PubMed · 7513415
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I Singer. 1994. AVID necessity.. https://doi.org/10.1111/j.1540-8159.1994.tb01382.x
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Cardiac arrhythmias frequently respond only to drugs that have as their predominant electrophysiologic effect the prolongation of repolarization and refractoriness. According to the Singh-Vaughan Williams classification, these drugs are known as class III agents. In the last few years, interest has increased in the development of class III antiarrhythmic drugs as alternatives to sodium channel blocking agents, which mainly affect cardiac conduction. Much of this interest results from a perceived danger of using drugs with sodium channel blocking properties, particularly in patients with ischemic heart disease, based on the results of the Cardiac Arrhythmia Suppression Trial (CAST) and several other trials. This article is a review of the pharmacology, including the pharmacokinetics and pharmacodynamics, of the most commonly used and investigated class III antiarrhythmic drugs. As will be seen from the discussion, each of these drugs has novel pharmacology that makes it applicable in specific clinical situations. Their putative effects on various arrhythmogenic mechanisms and their efficacy in treating specific target arrhythmias will be addressed.
Besides their proarrhythmic side-effects, most antiarrhythmic drugs exert varying degrees of depressant action on hemodynamics, which may limit their utility, especially in patients with compromised left ventricular function. Antiarrhythmic drugs have not only myocardial inotropic effects but also act on the coronary and peripheral circulation and the heart rate. Thus, sophisticated and appropriate experimental conditions are necessary to define the effect of their direct negative inotropic actions versus their circulatory effects and the impact of drug-induced autonomic modulation. This study describes an extended comparison of amiodarone, d-sotalol, d,l-sotalol, and dofetilide as class III antiarrhythmic drugs with the actions of several class I antiarrhythmic drugs in an open-chest model. The experimental model permits not only measurements in the intact circulation but also measurements of isovolumic indexes of contractility, which are independent of drug-induced changes in ventricular preload and afterload. Furthermore, after autonomic blockade, hemodynamic effects can be measured independently of modulatory adrenergic effects in such a model. d-Sotalol and amiodarone had cardiodepressant effects only at doses significantly higher than the highest doses used clinically. Dofetilide did not have a negative inotropic effect at doses up to 40 ng/kg. However, these results might be modified in experimental models with severely compromised left ventricular function, as was shown for class I antiarrhythmic drugs and for d,l- and d-sotalol. The sensitivity to a drug's negative inotropic action is markedly increased in functionally impaired myocardium. Furthermore, in a model of postischemic myocardial dysfunction, the depressant effect of d-sotalol could largely be avoided by previous autonomic blockade, indicating the importance of the residual beta-blocking potency of d-sotalol in the doses used in our experiments. Thus, in clinically relevant doses amiodarone, d-sotalol, and dofetilide were found to be devoid of negative inotropic actions in the setting of normal left ventricular myocardium. In failing hearts, such effects become more readily evident than they do in normal hearts after high doses of amiodarone and d-sotalol. From beta-blocking experiments in hearts with left ventricular dysfunction, it could be inferred that residual beta-blocking and other negative inotropic mechanisms may produce a net negative inotropic action, thus masking the minor positive class III effects postulated from in vitro experiments. These observations may have significant clinical implications, because they suggest that the intrinsic myocardial effects of antiarrhythmic drugs may be modified by autonomic effects, the status of ventricular function, and changes in preload and afterload.
Patients with symptomatic ventricular tachycardia, ventricular fibrillation, or aborted sudden cardiac death remain at high risk for arrhythmia recurrence. In recent years, strategies to treat these patients have changed. Concerns about the proarrhythmia risk and uncertain efficacy of class I agents have resulted in a shift in interest to non-class I antiarrhythmic drugs such as sotalol and amiodarone. Both drugs have class III antiarrhythmic properties (i.e., both lengthen repolarization and refractoriness); however, each also has its own additional electrophysiologic effects. Prospectively designed, randomized studies have shown that both sotalol and amiodarone have more potent antiarrhythmic actions than class I agents. However, even as the advantages of sotalol and amiodarone have been recognized, enthusiasm for nonpharmacologic modes of treatment, particularly the implantable cardioverter-defibrillator (ICD), has also markedly increased. The ICD has been shown to decrease dramatically the incidence of sudden death, which may lead to the reduction of total mortality. Whether patients with life-threatening ventricular tachyarrhythmias should be treated first with antiarrhythmic agents or with an ICD is an important question. The results of recent studies suggest that treatment with an ICD is more effective than electrophysiologically guided treatment with class I agents. However, results of prospectively designed randomized studies comparing the efficacy of the ICD with that of sotalol and amiodarone must become available before definitive recommendations can be made concerning the use of the ICD as first-line therapy in patients with ventricular tachycardia/ventricular fibrillation or aborted sudden cardiac death. In addition, there may be a significant role for the use of antiarrhythmic drugs in conjunction with ICDs.