Progress and prospects for optimum antiarrhythmic drug design

Summary Different class I drugs slow down to differing degrees the rate at which sodium channel availability, hence excitability, recovers after action potentials. Drugs that produce longer recovery half-times generally produce greater proarrhythmic side effects. Increased lipid solubility may improve a drug's potency for blocking channels yet with implications for adverse effects. Drug action may be potentiated in depolarized and acidotic tissue via modulation of the recovery process. A knowledge of molecular properties of antiarrhythmic drugs helps to define these modes of interraction with the sodium channels and, hence, will help in future drug design. Prospects for improving our understanding of ionic events involved in the repolarization phase of cardiac action potentials are also outlined. The development of successful strategies for controlling reentrant arrhythmias will probably require a thorough understanding of both class I and class III drug actions at the level of the membrane ion channel.Supported in part by NIH grants HL 24156, and a gift from the William Coldiron family.