Ionic mechanisms for prolongation of refractoriness and their proarrhythmic and antiarrhythmic correlates.
Drugs that prolong cardiac refractoriness exert antiarrhythmic effects, probably by reducing dispersion of refractoriness and thereby reducing the likelihood of reentrant excitation. This electrophysiologic effect can be achieved in fast-response tissues by sodium channel block or by action potential prolongation; drugs with either attribute can exert antiarrhythmic effects. However, both types of drugs can also cause proarrhythmic effects. For sodium channel blockers, proarrhythmic actions can be attributed to conduction slowing and include increased frequency of episodes of ventricular tachycardia as well as slowing of atrial flutter with 1:1 atrioventricular conduction and increases in ventricular rate. In addition, sodium channel block has been implicated as the mechanism underlying increased mortality with sodium channel blockers in the Cardiac Arrhythmia Suppression Trial (CAST); some data suggest that intercurrent ischemia increases this risk. For drugs that prolong action potentials, torsades de pointes is the most common proarrhythmic syndrome, occurring most often with underlying bradyarrhythmias and hypokalemia. The mechanism(s) underlying normal refractoriness and its modulation by antiarrhythmic drugs, as well as the mechanism(s) underlying these proarrhythmic syndromes, are discussed.
Roden
D M
DM
Department of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-6602, USA.
D000200:Action Potentials; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001145:Arrhythmias, Cardiac / Q000503:physiopathology*; D004594:Electrophysiology; D006329:Heart Conduction System / Q000503:physiopathology; D006801:Humans; D007473:Ion Channels / Q000502:physiology*; D012032:Refractory Period, Electrophysiological / Q000187:drug effects*; D026941:Sodium Channel Blockers; D015222:Sodium Channels / Q000502:physiology; D016171:Torsades de Pointes / Q000188:drug therapy / Q000503:physiopathology
D000889:Anti-Arrhythmia Agents; D007473:Ion Channels; D026941:Sodium Channel Blockers; D015222:Sodium Channels