Amiodarone

AMIODARONE

In the USA, amiodarone is approved for oral and intravenous use to treat serious ventricular arrhythmias. However, the drug is also highly effective for the treatment of supraventricular arrhythmias such as atrial fibrillation. As a result of its broad spectrum of anti-arrhythmic action, it is very extensively used for a wide variety of arrhythmias. Amiodarone has unusual pharmacokinetics and impor-tant extracardiac adverse effects. Dronedarone, an analog that lacks iodine atoms, recently received Food and Drug Administration approval for the treatment of atrial flutter and fibrillation. Celivarone is another noniodinated benzofuran derivative similar to drone-darone that is currently undergoing clinical trials for the preven-tion of ventricular tachycardia recurrence.

Cardiac Effects

Amiodarone markedly prolongs the action potential duration (and the QT interval on the ECG) by blockade of I_Kr. During chronic administration, I_Ks is also blocked. The action potential duration is prolonged uniformly over a wide range of heart rates; that is, the drug does not have reverse use-dependent action. In spite of its present classification as a class 3 agent, amiodarone also signifi-cantly blocks inactivated sodium channels. Its action potential-prolonging action reinforces this effect. Amiodarone also has weak adrenergic and calcium channel-blocking actions. Consequences of these actions include slowing of the heart rate and AV node conduction. The broad spectrum of actions may account for its relatively high efficacy and its low incidence of torsades de pointes despite significant QT-interval prolongation.

Extracardiac Effects

Amiodarone causes peripheral vasodilation. This action is promi-nent after intravenous administration and may be related to the action of the vehicle.

Toxicity

Amiodarone may produce symptomatic bradycardia and heart block in patients with preexisting sinus or AV node disease. The drug accumulates in many tissues, including the heart (10–50 times more so than in plasma), lung, liver, and skin, and is concentrated in tears. Dose-related pulmonary toxicity is the most important adverse effect. Even on a low dose of 200 mg/d or less, fatal pulmonary fibrosis may be observed in 1% of patients.

Abnormal liver function tests and hypersensitivity hepatitis may develop during amiodarone treatment and liver function tests should be monitored regularly. The skin deposits result in a pho-todermatitis and a gray-blue skin discoloration in sun-exposed areas, eg, the malar regions. After a few weeks of treatment, asymptomatic corneal microdeposits are present in virtually all patients treated with amiodarone. Halos develop in the peripheral visual fields of some patients. Drug discontinuation is usually not required. Rarely, an optic neuritis may progress to blindness.

Amiodarone blocks the peripheral conversion of thyroxine (T₄) to triiodothyronine (T₃). It is also a potential source of large amounts of inorganic iodine. Amiodarone may result in hypothy-roidism or hyperthyroidism. Thyroid function should be evaluated before initiating treatment and should be monitored periodically. Because effects have been described in virtually every organ system, amiodarone treatment should be reevaluated whenever new symp-toms develop in a patient, including arrhythmia aggravation.

Pharmacokinetics

Amiodarone is variably absorbed with a bioavailability of 35–65%. It undergoes hepatic metabolism, and the major metabolite, des-ethylamiodarone, is bioactive. The elimination half-life is com-plex, with a rapid component of 3–10 days (50% of the drug) and a slower component of several weeks. After discontinuation of the drug, effects are maintained for 1–3 months. Measurable tissue levels may be observed up to 1 year after discontinuation. A total loading dose of 10 g is usually achieved with 0.8–1.2 g daily doses. The maintenance dose is 200–400 mg daily. Pharmacologic effects may be achieved rapidly by intravenous loading. QT-prolonging effect is modest with this route of administration, whereas brady-cardia and AV block may be significant.

Amiodarone has many important drug interactions, and all medications should be reviewed when the drug is initiated and when the dose is adjusted. Amiodarone is a substrate for liver cyto-chrome CYP3A4, and its levels are increased by drugs that inhibit this enzyme, eg, the histamine H₂ blocker cimetidine. Drugs that induce CYP3A4, eg, rifampin, decrease amiodarone concentration when coadministered. Amiodarone inhibits several cytochrome P450 enzymes and may result in high levels of many drugs, includ-ing statins, digoxin, and warfarin. The dose of warfarin should be reduced by one third to one half following initiation of amio-darone, and prothrombin times should be closely monitored.

Therapeutic Use

Low doses (100–200 mg/d) of amiodarone are effective in main-taining normal sinus rhythm in patients with atrial fibrillation. The drug is effective in the prevention of recurrent ventricular tachycardia. It is not associated with an increase in mortality in patients with coronary artery disease or heart failure. In many centers, the implanted cardioverter-defibrillator (ICD) has suc-ceeded drug therapy as the primary treatment modality for ven-tricular tachycardia, but amiodarone may be used for ventricular tachycardia as adjuvant therapy to decrease the frequency of uncomfortable cardioverter defibrillator discharges. The drug increases the pacing and defibrillation threshold and these devices require retesting after a maintenance dose has been achieved.