Amiodarone - Drug Monograph

Introduction

Amiodarone is a Class III antiarrhythmic agent with additional Class I, II, and IV properties, making it one of the most potent and broad-spectrum antiarrhythmic medications available. Originally developed in the 1960s as an antianginal agent, it has become a cornerstone therapy for managing various cardiac arrhythmias. Its unique pharmacokinetic profile and multi-channel blocking effects distinguish it from other antiarrhythmic drugs.

Mechanism of Action

Amiodarone exerts its antiarrhythmic effects through multiple mechanisms:

• Class III action: Prolongs action potential duration and refractory period by blocking potassium channels (IKr, IKs)
• Class I action: Sodium channel blockade (use-dependent)
• Class II action: Non-competitive beta-adrenergic blockade
• Class IV action: Weak calcium channel blockade
• Additional effects: Inhibits thyroid hormone metabolism and action, possesses coronary and peripheral vasodilatory properties

Indications

• Recurrent hemodynamically unstable ventricular fibrillation (VF)
• Recurrent hemodynamically unstable ventricular tachycardia (VT)

• Atrial fibrillation and atrial flutter (rhythm and rate control)
• Supraventricular tachycardias
• Ventricular arrhythmias in structural heart disease
• Post-operative arrhythmias in cardiac surgery patients

Dosage and Administration

• Loading dose: 800-1600 mg/day in divided doses for 1-3 weeks
• Maintenance dose: 200-400 mg/day
• Lower maintenance doses (100-200 mg/day) may be effective for some patients

• Loading: 150 mg over 10 minutes, followed by 1 mg/min for 6 hours
• Maintenance: 0.5 mg/min for 18 hours or longer
• Maximum daily IV dose: 2.2 grams

• Hepatic impairment: Reduce dose or avoid use
• Renal impairment: No dosage adjustment needed
• Elderly: Lower doses may be required due to increased sensitivity

Pharmacokinetics

• Absorption: Variable oral bioavailability (35-65%), enhanced with food
• Distribution: Extensive tissue distribution, large volume of distribution (~5000 L)
• Metabolism: Hepatic via CYP3A4, CYP2C8 to active metabolite (desethylamiodarone)
• Elimination: Primarily biliary excretion, minimal renal excretion
• Half-life: Extremely long (25-110 days) due to extensive tissue binding

Contraindications

• Known hypersensitivity to amiodarone or iodine
• Severe sinus node dysfunction without pacemaker
• Second- or third-degree AV block without pacemaker
• Bradycardia-induced syncope without pacemaker
• Cardiogenic shock

Warnings and Precautions

• Potentially fatal toxicities: pulmonary, hepatic, and proarrhythmic effects
• Only for use in patients with life-threatening arrhythmias

• Pulmonary toxicity (fibrosis, pneumonitis) - monitor regularly
• Hepatotoxicity - baseline and periodic liver function tests
• Thyroid dysfunction (both hyperthyroidism and hypothyroidism)
• Corneal microdeposits and optic neuropathy/neuritis
• Photosensitivity and blue-gray skin discoloration
• Neurologic effects (tremor, peripheral neuropathy)

Drug Interactions

• QT-prolonging agents (increased risk of torsades de pointes)
• Warfarin (potentiates anticoagulant effect)
• Digoxin (increases serum levels)
• Beta-blockers and calcium channel blockers (additive bradycardia)
• Statins (increased risk of myopathy, especially simvastatin)
• CYP3A4 inhibitors/inducers (affects amiodarone metabolism)
• Phenytoin (decreased levels)

Adverse Effects

• Corneal microdeposits (virtually all long-term patients)
• Photosensitivity
• Nausea, vomiting, constipation
• Fatigue, malaise
• Tremor

• Pulmonary fibrosis (2-17%)
• Hepatotoxicity (elevated transaminases 15-30%)
• Thyroid dysfunction (2-22%)
• Proarrhythmia (torsades de pointes)
• Neurologic toxicity (peripheral neuropathy)
• Vision loss (optic neuritis)

Monitoring Parameters

• Complete cardiac evaluation (ECG, echocardiogram)
• Pulmonary function tests and chest X-ray
• Liver function tests
• Thyroid function tests (TSH, free T4)
• Electrolytes (especially potassium and magnesium)
• Ophthalmologic examination

• ECG every 3-6 months (monitor QT interval)
• Chest X-ray and pulmonary symptoms every 6-12 months
• Liver function tests every 6 months
• Thyroid function tests every 6 months
• Regular ophthalmologic exams

Patient Education

• Take with food to enhance absorption and reduce GI upset
• Use sun protection (sunscreen, protective clothing) due to photosensitivity
• Report any new or worsening symptoms immediately:

- Shortness of breath or cough - Visual changes - Unexplained weight change - Fatigue, heat or cold intolerance - Neurological symptoms

• Inform all healthcare providers about amiodarone use
• Do not stop taking abruptly without medical supervision
• Be aware of potential interactions with other medications

References

1. Goldschlager N, Epstein AE, Naccarelli G, et al. Practical guidelines for clinicians who treat patients with amiodarone. Arch Intern Med. 2000;160(12):1741-1748. 2. Vassallo P, Trohman RG. Prescribing amiodarone: an evidence-based review of clinical indications. JAMA. 2007;298(11):1312-1322. 3. Zimetbaum P. Amiodarone for atrial fibrillation. N Engl J Med. 2007;356(9):935-941. 4. Product Information: Cordarone® (amiodarone HCl). Wyeth Pharmaceuticals Inc. 5. Epstein AE, Olshansky B, Naccarelli GV, et al. Practical management guide for clinicians who treat patients with amiodarone. Am J Med. 2016;129(5):468-475. 6. Sanoski CA. Clinical pharmacology and therapeutic applications of the antiarrhythmic agent amiodarone. Am J Health Syst Pharm. 2009;66(9):829-839.