Potassium channel blockers as antiarrhythmic drugs

Abstract

Selective prolongation of cardiac repolarization i s 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 Ill 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.

QT interval prolongation by noncardiovascular drugs: A proposed assessment strategy

“…The same authors have shown that mutations in HERG lead to one form of hereditary LQTS. Interestingly, blockade of I kr by dofetilide, a class III antiarrhythmic agent, is thought to cause acquired LQTS [Colatsky and Argentieri, 1994]. Recently, a similar finding was obtained with sertindole, a drug exerting antipsychotic effects associated with significant increases in the corrected QT interval [van Kammen et al, 1996], which was shown to strongly inhibit HERG currents [Rampe et al, 1998].…”

HERG K+ currents in human prolactin-secreting adenoma cells

“…Accordingly, erg currents recorded in the prolactin-and growth hormone (GH)-secreting cell lines derived from a rat pituitary tumour (GH 3 /B 6 [9]; GH 3 [4]) or in native rat lactotroph cells [17] were described initially as inactivating, inwardly rectifying K + currents. More recently, the use of specific erg channel blockers from the class of methanesulphonanilides [15] has served to isolate these erg currents as the drug-sensitive currents [5,10,36,52] and has helped to demonstrate their physiological function. In native and clonal rat lactotroph cells, erg currents contribute to the maintenance of the resting membrane potential [7,12,52] and their inhibition by thyrotropinreleasing hormone (TRH) is thought to mediate the late phase of TRH-induced prolactin secretion (for review see [40]).…”

K+channels in the heart: new insights and therapeutic implications

“…In addition, this property would also reduce the rate of spontaneous discharge in abnormal automatic tissues. However, Review K + channels in the heart: new insights & therapeutic implications even given the superficial coverage in the preceding paragraphs, it is also apparent that increasing the APD has the potential to promote EADs and trigger activity ( Figure 2) [66][67][68].…”