The elimination half-life of amiodarone is highly variable and unusually long, averaging about 58 days. The long half-life is thought to be a result of the drug's slow release from lipid-rich tissues. However, the drug has many other effects: it slows heart rate and atrioventricular nodal conduction via calcium channel and beta-receptor blockade , prolongs refractoriness via potassium and sodium channel blockade , and slows intracardiac conduction via sodium channel blockade.
The relationship between plasma amiodarone concentrations and effect, as well as the contribution of the metabolite DEA, is not well established. Amiodarone is approved for use in the secondary prevention of life-threatening ventricular arrhythmias. The North American Society for Pacing and Electrophysiology NASPE recommends amiodarone as the antiarrhythmic agent of choice in patients who have survived sustained ventricular tachyarrhythmias, particularly those with left ventricular dysfunction.
Studies on the use of amiodarone for the primary prevention of sudden death in high-risk patients have had mixed results. One meta-analysis of 13 studies of patients with congestive heart failure or recent myocardial infarction showed a small reduction in total annual mortality, from Because implantable cardioverter-defibrillators ICDs are more effective than amiodarone in reducing mortality in high-risk patients with previous myocardial infarction, primary treatment should be an ICD.
The relative efficacy of amiodarone and ICDs in preventing sudden death in patients without coronary disease is under investigation. Amiodarone is used in the treatment of atrial fibrillation, although the FDA has not approved this indication.
Various practice guidelines recommend amiodarone as a second-line drug in the long-term treatment of atrial fibrillation in patients with structural heart disease and in highly symptomatic patients without heart disease. However, recent studies have shown that aggressive attempts to maintain sinus rhythm using amiodarone or other drugs do not improve outcomes in relatively asymptomatic patients.
Intravenously administered amiodarone is effective for the emergency treatment of ventricular tachyarrhythmias. Onset of the antiarrhythmic effect of intravenous amiodarone occurs in less than 30 minutes. In the Advanced Cardiac Life Support ACLS guidelines published in , amiodarone and procainamide are recommended for the initial treatment of hemodynamically stable wide-complex tachycardia. In contrast, a recent study comparing the use of amiodarone and lidocaine in patients with shock-resistant, out-of-hospital ventricular fibrillation showed that amiodarone therapy substantially improves survival and hospital admission rates.
Patients who received intravenous amiodarone for less than one week should take to 1, mg oral amiodarone per day. Bradycardia, QT prolongation, GI upset, constipation; rarely, torsades de pointes. Information from references 2 and Intravenously administered amiodarone is being used with increasing frequency in the acute treatment of atrial fibrillation. In a meta-analysis of 18 RCTs, amiodarone was similar to other antiarrhythmic drugs in its ability to convert patients to normal sinus rhythm Use of these drugs would be most appropriate in patients with recurrent hemodynamically unstable atrial fibrillation.
Amiodarone has been associated with toxicity involving the lungs, thyroid gland, liver, eyes, skin, and nerves Table 2. Therefore, physicians must use the lowest possible dosage of amiodarone and, if possible, discontinue treatment if adverse effects occur. Chest radiograph; pulmonary function tests, including D lco. Information from references 2 , 5 , 11 , and The most serious potential adverse effect of amiodarone therapy is pulmonary toxicity, which may result from direct drug-induced phospholipidosis or immune-mediated hypersensitivity.
A much less common presentation is adult respiratory distress syndrome. In early studies, the frequency of pulmonary toxicity in amiodarone therapy was 2 to 17 percent. A meta-analysis 11 of double-blind trials found the frequency of adult respiratory distress syndrome to be 1 percent annually. Routine screening for adult respiratory distress syndrome is of limited value, because pulmonary toxicity can develop rapidly with no antecedent abnormalities on chest radiographs or pulmonary function tests.
Any report from the patient of worsening dyspnea or cough should elicit a prompt assessment for pulmonary toxicity. Congestive heart failure can mimic amiodarone pneumonitis and, thus, must be ruled out early in the evaluation. High-resolution computed tomographic scanning can be helpful in making a diagnosis. The primary treatment for pulmonary toxicity is withdrawal of amiodarone and provision of supportive care and, in some cases, corticosteroids.
In most instances, the toxicity is reversible. Thyroid toxicity is the most common complication that requires intervention. Thyroid abnormalities have been described in up to 10 percent of patients receiving long-term amiodarone therapy. In hypothyroid patients with a strong clinical indication for amiodarone, the drug may be continued with appropriate thyroid hormone supplementation.
Treatments of amiodaroneinduced hyperthyroidism include the withdrawal of amiodarone if this can be done safely , the addition of antithyroid medications or prednisone, and surgical thyroidectomy.
Liver toxicity, manifested by elevation of liver transaminase levels, is common in patients who are receiving long-term amiodarone therapy.
This adverse effect occurs at a rate of 0. Patients with liver toxicity are rarely symptomatic. If liver enzyme levels are three times higher than normal, amiodarone should be discontinued unless a patient is at high risk for recurrence of life-threatening arrhythmia.
Gastrointestinal side effects of amiodarone include nausea, anorexia, and constipation. These symptoms often are dosage related and usually improve when the dosage is reduced.
Corneal microdeposits are visible on slit-lamp examination in nearly all patients treated with amiodarone. Optic neuropathy and optic neuritis, sometimes progressing to total blindness, have been described in a small number of patients treated with amiodarone. A causal relationship is not well established. Any patient who notes changes in visual acuity or peripheral vision should be referred for ophthalmologic evaluation.
Photosensitivity is common in patients receiving amiodarone therapy. Therefore, all patients should be cautioned to use sunblock and, whenever possible, to cover exposed skin when they are outdoors.
In patients with extended and recurrent sun exposure, bluish skin discoloration may develop in exposed areas. The discoloration resolves over several months after amiodarone is discontinued.
Neurologic toxicity associated with amiodarone therapy can include ataxia, paresthesias, and tremor. These conditions often are dosage related and improve when the dosage is reduced. Peripheral neuropathy has been reported to occur at a rate of 0. Bradycardia and heart block occur in 1 to 3 percent of patients receiving amiodarone.
Amiodarone therapy is contraindicated in patients with second- or third-degree heart block who do not have a pacemaker. Intravenously administered amiodarone causes heart block or bradycardia in 4.
Intravenous amiodarone therapy should not be used in patients with bradycardia or heart block who do not have a pacemaker. Because phlebitis may occur, the drug should be given through a central venous line when possible. Amiodarone is a potent inhibitor of the hepatic and renal metabolism of several drugs Table 3.
Interactions with warfarin and digoxin are the most clinically important. Warfarin Coumadin Simvastatin Zocor Increased incidence of myopathy when simvastatin dosage is higher than 20 mg per day.
Sildenafil Viagra Cyclosporine Sandimmune 4. Antiarrhythmic drugs 4. Additive effects: possible elevated plasma concentrations of quinidine, disopyramide Norpace , flecainide Tambocor , propafenone Rythmol , and dofetilide Tikosyn.
Antidepressants Increased plasma concentration of hepatically metabolized drugs: possible increased risk of proarrhythmia. Information from references 4 and 21 through Amiodarone reduces warfarin clearance and can lead to sudden and pronounced increases in the prothrombin time and International Normalized Ratio. Digoxin levels predictably double after coadministration with amiodarone. Patients taking amiodarone should not eat grapefruit or drink grapefruit juice because it can inhibit the conversion of amiodarone to an active metabolite.
In patients receiving oral amiodarone therapy, there may be a delay of two weeks or more before antiarrhythmic effects are noted. A loading regimen i. Typical dosing regimens are provided in Table 1. Patients treated with amiodarone should be followed regularly to assess ongoing need for amiodarone, efficacy of the drug, appropriateness of dosage, adverse effects, and potential drug interactions. Complete history and physical examination, with special attention to congestive heart failure, arrhythmia symptoms, and concomitant medications.
Pulmonary function tests, including D lco. History and physical examination directed at detecting anticipated adverse effects. Close monitoring of prothrombin time and INR at least once a week during first six weeks of treatment. Information from reference 4. Checklist for the monitoring of adult patients taking amiodarone. Already a member or subscriber?
Log in. Interested in AAFP membership? Learn more. LYLE A. Siddoway completed an internal medicine residency and clinical pharmacology and cardiology fellowships at Vanderbilt University Medical Center, Nashville. Address correspondence to Lyle A. Siddoway, M. Reprints are not available from the author. The author indicates that he does not have any conflicts of interest.
Sources of funding: none reported. Absolute bioavailability of amiodarone in normal subjects. Clin Pharmacol Ther. Physicians' desk reference. Montvale, N. Dramatic inhibition of amiodarone metabolism induced by grapefruit juice. Br J Clin Pharmacol. Practical guidelines for clinicians who treat patients with amiodarone.
Arch Intern Med. Effect of prophylactic amiodarone on mortality after acute myocardial infarction and in congestive heart failure: meta-analysis of individual data from patients in randomised trials. Amiodarone Trials Meta-Analysis Investigators.
Effectiveness of implantable defibrillators for preventing arrhythmic events and death: a meta-analysis. J Am Coll Cardiol. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med. A randomized study of the prevention of sudden death in patients with coronary artery disease. Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia.
Although amiodarone is an effective drug for the treatment of life-threatening ventricular arrhythmias, no standard oral loading dose protocol has been defined, and patients often undergo prolonged hospitalization for amiodarone loading.
The current study was designed to 1 examine the clinical and electrophysiologic effects of a high dose oral amiodarone loading regimen in more stable patients; and 2 ascertain its safety and tolerance, possibly allowing shortened amiodarone loading periods and potentially decreased length of hospital stay.
The study group included 16 patients with a history of recurrent ventricular arrhythmias and decreased left ventricular function, who were refractory to prior antiarrhythmic drug therapy. Electrophysiologic testing was performed at baseline, on days 1 and 5 and during week 6. Amiodarone and desethylamiodarone levels were measured and symptoms monitored.
Clinically, the high dose loading protocol was well tolerated in 15 of the 16 patients.
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