POTASSIUM CHANNEL BLOCKERS AS ANTIARRHYTHMIC DRUGS

Selective prolongation of cardiac repolarization is an effective means of suppressing a variety of cardiac arrhythmias, particularly those a rising from a re-entrant mechanism. Over the past several years, a var iety of novel compounds have been discovered that increase cardiac act ion potential duration without slowing conduction. Most of these agent s (e.g., dofetilide, E-4031, MK-499) act by selectively blocking the r apidly activating component of delayed rectification (I-Kr) although s ome (e.g., ibutilide, azimilide, terikalant) have been proposed to wor k 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., rev erse use-dependence) and to exert proarrhythmic effects at slow heart rates (i.e., torsade de pointes). The limited clinical results obtaine d to date suggest that these potential limitations may be less importa nt than previously thought, although clear pharmacodynamic differences among the various agents are beginning to emerge. While the effects o f some class III agents on repolarization and refractoriness are clear ly attenuated at rapid cycle lengths (e.g., sematilide, d-sotalol), th e effects of others appear to be largely rate-independent, at least do wn 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 th e class I agents. in summary, the rational design of selective blocker s of cardiac K channels for development as antiarrhythmic drugs appear s to have been relatively successful and continues to show considerabl e promise as a therapeutic approach. (C) 1994 Wiley-Liss, Inc.