Subclassification of Class I antiarrhythmic drugs: Enhanced relevance after CAST

Abstract

Class I antiarrhythmic drugs are traditionally divided into three subclasses--Ia, Ib, and Ic--on the grounds of differences in kinetics of interaction with the sodium channel and different effects on the duration of the action potential. The CAST study has highlighted our growing awareness of the proarrhythmic potential of this group of agents, particularly the Class Ic subgroup. Class I drugs can cause arrhythmias either by slowing conduction to critical levels, thus enhancing the possibility of reentrant arrhythmias, or in some cases by prolonging action potential duration, leading to early afterdepolarizations, which probably underlie triggered automaticity. Evidence is presented that the Class Ic compounds may be inherently more proarrhythmic than the Ib compounds, because of their lesser ability to depress ischemic myocardium selectively. Arguments are advanced for the continued use of a slightly modified subclassification of Class I antiarrhythmic drugs.

Therapeutic drug monitoring: antiarrhythmic drugs

“…These drugs of which quinidine is the most widely used, have very similar electrophysiological properties both in vitro and vivo. They block both the inward sodium currents (an action common to all Class I agents), and the outward potassium currents responsible for repolarization of the cardiac action potential at concentrations in or near the therapeutic range [3, 19]. For this reason they are capable of causing proarrhythmic complications both via conduction slowing and via the promotion of oscillatory behaviour of the action potential associated with delayed repolarization, giving rise to a form of polymorphic ventricular tachycardia often referred to as ‘torsades de pointes’ [5, 20–23].…”

Electrophysiological basis for antiarrhythmic efficacy, positive inotropy and low proarrhythmic potential of (—)‐caryachine

“…Most class I antiarrhythmic agents cause a use-dependent inhibition of INa, a slower recovery of Na channels from their inactivation state and a negative shift of the voltage-dependent inactivation curve of INa (Campbell 1992;Carmeliet & Saikawa 1982;Clarkson et al, 1988;Nattel 1991;1993;Grant & Wendt 1992;Tamargo et al, 1992). In this study (-)-caryachine had been shown to block the Na channel in a similar way.…”

Report and Recommendations of the Workshop of the European Centre for the Validation of Alternative Methods for Drug-Induced Cardiotoxicity

“…However, the CAST study showed such molecules to trigger ventricular tachycardia in patients treated for myocardial infarction [39]. Clearly, sodium channel block is a mechanism by which a given drug may display some cardiotoxicity [40]. Additionally, depending on their respective binding/unbinding time constants, drugs may or may not interact with the conduction velocity and modify the duration of the repolarization phase differently (e.g.…”