Electrophysiological specificity of antiarrhythmic drugs: Is it necessary?

Many factors have been identified in the genesis of cardiac arrhythmias. The relative importance of any given factor over another can vary from individual to individual, and may change with time. Successful antiarrhythmic drug therapy, therefore, must be effective against a multifaceted and evolving matrix. Clinically, the more successful antiarrhythmic agents have complex pharmacological profiles. For example, quinidine and amiodarone have several mechanistic actions which contribute to their antiarrhythmic efficacy. Multiple unfocused actions often result in side effects such as proarrhythmia, which has been demonstrated for both the above agents. Another approach to treating arrhythmias is to use different, selective agents in combination. Using programmed electrical stimulation techniques in dogs, we demonstrated that propranolol was ineffective in preventing reentrant tachycardia. However, subtherapeutic doses of the class III agent sematilide when combined with propranolol prevented reentry. A multivalent approach may also be useful in solving the problem of proarrhythmia. Using standard microelectrode techniques in vitro, we demonstrated that clofilium produced early after depolarizations, as well as an increase in triggered activity. In vivo, clofilium increased the number of ectopic events in infarcted dogs. The addition of a class I or a class IV antiarrhythmic agent in these animals was effective in suppressing the increased ectopic activity. These data suggest that combination therapy, by combining either single agents with selective actions or developing agents with multiple, focused actions may be an effective way to increase antiarrhythmic efficacy and decrease side effects.