Antiarrhythmic and Proarrhythmic Properties of QT-Prolonging Antianginal Drugs

Abstract

In recent years there has been a major reorientation of drug therapy for cardiac arrhythmias, its changing role, and above all, a radical change in the class of arrhythmia drugs because of their impact on mortality. The decline in the use of sodium-channel blockers has led to an ex panding use of beta-blockers and simple or complex class III agents for controlling cardiac arrhythmias. Success with these agents in the context of their side effects has spurred the development of compounds with simpler ion-channel blocking properties that have less complex adverse reactions. The resulting so-called pure class III agents, such as dofetilide or ibutilide, were found to have antifibrillatory effects in atrial fibrillation and flutter and in ventricular tachyarrhythmias. Such agents are effective and have diversity, but they have come into therapeutics with a price: the sometimes-fatal torsades de pointes. The drug amiodarone, a complex compound that was synthesized as an antianginal agent, has been an exception in this regard. Its therapeutic use is associated with a negligibly low incidence of torsades de pointes, even though the drug produces significant bradycardia and QT lengthening to 500 to 700 msec. Recent electrophysiologic studies suggest that this paradox is likely due to the differential block of ion channels in endocardium, epicardium, midmyocardial (M) cells, and Purkinje fibers in the ventricular myocardium. There is also clinical evidence suggesting that amiodarone reduces the "torsadogenic" effects of pure class III agents. Ranolazine was also synthesized for the development of antianginal properties that stem from a partial inhibition of fatty acid oxidation; it too has been found to have electrophysioloigic properties. These are somewhat similar to those of amiodarone on ion channels in endocardium, epicardium, M cells, and Purkinje fibers in the ventricular myocardium, but the drug does not prolong the QT interval to the same extent as amiodarone does. Thus, the drug produces modest increases in repolarization as judged by its effects on the action potential duration (APD) without the potential for the development of torsades de pointes. By virtue of its suppressant action on early afterdepolarizations and triggered activity in Purkinje fibers and M cells, the drug appears to have a powerful potential for reducing the torsadogenic proclivity of conventional class III antiarrhythmic compounds. The rationale for the therapeutic niche for amiodarone, and especially in the case of ranolazine, in the prevention of drug-induced torsades de pointes is discussed.

Sevoflurane and QTc Prolongation

“…Among the antiarrhythmic medications there are a variety of so-called pure class III antiarrhythmic agents, such as dofetilide or ibutilide, which, although effective in treating atrial fibrillation and flutter as well as ventricular tachyarrhythmias, are associated with sometimes fatal TdP, despite relatively modest increases in the QT interval. Conversely, the drug amiodarone, originally synthesized as an antianginal agent, has been associated with a negligibly low incidence of TdP, even though the drug can produce QT lengthening from 500 to 700 ms. 13 The reasons for this paradox are not entirely clear. Equally puzzling is the fact that not all drugs causing TdP are potent I-Kr blockers, and I-Kr block is not necessarily associated with TdP.…”

Biological Therapies for Cardiac Arrhythmias

“…On the flip side, the studies, although mostly limited to proof-of-concept, do highlight the potential utility of gene transfer in blunting ventricular arrhythmogenesis by overexpressing K ϩ channels (to accelerate repolarization), or blocking them selectively 23 to achieve focal class III 30 antiarrhythmic effects.…”

Role of Metabolic Modulation in the Management of Chronic Ischemic Heart Disease

“…There is also a risk of pharmacodynamic interactions with drugs that prolong the QT interval. 74 A recent study has shown that long-term therapy with ranolazine seems well tolerated in high-risk chronic stable angina patients, with evidence that symptomatic improvements attributable to ranolazine are not offset by increased mortality. 75 On this ground, together with the fact that comparative trials have failed to show whether ranolazine has a clear-cut impact on mortality, the efficacy of ranolazine in the prevention of angina attacks needs to be reassessed by further studies.…”