Mechanisms of action of class III agents and their clinical relevance

Antiarrhythmic agents are broadly classified according to their mode of action in order to provide a basis for rational drug choice when managing particular rhythm disturbances. However, a great deal of variability exists within each drug class and treatment decisions require a greater understanding of the pharmacological characteristics of individual drugs in order to tailor treatment to a specific clinical presentation. Class III drugs in particular form a heterogeneous group of agents, some of which selectively block ion channels while others have multi-channel blocking properties. An improved understanding of the relevance of the specific mechanism of action is now proving essential in predicting the value of individual drugs in clinical practice. Selective I(Kr) blocking agents increase action potential duration and refractoriness to the greatest extent at slow rates. Therefore, efficacy may be reduced at higher heart rates, the situation in which serious arrhythmias are most likely to occur. This so-called 'reverse use dependence' can be overcome with certain drug combinations, such as sotalol plus either quinidine or procainamide, drugs with multi-channel blocking properties, such as amiodarone, and possibly with drugs which block the I(Ks) as well as the I(Kr) potassium current, such as azimilide and ambasilide.