Class III Antiarrhythmic Drugs

Class III antiarrhythmic drugs block potassium channels, mainly the rapid delayed rectifier current, prolonging repolarisation, action potential duration and refractoriness without slowing conduction. They treat atrial and ventricular tachyarrhythmia, and they all can prolong the QT interval and cause torsades de pointes, except amiodarone, which has a low torsades rate.

Members. Amiodarone, sotalol, dofetilide, ibutilide, dronedarone and vernakalant (not available in all regions). Bretylium is withdrawn in most countries.

Mechanism. Block of the rapid potassium current (hERG) delays phase 3 repolarisation. Amiodarone also blocks sodium and calcium channels and beta receptors, giving class I, II, III and IV properties. Sotalol adds nonselective beta blockade. Dronedarone is a non-iodinated analogue with less thyroid toxicity. Vernakalant blocks atrial-selective currents.

Pharmacokinetics. Amiodarone is highly lipophilic with a volume of distribution over 60 L/kg and elimination half-life of 25 to 100 days, so effects persist for weeks to months after stopping. Sotalol and dofetilide are cleared by the kidney. Ibutilide is cleared by hepatic metabolism. Dronedarone is metabolised by CYP3A4.

• Amiodarone: broadest activity; atrial and ventricular arrhythmia; many organ toxicities.
• Sotalol: beta blocker with class III action; atrial fibrillation and ventricular arrhythmia.
• Dofetilide: atrial fibrillation and flutter; initiation in hospital.
• Ibutilide: intravenous cardioversion of atrial flutter and fibrillation.
• Dronedarone: atrial fibrillation maintenance in selected patients.
• Vernakalant: rapid intravenous conversion of recent-onset atrial fibrillation in some regions.

• Amiodarone, intravenous: 300 mg (or 5 mg/kg) over 20 to 120 minutes through a central line where possible, then 900 mg over 24 hours. In cardiac arrest, 300 mg as a bolus after the third shock, then 150 mg.
• Amiodarone, oral loading: 200 mg three times daily for 1 week, then 200 mg twice daily for 1 week, then 200 mg daily or the lowest effective dose.
• Sotalol: 80 mg twice daily, titrated to 160 mg twice daily (maximum 320 mg daily), started in hospital with monitoring for 3 doses.
• Ibutilide: 1 mg intravenously over 10 minutes (0.01 mg/kg if under 60 kg), repeated once after 10 minutes if needed, with electrocardiogram monitoring for at least 4 hours.
• Dronedarone: 400 mg twice daily with meals.
• Dofetilide: dose by creatinine clearance, started in hospital for 3 days.
• Selection: amiodarone for heart failure, structural heart disease and ventricular arrhythmia. Sotalol for coronary disease with preserved function. Avoid dronedarone in heart failure and permanent atrial fibrillation.

Contraindications. Long QT syndrome, QTc over 450 to 500 ms, uncorrected hypokalaemia or hypomagnesaemia, bradycardia, high-grade block, and creatinine clearance under 30 mL/min (sotalol and dofetilide). Dronedarone is contraindicated in permanent atrial fibrillation, NYHA class III or IV heart failure and previous amiodarone liver or lung injury. Amiodarone is avoided in iodine hypersensitivity, thyroid disease out of control and pregnancy.

Amiodarone toxicity. Thyroid (hypothyroidism and hyperthyroidism), lung (pneumonitis and fibrosis, risk with doses over 400 mg daily), liver (enzyme rise and rarely cirrhosis), eye (corneal microdeposits, optic neuropathy), skin (photosensitivity, blue-grey discolouration), neurological (tremor, neuropathy) and cardiac (bradycardia, block).

Interactions. Amiodarone raises warfarin effect (reduce warfarin dose by 30% to 50%), digoxin levels (halve dose), and simvastatin exposure (limit to 20 mg daily). It increases direct oral anticoagulant exposure and potentiates QT-prolonging drugs. Sotalol interacts with diuretics through hypokalaemia and with other QT-prolonging drugs.

Monitoring. Electrocardiogram for QTc and bradycardia. For amiodarone: thyroid function, liver function, chest radiograph and lung function at baseline, and thyroid and liver tests every 6 months, with ophthalmic review if visual symptoms arise.

Referral and escalation. New cough, dyspnoea or fever on amiodarone needs urgent assessment for pneumonitis. Syncope or QTc over 500 ms needs the drug stopped.

Special groups. Pregnancy: amiodarone causes foetal thyroid and growth effects and is avoided unless life saving. Older adults: higher bradycardia and thyroid risk. Kidney disease: avoid sotalol and dofetilide with low clearance. Women: higher torsades risk with sotalol and dofetilide.