Potassium channels as targets for antiarrhythmic drug action

Recent cellular electrophysiologic studies have begun to clarify the basis of antiarrhythmic drug action. The Class I agents have been shown to block cardiac sodium channels in a use‐dependent manner, and the kinetics and potency of sodium channel block correlated with molecular weight and lipid solubility of drug. The Class IA agents, like quinidine, which increase cardiac action potential duration and refractory period in addition to their effects on conduction, also appear to have potent blocking actions on the potassium channels responsible for repolarization in myocardial cells, whereas the Class IB agents, like lidocaine, shorten action potential duration and are relatively specific in their block of sodium channels. In contrast, Class III agents, which prolong the action potential without slowing conduction, appear to exert their primary blocking action on the potassium channel only. Conversion from Class I to Class III electrophysiologic profiles can be achieved by the substitution of electron‐withdrawing groups (e.g., NO 2 ) in place of electron‐donating groups (e.g., NH 2 ) on the aromatic portion of the basic local anesthetic pharmacophore. Class III agents appear to be most effective against ventricular fibrillation and ventricular tachycardia due to re‐entry, but are generally without activity in the 24 hr Harris dog arrhythmia model. Further evaluation of the mechanism of antiarrhythmic drug action will require use of well‐defined arrhythmia models in a combination with a detailed understanding of drug‐channel interactions.