Importance of metabolites in antiarrhythmic therapy

The presence of metabolites with pharmacologic activity can produce unanticipated drug efficacy or toxicity. This is particularly true during treatment with drugs that have narrow therapeutic-toxic ratios, such as the antiarrhythmic agents. The presence of active metabolites can often be inferred from variability in the relation between pharmacologic effect and steady-state plasma concentrations of the parent drug. Moreover, metabolites may ordinarily be unimportant but can accumulate to therapeutic (or toxic) levels in disease states such as congestive heart failure, renal failure and hepatic failure. Further characterization of the contribution of such metabolites during treatment requires direct evaluation of their pharmacology in vitro, in animal models and, if indicated, in man. Procainamide and its active metabolite N-acetylprocainamide provide the best and most complete example of this sequence of observations. Other drugs, including quinidine, disopyramide, verapamil and the investigational agents encainide and lorcainide, have active metabolites for which pharmacologic activity is less well-defined. Further studies in this area will help reduce the frequency of antiarrhythmic drug adverse effects, make successful therapy more frequent, and perhaps allow insights into structure-activity relations.