend upon the presence of a number of bonds of different types. In addition, van der Waals’ bonds, although relatively weak, when summed up over a large number of individual atoms may result in considerable binding strength. Furthermore, the combination of a number of bonds of different types over the surface of the drug molecule and its receptor probably helps to determine the degree of ‘fit’ which is achieved, and also helps to determine the degree of selectivity of the drug. This is illustrated for the cholinergic receptor in 4.6 (see Chapter 4).

There is a fourth type of chemical bond which needs to be considered as it does occur in pharmacology, although rarely. This is the covalent bond which is formed when two atoms share a pair of electrons. It is the bond which holds together the atoms of organic molecules and is relatively strong, with a bond strength of the order of 420 kJ mol–1 (100 kcal mol–1). Because of the high binding energy, covalent bonds are irreversible at normal temperatures. Thus, when they occur in pharmacology, long-lasting effects are produced.

The affinity of drugs for their receptors can now be measured, using radiolabelled compounds, in vitro.

Intrinsic activity

This is the ability of a drug to produce a biological response once it has become attached to the receptor. It is necessary to invoke the concept of intrinsic activity because drugs exist which show selectivity and affinity for receptors but do not evoke a response. Thus intrinsic activity, which is a measure of the biological effectiveness of a drug, is independent of affinity, which represents the ability of the drug to form a stable complex with the receptor. Intrinsic activity therefore represents the mechanism by which the binding of a drug to the receptor is...