Amiodarone

• What it does: Broad-spectrum antiarrhythmic used IV for life-threatening ventricular arrhythmias (VF/pulseless VT, unstable VT) and for rate/rhythm control of atrial arrhythmias in selected hemodynamically stable patients
• Mechanism: Predominantly blocks myocardial potassium channels (prolongs repolarization and QT), but also blocks sodium channels, beta-receptors, and calcium channels → slows conduction, prolongs refractoriness, and reduces automaticity in atrial and ventricular tissue and in the AV node
• Adult ACLS for VF/pulseless VT: 300 mg IV/IO bolus push after defibrillation and vasopressor; may give a second 150 mg bolus if VF/pVT persists or recurs (maximum 450–600 mg in the arrest algorithm)
• Adult Non-Arrest Dosing: 150 mg IV in 100 mL D5W over 10 minutes, followed by 1 mg/min for 6 hours, then 0.5 mg/min for 18 hours (total ~1 g in 24 hours); additional 150 mg boluses over 10 minutes can be given for recurrent VT/RVR to a typical max of 2–2.2 g in 24 hours
• Onset (IV): Antiarrhythmic effects begin within minutes; distribution into myocardium is rapid, with high myocardium:plasma ratios; hemodynamic effects from a bolus may last 30–90 minutes, while the drug remains in tissues for days to weeks
• Major Acute IV Risks: Hypotension (often from solvent/excipient and vasodilation), bradycardia, AV block, QT prolongation with risk of torsades (less than other class III agents but not zero), phlebitis with peripheral infusions, and acute hepatic enzyme elevation
• Major Chronic (Oral) Risks: Pulmonary toxicity (pneumonitis/fibrosis), hypo- or hyperthyroidism, hepatotoxicity, corneal microdeposits, optic neuropathy, photosensitivity and blue–gray skin discoloration, and peripheral neuropathy
• Special Considerations: Highly lipophilic with huge volume of distribution and extremely long terminal half-life (weeks); effects and toxicities can persist long after the drug is stopped; frequent and important drug–drug interactions via CYP3A4, CYP2C9, and P-glycoprotein inhibition (e.g., increases levels of warfarin, digoxin, many statins)

• Generic Name: Amiodarone
• Brand Names: Cordarone, Pacerone, Nexterone, plus multiple generics (availability is institution- and region-specific)

Class III antiarrhythmic with multi-channel blockade (shows properties of Class I, II, III, and IV)

Mechanism of Action:

Amiodarone is classed as a Vaughan–Williams Class III antiarrhythmic but exhibits properties of all four major classes:

• Class I (sodium-channel blockade): Inhibits fast inward Na⁺ current, particularly in the inactivated state, slowing phase 0 depolarization in atrial and ventricular myocytes and in accessory pathway tissue
• Class II (noncompetitive beta-blockade): Nonselective antiadrenergic effects reduce automaticity, slow sinus rate, and blunt catecholamine-driven arrhythmias
• Class III (potassium-channel blockade): Blocks multiple outward K⁺ currents (including IKr and IKs), prolonging phase 3 repolarization, action potential duration, and effective refractory period in atrial, AV nodal, and ventricular tissue → QT prolongation and suppression of re-entry
• Class IV (calcium-channel blockade): Modest L-type calcium-channel inhibition in nodal tissue contributes to slowed AV nodal conduction and rate control, though this is weaker than with verapamil/diltiazem
• Net electrophysiologic effects: Decreased SA node automaticity, slowed AV node conduction and increased refractoriness, reduced conduction velocity in atrial and ventricular myocardium, and prolongation of atrial and ventricular refractory periods
• Also causes systemic and coronary vasodilation (via calcium-channel blockade and antiadrenergic effects), which can reduce myocardial oxygen demand but also contribute to hypotension during rapid IV loading
• Compared with many other antiarrhythmics, amiodarone causes relatively little negative inotropy, making it useful in patients with structural heart disease and reduced EF—though IV loading can still depress blood pressure

Pharmacokinetics (IV vs. Oral):

• Routes: Intravenous (IV/IO) and oral are the main routes in acute and chronic therapy; IM and SQ routes are not used; IV is for acute control; oral is for maintenance
• Absorption (oral): Slow and highly variable; bioavailability ranges roughly 20–55%; food can increase absorption; steady state often requires many weeks without loading doses
• Distribution: Extremely large apparent volume of distribution (often 1–60 L/kg) due to high lipophilicity and extensive tissue binding; protein binding >95–96%; high concentrations accumulate in fat, liver, lungs, myocardium, skin, and cornea
• Onset: After IV bolus, electrophysiologic effects begin within minutes, with significant myocardial tissue uptake occurring within ~30 minutes; hemodynamic effects may wane over hours even though the drug stays in tissues much longer
• Metabolism: Hepatic via CYP3A4 and CYP2C8 to active metabolite desethylamiodarone (DEA), which shares antiarrhythmic properties and contributes to long-term effects/toxicity
• Elimination: Primarily biliary/fecal; renal excretion is minimal; terminal elimination half-life after chronic use is extremely long (often 15–60 days, with ranges reported up to >100 days)
• Half-life after single dose: Can range from several hours to a few days; however, because of redistribution and metabolite formation, clinically relevant effects last much longer than plasma half-life alone would suggest
• Because of slow elimination and tissue accumulation, oral loading regimens (e.g., 800–1600 mg/day then taper to 100–400 mg/day) are used to reach therapeutic myocardial concentrations more quickly
• In hepatic dysfunction, clearance is reduced and half-life prolonged; dose reductions and slow titration are essential; amiodarone is not dialyzable

• ACLS cardiac arrest for shock-refractory ventricular fibrillation (VF) or pulseless ventricular tachycardia (pVT) after defibrillation and vasopressor therapy
• Hemodynamically stable monomorphic VT (especially with structural heart disease) when synchronized cardioversion is not immediately available or as adjunct to cardioversion
• Control of ventricular rate and/or facilitation of rhythm conversion in atrial fibrillation/flutter with rapid ventricular response when other agents (beta-blockers, calcium channel blockers) are contraindicated, ineffective, or poorly tolerated, particularly in patients with LV dysfunction or significant structural heart disease
• Short-term suppression of recurrent ventricular arrhythmias (e.g., ICD shocks, recurrent VT storm) in the ICU when used as an infusion
• Chronic oral therapy: prevention of recurrent atrial fibrillation/flutter, suppression of recurrent VT/VF, and secondary prevention of sudden cardiac death in selected high-risk patients under specialist management (EP/cardiology)

Diseases & Conditions Treated:

• Ventricular fibrillation and pulseless ventricular tachycardia (ACLS setting)
• Hemodynamically stable monomorphic ventricular tachycardia (with a pulse)
• Polymorphic VT (including torsades) in some guidelines after correction of electrolytes and ischemia, particularly when other measures fail (specialist-level decision)
• Atrial fibrillation and atrial flutter with RVR (rate/rhythm control), especially in patients with structural heart disease and reduced ejection fraction when beta-blockers or non-DHP CCBs are unsuitable
• Supraventricular tachycardias refractory to other agents (less common role with modern adenosine use)
• Frequent ventricular ectopy or nonsustained VT in high-risk structural heart disease (chronic oral therapy, EP-directed)

Available Forms:

• IV injection/infusion concentrate: 50 mg/mL in 3 mL vials (150 mg/3 mL)
• Premixed IV bags (e.g., Nexterone): 150 mg in 100 mL D5W; 360 mg in 200 mL D5W (concentration 1.5–1.8 mg/mL depending on product)
• Oral tablets: Commonly 100 mg, 200 mg, and 400 mg strengths

Important Administration Notes:

• Use non-PVC tubing/bags according to product labeling and institutional protocol to minimize sorption; premixed formulations are often supplied in non-PVC containers
• Peripheral IV infusions should generally not exceed concentrations of ~2 mg/mL and should be limited in duration because of phlebitis; central venous access is preferred for prolonged infusions or higher concentrations

IV Dosing (Always Follow Local Protocols and ACLS/Arrhythmia Guidelines):

Administration Guidelines:

• Always administer IV loading doses on a monitor with continuous ECG and frequent blood pressure checks
• For non-arrest boluses, infuse over 10 minutes (or longer) to reduce risk of hypotension
• Use an infusion pump for continuous infusions
• For longer-term infusions or higher concentrations, central venous access is strongly preferred
• The standard 24-hour regimen (150 mg over 10 minutes, then 1 mg/min for 6 h, then 0.5 mg/min for 18 h) delivers approximately 1,000 mg in 24 hours
• Many protocols allow additional boluses up to a total of 2–2.2 g in the first 24 hours in refractory cases
• In patients with severe hypotension, bradycardia, or advanced conduction disease, reduce infusion rates or discontinue the infusion and manage per ACLS/toxicity guidelines

Transition from IV to Oral Therapy:

• Total IV dose and duration, patient size, and arrhythmia burden guide the oral loading strategy
• Typical oral loading regimens range from 800–1600 mg/day in divided doses for 1–3 weeks, then 400–600 mg/day for several weeks, then maintenance 100–400 mg/day as tolerated
• Remember that the myocardium is already loaded to some extent; adjust the oral loading regimen downward and coordinate with cardiology/EP to avoid unnecessary super-loading

Oral Dosing Overview (for Context – Chronic Therapy):

• Loading: 800–1600 mg/day in divided doses for 1–3 weeks, followed by 400–600 mg/day for several weeks
• Maintenance: Lowest effective dose, usually 100–400 mg/day
• For AF prevention: common maintenance dose is 100–200 mg once daily after loading
• For ventricular arrhythmias: doses of 200–400 mg/day are common depending on response and tolerance
• Because of very long half-life and cumulative toxicity, oral dosing should be managed by cardiology/electrophysiology with a clear long-term plan and regular monitoring (pulmonary, thyroid, hepatic, ocular)

Absolute Contraindications (IV and Generally Oral):

• Cardiogenic shock with severe hypotension not due to a treatable tachyarrhythmia
• Marked sinus bradycardia, sick sinus syndrome, or second-/third-degree AV block without a functioning pacemaker
• Severe sinus node dysfunction with symptomatic bradycardia
• Known hypersensitivity to amiodarone or iodine (though true iodine "allergy" is controversial, label lists it)
• Concurrent use of medications that clearly prolong QT and raise torsades risk, when safer alternatives exist, especially in the presence of baseline QT prolongation

Major Precautions:

• Baseline QT prolongation or history of torsades de pointes: Use extreme caution; correct potassium, magnesium, and calcium before and during therapy
• Severe hepatic dysfunction: Reduce doses and monitor liver enzymes frequently; discontinue if significant transaminase elevation or clinical hepatitis occurs
• Advanced pulmonary disease or prior amiodarone-induced pulmonary toxicity: Chronic oral use is high risk; short-term IV use may still be considered if benefits outweigh risks but should trigger specialist consultation
• Thyroid disease: Amiodarone can cause both hypo- and hyperthyroidism; baseline and periodic thyroid function tests are recommended, particularly in chronic therapy
• Concomitant drugs: Adjust doses and monitor levels for digoxin and warfarin when starting or changing amiodarone; monitor for interactions with statins (simvastatin, lovastatin), other antiarrhythmics, and strong CYP3A4 modulators
• Older adults, hypotensive or volume-depleted patients, and those with LV dysfunction: More susceptible to amiodarone-induced hypotension during IV loading; consider slower infusion rates or reduced doses
• Pregnancy and lactation: Amiodarone crosses the placenta and is found in breast milk; generally avoided unless life-threatening maternal arrhythmia warrants use

Common (More Prominent with IV Acute Use):

• Hypotension, often related to solvent/vehicle and vasodilation, especially with rapid loading doses
• Bradycardia and first-degree AV block
• Nausea, vomiting, and metallic taste during loading
• Infusion-site phlebitis and pain with peripheral administration
• Transient elevation of liver enzymes (AST/ALT)

Serious Acute (IV):

• Symptomatic hypotension or cardiogenic shock requiring vasopressors and/or inotropes
• High-grade AV block, sinus arrest, or severe bradycardia with syncope/asystole
• QT prolongation with torsades de pointes (less frequent than with many other class III agents but documented)
• Acute liver injury with marked transaminase elevations or hepatic failure (rare but reported, especially with high-dose IV)
• Rare anaphylactoid or hypersensitivity reactions

Major Chronic (Oral, but Relevant if Transitioning from IV):

• Pulmonary toxicity: Interstitial pneumonitis, organizing pneumonia, and pulmonary fibrosis presenting with cough, dyspnea, and infiltrates; can be fatal if unrecognized
• Thyroid dysfunction: Both hypothyroidism (more common) and hyperthyroidism (including thyroid storm)
• Hepatotoxicity: Chronic transaminase elevation or more severe liver injury
• Ocular effects: Corneal microdeposits (usually asymptomatic), optic neuropathy/neuritis with visual loss (rare but serious)
• Dermatologic: Photosensitivity, blue–gray skin discoloration in sun-exposed areas
• Neurologic: Peripheral neuropathy, tremor, ataxia, sleep disturbances
• GI: Anorexia, weight loss, nausea, and metallic taste

• Warfarin: Amiodarone inhibits CYP2C9; increases warfarin levels significantly → reduce warfarin dose by 30–50% and monitor INR closely
• Digoxin: Amiodarone inhibits P-glycoprotein; increases digoxin levels by 70–100% → reduce digoxin dose by 50% and monitor levels
• Statins (simvastatin, lovastatin): Increased statin levels via CYP3A4 inhibition → increased myopathy/rhabdomyolysis risk; use lowest dose or alternative statin
• Other antiarrhythmics: Additive QT prolongation and proarrhythmic effects; monitor closely
• Beta-blockers, calcium channel blockers: Additive bradycardia and AV block risk
• CYP3A4 substrates: Many drug interactions via CYP3A4 inhibition; always check interactions before starting therapy
• QT-prolonging agents: Increased torsades risk; avoid concurrent use when possible

Hepatic Impairment:

• Clearance is reduced and half-life prolonged
• Reduce doses and monitor liver enzymes frequently
• Discontinue if significant transaminase elevation occurs

Renal Impairment:

• No specific dose adjustment required (primarily hepatic elimination)
• Not removed by dialysis
• Monitor for fluid overload and electrolyte abnormalities

Pregnancy & Lactation:

• Pregnancy: Category D; generally avoided unless life-threatening maternal arrhythmia
• Crosses placenta; can cause neonatal hypothyroidism and other adverse effects
• Lactation: Excreted in breast milk; generally avoid or discontinue breastfeeding

Pediatric Considerations:

• IV dosing: 5 mg/kg over 20–60 minutes (max 300 mg single dose)
• May repeat up to 15 mg/kg/day total (max 2.2 g/24 h)
• Specialist-directed use only
• Adhere strictly to pediatric-specific guidelines

Geriatric Considerations:

• Increased susceptibility to hypotension during IV loading
• Higher risk of bradycardia and AV block
• More likely to have hepatic or renal impairment
• Consider slower infusion rates and reduced doses

Clinical Monitoring:

• Continuous ECG monitoring during IV bolus and infusion to detect bradycardia, AV block, QT prolongation, and ventricular arrhythmias
• Frequent blood pressure monitoring (q1–5 minutes during bolus and early infusion; arterial line in unstable ICU patients)
• Assessment of arrhythmia control: rhythm strips, ventricular rate in AF/flutter, number of ICD shocks or VT episodes
• Infusion site monitoring for signs of phlebitis (peripheral IV)

Laboratory Monitoring:

• Serum electrolytes (K⁺, Mg²⁺, Ca²⁺) and renal function; aggressively correct hypokalemia and hypomagnesemia to reduce proarrhythmic risk
• Liver function tests during prolonged infusions and periodically with oral therapy; discontinue or reduce dose if significant elevation occurs
• For chronic oral therapy: baseline and periodic thyroid function tests (TSH, free T4), liver enzymes, chest x-ray and/or pulmonary function in high-risk patients, and eye exams when indicated

• 1. Florek, J. B., & colleagues. (2023). Amiodarone. In StatPearls [Internet]. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK482154/
• 2. King, G. S., & colleagues. (2024). Antiarrhythmic medications. In StatPearls [Internet]. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK482322/
• 3. Yang, J., & colleagues. (2025). Adverse events in different administration routes of amiodarone. Frontiers in Pharmacology, 16, 1517616. https://doi.org/10.3389/fphar.2025.1517616
• 4. American Heart Association. (2020). 2020 AHA guidelines for CPR and ECC: Adult advanced life support algorithms. Circulation. https://cpr.heart.org
• 5. Medscape. (2024). Pacerone, Cordarone (amiodarone) dosing, indications, interactions, adverse effects, and more. Medscape Reference. https://reference.medscape.com/drug/pacerone-cordarone-amiodarone-342296