Drugs not only induce their known listed primary actions.

but they:

• Evoke compensatory responses in the complex interrelated physiological systems they perturb, and these systems need time to recover on withdrawal of the drug (gradual withdrawal can give this time: it is sometimes mandatory and never harmful)

• Induce metabolic changes that may be trivial in the short term, but serious if they persist for a long time

• May produce localised effects in specially susceptible tissues and induce serious cell damage or malfunction

• Increase susceptibility to intercurrent illness and to interaction with other" drugs that may be taken for new indications.

That such consequences will occur with prolonged drug use is to be expected. With a knowledge of physiology, pathology and pharmacology, combined with an awareness that the unexpected is to be expected ('There are more things in heaven and earth, Horatio, than are dreamt of in your philosophy'27) those patients requiring long-term therapy may be managed safely, or at least with minimum risk of harm, and enabled to live happy lives.

That individuals respond differently to drugs, both from time to time and from other individuals, is a matter of everyday experience. Doctors need to accommodate for individual variation, for it may explain both adverse response to a drug and failure of therapy. Sometimes there are obvious physical characteristics such as age, race (genetics) or disease that warn the prescriber to adjust drug dose, but there are no external features that signify, e.g., pseudocholinesterase deficiency, which causes prolonged paralysis after suxamethonium. An understanding of the reasons for individual variation in response to drugs is relevant to all who prescribe. Both pharmacodynamic and pharmacokinetic effects are involved and the issues fall in two general categories: inherited influences and environmental and host influences.

type of curve that describes the distribution of height, weight or metabolic rate in a population. The curve is the result of a multitude of factors, some genetic (multiple genes) and some environmental, that contribute collectively to the response of the individual to the drug; they include race, sex, diet, weight, environmental and body temperature, circadian rhythm, absorption, distribution, metabolism, excretion and receptor density, but no single factor has a predominant effect.

Less commonly, variation is discontinuous when differences in response reveal a discrete proportion, large or small, who respond differently from the rest, e.g. poor drug oxidisers or fast and slow acetylators of isoniazid. Discontinuous variation most commonly occurs when response to a drug is controlled by a single gene. The term genetic polymorphism refers to the existence in a population of two or more discontinuous forms of a species which are subject to simple inheritance. By convention the frequency of each species is 1% or more.

Pharmacogenetics is concerned with drug responses that are governed by heredity (see also pharma-cogenomics p. 42). Inherited factors causing different responses to drugs are commonly biochemical because single genes govern the production of enzymes. Pharmacogenetic polymorphism is often expressed in the form of different drug metabolising capacities, i.e. genetic differences in a single enzymes. Inherited abnormal responses to drugs mediated by single genes are called idiosyncrasy and cause Increased, decreased and bizarre responses to drugs.

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