Description

Simple

A medication used to regulate the rhythm of the heart.

Clinical

A class III antiarrhythmic indicated for the treatment of recurrent hemodynamically unstable ventricular tachycardia and recurrent ventricular fibrillation.

Overview

Amiodarone is a benzofuran derivative, anti-arrhythmic drug used commonly in a variety of settings.[4] Most known for its approved indication in life-threatening ventricular arrhythmias, it is also used off-label in the outpatient and inpatient setting for atrial fibrillation. Because of its ability to cause serious toxicity and possibly death, amiodarone use should be reserved for its approved indications, according to prescribing information.[18,19,20]

Pharmacology

Indication

The FDA approved indications for amiodarone are recurrent ventricular fibrillation (VF)
and recurrent hemodynamically unstable ventricular tachycardia (VT). The FDA emphasizes that this drug should only be given in these conditions when they are clinically documented and have not responded to norma... Read more

The FDA approved indications for amiodarone are recurrent ventricular fibrillation (VF)
and recurrent hemodynamically unstable ventricular tachycardia (VT). The FDA emphasizes that this drug should only be given in these conditions when they are clinically documented and have not responded to normal therapeutic doses of other antiarrhythmic agents, or when other drugs are not tolerated by the patient.[18]

Off-label indications include atrial fibrillation and supraventricular tachycardia.[7,8,9,20] Read Less

Pharmacodynamic

After intravenous administration, amiodarone acts to relax smooth muscles that line vascular walls, decreases peripheral vascular resistance (afterload), and increases the cardiac index by a small amount. Administration by this route also decreases cardiac conduction, preventing and treating arrhyth... Read more

After intravenous administration, amiodarone acts to relax smooth muscles that line vascular walls, decreases peripheral vascular resistance (afterload), and increases the cardiac index by a small amount. Administration by this route also decreases cardiac conduction, preventing and treating arrhythmias.[2,7,18] When it is given orally, however, amiodarone does not lead to significant changes in the left ventricular ejection fraction. Similar to other anti-arrhythmic agents, controlled clinical trials do not confirm that oral amiodarone increases survival.[18]

Amiodarone prolongs the QRS duration and QT interval. In addition, a decreased SA (sinoatrial) node automaticity occurs with a decrease in AV node conduction velocity. Ectopic pacemaker automaticity is also inhibited.[19] Thyrotoxicosis or hypothyroidism may also result from the administration of amiodarone, which contains high levels of iodine, and interferes with normal thyroid function.[11] Read Less

Mechanism of action

Amiodarone is considered a class III anti-arrhythmic drug. It blocks potassium currents that cause repolarization of the heart muscle during the third phase of the cardiac action potential. As a result amiodarone increases the duration of the action potential as well as the effective refractory peri... Read more

Amiodarone is considered a class III anti-arrhythmic drug. It blocks potassium currents that cause repolarization of the heart muscle during the third phase of the cardiac action potential. As a result amiodarone increases the duration of the action potential as well as the effective refractory period for cardiac cells (myocytes). Therefore, cardiac muscle cell excitability is reduced, preventing and treating abnormal heart rhythms.[5,10]

Unique from other members of the class III anti-arrhythmic drug class, amiodarone also interferes with the functioning of beta-adrenergic receptors, sodium channels, and calcium channels channels. These actions, at times, can lead to undesirable effects, such as hypotension, bradycardia, and Torsades de pointes (TdP).[19] In addition to the above, amiodarone may increase activity of peroxisome proliferator-activated receptors, leading to steatogenic changes in the liver or other organs.[14,15] Finally, amiodarone has been found to bind to the thyroid receptor due to its iodine content, potentially leading to amiodarone induced hypothyroidism or thyrotoxicosis.[11] Read Less

Absorption

The Cmax of amiodarone in the plasma is achieved about 3 to 7 hours after administration.[18] The general time to onset of action of amiodarone after one dose given by the intr... Read more

The Cmax of amiodarone in the plasma is achieved about 3 to 7 hours after administration.[18] The general time to onset of action of amiodarone after one dose given by the intravenous route is between 1 and 30 minutes, with therapeutic effects lasting from 1-3 hours. Steady-state concentrations of amiodarone in the plasma ranges between 0.4 to 11.99 μg/ml; it is advisable that steady-state levels are generally maintained between 1.0 and 2.5 μg/ml in patients with arrhythmias.[4,5]

Interestingly, its onset of action may sometimes begin after 2 to 3 days, but frequently takes 1 to 3 weeks, despite the administration of higher loading doses.[18] The bioavailability of amiodarone varies in clinical studies, averaging between 35 and 65%.[18]

Effect of food

In healthy subjects who were given a single 600-mg dose immediately after consuming a meal high in fat, the AUC of amiodarone increased by 2.3 and the Cmax by 3.8 times.[18] Food also enhances absorption, reducing the Tmax by about 37%.[18]
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Protein binding

The protein binding of amiodarone is about 96%.[4, Read more

The protein binding of amiodarone is about 96%.[4,18] Read Less

Volume of distribution

In a pharmacokinetic study of 3 healthy individuals and 3 patients diagnosed with supraventricular tachycardia (SVT), the volume of distribution was found to be 9.26-17.17 L/kg in healthy volunteers and 6.88-21.05 L/kg in the SVT patients.[ Read more

In a pharmacokinetic study of 3 healthy individuals and 3 patients diagnosed with supraventricular tachycardia (SVT), the volume of distribution was found to be 9.26-17.17 L/kg in healthy volunteers and 6.88-21.05 L/kg in the SVT patients.[6] Prescribing information mentions that the volume of distribution of amiodarone varies greatly, with a mean distribution of approximately 60 L/kg. It accumulates throughout the body, especially in adipose tissue[4] and highly vascular organs including the lung, liver, and spleen. One major metabolite of amiodarone, desethylamiodarone (DEA), is found in even higher proportions in the same tissues as amiodarone.[18] Read Less

Clearance

The clearance of amiodarone after intravenous administration in patients with ventricular fibrillation and ventricular tachycardia ranged from 220 to 440 ml/hr/kg in one clinically study.[ Read more

The clearance of amiodarone after intravenous administration in patients with ventricular fibrillation and ventricular tachycardia ranged from 220 to 440 ml/hr/kg in one clinically study.[18] Another study determined that the total body clearance of amiodarone varies from 0.10 to 0.77 L/min after one intravenous dose.[4] Renal impairment does not appear to affect the clearance of amiodarone, but hepatic impairment may reduce clearance. Patients with liver cirrhosis exhibited significantly lower Cmax and mean amiodarone concentration for DEA, but not for amiodarone. Severe left ventricular dysfunction prolongs the half-life of DEA.[18]A note on monitoringNo guidelines have been developed for adjusting the dose of amiodarone in renal, hepatic, or cardiac abnormalities. In patients on chronic amiodarone treatment, close clinical monitoring is advisable, especially for elderly patients and those with severe left ventricular dysfunction.[18] Read Less

Half life

The terminal half-life of amiodarone varies according to the patient, but is long nonetheless, and ranges from about 9-100 days. The half-life duration varies according to different sources. [ Read more

The terminal half-life of amiodarone varies according to the patient, but is long nonetheless, and ranges from about 9-100 days. The half-life duration varies according to different sources. [3,7] According to the prescribing information for amiodarone, the average apparent plasma terminal elimination half-life of amiodarone is of 58 days (ranging from 15 to 142 days). The terminal half-life range was between 14 to 75 days for the active metabolite, (DEA).[18] The plasma half-life of amiodarone after one dose ranges from 3.2 to 79.7 hours, according to one source.[4] Read Less

Route of elimination

Amiodarone is eliminated primarily by hepatic metabolism and biliary excretion.[4... Read more

Amiodarone is eliminated primarily by hepatic metabolism and biliary excretion.[4] A small amount of desethylamiodarone (DEA) is found in the urine.[18] Read Less

Toxicity

The LD50 of oral amiodarone in mice and rats exceeds 3,000 mg/kg.[18]
An overdose with amiodarone can have a fatal outcome due to its potential to cause arrhythmia. Signs or s... Read more

The LD50 of oral amiodarone in mice and rats exceeds 3,000 mg/kg.[18]
An overdose with amiodarone can have a fatal outcome due to its potential to cause arrhythmia. Signs or symptoms of an overdose may include, hypotension, shock, bradycardia, AV block, and liver toxicity. In cases of an overdose, initiate supportive treatment and, if needed, use fluids, vasopressors, or positive inotropic agents. Temporary pacing may be required for heart block. Ensure to monitor liver function regularly. Amiodarone and its main metabolite, DEA, are not removable by dialysis.[17] Read Less

Adverse Effects

Contraindications