Amiodarone

Abstract

Amiodarone, originally developed over 20 years ago, is a potent antiarrhythmic drug with the actions of all antiarrhythmic drug classes. It has been successfully used in the treatment of symptomatic and life- threatening ventricular arrhythmias and symptomatic supraventricular arrhythmias. In patients with left ventricular dysfunction amiodarone does not usually produce any clinically significant cardiodepression and the drug has relatively high antiarrhythmic efficacy. Preliminary studies indicate that amiodarone may have a beneficial effect on mortality and survival in certain groups of patients with ventricular arrhythmias, an action probably related to both its antiarrhythmic and antifibrillatory effects. The adverse effect profile of amiodarone is diverse, involving the cardiac, thyroid, pulmonary, hepatic, gastrointestinal, ocular, neurological and dermatological systems. Interstitial pneumonitis and hepatitis are potentially fatal, but the vast majority of adverse events are less serious, and some may be dose dependent. Pretreatment monitoring, regular assessments and the use of minimum effective doses are, therefore, necessary. Thus, with appropriate monitoring to control its well recognised adverse effects amiodarone has an important place as an effective ‘broad spectrum’ antiarrhythmic drug which has, so far, been used when other treatments have proved ineffective. More recent preliminary data also suggest that it may also have a beneficial effect in the prevention of sudden death in some patients. Amiodarone was originally described as a class III antiarrhythmic owing to its ability to increase the action potential duration, thereby prolonging repolarisation and refractoriness. In addition, class I antiarrhythmic effects, calcium channel blocking effects and a propensity to non-competitively antagonise α- and β-adrenergic receptors have been seen. On acute administration amiodarone inhibits inactivated membrane sodium channels, producing a decrease in the rate of phase 0 depolarisation $(\dot V_{\max } )$ . In ischaemic conditions class I antiarrhythmic effects predominate. Long term administration results in prolongation of the action potential duration in conjunction with a decrease in $\dot V_{\max }$ . In clinical electrophysiological studies long term oral amiodarone increases atrial, atrioventricular nodal, His-Purkinje and ventricular refractoriness, sinus cycle length and QT interval, and moderately slows intracardiac conduction. In animal models of arrhythmia amiodarone reduced the incidence of ischaemia-induced ventricular arrhythmias in the dog. Furthermore, there is some evidence of a cardioprotective effect in ischaemic models, with reductions in the area of necrosis following infarction. Neither intravenous nor oral amiodarone appears to alter haemodynamic function in a clinically significant way, although in patients with severely depressed left ventricular function hypotension has been reported. The pharmacokinetics of amiodarone and its main metabolite, desethylamiodarone (DEA), are not completely understood and there are large interindividual variations in bioavailability, plasma concentrations and elimination half-life. Oral bioavailability of amiodarone is approximately 40%, probably reflecting incomplete and slow gastrointestinal absorption, and the time to reach peak plasma concentration ranges from 2 to 10 hours. Long term oral treatment does not produce steady-state plasma concentrations for at least 1 month, although antiarrhythmic effects are seen before this time. A therapeutic plasma concentration range of 1 to 2.5 mg/L has been suggested as a rough guide, but clinical response should also be used for determining dose. Amio- darone displays extensive tissue distribution, with the highest concentrations found in adipose tissue. DEA concentrations exceed those of amiodarone in all tissues except fat. The volume of distribution is high, approximately 5000L, and in plasma the drug is approximately 95% protein bound. Metabolism is partly intestinal but mainly hepatic and virtually all the drug is metabolised. Biliary and faecal excretion are the major routes of elimination, with renal excretion responsible for less than 1% of the administered dose, making dosage adjustment unnecessary in cases of renal impairment. Elimination appears biphasic following single oral and intravenous doses, with terminal elimination half-lives of 3.2 to 21 hours reported. Following long term oral administration the average terminal elimination half-life is 40 days. This has important implications for dosage adjustment, as it may take at least 1 month for new plasma concentrations to stabilise, while total clearance from the body can take more than 4 months. The vast majority of patients treated with amiodarone have generally presented with the more severe and sustained refractory arrhythmias. In ventricular arrhythmias intravenous amiodarone (usually 5 mg/kg over 20 to 30 minutes as a loading dose) has suppressed life-threatening sustained ventricular tachycardia or ventricular fibrillation in approximately 40% of patients. Oral treatment (loading plus maintenance therapy) has reduced the recurrence of ventricular tachycardia or ventricular fibrillation in 70 to 95% of patients in noncomparative studies and these effects persisted for long periods. In comparative studies oral amiodarone has proved significantly more effective than placebo, and of comparable efficacy to sotalol, propranolol, flecainide, encainide, propafenone and moricizine in patients with ventricular arrhythmias. Several studies indicated that amiodarone may reduce the incidence of sudden death in patients with arrhythmias associated with organic heart disease, an effect probably related to its antiarrhythmic and antifibrillatory effects. In patients with atrial tachyarrhythmias amiodarone has proved very successful in both restoring and maintaining sinus rhythm in 30 to 95% of...