Potassium channel blockers as antiarrhythmic drugs

Selective prolongation of cardiac repolarization is an effective means of suppressing a variety of cardiac arrhythmias, particularly those arising from a re‐entrant mechanism. Over the past several years, a variety of novel compounds have been discovered that increase cardiac action potential duration without slowing conduction. Most of these agents (e.g., dofetilide, E‐4031, MK‐499) act by selectively blocking the rapidly activating component of delayed rectification (IKr), although some (e.g., ibutilide, azimilide, terikalant) have been proposed to work via alternate mechanisms. While the overall efficacy of these agents against tachyarrhythmias appears to be greater than obtained for the sodium channels blockers, primary concerns remain about the ability of these agents to prolong repolarization at fast heart rates (i.e., reverse use‐dependence) and to exert proarrhythmic effects at slow heart rates (i.e., torsade de pointes). The limited clinical results obtained to date suggest that these potential limitations may be less important than previously thought, although clear pharmacodynamic differences among the various agents are beginning to emerge. While the effects of some class III agents on repolarization and refractoriness are clearly attenuated at rapid cycle lengths (e.g., sematilide, d‐sotalol), the effects of others appear to be largely rate‐independent, at least down to cycles as short as 350 msec. Also, the currently available data suggest that the risk of serious proarrhythmia may be lower (1–3%) and considerably more predictable than that seen during treatment with the class I agents. In summary, the rational design of selective blockers of cardiac K channels for development as antiarrhythmic drugs appears to have been relatively successful and continues to show considerable promise as a therapeutic approach. © 1994 Wiley‐Liss, Inc.