Amiodarone

Details

Amiodarone is a benzofuran-derived iodine-rich antiarrhythmic agent classified as class III (potassium channel blockade) but uniquely affecting all four phases of the cardiac action potential. It is the most widely used antiarrhythmic in clinical practice due to its broad spectrum of efficacy across ventricular and atrial arrhythmias. Its major clinical limitation is a multisystem toxicity profile requiring lifelong structured monitoring.

Mechanism of Action

• Class III effect (primary): Inhibits IKr (rapid delayed rectifier K⁺ channel) during phase 3 → prolongs action potential duration and QTc. The active metabolite desethylamiodarone mediates this effect after the loading phase. (sources/amiodarone-cvdrug-2020, rating: high)
• Class I effect: Inhibits sodium channels (phase 0) → slows conduction velocity. (sources/amiodarone-cvdrug-2020)
• Class II effect: Non-competitive β-receptor blockade → reduces automaticity and AV nodal conduction. (sources/amiodarone-cvdrug-2020)
• Class IV effect: L-type calcium channel blockade → slows AV nodal conduction. (sources/amiodarone-cvdrug-2020)
• IV vs. oral effects: Acute IV amiodarone acts primarily via Na/Ca/β-blockade; the class III effect is delayed until desethylamiodarone accumulates post-loading. (sources/amiodarone-cvdrug-2020)
• Unlike quinidine and sotalol, amiodarone does not increase transmural dispersion of repolarization — this partly explains its relatively low TdP incidence despite significant QTc prolongation. (sources/amiodarone-cvdrug-2020, sources/drug-arrhythmia-aha-2020)

Pharmacokinetics

• Oral bioavailability 30–50%; absorption enhanced 2.4–3.8× with high-fat meal — take with food. (sources/amiodarone-cvdrug-2020)
• Three-phase distribution: central (~24h) → peripheral/solid organ (~7 days) → deep fat tissue (~4 weeks)
• Full ventricular antiarrhythmic effect at ~10 weeks of loading. (sources/amiodarone-cvdrug-2020)
• Half-life 50–60 days; drug effect persists up to 3 months after discontinuation. (sources/amiodarone-cvdrug-2020)
• No renal dose adjustment required; initiate at low dose in hepatic impairment. (sources/amiodarone-cvdrug-2020)

Key Facts

Ventricular Arrhythmias

• VF / Cardiac arrest: AHA Class IA recommendation; only antiarrhythmic in the ACLS algorithm. (sources/amiodarone-cvdrug-2020)
  • ARREST trial: amiodarone vs placebo — higher survival to hospital admission (44 vs 34%; P=0.03)
  • ALIVE trial: amiodarone vs lidocaine in shock-resistant VF — 22.8 vs 12.0% survival (P=0.009)
  • Kudenchuk 2016 (n=3026): no overall survival benefit; benefit signal in witnessed arrest subgroup only
• Hemodynamically tolerated VT: PROCAMIO RCT (n=62) showed procainamide superior to amiodarone for acute termination and safety — but amiodarone remains widely used due to clinical familiarity. (sources/amiodarone-cvdrug-2020)
• ICD storm / recurrent VT prevention: First-line for ICD shocks. OPTIC study: amiodarone + β-blocker had lowest ICD shock rate vs β-blocker alone or sotalol (higher adverse events). (sources/amiodarone-cvdrug-2020)
• Prophylactic amiodarone in HFrEF: SCD-HeFT (n=2521) — amiodarone showed no mortality benefit vs placebo in symptomatic patients with LVEF <35%. Amiodarone does not replace ICD for primary prevention. (sources/amiodarone-cvdrug-2020)
• VANISH trial: Catheter ablation superior to drug escalation (including amiodarone) in ischaemic cardiomyopathy with recurrent VT. (sources/amiodarone-cvdrug-2020)

Atrial Fibrillation

• Acute cardioversion efficacy: 35–65% (lower than electrical cardioversion 70–90%). Suitable when patient prefers pharmacologic approach or has ischaemic heart disease (unlike propafenone/flecainide). (sources/amiodarone-cvdrug-2020)
• Long-term rhythm maintenance: Pooled AFFIRM + AF-CHF (n=3307) — freedom from AF 84% at 1 year, 45% at 5 years. (sources/amiodarone-cvdrug-2020)
• In HF with AF: Catheter ablation superior (70% vs 34% AF-free at 2 years; Di Biase 2016 RCT). Amiodarone the only safe antiarrhythmic in HFrEF (propafenone, flecainide, dronedarone associated with worse outcomes). (sources/amiodarone-cvdrug-2020, sources/HF-ESC-2021)
• Maintenance dose: 200 mg/day; 100 mg/day in elderly. Consider dose reduction in women and low body weight patients to reduce risk of pacemaker requirement. (sources/amiodarone-cvdrug-2020)
• For SVT (flutter, AVNRT, AVRT): Prefer catheter ablation over long-term amiodarone (high cure rates). Reserve amiodarone for critically ill patients unable to undergo ablation. (sources/amiodarone-cvdrug-2020)

Dosing

• IV loading (VF/hemodynamically unstable VT): 150–300 mg bolus → 1 mg/min × 6h → 0.5 mg/min × ≥18h
• IV loading (hemodynamically stable VT): 150 mg IV bolus → 1 mg/min × 6h → 0.5 mg/min × 18h
• IV-to-oral conversion: <1 week IV → 800–1600 mg/day PO; 1–3 weeks → 600–800 mg/day; >3 weeks → 400 mg/day
• Overlapping IV and oral amiodarone does not reduce early arrhythmia recurrence. (sources/amiodarone-cvdrug-2020)

Dronedarone vs Amiodarone

• Structural differences: Dronedarone is a non-iodinated benzofuran derivative of amiodarone -- iodine atoms removed (eliminating thyroid/pulmonary toxicity), methanesulfonyl group added (reduces lipophilicity), resulting in a half-life of ~24 hours vs amiodarone's 40-55 days. (sources/dronedarone-circ-2009, rating: medium)
• Relative potency differences: Dronedarone is 10x more potent as an INa blocker and 100x more potent as an IK-Ach blocker than amiodarone at equal concentrations. Amiodarone has greater IKr blockade and longer duration of action. The superior INa blockade of dronedarone likely accounts for its better ventricular arrhythmia suppression in ischaemia models -- but also for its contractility hazard in severe HF (ANDROMEDA). (sources/dronedarone-circ-2009)
• DIONYSOS head-to-head: Amiodarone is significantly more effective than dronedarone for maintaining sinus rhythm in persistent AF (primary composite endpoint: 55.3% amiodarone vs 73.9% dronedarone); amiodarone has more cardiac adverse events (bradycardia, QT prolongation), dronedarone has more GI effects. When extracardiac toxicity or thyroid comorbidity limits amiodarone use, dronedarone is the preferred alternative -- provided the patient does not have NYHA III/IV HF with LVEF <=35%. (sources/dronedarone-circ-2009)

Drug Interactions

• Warfarin: Inhibits CYP2C9/3A4 + S-warfarin → reduce warfarin dose by 30–50%; monitor INR closely. (sources/amiodarone-cvdrug-2020)
• Simvastatin / atorvastatin: CYP3A4 inhibition → increased statin levels → myopathy/rhabdomyolysis risk. Max simvastatin 20 mg with amiodarone. Consider pravastatin (unaffected). (sources/amiodarone-cvdrug-2020)
• Digoxin: P-glycoprotein inhibition → elevated digoxin levels → toxicity risk. Monitor closely. (sources/amiodarone-cvdrug-2020)
• Class Ia antiarrhythmics (quinidine, procainamide, disopyramide): contraindicated — dose-independent QTc prolongation. (sources/amiodarone-cvdrug-2020)
• Class III antiarrhythmics (sotalol, dofetilide, ibutilide): avoid combination — additive QTc prolongation. (sources/amiodarone-cvdrug-2020)
• Flecainide: Reduce flecainide dose by 50% (CYP2D6 inhibition). (sources/amiodarone-cvdrug-2020)
• β-blockers / non-DHP CCBs: Additive sinus nodal and AV nodal depression → bradycardia risk; use cautiously. (sources/amiodarone-cvdrug-2020)
• Sofosbuvir-containing HCV regimens (Harvoni, Sovaldi): FDA black box warning — rare but potentially fatal bradycardia. (sources/amiodarone-cvdrug-2020)
• Indinavir / ritonavir (HIV): Increase amiodarone concentration — Class X (avoid). (sources/amiodarone-cvdrug-2020)
• Cholestyramine: Reduces amiodarone bioavailability. (sources/amiodarone-cvdrug-2020)
• Ivabradine / fosphenytoin / lopinavir-ritonavir: Additive QTc prolongation — use with caution. (sources/amiodarone-cvdrug-2020)
• Doxorubicin: Inhibits CYP2D6/3A4/P-gp → increased doxorubicin concentration → increased toxicity. (sources/amiodarone-cvdrug-2020)

Toxicity and Monitoring

Thyroid Management

See dedicated concept page: concepts/Amiodarone-Induced-Thyroid-Disorders

• Incidence: 2–24% overall; thyroid toxicity is NOT dose-dependent — similar risk on low and high doses (sources/amiodarone-thyroid-jcem-2021, rating: high)
• Mechanism — iodine-related: each 200 mg tablet releases ~7 mg free iodine (23–47× daily requirement); triggers Wolff-Chaikoff effect (→ AIH) or Jod-Basedow phenomenon (→ Type 1 AIT in autonomous glands) (sources/amiodarone-thyroid-jcem-2021)
• Mechanism — non-iodine: inhibits deiodinases (↓ T3, ↑ rT3), blocks T3 nuclear receptor, directly cytotoxic to follicular cells (→ Type 2 AIT destructive thyroiditis); euthyroid patients show transient ↑ TSH/FT4/rT3 in first month, normalising by 3–6 months; T3 remains persistently low (sources/amiodarone-thyroid-jcem-2021)
• Hypothyroidism (AIH): Wolff-Chaikoff failure ± Hashimoto thyroiditis; treat with levothyroxine (increase gradually — rapid escalation risks arrhythmias); 60% transient (resolves 2–4 months after amiodarone cessation); continue amiodarone if needed for life-threatening arrhythmia (sources/amiodarone-cvdrug-2020, sources/amiodarone-thyroid-jcem-2021)
• Type 1 AIT (iodine-driven autonomous overproduction in abnormal thyroid — goiter, Graves'): methimazole 40–60 mg/day preferred (up to 120 mg/day); PTU if methimazole contraindicated; suspect mixed type if no response at 3–4 weeks (sources/amiodarone-thyroid-jcem-2021)
• Type 2 AIT (destructive thyroiditis in previously normal gland; often onset >2 years or post-discontinuation): prednisone 30–40 mg/day for 2–4 weeks then taper; FT3 normalisation expected ~8 days; 16% permanently hypothyroid after treatment; amiodarone continuation often feasible (self-limited process) (sources/amiodarone-thyroid-jcem-2021)
• Mixed Type 1/2 AIT: treat with both methimazole 40 mg/day + prednisone 40 mg/day simultaneously; taper thionamide if FT3/TT3 declines >50%; no response → thyroidectomy (sources/amiodarone-thyroid-jcem-2021)
• Thyroidectomy: for refractory AIT, reduced LVEF with deteriorating cardiac function, or malignant arrhythmias unresponsive to medical therapy; 5-and-10-year mortality benefit confirmed in moderate-to-severe LVEF impairment subgroup (Capellani n=207); multidisciplinary team decision (sources/amiodarone-thyroid-jcem-2021)
• AIT + anticoagulation: thyrotoxicosis enhances warfarin effect; amiodarone inhibits CYP2C9/3A4 (warfarin) and P-gp/CYP3A4 (rivaroxaban, apixaban) — triple interaction in AIT patients on OAC requires careful monitoring and dose adjustment (sources/amiodarone-thyroid-jcem-2021)
• Late-onset/post-discontinuation AIT: 7% develop Type 2 AIT up to 7–16 months after stopping amiodarone — monitor thyroid for ≥1 year post-cessation; 75% risk re-AIT if restarted (sources/amiodarone-thyroid-jcem-2021)
• AIT ICU mortality: 23% when complicated by thyroid storm (sources/amiodarone-thyroid-jcem-2021)
• Refer to endocrinologist for all thyroid toxicities (sources/amiodarone-cvdrug-2020)

Pulmonary Management

See dedicated concept page: concepts/Amiodarone-Pulmonary-Toxicity

• Mechanism: amiodarone and desethylamiodarone concentrate 100–500× in lung tissue; drug persists up to 1 year post-cessation; foamy macrophages = exposure marker (not diagnostic of toxicity) (sources/amiodarone-pulmonary-clin-chest-2004, rating: medium)
• 6 clinical patterns: subacute infiltrative pneumonitis (most common), organising pneumonia, pulmonary fibrosis (~0.1%; irreversible), pulmonary nodules/masses (6–12%), ARDS (post-thoracic surgery; ~50% fatality), subclinical APT (reversible) (sources/amiodarone-pulmonary-clin-chest-2004)
• Key imaging feature: high-attenuation CT changes (iodine content); asymmetric involvement; right upper lobe predilection; subpleural distribution (sources/amiodarone-pulmonary-clin-chest-2004)
• DLCO — key monitoring tool: earliest functional marker; DLCO ≥15% decrease = sensitivity threshold; ≥30% = specificity threshold; isolated DLCO decrease without clinical/imaging evidence does NOT warrant stopping amiodarone (sources/amiodarone-pulmonary-clin-chest-2004)
• ARDS trigger: high-concentration oxygen + amiodarone during cardiac or pulmonary surgery; also reported with iodinated contrast media (2 fatal cases — use caution) (sources/amiodarone-pulmonary-clin-chest-2004)
• Treatment: stop amiodarone (under cardiological supervision) + prednisolone 0.75–1 mg/kg/day; maintain until definite clinical + radiographic response; taper slowly over minimum 6 months (often 1 year); early withdrawal → recurrence (potentially fatal) (sources/amiodarone-pulmonary-clin-chest-2004)
• "Amiodarone effect" vs "amiodarone toxicity": All chronically treated patients develop ubiquitous lipoid pneumonia (foamy macrophages, asymptomatic DLCO decline) — this is NOT a reason to stop; "amiodarone toxicity" refers to distinct inflammatory patterns requiring intervention (sources/amiodarone-pulmonary-drugsafety-2010, rating: medium)
• Full clinical taxonomy (9 patterns): CEP, COP, AFOP, amiodaronoma (PET-positive mass, right upper lobe, mimic malignancy), NSIP-like, IPF-like, DIP, ALI/ARDS, DAH (sources/amiodarone-pulmonary-drugsafety-2010)
• ACE inhibitors/ARBs potentially protective: Angiotensin II (elevated in HF) enhances amiodarone-induced AEC apoptosis; two retrospective studies show lower APT rates in patients on ACE-I/ARBs (sources/amiodarone-pulmonary-drugsafety-2010)
• KL-6 biomarker: NPV 92% at >500 U/mL (useful to rule out APT); sensitivity only 25% (sources/amiodarone-pulmonary-drugsafety-2010)
• CT density >70 HU: suggestive of APT but absent in 27–55% of confirmed cases — not a reliable rule-out criterion (sources/amiodarone-pulmonary-drugsafety-2010)
• Corticosteroid taper: ≤5 mg/day reduction; relapse risk persists up to 8 months after complete cessation (sources/amiodarone-pulmonary-drugsafety-2010)
• If amiodarone cannot be stopped: dose reduction + corticosteroids can achieve adequate control of both APT and arrhythmia in selected patients (sources/amiodarone-pulmonary-clin-chest-2004, sources/amiodarone-pulmonary-drugsafety-2010)
• Higher risk in pre-existing lung disease (COPD, emphysema), prior pneumonectomy, or O₂-dependent patients; AFFIRM data: pre-existing lung disease does NOT increase pulmonary death or all-cause mortality (sources/amiodarone-cvdrug-2020, sources/amiodarone-pulmonary-clin-chest-2004, sources/amiodarone-pulmonary-drugsafety-2010)

Cardiac Monitoring

• HR >40 bpm asymptomatic: maintain dose. HR <40 bpm: reduce by 50%. Symptomatic bradycardia: reduce 50% or stop. (sources/amiodarone-cvdrug-2020)
• Consider pacemaker for SVT with intolerable bradycardia; ICD for VT cases. (sources/amiodarone-cvdrug-2020)

Pregnancy and Lactation

• Class D drug: cardiac, endocrine, and neurodevelopmental anomalies reported. Use only as drug of last resort. (sources/amiodarone-cvdrug-2020)
• Avoid in breastfeeding or stop breastfeeding to prevent neonatal hypothyroidism. (sources/amiodarone-cvdrug-2020)
• See concepts/LQTS-Pregnancy-Management — amiodarone is contraindicated in pregnancy in that context too.

Alternatives When Amiodarone Must Be Stopped

• VA: mexiletine, sotalol; rarely quinidine or procainamide (high TdP risk) (sources/amiodarone-cvdrug-2020)
• AF (no CAD/HF): class Ic agents (flecainide, propafenone), dronedarone (structurally normal heart) (sources/amiodarone-cvdrug-2020)
• AF (if adequate renal function + normal baseline QTc): sotalol, dofetilide (sources/amiodarone-cvdrug-2020)

Contradictions / Open Questions

• Amiodarone in Anderson–Fabry Disease — contraindicated: Amiodarone should be avoided in AFD patients because it interferes with lysosomal function, potentially worsening α-Gal A enzymatic deficiency and impairing the efficacy of both ERT and migalastat chaperone therapy. This is distinct from its general safety profile in HFrEF. Antiarrhythmic drug choices in AFD are severely constrained by coexisting LVH, HF, and renal dysfunction. (sources/fabry-ehj-2024, rating: high)
• Amiodarone vs. procainamide for stable VT: PROCAMIO RCT showed procainamide superior in acute termination; however the trial was small (n=62) and procainamide is unavailable as a long-term oral agent in the USA — the practical clinical choice between these two agents is context-dependent. (sources/amiodarone-cvdrug-2020)
• Amiodarone in HFrEF — no mortality benefit (SCD-HeFT) but remains only safe AAD: Amiodarone showed no mortality benefit vs placebo in HFrEF (LVEF <35%) in SCD-HeFT, yet guidelines still designate it the only safe antiarrhythmic for rhythm control in HFrEF. This creates a tension: amiodarone is "safe" in HFrEF in the sense of not worsening mortality, but it does not improve it — it is reserved for arrhythmia suppression as adjunct to ICD/ablation. (sources/amiodarone-cvdrug-2020, sources/HF-ESC-2021)
• Amiodarone + sofosbuvir (HCV) interaction: The FDA black box warning for fatal bradycardia with amiodarone + sofosbuvir-containing regimens represents a growing clinical risk as HCV treatment rates rise in older AF/VT patients. The mechanism (additive sinus/AV nodal depression) is not fully characterized. No prospective management protocol exists. (sources/amiodarone-cvdrug-2020)
• AIT management — amiodarone continuation vs withdrawal: ETA 2018 recommends continuing amiodarone for life-threatening arrhythmias in AIT. However, continuation prolongs iodine overload in Type 1 AIT and may delay Type 2 resolution. 75% of patients restarting amiodarone experience another AIT episode. The decision requires joint cardiologist-endocrinologist risk stratification with no high-quality trial to guide it. (sources/amiodarone-thyroid-jcem-2021)
• APT and high-concentration oxygen: Amiodarone-treated patients undergoing cardiac or pulmonary surgery face an ARDS risk with high FiO₂ — estimated 50% fatality; also reported with iodinated contrast media (2 fatal cases). No prospective protocol exists for managing amiodarone-treated patients perioperatively regarding oxygen concentration. Clinicians may not recognise this specific drug-oxygen interaction. (sources/amiodarone-pulmonary-clin-chest-2004)

Connections

• Related to entities/Dronedarone — non-iodinated structural derivative; DIONYSOS head-to-head comparison
• Related to entities/Fabry-Disease — contraindicated; impairs lysosomal function and ERT/migalastat efficacy
• Related to concepts/Fabry-Cardiomyopathy
• Related to entities/Atrial-Fibrillation
• Related to entities/Heart-Failure
• Related to entities/Long-QT-Syndrome
• Related to entities/Short-QT-Syndrome
• Related to entities/Brugada-Syndrome
• Related to concepts/Torsades-de-Pointes
• Related to concepts/Drug-Induced-Arrhythmia
• Related to concepts/Cardiac-Action-Potential
• Related to concepts/Electrical-Storm
• Related to concepts/LQTS-Pregnancy-Management
• Related to concepts/Amiodarone-Induced-Thyroid-Disorders — full Type 1/2/AIH/mixed diagnosis and management framework
• Related to concepts/Amiodarone-Pulmonary-Toxicity — 6 clinical patterns, DLCO monitoring, corticosteroid regimen, oxygen/surgery triggers

Sources

• Related to sources/dronedarone-circ-2009
• Related to sources/amiodarone-thyroid-jcem-2021
• Related to sources/amiodarone-pulmonary-clin-chest-2004
• Related to sources/amiodarone-pulmonary-drugsafety-2010