The law of mass action and the pharmacological concentration–effect curve: resolving the paradox of apparently non‐dose‐related adverse drug reactions

Background Adverse drug reactions are sometimes described as being ‘non‐dose‐related’ because no relationship has been found between increasing doses and either the intensity of the response or the proportion of individuals in whom the response occurs; furthermore, hypersensitivity reactions are often regarded as being non‐dose‐related, even if different doses have not been studied. However, the law of mass action implies that all pharmacological effects are concentration related and should increase in intensity with increasing dose. We set out to explain this paradox. Methods We searched for published adverse drug reactions that have been described as non‐dose‐related and analysed them. Results We identified four categories of explanations that resolve the paradox: (i) the reaction is not real; it may have occurred by chance or there may be methodological problems, such as bias or confounding factors; (ii) the dose–response curve for the adverse effect reaches a maximum at doses lower than were studied (i.e. a hypersusceptibility reaction); this underpins the use of test doses to predict the possibility of an adverse reaction at therapeutic doses; (iii) susceptibility to the adverse reaction differs widely among individuals; and (iv) imprecision or inaccuracy in the measurement of either dose or effect obscures dose responsiveness. This last explanation encompasses: (a) reactions related to cumulative dose; (b) dissociation between dose and concentration through saturable pharmacokinetics; and (c) variability in the measurement of the effect. Conclusions and implications If an adverse drug reaction appears to be non‐dose‐related, the reasons should be sought, having these mechanisms in mind.