At the time of the last review of antiarrhythmic drugs in this series in 1 975 (1) , the important developments in the field centered around the "classical" agents: lidocaine, procainamide, quinidine, diphenylhydantoin (now phenytoin), and propranolol. That review properly emphasized the importance of new informa­ tion regarding the effects of these agents on diseased tissue (e.g. obtained from infarcted hearts) or on normal tissue stressed in the muscle chamber (e.g. by depolarization with potassium). However, data and concepts available at that time were not sufficient to explain the important differences among the effects of these drugs on different types of cardiac tissue, or the difference in sensitiv­ ity of diseased and depolarized tissue as compared to normal tissue. Since 1 975, a modest revolution in antiarrhythmic drug development, re­ search, and clinical application has occurred. The number of agents in active clinical use or investigation in the U.S. is now more than 18 (2, 3). In addition, a major new class of agents, the calcium channel blockers, has come into general use (4, 5) . Furthermore, an attempt has been made to extend our understanding of the mechanism of action at the molecular level: the modulated receptor hypothesis (6, 7). This review concentrates on the antiarrhythmic drug literature pertinent to an evaluation of the modulated receptor hypothesis. A number of general reviews

Antiarrhythmic Agents: The Modulated Receptor Mechanism of Action of Sodium and Calcium Channel-Blocking Drugs

We evaluated the effects of amiodarone in 45 patients with recurrent ventricular tachycardia or ventricular fibrillation. At a mean follow-up time of 12.7 +/- 8.8 months (range, three to 36), amiodarone was successful in nine of 16 patients with recurrent ventricular fibrillation and 21 of 29 with recurrent ventricular tachycardia. During amiodarone therapy, ventricular tachycardia could be induced in 18 of 19 patients in whom it had been induced before therapy, but only six of these 19 had spontaneous recurrence during follow-up. Side effects included corneal microdeposits, hyperthyroidism, blue skin, nausea, and symptomatic bradycardia. Pulmonary fibrosis occurred in three patients. Doses of up to 2000 mg a day did not produce cardiac toxicity, but neurologic side effects precluded long-term therapy at this dose. We conclude that amiodarone is effective for long-term therapy of recurrent ventricular tachyarrhythmias, that induction of arrhythmia during therapy does not always predict efficacy, and that side effects are frequent but do not usually limit therapy.

Clinical efficacy and electrophysiology during long-term therapy for recurrent ventricular tachycardia or ventricular fibrillation.

Adverse Effects of Low Dose Amiodarone: A Meta-Analysis

ContextAlthough amiodarone is approved by the US Food and Drug Administration only for refractory ventricular arrhythmias, it is one of the most frequently prescribed antiarrhythmic medications in the United States.ObjectiveTo evaluate and synthesize evidence regarding optimal use of amiodarone for various arrhythmias.Evidence AcquisitionSystematic search of MEDLINE to identify peer-reviewed clinical trials, randomized controlled trials, meta-analyses, and other studies with clinical pertinence. The search was limited to human-participant, English-language reports published between 1970 and 2007. Amiodarone was searched using the terms adverse effects, atrial fibrillation, atrial flutter, congestive heart failure, electrical storm, hypertrophic cardiomyopathy, implantable cardioverter-defibrillator, surgery, ventricular arrhythmia, ventricular fibrillation, and Wolff-Parkinson-White. Bibliographies of identified articles and guidelines from official societies were reviewed for additional references. Ninety-two identified studies met inclusion criteria and were included in the review.Evidence SynthesisAmiodarone may have clinical value in patients with left ventricular dysfunction and heart failure as first-line treatment for atrial fibrillation, though other agents are available. Amiodarone is useful in acute management of sustained ventricular tachyarrythmias, regardless of hemodynamic stability. The only role for prophylactic amiodarone is in the perioperative period of cardiac surgery. Amiodarone may be effective as an adjunct to implantable cardioverter-defibrillator therapy to reduce number of shocks. However, amiodarone has a number of serious adverse effects, including corneal microdeposits (>90%), optic neuropathy/neuritis (≤1%-2%), blue-gray skin discoloration (4%-9%), photosensitivity (25%-75%), hypothyroidism (6%), hyperthyroidism (0.9%-2%), pulmonary toxicity (1%-17%), peripheral neuropathy (0.3% annually), and hepatotoxicity (elevated enzyme levels, 15%-30%; hepatitis and cirrhosis, <3% [0.6% annually]).ConclusionAmiodarone should be used with close follow-up in patients who are likely to derive the most benefit, namely those with atrial fibrillation and left ventricular dysfunction, those with acute sustained ventricular arrhythmias, those about to undergo cardiac surgery, and those with implantable cardioverter-defibrillators and symptomatic shocks.

https://jamanetwork.com/journals/jama/articlepdf/208819/jcr70010_1312_1322.pdf

Prescribing Amiodarone: An Evidence-Based Review of Clinical Indications

Criteria for intraventricular conduction disturbances and pre-excitation

Amiodarone, administered orally in doses of 200 to 600 mg/day, was remarkably effective in the treatment and prevention of a wide variety of atrial and ventricular arrhythmias. Total suppression and control was provided in 98 (92.4 percent) of 106 patients with supraventricular arrhythmias and in 119 (82 percent) of 145 patients with ventricular arrhythmias. The rates of total control of the arrhythmia were: 96.6 percent in 30 patients with recurrent atrial flutter or fibrillation, 96.6 percent in 59 patients with repetitive supraventricular tachycardia, 100 percent in 27 patients with Wolff-Parkinson-White syndrome and 77.2 percent in 44 patients with recurrent ventricular tachycardia unsuccessfully treated with other drugs. Excellent results were obtained in 6 of 8 patients with repetitive ventricular tachycardia and ventricular fibrillation related to postinfarction ventricular aneurysm and in 12 of 14 patients with ventricular extrasystoles and ventricular tachycardia related to Chagasic myocarditis. Amiodarone proved safe in patients with severe congestive heart failure and severe myocardial damage. Its clinical efficacy was related to its electrophysiologic properties and to two unique properties: its wide safety margin and its cumulative effect. The latter liberates patients from a rigid hourly schedule and provides for continuous antiarrhythmic control, days and even weeks after treatment is discontinued.

Raúl J. Levi

Papers

Clinical efficacy of amiodarone as an antiarrhythmic agent

The Mechanism of Intermittent Bundle Branch Block: Relationship to Prolonged Recovery, Hypopolarization and Spontaneous Diastolic Depolarization

Intraventricular trifascicular blocks. Review of the literature and classification.

Intraventricular trifascicular blocks. The syndrome of right bundle branch block with intermittent left anterior and posterior hemiblock.

Paroxysmal Atrioventricular Block Related to Hypopolarization and Spontaneous Diastolic Depolarization