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

Abstract

Roden, D.M.: Clinical features of arrhythmia aggravation by antiarrhythmic drugs and theirimplications for basic mechanisms. Drug Dev. Res. 19:153-172, 1990.Although cardiac arrhythmias are a 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 effects 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 form 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 154Roden reentrant circuits. A variation on this clinical entity is the increasingly recognized phenomenon of drug-induced impaired ventricular defibrillation. Although this is recognized with agents of the "class Ic" subtype, other sodium channel blockers have also been implicated, while action potential prolongation actually appears associated with a decrease in defibrillation energy requirements. These adverse electrophysiologic drug actions 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 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 responsi...

Characterization of the effects of the new inotropic agent BDF 9148 in isolated papillary muscles and myocytes of the guinea‐pig heart

“…This in vitro effect is parallelled in vivo by a prolongation of the QT-interval of the electrocardiogram (Ruegg & Niiesch, 1987) which limits its clinical use because of the danger of developing torsades de pointes arrhythmias (for literature, see Roden, 1990). Therefore, a drug with a similar mechanism of action would be considered more favourable if it exhibited less prolongation of action potential duration and hence showed less prolongation of QT time.…”

Electrophysiological interactions between disopyramide and its major metabolite, mono-N-dealkyldisopyramide, in canine ventricular tissue

“…A1though the aim of antiarrhythmic drug therapy ls suppression or control of 1ife-threatening cardiac arrhythmias, paradoxical provocation or aggravation of arrhythmias can be a side effect of these agents (Bigger and Sahar, 1987;Roden, 199C commonly implicated with such events (Roden, 1990). This subclass of sodium channel blockers have characteristic long time constants of recovery (Campbell, 1983b) which do not al10w relief of block even at long clinica1 diastolic intervals.…”

“…A second characteristic proarrhythmic response ta antiarrhythmic agents is torsade de pointes multiform ventricular accompanied by prolongation of the QT interva1 (Bigger and tachycardias Sahar, 1987; Roden, 1990). The term torsade de pointes i5 used to describe ( ( polymorphie ventrieular tachycardia in the setting of rnarked QT interval prolongation (long QT syndrome) (Tzivoni et al, 1983).…”

“…The etiology of torsade de pointes is frequent1y associated with the administration of action potential prolonging antiarrhythrnic drugs i1Inongst which are the Class la agents, sotalo1 and NAPA (Stratmann and Kennedy, 1987;Jackman et al, 1988;Roden, 1990). In partieular, the Class la drug quinidine is most often cited as the culprit.…”

“…In fact, the mechanism of termination of reentrant excitation by disopyramide in one model was correlated with the depression of conduction (Spinelli and Hoffman, 1989). Furthermore, studies with the new antiarrhythmic agent penticainide (a disopyramide derivative) which produces e1ectrophysio1ogical effects similar to MND in canine ventricular tissue (Gautier et al, 1987), show that drugs with this pharmacodynamic profile are effective against chronic ventricular arrhythmias in patients (Priori et al, 1987 C'ncainide or flecainide (Roden et al, 1990). Development of ,>u<,t ained vpntricular drrhythmias have been observed previously during trUJtmûnt with disopyramide (Kudenchuk et al, 1990).…”