Definition

Some individuals can be especially sensitive to the effects of a particular drug, whereas others can be quite resistant. Such individual variation can be the result of factors that are not genetic. For example, both the young and the elderly are very sensitive to morphine and its derivatives, as are people with liver disease. Individual differences in response to drugs in humans are, however, often genetically determined.

The term pharmacogenetics was introduced by Vogel in 1959 for the study of genetically determined variations that are revealed solely by the effects of drugs. Pharmacogenetics is now used to describe the influence of genes on the efficacy and side effects of drugs. Pharmacogenomics describes the interaction between drugs and the genome (i.e., multiple genes), but the two terms are often used interchangeably. Pharmacogenetics/pharmacogenomics is important because adverse drug reactions are a major cause of morbidity and mortality. It is also likely to be of increasing importance in the future, particularly as a result of the development of new drugs from information that has become available from the Human Genome Project (see Chapter 5). The human genome influences the effects of drugs in at least three ways. Pharmacokinetics describes the metabolism of drugs, including the uptake of drugs, their conversion to active metabolites, and detoxification or breakdown. Pharmacodynamics refers to the interaction between drugs and their molecular targets. An example would be the binding of a drug to its receptor. The third way relates to palliative drugs that do not act directly on the cause of a disease, but rather on its symptoms. Analgesics, for example, do not influence the cause of pain but merely the perception of pain in the brain.

Drug Metabolism

The metabolism of a drug usually follows a common sequence of events (Figure 12.1). A drug is first absorbed from the gut, passes into the bloodstream, and becomes distributed and partitioned in the various tissues and tissue fluids. Only a small proportion of the total dose of a drug will be responsible for producing a specific pharmacological effect, most of it being broken down or excreted unchanged.

FIGURE 12.1 Stages of metabolism of a drug.

Biochemical Modification

The actual breakdown process, which usually takes place in the liver, varies with different drugs. Some are oxidized completely to carbon dioxide, which is exhaled through the lungs. Others are excreted in modified forms either via the kidneys into the urine, or by the liver into the bile and thence the feces. Many drugs undergo biochemical modifications that increase their solubility, resulting in their being more readily excreted.

One important biochemical modification of many drugs is conjugation, which involves union with the carbohydrate glucuronic acid. Glucuronide conjugation occurs primarily in the liver. The elimination of morphine and its derivatives, such as codeine, is dependent almost entirely on this process. Isoniazid, used in the treatment of tuberculosis, and a number of other drugs, including the sulfonamides, are modified by the introduction of an acetyl group into the molecule, a process known as acetylation (Figure 12.2).

FIGURE 12.2 Acetylation of the antituberculosis drug isoniazid.

Kinetics of Drug Metabolism

The study of the metabolism and effects of a particular drug usually involves giving a standard dose of the drug and then, after a suitable time interval, determining the response, measuring the amount of the drug circulating in the blood or determining the rate at which it is metabolized. Such studies show that there is considerable variation in the way different individuals respond to certain drugs. This variability in response can be continuous or discontinuous.

If a dose–response test is carried out on a large number of subjects, their results can be plotted. A number of different possible responses can be seen (Figure 12.3). In continuous variation, the results form a bell-shaped or unimodal distribution. With discontinuous variation the curve is bimodal or sometimes even trimodal. A discontinuous response suggests that the metabolism of the drug is under monogenic control. For example, if the normal metabolism of a drug is controlled by a dominant gene, R, and if some people are unable to metabolize the drug because they are homozygous for a recessive gene, r, there will be three classes of individual: RR, Rr, and rr. If the responses of RR and Rr are indistinguishable, a bimodal distribution will result. If RR and Rr are distinguishable, a trimodal distribution will result, each peak or mode representing a different genotype. A unimodal distribution implies that the metabolism of the drug in question is under the control of many genes—i.e., is polygenic (p. 143).

FIGURE 12.3 Various types of response to different drugs consistent with polygenic and monogenic control of drug metabolism. A, Continuous variation, multifactorial control of drug metabolism. B, Discontinuous bimodal variation. C, Discontinuous trimodal variation.

Genetic Variations Revealed by the Effects of Drugs

Among the best known examples of drugs that have been responsible for revealing genetic variation in response are isoniazid, succinylcholine, primaquine, coumarin anticoagulants, certain anesthetic agents, the thiopurines, and debrisoquine.