Choice and chance in drug therapy of cardiac arrhythmias: technique versus drug-specific responses in evaluation of efficacy.
Numerous recent advances in pharmacotherapy for arrhythmia have necessitated a reorientation in terms of choice of specific agents, techniques for predicting drug effects, and the endpoints for judging therapeutic efficacy. For the management of ventricular arrhythmias and preventing mortality, several trends are becoming clear. It is unlikely that sodium channel blockers will continue to play a major role, except in patients with structurally normal hearts. Emphasis is shifting way from class I agents to those that act by prolonging repolarization without effect on conduction. These latter agents have been termed pure class III agents and have been developed because of the clinical experience with sotalol and amiodarone. On the other hand, there is compelling evidence that sympathetic inhibition per se (as exemplified by beta blockers) or as an integral component of more complex molecules (e.g., sotalol, amiodarone) is a critical feature of desirable antifibrillatory agents. Thus, compared with D,L-sotalol or amiodarone, pure class III agents are likely to be much less effective and may need to be used in combination with antiadrenergic compounds. Compared with amiodarone, they are likely to induce a higher incidence of torsades de pointes, especially in the case of concomitant diuretic therapy. Therapy guided by programmed electrical stimulation or Holter monitoring is likely to play a diminishing role in the development of antiarrhythmic drug regimens, and thus an antiarrhythmic agent's effectiveness may need to be evaluated against the background of implantable cardioverter-defibrillators or against amiodarone therapy. There is increasing evidence that "guided" therapy may simply identify responders from nonresponders and objective endpoints of therapy may be influenced more by drug-specific responses than by the techniques used for their selection. The data raise the issue whether in the future, therapy for ventricular tachycardia or fibrillation might be chosen empirically but from a limited range of compounds, such as beta blockers, amiodarone, sotalol, and possibly certain pure class III agents that are presently under development. Although it is reasonably certain that there is a need to shift from delaying conduction as a means for treating arrhythmias to one that entails prolongation of repolarization, it remains to be determined what might be the characteristics of an ideal antifibrillatory compound. The greatest promise is the area of complex molecules with a diversity of electrophysiologic actions, as exemplified by amiodarone and similar compounds that have the property of blunting sympathetic excitation. The complexity of their electrophysiologic and pharmacodynamic properties might provide a more favorable match with the vulnerable substrate for reducing electrical instability, thereby preventing ventricular fibrillation.
Singh
B N
BN
Department of Cardiology, Veterans Affairs Medical Center, West Los Angeles, California.
D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D001145:Arrhythmias, Cardiac / Q000188:drug therapy*; D006801:Humans; D017180:Tachycardia, Ventricular / Q000188:drug therapy; D016896:Treatment Outcome; D014693:Ventricular Fibrillation / Q000188:drug therapy
D000889:Anti-Arrhythmia Agents