Amiodarone.

Antiarrhythmic drug therapy is in a state of continuous flux. In the last decade or so, numerous experimental and clinical studies have revealed that drugs that act by delaying conduction, while markedly suppressing ventricular arrhythmias, have the proclivity to increase mortality in subsets of patients with significant cardiac disease. The adverse impact on mortality was confirmed by placebo-controlled randomized trials as well as meta-analysis of smaller randomized clinical trials. The latter indicated that beta blockers exert a beneficial effect on mortality. Benefit from drugs that lengthen repolarization, especially drugs that have the additional property of blocking sympathetic excitation, was also seen in relatively small numbers of patients. Sotalol and amiodarone fell into this category of antiarrhythmic drugs. There were 2 major consequences that stemmed from the results of these trials. First, the endpoint of clinical trials shifted to total mortality from surrogates such as defined degree of suppression of ventricular arrhythmias. Second, concern regarding increases in mortality produced by class I drugs engendered a shift in favor of drugs that prolong repolarization. Such a shift was bolstered by the growing body of data that established the efficacy of sotalol and amiodarone as potent agents for the control of life-threatening ventricular arrhythmias. They were both found to be superior to class I agents. The perception that the critical factor that mediates their efficacy is the homogeneous prolongation of repolarization has led to the synthesis and characterization of so-called pure class III agents, which include d-sotalol and other lKr blockers such as dofetilide, sematilide, E-4031, and almokalant, among numerous others. The increase in mortality produced by d-sotalol in patients with myocardial infarction and lowered ejection fraction and in patients with and without heart failure has led researchers to question how to design future antiarrhythmic molecules. In the search for an ideal antifibrillatory agent, should emphasis be placed on simple molecules such as pure class III agents or on those with more complex profiles, such as sotalol and amiodarone, which exhibit antiadrenergic actions and the ability to prolong cardiac repolarization? The available data are in favor of the latter approach.

Amiodarone↗

PubMed1996

Antiarrhythmic actions of amiodarone: a profile of a paradoxical agent.

Amiodarone, a complex compound with variegated electropharmacologic and pharmacokinetic properties and an equally complex side-effect profile, continues to have a critical role in the control of ventricular and supraventricular tachyarrhythmias as the use of class I agents has declined. Such is also the case with sotalol. Unlike other so-called class III agents, amiodarone non-competitively blocks sympathetic stimulation, and its effects on repolarization are not associated with reverse use dependency. Rarely does it produce torsades de pointes despite its propensity to induce significant bradycardia and marked prolongation of the QT interval. During long-term therapy with the drug, there is no impairment of ventricular function; in fact, there are significant increases in the left ventricular ejection fraction during protracted amiodarone therapy in patients with heart failure. Long-term amiodarone administration consistently demonstrates marked efficacy in a wide spectrum of arrhythmias. The major limitation of amiodarone during long-term therapy is its unusual side-effect profile, although the increasing trend for low-dose drug therapy has demonstrated a major decline in the overall incidence of serious adverse reactions. Amiodarone is effective in controlling symptomatic ventricular tachycardia and fibrillation (VT/VF) in > 60-70% of patients when conventional agents (especially class I) are ineffective or not well tolerated. The efficacy of amiodarone compared with that of an implantable cardioverter-defibrillator in patients with VT/VF and in survivors of cardiac arrest remains uncertain when total mortality is used as the primary endpoint of comparison. Amiodarone suppresses ventricular ectopy and markedly suppresses nonsustained VT. It prevents inducible VT/VF in a small number of patients, but slows VT rate in a larger number. The role of the drug in prolonging survival in the postmyocardial infarction patient is unclear, although preliminary data from blinded studies suggest that the drug decreases arrhythmia-related mortality. Similarly, in heart failure, amiodarone has the potential to reduce total mortality but appears to be selectively effective in nonischemic rather than in ischemic cardiomyopathy. Intravenous amiodarone was recently introduced in the United States for the control of recurrent destabilizing VT or VF resistant to conventional therapy. There is also evolving data indicating that the drug might be the most potent agent in maintaining sinus rhythm in patients with atrial fibrillation or flutter converted chemically or electrically to sinus rhythm. However, blinded controlled comparative studies involving sotalol, quinidine, or pure class III drugs have not been carried out. The available data nevertheless suggest that, barring its side-effect profile, amiodarone is a desirable prototype of a broad-spectrum antifibrillatory and antiarrhythmic compound.

Amiodarone↗