What are the potential side effects of Amiodarone (antiarrhythmic medication) therapy, particularly in older adults or those with pre-existing medical conditions?

Side Effects of Amiodarone

Amiodarone causes adverse effects in virtually all patients on long-term therapy, with the most serious being pulmonary toxicity, which can be fatal if not recognized early. 1

Most Serious and Life-Threatening Side Effects

Pulmonary Toxicity

• This is the most serious potential adverse effect of amiodarone therapy 1
• Presents as subacute cough and progressive dyspnea with patchy interstitial infiltrates on chest radiograph and reduced diffusing capacity on pulmonary function tests 1
• Historical incidence ranged from 2-17%, but more recent studies show lower rates (approximately 1% annually) with maintenance doses ≤300 mg/day 1
• Can develop rapidly with no antecedent abnormalities on baseline imaging or pulmonary function tests 1
• Adult respiratory distress syndrome is a rare but potentially fatal presentation 1
• Treatment requires immediate withdrawal of amiodarone, supportive care, and often corticosteroids; toxicity is usually reversible 1

Thyroid Dysfunction

• Occurs in 2-10% of patients receiving long-term therapy 1
• Hypothyroidism is 2-4 times more common than hyperthyroidism 1
• Amiodarone inhibits peripheral conversion of T4 to T3 and is a source of large amounts of inorganic iodine 2
• Hyperthyroidism poses greater hazard than hypothyroidism due to risk of thyrotoxicosis, arrhythmia breakthrough, and death 2
• Thyroid function should be monitored before treatment and at least every 6 months during therapy 1
• Abnormal thyroid function may persist for weeks to months after discontinuation due to amiodarone's long half-life 2
• Postmarketing reports document thyroid nodules and thyroid cancer in amiodarone-treated patients 2

Hepatic Toxicity

• Liver transaminase elevation occurs at a rate of 0.6% annually 1
• Patients are rarely symptomatic 1
• Amiodarone should be discontinued if liver enzyme levels are three times higher than normal, unless the patient is at high risk for life-threatening arrhythmia recurrence 1
• Liver function tests should be monitored at least every 6 months 1

Cardiovascular Side Effects

Bradycardia and Conduction Abnormalities

• Bradycardia and heart block occur in 1-3% of patients on oral amiodarone 1
• Intravenous amiodarone causes heart block or bradycardia in 4.9% of patients 1
• Amiodarone is contraindicated in patients with second- or third-degree heart block without a pacemaker 1

Hypotension

• Intravenous amiodarone causes hypotension in 16% of patients 1
• Treatment-emergent hypotension occurred in 288 of 1836 patients (16%) in clinical studies of IV amiodarone 2
• If hypotension or bradycardia occurs with IV administration, the infusion should be discontinued or the rate reduced 1
• Hypotension is not a significant adverse effect with oral formulations 3

Proarrhythmia

• Amiodarone-induced proarrhythmia occurs at an annual rate of less than 1% 1
• Although QT prolongation occurs in almost all patients, torsades de pointes is rare 1
• The first sign of antiarrhythmic failure may manifest as sudden cardiac death 4

Ocular Side Effects

Corneal Microdeposits

• Visible on slit-lamp examination in nearly all patients treated with amiodarone 1
• Seldom affect vision and rarely necessitate drug discontinuation 1

Optic Neuropathy

• Optic neuropathy and optic neuritis, sometimes progressing to total blindness, have been described 1
• Any patient noting changes in visual acuity or peripheral vision should be referred for immediate ophthalmologic evaluation 1

Dermatologic Side Effects

Photosensitivity

• Photosensitivity is common in patients receiving amiodarone 1
• All patients should be cautioned to use sunblock and cover exposed skin when outdoors 1

Skin Discoloration

• Bluish skin discoloration may develop in sun-exposed areas with extended and recurrent exposure 1
• Discoloration resolves over several months after amiodarone discontinuation 1

Neurologic Side Effects

• Neurologic toxicity includes ataxia, paresthesias, and tremor 1
• These conditions are often dose-related and improve with dosage reduction 1
• Peripheral neuropathy occurs at a rate of 0.3% annually 1

Gastrointestinal Side Effects

• Include nausea, anorexia, and constipation 1
• These symptoms are often dose-related and usually improve when dosage is reduced 1
• Constipation is the most common gastrointestinal complaint 4

Frequency and Dose-Dependency of Side Effects

• Side effects occur in 93% of patients on long-term therapy 4
• Most adverse effects are related to total amiodarone exposure (dosage and duration) 1
• 13-19% of patients discontinue medication due to severe side effects 4
• The dosage should be kept at the lowest effective level to minimize toxicity 1
• Lower maintenance doses (≤300 mg/day) are associated with fewer side effects compared to 600 mg/day 1, 4

Critical Drug Interactions

Warfarin

• Amiodarone potentiates warfarin response, increasing prothrombin time by 100% after 3-4 days 2
• Warfarin dose should be reduced by one-third to one-half when starting amiodarone 1, 2
• Prothrombin time should be monitored at least once weekly during the first 6 weeks 1
• Peak interaction effects occur approximately 7 weeks after initiation 1

Digoxin

• Amiodarone increases serum digoxin concentration by 70% after one day 2
• Digoxin dose should be reduced by approximately 30-50% when amiodarone is initiated 1, 2
• Serum digoxin levels should be closely monitored 1, 2

Statins

• Simvastatin in combination with amiodarone has been associated with myopathy and rhabdomyolysis 2
• Amiodarone inhibits CYP3A4, which metabolizes many statins 2

Monitoring Requirements

Baseline Assessment

• Complete history and physical examination with attention to heart failure, arrhythmia symptoms, and concomitant medications 1
• Chest radiograph 1
• Thyroid studies and liver transaminase levels 1
• Pulmonary function tests including diffusing capacity 1
• Ophthalmologic examination if preexisting visual impairment 1

During Treatment

• Thyroid studies and liver transaminase levels at least every 6 months 1
• Close heart rate surveillance, especially during the first week 1
• Chest radiograph and pulmonary function tests if pulmonary toxicity suspected 1
• Ophthalmologic examination if visual symptoms develop 1

Special Considerations for Older Adults

• Patients over 65 years show lower clearances and increased half-life (from 20 to 47 days) 2
• Close clinical monitoring is particularly prudent for elderly patients 2
• Thyroid dysfunction monitoring is especially important in elderly patients 2