EMERGING CLASS-III ANTIARRHYTHMIC AGENTS - MECHANISM OF ACTION AND PROARRHYTHMIC POTENTIAL

The goal of developing an antiarrhythmic agent effective against malig nant ventricular arrhythmias while maintaining a low side-effect profi le remains elusive. The class III drugs amiodarone and sotalol are the best available agents. However, both drugs possess properties outside the realm of a pure class III effect, and their use is limited by a v ariety of dose-related side effects. There are several drugs with more selective class III properties currently in development. This review provides an overview of the optimal characteristics of an effective th eoretical class III drug and a summary of the properties of a number o f class III drugs under active investigation. An ideal class III antia rrhythmic agent for a reentrant arrhythmia should provide use-dependen t prolongation of the action potential duration with slow onset and ra pid offset kinetics. This drug would prolong the effective refractory period of cardiac tissue selectively at the rapid heart rates achieved during ventricular tachycardia or fibrillation with a delayed onset o f action, and a rapid resolution of its effects on resumption of physi ologic heart rates. With little effect on the refractory period at nor mal or slow heart rates, the ability to induce torsade de pointes woul d be lessened. In contrast to these ideal properties, most currently a vailable and investigational agents have a reverse use-dependent effec t on the action potential duration, producing more effects on the refr actory period at slower heart rates. This property results in part fi om preferential block of the rapidly activating component of the delay ed rectifier potassium channel (I-Kr), with little or no effect on the slowly activating component (I-Ks) The development of a drug with fav orable blocking kinetics that selectively blocks IK, may result in low er proarrhythmic events while still maintaining effective antiarrhythm ic properties.