Mechanism of action
Amiodarone is classified as a class III antiarrhythmic but exhibits properties of all four Vaughan Williams classes. Its primary mechanism involves blockade of potassium channels (IKr), which prolongs phase 3 repolarization of the cardiac action potential. This increases the effective refractory period in all cardiac tissues including the AV node, ventricles, and accessory pathways.
Amiodarone also blocks:
- Sodium channels (class I effect): slows phase 0 depolarization
- Calcium channels (class IV effect): negative inotropic and chronotropic effects
- Alpha and beta adrenergic receptors (non-competitive): reduces sympathetic tone
The drug prolongs the QT interval and QRS duration on ECG. Unlike pure class III agents (sotalol, dofetilide), amiodarone rarely causes torsades de pointes despite QT prolongation, likely due to its multichannel blocking properties. The extensive pharmacologic profile makes it highly effective for refractory arrhythmias but also responsible for its complex adverse effect profile.
- Amiodarone is a class III antiarrhythmic that blocks potassium channels but also has class I, II, and IV effects (multichannel blocker).
- Most testable adverse effect: pulmonary fibrosis (5-15%), which can be fatal and requires immediate discontinuation.
- Amiodarone contains 37% iodine, causing both hypothyroidism (more common) and hyperthyroidism; monitor TSH and free T4 every 3-6 months.
- Extremely long half-life (25-110 days) means effects and interactions persist weeks to months after discontinuation.
- Prolongs QT interval but rarely causes torsades de pointes, unlike sotalol and dofetilide.
- Warfarin dose must be reduced by 30-50% when starting amiodarone (CYP2C9 inhibition); digoxin dose reduced by 50% (P-gp inhibition).
- Preferred antiarrhythmic in heart failure and structural heart disease because it does not increase mortality.
- ACLS protocol: 300 mg IV push in cardiac arrest after third shock and epinephrine, followed by 150 mg if needed.
- Contraindicated in pre-excited atrial fibrillation (WPW) — can accelerate accessory pathway conduction and cause VF; use procainamide instead.
Indications
Amiodarone is reserved for serious, life-threatening arrhythmias due to its toxicity profile:
Ventricular arrhythmias
- Ventricular fibrillation and pulseless ventricular tachycardia: first-line after defibrillation and epinephrine in ACLS protocols
- Hemodynamically stable ventricular tachycardia: when other antiarrhythmics fail
- Prevention of recurrent VT/VF in patients with ICDs
Supraventricular arrhythmias
- Atrial fibrillation: rhythm control when other agents are ineffective or contraindicated, especially in patients with heart failure or structural heart disease
- Atrial flutter: cardioversion and rate control
- Paroxysmal supraventricular tachycardia: refractory cases
Amiodarone is particularly valuable in patients with structural heart disease or reduced ejection fraction, where other antiarrhythmics may increase mortality. Dosing follows established loading and maintenance protocols per product labeling.
Pharmacokinetics
Amiodarone has unique and complex pharmacokinetics:
Absorption and distribution: Oral bioavailability is 35-65% with significant first-pass metabolism. The drug is highly lipophilic and extensively distributes into tissues (liver, lungs, adipose, skin) with a massive volume of distribution (60 L/kg). Peak plasma levels occur 3-7 hours after oral dosing.
Metabolism: Hepatic metabolism via CYP3A4 and CYP2C8 produces the active metabolite desethylamiodarone (DEA), which has similar antiarrhythmic effects. Both parent drug and metabolite undergo enterohepatic recirculation.
Elimination: The elimination half-life is extraordinarily long, ranging from 25-110 days (average 58 days), with even longer tissue half-lives. This means:
- Steady state requires months to achieve
- Loading doses are necessary for acute effect
- Adverse effects can persist for months after discontinuation
- Drug interactions continue long after stopping amiodarone
Clinical implications: The long half-life necessitates loading regimens and means that both therapeutic and toxic effects accumulate slowly. When switching from amiodarone to another QT-prolonging drug, wait several weeks to months depending on clinical context.
Adverse effects
Amiodarone causes adverse effects in up to 75% of patients on long-term therapy. Many are dose-dependent and related to tissue accumulation.
Pulmonary toxicity (most serious)
- Pulmonary fibrosis: occurs in 5-15% of patients, can be fatal
- Presents with dyspnea, dry cough, pleuritic chest pain
- Chest X-ray shows interstitial infiltrates; PFTs show restrictive pattern
- Risk factors: high dose (>400 mg/day), duration >6 months, pre-existing lung disease
- Requires immediate discontinuation; may respond to corticosteroids
- Baseline and periodic PFTs and chest imaging recommended
Thyroid dysfunction (15-20%)
Amiodarone contains 37% iodine by weight and releases large amounts of inorganic iodide:
- Hypothyroidism (more common in iodine-sufficient areas): TSH elevated, may continue amiodarone with levothyroxine replacement
- Hyperthyroidism (more common in iodine-deficient areas): Type 1 (iodine-induced) or Type 2 (destructive thyroiditis); may require discontinuation
- Monitor TSH and free T4 at baseline, 3 months, then every 6 months
Hepatotoxicity
- Elevated transaminases (15-50%): usually mild, transient
- Cirrhosis with chronic use (rare)
- Monitor LFTs at baseline and periodically
Ocular effects
- Corneal microdeposits (>90%): virtually universal, rarely affect vision, reversible
- Optic neuropathy/neuritis (rare): can lead to blindness, requires discontinuation
- Annual ophthalmologic examination recommended
Dermatologic
- Photosensitivity: common, recommend sunscreen and protective clothing
- Blue-gray skin discoloration: face and sun-exposed areas, may be irreversible
Cardiovascular
- Bradycardia and AV block: due to SA and AV nodal suppression
- QT prolongation: torsades de pointes is rare (<1%) compared to other class III agents
- Hypotension with IV administration: due to solvent (polysorbate 80)
Neurologic
- Peripheral neuropathy, ataxia, tremor, sleep disturbances
Gastrointestinal
- Nausea, anorexia, constipation (common with loading doses)
Contraindications and warnings
Absolute contraindications
- Severe sinus node dysfunction or marked sinus bradycardia (unless pacemaker present)
- Second- or third-degree AV block (unless pacemaker present)
- Cardiogenic shock
- Known hypersensitivity to amiodarone or iodine
- Pre-excited atrial fibrillation in Wolff-Parkinson-White syndrome: amiodarone's AV nodal blocking properties can accelerate conduction down the accessory pathway and precipitate ventricular fibrillation
Black box warnings (US FDA)
- Pulmonary toxicity: potentially fatal; monitor clinically and with chest X-ray and PFTs
- Hepatotoxicity: can be fatal; monitor LFTs
- Proarrhythmia: can worsen arrhythmias or precipitate new ones, including torsades de pointes (rare) and bradycardia
- Use only for life-threatening arrhythmias due to substantial toxicity
Warnings and precautions
- Pregnancy category D: causes fetal harm including hypothyroidism, bradycardia, and growth restriction; use only if benefit clearly outweighs risk
- Breastfeeding: contraindicated due to high iodine content and risk to infant thyroid
- Electrolyte abnormalities: correct hypokalemia and hypomagnesemia before initiating (increases risk of torsades)
- Thyroid disease: use with caution; baseline and periodic monitoring essential
- Hepatic impairment: dose adjustment may be needed; enhanced monitoring required
- Surgery: inform anesthesiologists, as amiodarone increases risk of ARDS, bradycardia, and hypotension perioperatively
Drug interactions
Amiodarone is a potent inhibitor of multiple CYP enzymes (CYP3A4, CYP2C9, CYP2D6) and P-glycoprotein, leading to numerous clinically significant interactions. The long half-life means interactions persist for weeks to months after discontinuation.
QT-prolonging drugs (increased torsades risk)
- Fluoroquinolones, macrolides, antipsychotics, class IA and III antiarrhythmics
- Avoid concomitant use when possible; if necessary, monitor ECG closely
Warfarin
- Amiodarone inhibits CYP2C9, increasing warfarin levels significantly
- Reduce warfarin dose by 30-50% and monitor INR closely
- Interaction persists for weeks after stopping amiodarone
Digoxin
- Amiodarone inhibits P-glycoprotein, increasing digoxin levels by 70-100%
- Reduce digoxin dose by 50% and monitor digoxin levels
- Increased risk of bradycardia and AV block
Statins (simvastatin, lovastatin, atorvastatin)
- CYP3A4 inhibition increases statin levels, raising myopathy and rhabdomyolysis risk
- Use lowest effective statin dose; consider rosuvastatin or pravastatin (not CYP3A4 substrates)
Beta-blockers and calcium channel blockers
- Additive effects on SA/AV node: severe bradycardia, heart block, cardiac arrest
- Use cautiously with reduced doses and ECG monitoring
Phenytoin
- Amiodarone increases phenytoin levels (CYP2C9 inhibition)
- Monitor phenytoin levels and reduce dose as needed
Other interactions
- Fentanyl: bradycardia, sinus arrest, hypotension
- Dabigatran, apixaban, rivaroxaban: increased anticoagulant levels (P-gp inhibition)
- Clopidogrel: reduced antiplatelet effect (CYP2C19 inhibition)
- Cyclosporine, tacrolimus: increased immunosuppressant levels
Clinical pearls
- Amiodarone rarely causes torsades de pointes despite significant QT prolongation, unlike other class III agents (sotalol, dofetilide). This is attributed to its multichannel blocking effects and uniform prolongation of repolarization across the myocardium.
- The 37% iodine content (each 200 mg tablet contains 75 mg iodine) delivers 50-100 times the daily iodine requirement, making thyroid dysfunction almost inevitable with long-term use. The effects on thyroid function can persist 6-12 months after discontinuation.
- Amiodarone is the preferred antiarrhythmic in heart failure and structural heart disease because it does not increase mortality, unlike class IC agents (flecainide, propafenone) which are contraindicated in these patients.
- Loading is essential for acute effect: due to the enormous volume of distribution and long half-life, therapeutic tissue levels require weeks to months without loading. Loading regimens vary by indication and route (IV vs oral).
- Pulmonary toxicity can occur at any time but risk increases with cumulative dose and duration. Maintain the lowest effective dose. New respiratory symptoms require immediate evaluation with chest imaging, PFTs, and consideration of discontinuation.
- In cardiac arrest (VF/pulseless VT), amiodarone 300 mg IV is given after the third shock and epinephrine, with a second dose of 150 mg if needed. It is preferred over lidocaine in ACLS protocols.
- Blue-gray skin discoloration occurs in sun-exposed areas after years of therapy and may be permanent. It results from lipofuscin deposition and is more common with cumulative doses >100 g.
- Corneal microdeposits are not a reason to stop amiodarone unless vision is affected. They occur in virtually all patients and resolve over months after discontinuation.
- When transitioning from amiodarone to another antiarrhythmic, allow several weeks for washout due to the long half-life. Overlapping QT-prolonging agents can be dangerous.
- Patients on amiodarone should carry identification indicating its use, especially for emergency situations, surgery, or when seeing new healthcare providers.
- Pre-excited atrial fibrillation in WPW is a contraindication: amiodarone's AV nodal blocking effects can preferentially block the AV node and accelerate conduction through the accessory pathway, potentially triggering ventricular fibrillation. Procainamide or ibutilide are preferred.
Amiodarone toxicity mnemonic – "PULMONARY THYROID": Pulmonary fibrosis (most serious), Unusual skin color (blue-gray), Liver toxicity (elevated LFTs), Micro-deposits corneal (>90% of patients), Ocular neuropathy (rare, can blind), Neuropathy peripheral, Atrial and ventricular arrhythmias (proarrhythmic), Reduced heart rate (bradycardia), Yellow vision is NOT amiodarone (that's digoxin), Thyroid dysfunction (hypo- or hyperthyroidism), Half-life extremely long (weeks to months), Yields drug interactions (warfarin, digoxin), Refractory period prolonged (↑QT), Only for life-threatening arrhythmias, Iodine content 37%, Don't use in pregnancy (category D).
Practice questions
1. A 68-year-old man with ischemic cardiomyopathy (ejection fraction 30%) presents with recurrent episodes of ventricular tachycardia despite an implantable cardioverter-defibrillator. He has received multiple shocks over the past month. His medications include metoprolol, lisinopril, and furosemide. The cardiologist initiates amiodarone therapy. Six months later, the patient develops progressive dyspnea and dry cough. Chest X-ray shows bilateral interstitial infiltrates. Pulmonary function tests reveal a restrictive pattern with reduced DLCO. What is the most appropriate next step?
2. A 72-year-old woman on chronic amiodarone therapy for atrial fibrillation presents for routine follow-up. Laboratory results show TSH 0.1 mIU/L (normal 0.4-4.0), free T4 2.8 ng/dL (normal 0.8-1.8), and free T3 elevated. She reports palpitations, weight loss, and heat intolerance over the past 2 months. Heart rate is 110/min and irregular. Which of the following best explains her thyroid dysfunction?
3. A 55-year-old man is brought to the emergency department in cardiac arrest. The rhythm shows ventricular fibrillation. After the third defibrillation attempt and administration of epinephrine, the patient remains in ventricular fibrillation. High-quality CPR is ongoing. Which of the following is the most appropriate next pharmacologic intervention?
Frequently asked questions
How does amiodarone work?
Amiodarone primarily blocks potassium channels (class III effect), prolonging the cardiac action potential and refractory period. It also blocks sodium channels, calcium channels, and alpha/beta receptors (class I, II, IV effects). This multichannel blockade makes it highly effective for refractory arrhythmias but also contributes to its complex side effect profile. Unlike pure class III agents, it rarely causes torsades de pointes despite prolonging the QT interval.
What are the most serious side effects of amiodarone?
Pulmonary fibrosis is the most serious adverse effect, occurring in 5-15% of patients and potentially fatal. Patients present with dyspnea, dry cough, and interstitial infiltrates on chest X-ray. Other major toxicities include thyroid dysfunction (both hypo- and hyperthyroidism due to 37% iodine content), hepatotoxicity with elevated transaminases or cirrhosis, and rare optic neuropathy that can cause blindness. Baseline and periodic monitoring of pulmonary function, thyroid function, liver enzymes, and ophthalmologic exams are essential.
Why does amiodarone cause thyroid problems?
Amiodarone contains 37% iodine by weight, delivering massive iodine loads (75 mg per 200 mg tablet, 50-100 times the daily requirement). This causes hypothyroidism in iodine-sufficient populations through Wolff-Chaikoff effect, and hyperthyroidism in iodine-deficient areas or patients with nodular goiters. The drug also inhibits peripheral conversion of T4 to T3. Thyroid dysfunction occurs in 15-20% of patients and can persist for 6-12 months after discontinuation due to amiodarone's long half-life and tissue stores.
What drug interactions does amiodarone have?
Amiodarone is a potent CYP3A4, CYP2C9, and P-glycoprotein inhibitor causing major interactions. It increases warfarin effect by 50-100% (reduce warfarin dose by 30-50%), increases digoxin levels by 70-100% (reduce digoxin dose by 50%), and raises statin levels increasing myopathy risk. It potentiates QT prolongation with fluoroquinolones and antipsychotics. Beta-blockers and calcium channel blockers combined with amiodarone increase bradycardia and heart block risk. Interactions persist for weeks to months after stopping amiodarone due to its 25-110 day half-life.
Amiodarone vs sotalol — what is the difference?
Both are class III antiarrhythmics that prolong the QT interval, but amiodarone has additional class I, II, and IV properties (multichannel blocker) while sotalol is a pure class III agent with beta-blocking activity. Amiodarone rarely causes torsades de pointes despite QT prolongation, whereas sotalol carries a 2-4% torsades risk and requires dose adjustment in renal impairment. Amiodarone has a 25-110 day half-life versus sotalol's 12 hours, and causes multi-organ toxicity requiring long-term monitoring. Amiodarone is preferred in structural heart disease and heart failure, while sotalol requires normal renal function and is contraindicated in these conditions.
Conditions it is used for
Related drugs
Sources and further reading
DailyMed (FDA labels)StatPearls (NCBI Bookshelf)MedlinePlusWHO ATC/DDD index: C01BD01
Educational content for medical students, prepared by the WhiteCoat Pro editorial team with AI assistance; every page is reviewed by a second AI model for factual errors. It is not medical advice and does not replace the product label, local guidelines or a clinician.