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Rate-dependence of antiarrhythmic and proarrhythmic properties of class I and class III antiarrhythmic drugs.

Abstract：

:Rate or frequency-dependence is a characteristic property of antiarrhythmic drugs belonging to the Vaughan William classes I and III. The rate-dependence of class I drugs (i.e., increasing blockade of fast Na(+)-channels with faster rates) results from periodical drug binding to Na(+)-channel sites which are preferably available in the activated and/or inactivated channel states (use-dependence). With respect to their binding and unbinding kinetics, class I drugs can be subdivided into three groups (group 1-group 3) which differ in their block-frequency relations as well as in their onset kinetics of channel blockade. These properties can serve as predictors of the anti- and proarrhythmic potential of class I drugs. Class III drugs (blockers of potassium channels) are mostly characterized by reverse rate-dependence (loss of class III action at faster rates). However, this property cannot be attributed to reverse use-dependence, i.e., binding to channels in the rested state. It is more likely due to different rate-dependent contributions of the two components of the delayed rectifier potassium current to repolarization, when the rapidly activating, the rectifying component IKr is specifically blocked by class III drugs, while the slowly activating component IKs remains unchanged. In spite of their reverse rate-dependence, class III drugs exert an antifibrillatory effect when fibrillation is induced by frequent stimulation. This can be attributed to the slow time course of the decline (offset kinetics) of the class III effect accompanying a sudden increase in frequency. Proarrhythmic effects of class III drugs result from the delay in repolarization that may favor the development of early afterdepolarizations. The proarrhythmic potential of class III drugs is species dependent and is favored if the contribution of IKr to the repolarization phase of the action potential is comparatively large.

journal_name

Basic Res Cardiol

journal_title

Basic research in cardiology

authors

Weirich J,Antoni H

doi

10.1007/s003950050236

subject

Has Abstract

pub_date

1998-01-01 00:00:00

pages

125-32

eissn

0300-8428

issn

1435-1803

journal_volume

93 Suppl 1

pub_type

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Rate-dependence of antiarrhythmic and proarrhythmic properties of class I and class III antiarrhythmic drugs.