Clinical features of arrhythmia aggravation by antiarrhythmic drugs and their implications for basic mechanisms

Abstract Although cardiac arrhythmias are major cause of morbidity and mortality, widespread use of antiarrhythmic drugs is not appropriate at this time for two major reasons: (1) There is no evidence that antiarrhythmic drugs alter mortality in the vast majority of patients; further data will be forthcoming from large‐scale multicentered clinical trials which are currently underway. (2) Side effect are a prominent feature of therapy with antiarrhythmic drugs. The most striking of these toxicities is apparently paradoxical provocation of, rather than suppression of, cardiac arrhythmias by these agents. Two common clinical entities have been recognized. Therapy with action‐potential‐prolonging agents, including quinidine, sotalol, and the major active metabolite of procainamide, N‐acetyl procainamide, has been associated with the development of a morphologically distinctive polymorphic ventricular tachycardia, Torsades de Points, in approximately 5% of patients. Bradycardia and hypokalemia are commonly associated clinical features. In vitro studies indicate that triggered automaticity, in the from of early afterdepolarizations, are responsible for the genesis of Torsades de Pointes. The second common form of arrhythmia aggravation by antiarrhythmic drugs is the development of a marked increase in frequency of sustained ventricular tachycardia events in patients being treated for ventricular tachycardia. Therapy with sodium channel blockers of the “class Ic” subtype, including flecainide and encainide, are most commonly implicated. Since the underlying mechanism for sustained ventricular tachycardia in this patient population is thought to be microreentry, it appears likely that slow conduction due to the “class Ic” properties of the drugs may under appropriate conditions enable rather than block reentrant circuits. A variation on this clinical entity is the increasingly recognized phenomenon of drug‐induced impaired ventricular defibrillation. Although this is recognised with agents of the “class Ic” subtype, other sodium channel blockers have also been implicated, while action potential prologation actually appears associated with a decrease in defibrillation energy requirements. These adverse electrophysiologic drug action are not tightly linked to high plasma concentrations; rather, they represent an interplay among drug dose, plasma concentration, and underlying substrate. However, subsets of patients with variant drug metabolism on a genetic on a genetic basis have been identified and, under appropriate circumstances, these may be at increased risk for adverse electrophysiologic drug actions. Thus, intensive study of the clinical features of arrhythmia aggravation by antiarrhythmic drugs and their correlates in the basic laboratory have resulted not only in improved patient care but also in an increased understanding of the fundamental mechanisms responsible, and, potentially, may result in improved method for identifying new and safer antiarrhythmic compounds.