Antiarrhythmic agents: the modulated receptor mechanism of action of sodium and calcium channel-blocking drugs.

At the time of the last review of antiarrhythmic drugs in this series in 1 975 (1) , the important developments in the field centered around the "classical" agents: lidocaine, procainamide, quinidine, diphenylhydantoin (now phenytoin), and propranolol. That review properly emphasized the importance of new informa­ tion regarding the effects of these agents on diseased tissue (e.g. obtained from infarcted hearts) or on normal tissue stressed in the muscle chamber (e.g. by depolarization with potassium). However, data and concepts available at that time were not sufficient to explain the important differences among the effects of these drugs on different types of cardiac tissue, or the difference in sensitiv­ ity of diseased and depolarized tissue as compared to normal tissue. Since 1 975, a modest revolution in antiarrhythmic drug development, re­ search, and clinical application has occurred. The number of agents in active clinical use or investigation in the U.S. is now more than 18 (2, 3). In addition, a major new class of agents, the calcium channel blockers, has come into general use (4, 5) . Furthermore, an attempt has been made to extend our understanding of the mechanism of action at the molecular level: the modulated receptor hypothesis (6, 7). This review concentrates on the antiarrhythmic drug literature pertinent to an evaluation of the modulated receptor hypothesis. A number of general reviews