Mechanisms of unpredictable adverse drug reactions

Adverse drug reactions are common problems associated with therapy, and are major sources of morbidity and mortality. There are numerous types of drug reactions, including predictable drug reactions such as side effects, toxicity, drug interactions and secondary effects that can be anticipated when planning therapy. There are also a number of unpredicted adverse effects, which are unexpected consequences of therapy. The least severe unpredicted adverse drug reaction is intolerance, which appears to be an exaggeration of pharmacological or toxic effects of the drug among vulnerable subsets of patients. Some of the most severe and life-threatening adverse drug reactions are allergic. These adverse effects can be mediated by a number of mechanisms, including the development of drug-specific IgE, serum-sickness-like reactions in response to drug-antibody complexes, direct release of inflammatory mediators, or involvement of the immune system by mechanisms that are poorly understood. Idiosyncratic adverse drug reactions are a heterogeneous group of adverse effects that are not predictable from the pharmacological actions of the drug. Many of these reactions occur as a consequence of pharmacogenetic variations in drug bioactivation and drug or metabolite detoxification or clearance. The physician must be vigilant for the possibility of unpredictable adverse drug reactions during or after therapy. Research currently underway may afford the opportunity to predict, and hopefully prevent, some of these adverse reactions in the future.