Amiodarone

Mechanism of Action

Amiodarone, alongside sotalol and dronedarone, is a class III antiarrhythmic drug, due to its substantial prolongation of the cardiac action potential. Its mechanism of action involves blocking potassium channels involved in cardiac repolarisation. Oral amiodarone also inhibits inactivated sodium channels (phase 0) and L-type slow calcium channels. 

Prolongation of the action potential increases the refractory period, which elicits an antidysrhythmic activity by interrupting re-entrant tachycardias and suppressing ectopic activity. Interestingly, IV amiodarone produces a smaller increase in the action potential duration compared to oral amiodarone, and little or no increase in the QRS duration or QT interval.

Created in BioRender. Boucher, M. (2026) https://BioRender.com/nlegmb1

Fig 1: Effect of Amiodarone on The Cardiac Action Potential

Pharmacokinetics

Absorption

Oral amiodarone has a bioavailability of 30-70%. In life-threatening dysrhythmias, intravenous administration is used, via a central vein. IV amiodarone acts quickly and is effective within minutes of a bolus dose.

Distribution

Oral amiodarone is lipophilic and therefore extensively taken up by tissue (volume of distribution = 66L/kg); amiodarone accumulates in the liver and the lung which explains reported adverse effects such as hepatitis and pulmonary toxicity. 

Amiodarone is highly protein-bound contributing to a long half life. 

After IV administration, the initial distribution phase is rapid, producing a relatively quick clinical effect.

Metabolism

The main elimination route is via the liver and the bile, with only 10% of the substance renally eliminated, meaning that amiodarone does not require adjustment in renal impairment. Amiodarone is metabolised by CYP3A4 (major) and CYP2C8. 

Elimination 

Oral amiodarone has a mean plasma half-life of approximately 50 days, with a reported range of 20 to 100 days. Due to this prolonged half-life, adequate time must be allowed between dose adjustments to reach a new steady-state distribution. Furthermore, initiation with therapy requires a loading dose. A common example of dosing is initially 200mg three times daily for 1 week followed by 200mg twice daily for 1 week, followed by a maintenance dose of 200mg once daily. 

In patients with potentially life-threatening arrhythmias, the extended half-life can be advantageous, as missing an occasional dose is unlikely to significantly affect the overall therapeutic response. It is essential to use the lowest effective dose and to monitor patients regularly for signs of excessive dosing, as amiodarone has several clinically significant adverse effects. 

Dronedarone

Dronedarone is a related class III antiarrhythmic drug, which does not cause iodine-related thyroid dysfunction. It is also less lipophilic and has a shorter T½, however safety concerns include increased rates of stroke, heart failure and death from cardiovascular causes.

Contraindications

Amiodarone is contraindicated in patients with known hypersensitivity to amiodarone, iodine, or any of the excipients in the formulation, noting that each 200 mg tablet contains approximately 75 mg of iodine. Due to its high iodine content, It is also contraindicated in patients with current or previous thyroid dysfunction, and thyroid function tests must be performed in all patients prior to initiating therapy.

It should not be used in individuals with sinus bradycardia or sinoatrial block. In patients with significant conduction abnormalities, such as high-grade atrioventricular block, bifascicular or trifascicular block, or sinus node dysfunction, amiodarone should only be administered if a pacemaker is in place. 

Concomitant use with medicinal products known to induce Torsades de Pointes is contraindicated. Amiodarone must not be used during breastfeeding and should not be used during pregnancy except in exceptional circumstances where treatment is considered essential.

Cautions and Adverse Effects

Amiodarone is associated with a broad and sometimes serious adverse-effect profile, requiring careful patient selection, baseline assessment and ongoing monitoring. Owing to its long half-life and tissue accumulation, adverse reactions may be delayed and are often dose related; therefore, the lowest effective maintenance dose should always be used. The tablets contain lactose and are unsuitable for patients with rare hereditary disorders of galactose metabolism.

Cardiac effects are common and clinically significant. Dose-related bradycardia and conduction disturbances may occur, and treatment should be discontinued in cases of second- or third-degree atrioventricular block, sinoatrial block, or bifascicular block. Hypotension is a common adverse effect with IV amiodarone, affecting up to 25% of patients. 

Although amiodarone has a relatively low pro-arrhythmic potential compared with other antiarrhythmics, new or worsening arrhythmias, including Torsade de Pointes, have been reported (≦1% incidence). Torsades de pointes associated with amiodarone therapy is more likely to occur in females. QT prolongation is expected pharmacologically and does not necessarily indicate toxicity, although it is less likely to occur with IV amiodarone compared with oral. 

Caution is also required in patients with implantable cardioverter-defibrillators or pacemakers, as amiodarone may increase pacing and defibrillation thresholds. Baseline and periodic ECG monitoring, as well as correction of electrolyte abnormalities, is recommended.

Thyroid dysfunction is a well-recognised complication due to the drug’s high iodine content and effects on thyroid hormone metabolism. Amiodarone inhibits peripheral conversion of levothyroxine (T4) to triiodothyronine (T3). Both hypothyroidism and hyperthyroidism may occur, and either can present during treatment or months after discontinuation. Routine thyroid function testing before initiation, every six months during therapy, and for several months after stopping is advised. Hyperthyroidism may be severe and occasionally fatal.

Pulmonary toxicity is one of the most serious adverse effects and may manifest as interstitial pneumonitis, pulmonary fibrosis, organising pneumonia, or, rarely, pulmonary haemorrhage. Patients presenting with unexplained dyspnoea or non-productive cough require prompt evaluation. Early recognition and withdrawal are critical, as progression can occur despite discontinuation.

In addition to this, hepatotoxicity ranges from asymptomatic transaminase elevations to acute hepatitis, cirrhosis, and hepatic failure, including fatal cases. Liver function tests should be performed prior to treatment and monitored at least six-monthly. Dose reduction or discontinuation is indicated if transaminases exceed three times the upper limit of normal or if clinical liver disease develops. During loading phase of dosing, elevated LFTs may occur (1.5-3x upper limit) which may resolve spontaneously or following a dose reduction.

Ocular effects are frequent. Corneal microdeposits occur in most patients and are usually benign and reversible, although visual halos or blurred vision may occur. Optic neuropathy and optic neuritis are rare but potentially sight-threatening and require immediate discontinuation. Annual ophthalmological review is recommended or sooner if visual symptoms develop.

Neurological adverse effects include tremor, sleep disturbance, peripheral neuropathy, myopathy, ataxia and, rarely, benign intracranial hypertension. Neuropathy and myopathy may be severe and recovery after withdrawal can be slow or incomplete. Psychiatric reactions such as confusion or hallucinations have also been reported.

Cutaneous reactions are common, particularly photosensitivity, which may persist after discontinuation; patients should be counselled regarding sun protection. Long-term high-dose therapy may cause blue-grey skin discoloration, also known as blue man syndrome (slowly resolves following treatment discontinuation). Rare but life-threatening reactions such as Stevens–Johnson syndrome, toxic epidermal necrolysis, and DRESS have been reported and necessitate immediate cessation.

Additional reported adverse effects include gastrointestinal disturbances (particularly during loading), haematological abnormalities such as thrombocytopenia or agranulocytosis, SIADH, decreased libido, epididymo-orchitis, vasculitis, and hypersensitivity reactions including anaphylaxis.

Overall, amiodarone remains an effective antiarrhythmic, but its complex safety profile demands structured monitoring and vigilance from pharmacy professionals involved in its prescribing and long-term management.

Interactions

Amiodarone has extensive drug-drug interactions that may increase the risk of serious adverse effects, particularly cardiac arrhythmias. Concomitant use with medications that prolong the QT interval or induce Torsades de pointes is contraindicated due to the increased risk of life-threatening ventricular arrhythmias. These include the following:

• Class Ia and Class III antiarrhythmics
• Certain antipsychotics
• Tricyclic antidepressants
• Antihistamines
• Antimalarials
• Macrolides and quinolones

Furthermore, drugs that induce electrolyte disturbances, such as hypokalaemia or hypomagnesaemia (e.g., stimulant laxatives, diuretics, corticosteroids, amphotericin B), increase the risk of Torsades de pointes and should be avoided or used with caution with appropriate electrolyte monitoring.

Drugs that reduce heart rate or impair cardiac conduction, including beta-blockers and non-dihydropyridine calcium channel blockers (verapamil, diltiazem), may potentiate bradycardia and atrioventricular conduction disturbances and are generally not recommended with amiodarone. 

Amiodarone may also interact with general anaesthesia, increasing the risk of bradycardia, hypotension, conduction disturbances, reduced cardiac output, and rarely acute respiratory distress syndrome (ARDS), particularly with high oxygen concentrations.

Additionally, coadministration with sofosbuvir-based hepatitis C antiviral regimens has been associated with severe symptomatic bradycardia and is not recommended without cardiac monitoring.

CYP-related interactions

Amiodarone is an inhibitor of the following CYP enzymes: CYP1A1, CYP1A2, CYP2C9, CYP2D6, CYP3A4 and of P-glycoprotein (P-gp) efflux pump, which can increase plasma concentrations of many drugs. The interaction risk persists for several months after discontinuation due to amiodarone’s long half-life.

Clinically important interactions include the following:

• Increased plasma concentrations of P-gp substrates, such as digoxin and dabigatran. Amiodarone also displaces digoxin from tissue binding sites and inhibits renal tubular excretion, further increasing plasma levels of digoxin.
• Increased plasma concentrations of CYP2C9 substrates, including warfarin (including the S- and R- isomers) and phenytoin. This is further complicated as warfarin effects can be potentiated by thyrotoxicosis and reduced in hypothyroidism. 
• Increased plasma concentrations of CYP3A4 substrates, such as ciclosporin and statins metabolised by CYP3A4 (e.g., simvastatin, atorvastatin, lovastatin)
• Increased plasma concentrations of CYP2D6 substrates, including flecainide

All combinations often require dose reduction and monitoring. 

Amiodarone is metabolised by CYP3A4 or CYP2C8, therefore inhibitors of these enzymes may increase exposure and should be avoided (e.g. grapefruit juice inhibits CYP3A4). 

References

1. Amiodarone Hydrochloride 200mg Tablets – Summary of Product Characteristics (SmPC) – (emc) | 101141 Accessed 7/3/26
2. https://www.uptodate.com/contents/amiodarone-clinical-uses-administration-and-adverse-effects Accessed 7/3/26
3. Amiodarone 30mg/ml Solution for injection/infusion in pre-filled syringe – Summary of Product Characteristics (SmPC) – (emc) | 3453 Accessed 7/3/26
4. Ritter JM, Flower RJ, Henderson G, Loke YK, MacEwan DJ. Rang & Dale’s Pharmacology. 9th ed. London: Elsevier; 2019.