Amiodarone

Summary

Synopsis

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.

Pharmacodynamic Properties

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.

Pharmacokinetic Properties

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.

Therapeutic Use

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 patients when used in conjunction with electrocardioversion, particularly in paroxysmal arrhythmias. Amiodarone has generally been more successful than either verapamil or quinidine, and appears promising in moderate to marked left atrial dilatation.

Suppression of paroxysmal supraventricular tachycardia (SVT) [with or without Wolff-Parkinson-White syndrome] is seen in approximately 75% of patients following treatment with amiodarone. This, along with efficacy in a range of re-entry arrhythmias, may relate to amiodarone’s propensity to suppress premature beats and increase the refractory periods of the atrioventricular node and accessory conduction pathways.

In both hypertrophic and dilated cardiomyopathy amiodarone has proved effective in suppressing both ventricular tachycardia and SVT, and may be associated with improved survival in those patients with hypertrophic cardiomyopathy.

Tolerability

Adverse effects of amiodarone are mainly dose dependent, and predominantly endocrine (hypo-or hyperthyroidism), pulmonary (interstitial pneumonitis), hepatic (abnormally elevated liver enzymes, hepatitis), cardiac (proarrhythmia, bradycardia, worsening congestive heart failure), gastrointestinal (nausea, anorexia, constipation), ocular (corneal microdeposits), neurological (tremor, neuropathy) and dermatological (photosensitivity, grey/blue discoloration). These range from minor asymptomatic problems requiring no intervention to life-threatening problems necessitating drug withdrawal and supportive measures. Interstitial pneumonitis is probably the most serious toxic reaction. Pretreatment assessment and regular monitoring, in conjunction with the use of minimum effective doses, provide the basis for early recognition and appropriate effective management.

Drug Interactions

Amiodarone alters the pharmacokinetics of digoxin, oral anticoagulants, class I antiarrhythmic drugs, β-blockers and calcium channel blockers. Importantly, the long plasma elimination half-life of amiodarone means that the potential for significant drug interaction persists for some time after treatment has stopped. Dosages of digoxin should be reduced by 25 to 50%, while those of oral anticoagulants (warfarin, acenocoumarol) should be reduced by about 50%. Close monitoring of plasma digoxin levels and prothrombin time is essential. There is a possibility of potentiating sinus bradycardia or arrest, or proarrhythmic effects when amiodarone is used in conjunction with class I antiarrhythmics, β-blockers and calcium channel blockers.

Dosage and Administration

The recommended dosage of amiodarone administered intravenously in adults with any tachyarrhythmia is up to 5 mg/kg over 20 to 120 minutes, in conjunction with ECG monitoring. Doses of 10 to 20 mg/kg may be infused in a 24-hour period. Rapid intravenous bolus injection may induce hypotension. When administered orally loading doses of 600 to 1200 mg/day are generally given for 1 to 2 weeks and then the dose is titrated down to 400 to 800 mg/day for a month. Maintenance therapy is usually 200 to 400 mg/day.