Susceptibility to adverse drug reactions

Abstract

The pharmacological effects of a drug depend on its concentration at the site of action, and therefore on the concentration in blood and on the dose. The relationship between the concentration or dose and the corresponding effect can usually be represented mathematically as a rectangular hyperbola; when effect is plotted against log concentration or log dose, the curve is sigmoidal. Inevitably, the effect size and the doses causing benefit and harm will differ among individuals, since they are biological phenomena: some individuals are more likely than others to suffer harm at any given dose. Some harmful effects can occur at much lower doses than those used in therapeutics; that is, the log dose-response curve for harm lies far to the left of the log dose-response curve for benefit. Those who suffer such reactions are hypersusceptible. When the dose-response curves for harm and therapeutic effect are in the same range, dose cannot separate the harmful effects from the therapeutic effects, and adverse reactions are collateral. Toxic effects occur when harmful doses are above the doses needed for benefit. In this review we consider factors that influence a subject's susceptibility to adverse drug reactions. Determinants of susceptibility include Immunological, Genetic, demographic (Age and Sex), Physiological and Exogenous factors (drug-drug interactions, for example), and Diseases and disorders such as renal failure, giving the mnemonic I GASPED. Some susceptibility factors are discrete (for example, all-or-none) and some are continuous; susceptibility can therefore be discrete or continuous; and the factors can interact to determine a person's overall susceptibility to harm.

Keywords: adverse drug reactions; genetic polymorphisms; pharmacodynamics; pharmacokinetics; prescribing.

Figure 1

Cumulative percentage of patients who have become salicylate‐toxic plotted against log dose of salicylate (in grains; 1 grain ~ 65 mg) [after references 6, 7]

Figure 2

Hanzlik's data6 plotted as a cumulative distribution curve (cumulative percentage vs standard deviation from a mean dose of 186 grains)

Figure 3

(A) Percentage of subjects sensitized vs dose of dinitrochlorobenzene on a logarithmic scale [after reference 19]. (B) Wheal thickness response to topical dinitrochlorobenzene vs dose of dinitrochlorobenzene on a logarithmic scale in subjects sensitized to DNCB [after reference 20]; note that the dose required to provoke a response is 2 orders of magnitude less than the dose required to sensitize a subject

Figure 4

Duration of apnoea (minutes) vs dose of suxamethonium in mg (log scale) for normal subjects (UU, dashed line) and those with 2 abnormal alleles (AA, solid line) [after reference 24]

Figure 5

The number of pair‐wise interactions of n drugs, two at a time