Immunopharmacology and Adverse Drug Reactions

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Abstract
Adverse drug reactions are common and troublesome complications of contemporary pharmacotherapy. Adverse drug reactions are frequently, and often incorrectly, referred to as “allergy.” Although there are multiple mechanisms for adverse drug reactions, adverse drug reactions mediated by the immune system account for a disproportionate number of fatal and serious adverse reactions, and constitute a major clinical problem for patients and physicians. The immune system has evolved in multicellular organisms as a defence against infection, interactions between drugs and the immune system occur as inadvertent consequences of the protective function of the immune system, with drug molecules or drug‐carrier haptens being recognized as “non‐self” by the immune system. The classical mechanisms for drug hypersensitivity described by Gell and Coombs (Types 1 to 4) include IgE‐mediated, cytotoxic, immune complex‐mediated and delayed mechanism. These mechanisms provide elegant models for drug‐immune interactions that can provide mechanistic explanations for events such as urticaria associated with penicillins. However, these mechanisms do not account for many of the immunologically mediated adverse reactions commonly encountered in clinical practice. Over the last two decades, there has been an increasing awareness of the importance of reactive drug metabolites and drug‐protein interactions in the initiation of immunologic events mediating adverse drug reactions. Reactive drug metabolites may produce direct and profound effects on various functions of the immune system. Although some adverse reactions mediated by the immune system occur with equal frequency among adults and children, some of these reactions appear to be markedly more common among children than adults. There are a number of confounding factors that make the evaluation of immunologically mediated adverse reactions among children difficult, including differences in the formulations commonly used among children. There are considerable gaps in our understanding of the role and importance of the immune system in producing adverse reactions to drugs and chemicals. Laboratory assessment has a limited role in the investigation of adverse drug reactions believed to be mediated by the immune system. Clinical examination remains the cornerstone for the evaluation of adverse drug reactions.