Amiodarone

Amiodarone is a class III antiarrhythmic with multi channel blocking properties. It treats atrial fibrillation, ventricular tachycardia and ventricular fibrillation, and is given in cardiac arrest. It is highly effective and has the widest range of toxicity of any antiarrhythmic: thyroid, lung, liver, eye, skin, nerve and heart. It has a half life of weeks, so adverse effects and interactions last for months after stopping. It is available in most East African hospitals.

Classification. Class III antiarrhythmic (also has class I, II and IV properties); iodinated benzofuran.

Mechanism. Blocks potassium channels (prolonging the action potential and refractory period), sodium and calcium channels, and beta adrenoceptors. It slows the sinus rate and atrioventricular conduction and prolongs the QT interval.

Pharmacodynamics. IV onset within minutes to an hour; oral onset takes days to weeks without loading. Effects last for weeks to months after stopping. Prolongs PR, QRS and QT intervals.

Pharmacokinetics. Oral bioavailability 30 to 65% and variable; food increases absorption. Highly lipid soluble; volume of distribution about 60 L/kg. Half life 40 to 55 days (range 20 to 100). Metabolised by CYP3A4 and CYP2C8 to active desethylamiodarone; excreted in bile and faeces. About 37% iodine by weight.

Cardiac arrest with ventricular fibrillation or pulseless ventricular tachycardia, adult. 300 mg IV bolus after the third shock; a further 150 mg after the fifth shock.

Stable ventricular tachycardia and rhythm control of atrial fibrillation (IV), adult.

• Loading: 300 mg (or 5 mg/kg) in 250 mL of 5% glucose over 20 to 120 minutes through a central line (peripheral only in an emergency), by pump.

• Then 900 mg over 24 hours (for example 1 mg/minute for 6 hours, then 0.5 mg/minute for 18 hours).

• Maximum 1200 mg in 24 hours.

Oral loading and maintenance, adult.

• 200 mg three times daily for 1 week, then 200 mg twice daily for 1 week, then 200 mg once daily (maintenance 100 to 200 mg once daily).

• Use the lowest dose that maintains rhythm.

Pharmacological cardioversion of atrial fibrillation, adult. Oral: 600 to 800 mg daily in divided doses to a total of 10 g, then 200 mg daily maintenance. IV: 300 mg over 20 to 120 minutes through a central line, then 900 mg over 24 hours.

Children (specialist). IV 5 mg/kg over 20 to 60 minutes, repeated up to 15 mg/kg a day. Oral: 10 to 15 mg/kg daily in 2 divided doses for 7 to 10 days, then 5 mg/kg once daily.

Contraindications. Sinus bradycardia, sinoatrial block, sick sinus syndrome or atrioventricular block without a pacemaker; thyroid dysfunction; iodine hypersensitivity; severe hypotension or circulatory collapse (IV); marked QT prolongation or torsades de pointes; concurrent QT prolonging drugs; pregnancy and breastfeeding unless essential; severe respiratory failure, cardiomyopathy and heart failure (IV).

Warnings.

• Thyroid: hypothyroidism or thyrotoxicosis (up to 10% of patients; thyrotoxicosis can occur months after stopping).
• Lungs: pneumonitis and fibrosis (cough, dyspnoea, weight loss, fever); can be fatal.
• Liver: raised enzymes, rarely hepatitis or cirrhosis.
• Eyes: corneal micro deposits, optic neuropathy.
• Skin: photosensitivity, blue grey discolouration.
• Nervous system: tremor, ataxia, peripheral neuropathy.
• Heart: bradycardia, atrioventricular block, QT prolongation, torsades.
• IV: hypotension, phlebitis; large peripheral infusions cause tissue damage.

Adverse effects. Bradycardia, nausea, constipation, taste disturbance, photosensitivity, tremor, thyroid disease, abnormal liver tests, pulmonary toxicity, corneal deposits, sleep disturbance, hypotension on IV use.

Interactions. Warfarin: INR rises; reduce the dose by 30 to 50%. Digoxin: levels double; halve the dose. Simvastatin: limit to 20 mg daily; atorvastatin: use caution. Beta blockers, verapamil, diltiazem: bradycardia and block. QT prolonging drugs (antimalarials such as artemether lumefantrine, quinine, chloroquine; macrolides; fluoroquinolones; antipsychotics; ondansetron): torsades. Sofosbuvir containing regimens: severe bradycardia.

Ciclosporin and tacrolimus: higher levels. Phenytoin: raised levels. Rifampicin lowers levels. Grapefruit juice raises levels. Loop and thiazide diuretics: hypokalaemia raises the arrhythmia risk. Interactions persist for months after stopping.

Special groups.

• Pregnancy: avoid; foetal goitre, hypothyroidism, bradycardia and growth restriction. Use only in life threatening arrhythmias.

• Breastfeeding: excreted in milk with high iodine content; avoid.

• Patients of African ancestry: no dose change.

• Older adults: increased risk of bradycardia and thyroid disease; use the lowest effective dose.

• Kidney impairment: no adjustment; not dialysable.

• Liver impairment: reduce the dose; avoid in significant liver disease.

Formulations. Tablets 100 and 200 mg; injection 50 mg/mL (3 mL ampoules).

Administration. Oral once daily with food, consistently with or without food. IV: dilute only in 5% glucose (not 0.9% sodium chloride), in a glass or polyolefin container; give via a central line when the concentration is above 2 mg/mL; use an in-line filter; do not mix with other drugs.

Baseline. ECG (QT, heart rate), chest X-ray and lung function (with gas transfer), thyroid function, liver function, potassium, magnesium, eye examination if visual symptoms, pregnancy status.

Monitoring. Thyroid function and liver function every 6 months. ECG at each dose change and yearly. Chest X-ray yearly or if symptoms. Heart rate and blood pressure continuously during IV use. Check potassium and magnesium (target potassium above 4.0 mmol/L and magnesium above 0.8 mmol/L). Skin and eye review yearly. INR twice weekly after starting with warfarin until stable.

Stopping. Stop for pulmonary toxicity, hepatitis, optic neuropathy, severe thyroid disease or intolerable bradycardia. Effects last for months.

Common prescribing errors. Not reducing warfarin and digoxin doses; giving peripherally for days; diluting in 0.9% sodium chloride; prescribing with artemether lumefantrine, chloroquine or quinine without ECG checks; skipping baseline lung and thyroid tests; failing to warn about sun exposure; treating thyrotoxicosis as a relapse of the arrhythmia.