Monitoring and management of amiodarone side effects
- Elsa-Grace Giardina, MD, MS, FACC, FACP, FAHA
Elsa-Grace Giardina, MD, MS, FACC, FACP, FAHA
- Professor of Medicine
- Director, Center for Women’s Health
- Columbia University Medical Center
- Peter J Zimetbaum, MD
Peter J Zimetbaum, MD
- Section Editor — Cardiac Arrhythmias
- Professor of Medicine
- Harvard Medical School
Amiodarone has multiple effects on myocardial depolarization and repolarization that make it an extremely effective antiarrhythmic drug. Its primary effect is to block the potassium channels, but it can also block sodium and calcium channels and the beta and alpha adrenergic receptors. (See "Myocardial action potential and action of antiarrhythmic drugs".)
The approved clinical use of amiodarone has been limited to refractory ventricular arrhythmias because of a relatively high incidence of side effects that can range in severity from mild to potentially lethal (table 1) . The use of lower doses (200 to 300 mg/day) may allow amiodarone to be given safely and effectively in atrial arrhythmias such as atrial fibrillation or flutter. However, as will be described below, even low doses of therapy are associated with significant adverse effects, particularly thyroid, pulmonary, neurologic, skin, ocular, and bradycardic events (table 1) . Many of these effects are due to the tissue accumulation of amiodarone with long-term oral therapy and are not seen with short-term intravenous therapy.
Guidelines for the use of amiodarone were published by the North American Society of Pacing and Electrophysiology (NASPE) in 2000 . It was estimated that the prevalence of side effects was as high as 15 percent in the first year and as high as 50 percent with long-term therapy. On the other hand, the need to stop amiodarone because of serious adverse effects is thought to be about 20 percent. In a meta-analysis of trials of low-dose therapy, there was a significantly higher rate of drug discontinuation with amiodarone compared to placebo (22.9 versus 15.4 percent) .
The major side effects of amiodarone will be reviewed here. The clinical uses of amiodarone, including recommendations for its use in the treatment of various arrhythmias, are discussed separately. (See "Clinical uses of amiodarone" and "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations" and "Supportive data for advanced cardiac life support in adults with sudden cardiac arrest", section on 'Amiodarone'.)
FOLLOW-UP AND MONITORING
The long half-life of amiodarone (25 to 100 days) and the potential severity of some of the adverse effects make early recognition important. As a result, careful monitoring of patients taking amiodarone is essential.
- Zimetbaum P. Amiodarone for atrial fibrillation. N Engl J Med 2007; 356:935.
- Vorperian VR, Havighurst TC, Miller S, January CT. Adverse effects of low dose amiodarone: a meta-analysis. J Am Coll Cardiol 1997; 30:791.
- Goldschlager N, Epstein AE, Naccarelli G, et al. Practical guidelines for clinicians who treat patients with amiodarone. Practice Guidelines Subcommittee, North American Society of Pacing and Electrophysiology. Arch Intern Med 2000; 160:1741.
- Martin WJ 2nd, Rosenow EC 3rd. Amiodarone pulmonary toxicity. Recognition and pathogenesis (Part I). Chest 1988; 93:1067.
- Kharabsheh S, Abendroth CS, Kozak M. Fatal pulmonary toxicity occurring within two weeks of initiation of amiodarone. Am J Cardiol 2002; 89:896.
- Mason JW. Amiodarone. N Engl J Med 1987; 316:455.
- Dusman RE, Stanton MS, Miles WM, et al. Clinical features of amiodarone-induced pulmonary toxicity. Circulation 1990; 82:51.
- Mason JW. Prediction of amiodarone-induced pulmonary toxicity. Am J Med 1989; 86:2.
- Gleadhill IC, Wise RA, Schonfeld SA, et al. Serial lung function testing in patients treated with amiodarone: a prospective study. Am J Med 1989; 86:4.
- Martino E, Safran M, Aghini-Lombardi F, et al. Environmental iodine intake and thyroid dysfunction during chronic amiodarone therapy. Ann Intern Med 1984; 101:28.
- Kurnik D, Loebstein R, Farfel Z, et al. Complex drug-drug-disease interactions between amiodarone, warfarin, and the thyroid gland. Medicine (Baltimore) 2004; 83:107.
- Essebag V, Hadjis T, Platt RW, Pilote L. Amiodarone and the risk of bradyarrhythmia requiring permanent pacemaker in elderly patients with atrial fibrillation and prior myocardial infarction. J Am Coll Cardiol 2003; 41:249.
- Essebag V, Reynolds MR, Hadjis T, et al. Sex differences in the relationship between amiodarone use and the need for permanent pacing in patients with atrial fibrillation. Arch Intern Med 2007; 167:1648.
- Hohnloser SH, Klingenheben T, Singh BN. Amiodarone-associated proarrhythmic effects. A review with special reference to torsade de pointes tachycardia. Ann Intern Med 1994; 121:529.
- Podrid PJ. Amiodarone: reevaluation of an old drug. Ann Intern Med 1995; 122:689.
- Hohnloser SH, Singh BN. Proarrhythmia with class III antiarrhythmic drugs: definition, electrophysiologic mechanisms, incidence, predisposing factors, and clinical implications. J Cardiovasc Electrophysiol 1995; 6:920.
- van Opstal JM, Schoenmakers M, Verduyn SC, et al. Chronic amiodarone evokes no torsade de pointes arrhythmias despite QT lengthening in an animal model of acquired long-QT syndrome. Circulation 2001; 104:2722.
- Makkar RR, Fromm BS, Steinman RT, et al. Female gender as a risk factor for torsades de pointes associated with cardiovascular drugs. JAMA 1993; 270:2590.
- Goldschlager N, Epstein A, Friedman P, et al. Environmental and drug effects on patients with pacemakers and implantable cardioverter/defibrillators: a practical guide to patient treatment. Arch Intern Med 2001; 161:649.
- Zhou L, Chen BP, Kluger J, et al. Effects of amiodarone and its active metabolite desethylamiodarone on the ventricular defibrillation threshold. J Am Coll Cardiol 1998; 31:1672.
- Pelosi F Jr, Oral H, Kim MH, et al. Effect of chronic amiodarone therapy on defibrillation energy requirements in humans. J Cardiovasc Electrophysiol 2000; 11:736.
- Nielsen TD, Hamdan MH, Kowal RC, et al. Effect of acute amiodarone loading on energy requirements for biphasic ventricular defibrillation. Am J Cardiol 2001; 88:446.
- Piccini JP, Berger JS, O'Connor CM. Amiodarone for the prevention of sudden cardiac death: a meta-analysis of randomized controlled trials. Eur Heart J 2009; 30:1245.
- Effect of prophylactic amiodarone on mortality after acute myocardial infarction and in congestive heart failure: meta-analysis of individual data from 6500 patients in randomised trials. Amiodarone Trials Meta-Analysis Investigators. Lancet 1997; 350:1417.
- Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 2005; 352:225.
- Ullal AJ, Than CT, Fan J, et al. Amiodarone and risk of death in contemporary patients with atrial fibrillation: Findings from The Retrospective Evaluation and Assessment of Therapies in AF study. Am Heart J 2015; 170:1033.
- www.theheart.org/viewArticle.do?primaryKey=460115&nl_id=tho25may05#bib_1 (Accessed on January 05, 2012).
- Lewis JH, Ranard RC, Caruso A, et al. Amiodarone hepatotoxicity: prevalence and clinicopathologic correlations among 104 patients. Hepatology 1989; 9:679.
- Richer M, Robert S. Fatal hepatotoxicity following oral administration of amiodarone. Ann Pharmacother 1995; 29:582.
- Chang CC, Petrelli M, Tomashefski JF Jr, McCullough AJ. Severe intrahepatic cholestasis caused by amiodarone toxicity after withdrawal of the drug: a case report and review of the literature. Arch Pathol Lab Med 1999; 123:251.
- Macarri G, Feliciangeli G, Berdini V, et al. Canalicular cholestasis due to amiodarone toxicity. A definite diagnosis obtained by electron microscopy. Ital J Gastroenterol 1995; 27:436.
- Simon JB, Manley PN, Brien JF, Armstrong PW. Amiodarone hepatotoxicity simulating alcoholic liver disease. N Engl J Med 1984; 311:167.
- Rigas B, Rosenfeld LE, Barwick KW, et al. Amiodarone hepatotoxicity. A clinicopathologic study of five patients. Ann Intern Med 1986; 104:348.
- Poucell S, Ireton J, Valencia-Mayoral P, et al. Amiodarone-associated phospholipidosis and fibrosis of the liver. Light, immunohistochemical, and electron microscopic studies. Gastroenterology 1984; 86:926.
- Somani P, Bandyopadhyay S, Klaunig JE, Gross SA. Amiodarone- and desethylamiodarone-induced myelinoid inclusion bodies and toxicity in cultured rat hepatocytes. Hepatology 1990; 11:81.
- Mäntyjärvi M, Tuppurainen K, Ikäheimo K. Ocular side effects of amiodarone. Surv Ophthalmol 1998; 42:360.
- Ingram DV. Ocular effects in long-term amiodarone therapy. Am Heart J 1983; 106:902.
- Flach AJ, Dolan BJ. Progression of amiodarone induced cataracts. Doc Ophthalmol 1993; 83:323.
- Macaluso DC, Shults WT, Fraunfelder FT. Features of amiodarone-induced optic neuropathy. Am J Ophthalmol 1999; 127:610.
- Cheng HC, Yeh HJ, Huang N, et al. Amiodarone-Associated Optic Neuropathy: A Nationwide Study. Ophthalmology 2015; 122:2553.
- Mindel JS, Anderson J, Hellkamp A, et al. Absence of bilateral vision loss from amiodarone: a randomized trial. Am Heart J 2007; 153:837.
- Mansour AM, Puklin JE, O'Grady R. Optic nerve ultrastructure following amiodarone therapy. J Clin Neuroophthalmol 1988; 8:231.
- Enseleit F, Wyss CA, Duru F, et al. Images in cardiovascular medicine. The blue man: amiodarone-induced skin discoloration. Circulation 2006; 113:e63.
- Alinovi A, Reverberi C, Melissari M, Gabrielli M. Cutaneous hyperpigmentation induced by amiodarone hydrochloride. J Am Acad Dermatol 1985; 12:563.
- Delage C, Lagacé R, Huard J. Pseudocyanotic pigmentation of the skin induced by amiodarone: a light and electron microscopic study. Can Med Assoc J 1975; 112:1205.
- Kounis NG, Frangides C, Papadaki PJ, et al. Dose-dependent appearance and disappearance of amiodarone-induced skin pigmentation. Clin Cardiol 1996; 19:592.
- Blackshear JL, Randle HW. Reversibility of blue-gray cutaneous discoloration from amiodarone. Mayo Clin Proc 1991; 66:721.
- Orr CF, Ahlskog JE. Frequency, characteristics, and risk factors for amiodarone neurotoxicity. Arch Neurol 2009; 66:865.
- Hamoud K, Kaneti J, Smailowitz Z, Lissmer L. Amiodarone-induced epididymitis. Report of 2 cases. Eur Urol 1996; 29:497.
- Ahmad S. Amiodarone and sexual dysfunction. Am Heart J 1995; 130:1320.
- Pollak PT, Sharma AD, Carruthers SG. Elevation of serum total cholesterol and triglyceride levels during amiodarone therapy. Am J Cardiol 1988; 62:562.
- Pollak PT, Tan MH. Elevation of high-density lipoprotein cholesterol in humans during long-term therapy with amiodarone. Am J Cardiol 1999; 83:296.
- Desai AD, Chun S, Sung RJ. The role of intravenous amiodarone in the management of cardiac arrhythmias. Ann Intern Med 1997; 127:294.
- Scheinman MM, Levine JH, Cannom DS, et al. Dose-ranging study of intravenous amiodarone in patients with life-threatening ventricular tachyarrhythmias. The Intravenous Amiodarone Multicenter Investigators Group. Circulation 1995; 92:3264.
- Gallik DM, Singer I, Meissner MD, et al. Hemodynamic and surface electrocardiographic effects of a new aqueous formulation of intravenous amiodarone. Am J Cardiol 2002; 90:964.
- Sanoski CA, Bauman JL. Clinical observations with the amiodarone/warfarin interaction: dosing relationships with long-term therapy. Chest 2002; 121:19.
- Holm J, Lindh JD, Andersson ML, Mannheimer B. The effect of amiodarone on warfarin anticoagulation: a register-based nationwide cohort study involving the Swedish population. J Thromb Haemost 2017; 15:446.
- FOLLOW-UP AND MONITORING
- Oral amiodarone
- Intravenous amiodarone
- SIDE EFFECTS OF ORAL AMIODARONE
- Pulmonary disease
- - Preexisting pulmonary disease
- Thyroid dysfunction
- Cardiac toxicity
- - Sinus bradycardia
- - Ventricular arrhythmias
- - Interaction with ICDs
- - Toxicity in patients without an ICD
- - Mortality
- Ocular changes
- - Corneal microdeposits
- - Optic neuropathy
- - Skin reactions
- - Gastrointestinal side effects
- - Neurologic dysfunction
- - Genitourinary effects
- - Changes in serum lipids
- SIDE EFFECTS OF IV AMIODARONE
- USE IN PREGNANCY
- DRUG INTERACTIONS
- SUMMARY AND RECOMMENDATIONS