Antiarrhythmic agents amiodarone

Zipes DP, Troup PJ. New antiarrhythmic agents amiodarone, aprindine, disopyramide, ethmozin, mexiletine, tocainide, verapamil. Am J Cardiol 1978 41(6) 1005-24. 

ICDs have been found to be significantly more effective than antiarrhythmic agents such as amiodarone or sotalol for reducing the risk of sudden cardiac death 45,46 therefore, ICDs are preferred therapy.44 However, many patients with ICDs receive concurrent antiarrhythmic drug therapy to reduce the frequency with which patients experience the discomfort of shocks and to prolong battery life of the devices. Combined pharmacotherapy with amiodarone and a 3-blocker is more effective than monotherapy with sotalol or (i-blockers for reduction in the frequency of ICD shocks.47... 

AF often recurs after initial cardioversion because most patients have irreversible underlying heart or lung disease. A metaanalysis confirmed that quinidine maintained sinus rhythm better than placebo however, 50% of patients had recurrent AF within 1 year, and more importantly, quinidine increased mortality, presumably due in part to proarrhythmia. Type Ic (e.g., flecainide, propafenone) and type III (e.g., amiodarone, sotalol, dofetilide) antiarrhythmic agents may be alternatives to quinidine however, these agents are also associated with proarrhythmia. Consequently, chronic antiarrhythmic drugs should be reserved for patients with recurrent paroxysmal AF associated with intolerable symptoms during episodes of AF. 

Amiodarone (11), a benzofuran derivative, was initially developed as a coronary vasodilator in the early 1960 s [11,12]. Several years later, the efficacy of the compound as an antiarrhythmic agent began to be exploited. The first clinical trials with amiodarone were reported in 1974 [13]. Amiodarone was effective in controlling the tachyarrhythmias of eleven patients with Wolff-Parkinson-White syndrome. Since that time the compound has been studied extensively [14,15]. Recently, in the Canadian Amiodarone Myocardial Infarction Arrhythmia Trial (CAMIAT), amiodarone was shown to reduce mortality during a mean 18 month period following myocardial infarction (13.8% deaths in placebo group vs. 2.1 % deaths in the treatment group) [16]. 

In addition to the amiodarone-related compounds, (81) and (82), described above, BASF has been exploring some novel heterocyclic compounds as Class III antiarrhythmic agents. A series of imidazo[l,2-c]pyrro-lo[l,2-a]quinazoline derivatives have been patented which are several times more potent than (-I- )-sotalol in lengthening QT interval of the electrocardiogram in the anaesthetized guinea-pig model [230], One of the most potent compounds is (85), which was 17-times more potent than the standard. These compounds represent one of the unique Class III structural types described to date. 

Cardiac toxicity Moxifloxacin and gatifloxacin have been shown to prolong the QT interval of the electrocardiogram in some patients. Avoid in patients with known prolongation of the QT interval, patients with uncorrected hypokalemia, and patients receiving class lA (eg, quinidine, procainamide) or class III (eg, amiodarone, sotalol) antiarrhythmic agents. 

The most notable electrophysiological effect of amiodarone after long-term administration is prolongation of repolarization and refractoriness in all cardiac tissues, an action that is characteristic of class III antiarrhythmic agents. 

Amiodarone is regarded as one of the most efficacious antiarrhythmic agents because of its usefulness in the management of a variety of cardiac rhythm disorders with minimal tendency for induction of torsades de pointes tachyarrhythmia. Its use, however, is limited by the multiple and severe noncardiac side effects that it produces. 

Amiodarone may elicit life-threatening side effects in addition to presenting substantial management difh-culties associated with its use. The oral formulation of amiodarone is indicated only for the treatment of life-threatening recurrent ventricular arrhythmias (e.g., recurrent ventricular hbrillation and/or recurrent hemo-dynamicaUy unstable ventricular tachycardia) that have not responded to other potentially effective antiarrhythmic drugs or when alternative interventions could not be tolerated. Despite its efficacy as an antiarrhythmic agent, there is no evidence from clinical trials that the use of amiodarone favorably affects survival. 

For example, amiodarone shares all four classes of action. Drugs are usually discussed according to the predominant class of action. Certain antiarrhythmic agents, eg, adenosine and magnesium, do not fit readily into this scheme and are described separately. 

The only other anesthetic to cause serious toxicity for which a metabolic drug interaction has been reasonably well characterized is the local anesthetic and antiarrhythmic agent lidocaine. Amiodarone decreased lidocaine systemic clearance in a patient (primarily by inhibition of CYP3A4 N-dealkylation of lidocaine) and yielded concentrations of lidocaine that led to seizures (78,79). 

Arrhythmias are frequently asymptomatic but may be fatal. Indeed an estimated 70 000 deaths per year are ascribed to ventricular arrhythmias in the United Kingdom. In addition, all antiarrh5dhmics are also capable of generating arrhythmias and should be used only in the presence of clear indications. In addition, antiarrhythmic agents are to a variable degree negatively inotropic (except for digoxin and amiodarone). 

Rosenbaum MB, Chiale PA, Halpern MS, Nau GJ, Przybylski J, Levi RJ, Lazzari JO, Elizari MV. Clinical efficacy of amiodarone as an antiarrhythmic agent. Am J Cardiol 1976 38(7) 934 4. 

Amiodarone, lidocaine, and procainamide are commonly used antiarrhythmics for conversion in VF. Of these, amiodarone is the antiarrhythmic agent recommended first. In the Amiodarone versus Lidocaine in Ventricular Emergency (ALIVE) trial, patients administered amiodarone had a better rate of survival to hospital admission than those... 

Amiodarone is primarily a class III antiarrhythmic agent but does display activity in each of the four Vaughn-Williams antiarrhythmic classes. The drug delays repolarization via prolongation of the action potential duration and effective refractory period, decreases AV conduction, depresses sinus node and junctional automaticity, acts as a noncompetitive a- and jS-adrenergic inhibitor, and slows automaticity of Purkinje fibers. 

A recommendation for a specific antiarrhythmic agent of first choice does not exist. Amiodarone, lidocaine, and procainamide are the available options. 

The pharmacokinetics of the antiarrhythmic agents are summarized in Table 17-4, and a nomogram for estimating effective dosages of the oral forms (except amiodarone) is shown in Fig. 17-5. Dosing recommendations for the intravenous forms are shown in Table 17-5. 

Although nearly every type I or III antiarrhythmic drug has some published evidence of effectiveness in preventing recurrences of atrial fibrillation, amiodarone is clearly the most effective agent and now the most frequently chosen despite its impressive toxicity. Initially, uncontrolled studies indicated that low doses (100 to 200 mg/day) of amiodarone are effective. Later, in a comparative trial,amiodarone was shown to be superior to either sotalol or propafenone in maintaining sinus rhythm. Further, in a substudy of AFFIRM,amiodarone was demonstrated to be the most effective antiarrhythmic agent of those used in the study. 

---