(am-ee-OH-da-rone)

Critical Points

• Amiodarone is a powerful, effective antiarrhythmic with substantial toxicity, especially in the long term
• Intravenous and oral behaviour are quite different
• Volume of distribution is large, half-life is long.
• Avoid use together with warfarin, digoxin, or other anti-arrhythmics, if possible.
• Be alert for potential disaster if you are administering an anaesthetic to someone on amiodarone
• This drug may become extremely useful in acute resuscitative situations.

Common trade names

Cordarone, Cordarone X.
Also: Amiodar, Ancoron, Angiodarona, Atlansil, Cordarex, Miocard, Miodaron, Ortacrone, Ritmocardyl, Rythmarone, Trangorex.

Main Uses and Contra-indications

• Amiodarone is used to suppress and treat cardiac arrhythmias, both ventricular and supraventricular.
• Given intravenously it is effective in suppressing serious arrhythmias
• Given over a long period of time by mouth, it effectively suppresses life-threatening ventricular arrhythmias, and also chronic atrial fibrillation.
• Amiodarone is of particular value in patients who have severe arrhythmias due to accessory pathways (e.g. Wolff-Parkinson-White syndrome).

Strong Contra-indications include:

• second or third degree AV block (unless paced)
• Severe bradycardia
• Pregnancy
• Breast-feeding (excreted in breast milk)
• Possible drug interactions

• Congestive cardiac failure
• Liver dysfunction
• Hypokalaemia (correct this!)
• Thyroid dysfunction (hyper or hypothyroidism, or goitre)
• Cardio-pulmonary bypass (?)
• Lactose intolerance (the tablet form may contain lactose)

• Porphyria: safe. [ Gen Pharmacol 1999 Feb;32(2):259-63 ]
• Thalassaemia: hypothyroidism is common, must be watched for. [J Endocrinol Invest 1999 Jan;22(1):55-63 ]
• Extrapyramidal features may occur following acute stroke! [Arch Phys Med Rehabil 1999 Jan;80(1):112-4 ]
• Diabetics may respond more slowly to amiodarone therapy {hmm} [Int J Clin Pharmacol Res 1998;18(3):109-20]
• Renal failure: no dose adjustment needed
• Intra-ocular silicone lenses may become discoloured!

Dose and Monitoring

1. Intravenous
   In a 70kg adult we would use:
   • Loading dose: 300mg in 100ml 5% Dextrose water over 20 - 30 minutes;
   • Maintenance: 600mg in 200ml 5% dextrose water at 17ml/hour.
   Others have used lesser doses or greater dilutions. There has been recent interest in more rapid initial administration in emergency situations (eg 5mg/kg IV over 1 minute). Ampoules are usually 150mg.

   As a minimum we recommend:

   • This drug should ideally be given in a high-care or intensive care setting
   • Baseline 12 lead surface ECG
   • Continuous ECG monitoring
   • Regular checking of electrolyte levels (notably serum potassium)
   • Baseline liver function tests
   • The value of following serum amiodarone levels is not clear, especially during loading. Side effects are said to be more common at levels of over 2.5 mg/l. Some regard a plasma level of 0.75 to 3.5 mg/L as "satisfactory".

2. Oral
   Various doses have been used. Some have recommended:
   • In adults, a loading dose of 800mg to 1200 or even 1600mg / day for up to three weeks, followed by a taper down to a maintenance dose of 600mg/day or even down to 200mg/day. Lower doses are desirable as they probably lessen the risk of lung toxicity. It has been suggested that initial dosing be performed in hospital (?!). Tablets are usually 200mg, in a lactose base.
   • In children, a loading dose of 10mg/kg/day, or 800mg/1.72m ² /day for 10 days, thereafter tapering to a maintenance of 2.5mg/kg/day

   Long term monitoring and precautions should probably include:

   • Regular clinical assessment, being particularly aware of possible lung toxicity. Baseline chest x-ray is mandatory.
   • Monitoring of liver function tests
   • Thyroid function testing
   • Protection from sunlight (for up to three months AFTER stopping treatment) using a Zn or Ti based sunblock - patients can burn even through window glass!
   • A "medic-alert" bracelet and patient information sheet
   • Some have used repeated electrophysiological studies to monitor effectiveness. This is controversial and may not be necessary.

• The most worrying long-term side effect is lung toxicity. This is be significant in 3 to 9% of patients (possibly even up to 17%), and may kill the patient if missed. There may be:
  • Interstitial pneumonitis
  • Lung fibrosis
  • Hypersensitivity pneumonitis
  • Bronchiolitis obliterans organising pneumonia (BOOP) has been reported.
    [ Neth J Med 1998 Sep;53(3):109-12 ]
  Suspect lung toxicity if there is cough, chest pain, shortness of breath or even mild fever. Onset of toxicity may be delayed for 3 years after starting amiodarone. Symptoms commonly start with dry cough and dyspnoea, but there may be pleuritic chest pain and anorexia. The ESR is often high, and leukocytosis may occur. This topic has recently been reviewed by Jessurun et al. Lung toxicity was uncommon in recent trials ( CAMIAT, EMIAT). Remember that patients on amiodarone often have dyspnoea attributable to other problems such as heart failure - amiodarone lung toxicity is difficult to diagnose. Chest x-ray and CT scan may show reticular patterns or a "ground-glass" appearance, or simply hyperinflation. Lung function tests may be obstructive or restrictive.

  Histologically or in sputum lamellar inclusion bodies are said by some to be specific for amiodarone cytotoxicity; this is probably not true [ Kennedy JI, Clin Chest Med 1990 Mar;11(1):119-29 ], as many patients on amiodarone will have lamellar bodies and foamy macrophages, whether they have pulmonary toxicity or not [Hum Pathol 1987 Apr;18(4):349-54 ]. There is an increase in lung CD8-positive cytotoxic lymphocytes, as well as neutrophils and "foamy" macrophages. LDH levels may be raised. Gallium scanning may be of value in identifying this disorder.

• Neurotoxicity has been reported in up to 40%, manifesting mainly as peripheral neuropathy with proximal motor weakness(!) or distal sensory disturbance. Sleep disturbance, ataxia, vivid dreams and fine resting tremor are said to be common, and worse in the elderly.

• Phototoxicity is common, a response to UV-A so conventional sunblock doesn't work, and may be severe. Blue-grey skin discolouration may occur. Nonspecific rashes and even itch, petechiae and erythema nodosum have been seen.

• Hyper- and hypo-thyroidism have been reported, in 1 to 10%, but possibly more commonly in older persons. Free T3 levels are often low, with high rT3.

• Eye involvement may include corneal infiltrates which are commonly asymptomatic, but may result in visual blurring / haloes around lights in about 2% of patients. Optic neuritis, macular degeneration and blindness have been reported. Most patients on amiodarone for over 3 months get corneal microdeposits visible on slit-lamp examination.

• Asymptomatic, mild sinus bradycardia is common but symptomatic bradycardia occurs in only 2-4% of patients. Hypotension may occur, more related to the intravenous preparation.

• Hepatitis may occur. Elevated aminotransferase and alkaline phosphatase levels occur in 4-25% of cases [Hilleman D et al Pharmacotherapy 1998 Nov-Dec;18(6 Pt 2):138S-145S ]

• Mild but common reported side effects include constipation, nausea, loss of appetite;

• Mild uncommon side effects are taste disturbances (bitter), impaired libido (males), facial flushing and dizziness.
• Rat studies have suggested that amiodarone may cause thyroid tumours.
• Fine print:
  • Cholestasis may occur [Arch Pathol Lab Med 1999 Mar;123(3):251-6 ] as may
  • Epididymitis! [ Urol 1999 Mar;161(3):921 ]
  • Photosensitivity seems to be common in drugs such as amiodarone which are "benzophenone" derivatives (ketoprofen, tiaprofenic acid, suprofen, tolmetin(?), fenofibrate too)! [ See Photochem Photobiol B 1998 Apr;43(1):1-26 ]
  • Parkinsonism may be induced by dopaminergic receptor blockade by the drug [ J Pharmacol Exp Ther 1998 Nov;287(2):725-32 ]

Management of Toxicity

• Massive overdose - Symptomatic treatment. If recent ingestion, consider emesis or lavage; appropriate management of hypotension or bradycardia.
• Widthdraw the drug
• Because of the long half-life, toxicity may continue for months after drug withdrawal, but side effects often resolve over a period of months (for example, corneal infiltrates, and even lung toxicity).
• Gallium scanning has been used to assess and follow-up pulmonary toxicity. Steroids have been used for lung toxicity - they are of uncertain value, but are claimed (Jessurun) to work in up to 60% of patients with subacute BOOP due to amiodarone toxicity.

Pharmacology

• Absorption:
  Oral absorption is slow, variable and fair (20-55%). Peak plasma concentrations after oral dosage occur after 3 to 7 hours.
• Distribution:
  The volume of distribution is enormous, and variable (about 5000 litres in a 70kg adult)! The drug is 96% protein bound. It accumulates in fat, skin, liver, lung, heart and muscle. A three-compartment model has been used to model its distribution: a small central compartment, a large deep compartment (lymph nodes, liver, lung, fat) and a peripheral compartment (muscle and brain). Amiodarone crosses the placenta, as does desethylamiodarone - rat studies showed embryotoxicity, but this has not (yet?) been shown in humans. There is concern about potential fetal hypothyroidism.

• Metabolism
  
  • Extensive liver metabolism (under 1% unchanged in urine).
  • desethylamiodarone is active, has a half-life of 61 days(mean)
  • 300mg releases 9mg elemental iodine
  • Initial half-life is 2.5 to 10 days or more, terminal 26-107 days (40-55 days in most patients)
• Elimination is in bile, and breast milk. It is NOT removed by haemodialysis.

Mechanism of Action

Amiodarone has actions in classes I,II,III and IV of the Vaughan Williams classification, but is predominantly a membrane stabilizer (class III).
Its class III action is mediated by inhibition of the rapid component of the delayed potassium rectifier IKr (as with sotalol) but also an effect on the slow component. It is the latter effect that probably explains why amiodarone only minimally increases the risk of torsades de point (polymorphic ventricular tachycardia), unlike sotalol.
Desethylamiodarone alters gene expression, antagonising the effects of T3! [ J Cardiovasc Pharmacol 1998 Oct;32(4):654-61 ]

• Action potential duration and refractory period are prolonged in ALL cardiac tissues
• Membrane potential is NOT affected
• Automaticity is decreased in SA and AV nodes and Purkinje system
• AV conduction is slowed, and a similar effect is seen with accessory pathways
• Mild negative inotropy occurs
• Relaxation (lusiotropy) is inhibited
• Peripheral and coronary vasodilatation may occur (it was initially devised as an anti-anginal)
• Mild alpha blockade may occur, and neurotransmitter release from presynaptic adrenergic neurones may be inhibited.
• Defibrillation threshold may be decreased by amiodarone!
• Amiodarone actually down-regulates beta-adrenoreceptors! [ Biochem Biophys Res Commun 1999 Feb 16;255(2):515-20 ]
• IV administration seems to mainly affect the AV node, and the increased conduction delay seen at faster heart rates that is characteristic of oral therapy doesn't occur with IV administration.

Chemistry

Amiodarone is a white powder derived from benzofuran, and has a molecular weight of 645.32, C ₂₅ H ₂₉ I ₂ NO ₃ , usually presented as a hydrochloride (MW 681.8); it is not very soluble in water, and is very lipophilic.

1. Amiodarone and sudden death post-myocardial infarction

   • We await the PIAF trial (Pharmacological intervention in Atrial Fibrillation) [ cf J Cardiovasc Electrophysiol 1998 Aug;9(8 Suppl):S121-6 ]

   • We await results of the Sudden Cardiac Death in heart failure trial (SCD-Heft) and Multicenter Automatic Defibrillator Trial (MADIT II ) which should tell us whether amiodarone or implantable defibrillators best decrease mortality in patients with poor left ventricular function and risk of arrhythmias. [See Klein et al. Am J Cardiol 1999 Mar 11;83(5B):91D-97D, also Am J Cardiol 1999 Mar 11;83(5B):83D-87D] MADIT had previously showed the benefits of implantable defibrillators in high risk patients, as have other trials (AVID, CASH, CIDS and the Dutch study), according to [Am J Cardiol 1999 Mar 11;83(5B):68D-73D].

   • "The ARREST trial, a randomized trial comparing IV amiodarone to placebo, found a significant improvement in the proportion of patients surviving to the emergency department following out-of-hospital cardiac arrest in amiodarone-treated patients." [Gonzalez ER et al Resuscitation 1998 Oct-Nov;39(1-2):33-42 ]

   • Amiodarone appears to substantially decrease the risk of sudden death in post-infarction patients, but there is no evidence of a reduction in total mortality, according to the two big studies that have looked at this - -the European Amiodarone Myocardial Infarction Arrhythmia Trial (EMIAT) and the Canadian Amiodarone Myocardial Infarction Arrhythmia Trial (CAMIAT). If patients have left ventricular dysfunction and complex arrhythmias, amiodarone is probably the drug of choice, but there is not enough evidence to support prophylactic use of amiodarone, in patients with left ventricular dysfunction. [Farre et al, Am J Cardiol 1999 Mar 11;83(5B):55D-63D ]

   • EMIAT (European Amiodarone Myocardial Infarction Arrhythmia Trial) did not show a significant reduction in mortality with amiodarone post MI. The expected baseline 15% 2yr mortality was seen. Amiodarone was associated with 35% fewer arrhythmic deaths.
     [ See Lancet 1997 Mar 8;349(9053):667-74, errata in Lancet 1997 Apr 19;349(9059):1180 and 1997 Jun 14;349(9067):1776]
     (The sample population was 1486 patients, with 103/743 deaths in the amiodarone group, 102/743 in controls. Patients were post myocardial infarction with an ejection fraction of under 40%, and median follow-up was 21 months. }

   • CAMIAT (Canadian Amiodarone Myocardial Infarction Trial) also showed a significant decrease in arrhythmic deaths, with a relative risk reduction of 48.5%. [ Lancet 1997 Mar 8;349(9053):675-82, erratum 1997 Jun 14;349(9067):1776 ]
     Resuscitated VF or death occurred in 39/596 patients in the placebo group and 25/606 of the amiodarone group.

   • The CASCADE study (Cardiac Arrest in Seattle, Conventional versus Amiodarone Drug Evaluation) showed that patients with implantable defibrillators experienced far fewer shocks on amiodarone than on conventional therapy. [ Am J Cardiol 1994 Feb 1;73(4):237-41 ]

   • The BASIS (Basel Antiarrhythmic Study of Infarct Survival) trial showed a reduction in total mortality, sudden death, and life-threatening ventricular arrhythmias with amiodarone therapy. [ Burkart F et al, J Am Coll Cardiol 1990 Dec;16(7):1711-8 ]
     In this study 312 patients were randomised to individualised antiarrhythmic treatment, 200mg amiodarone daily or no therapy. The amiodarone group showed a lower death rate than controls, and significantly fewer arrhythmic events. The number of deaths was 10/100, 5/98 and 15/114.

2. Side effects

   • "Amiodarone-induced arrhythmia is rare, with frequency of 0.3% in one study." [ Pharmacotherapy 1998 Nov-Dec;18(6 Pt 2):138S-145S ]
   • Acute amiodarone lung toxicity: Donaldson et al [ Intensive Care Med 1998 Jun;24(6):626-30 ] describe lipoid pneumonia in three patients who died in ICU after receiving over 48 hrs of amiodarone therapy.

3. Amiodarone in atrial fibrillation

   • Amiodarone is good in preventing recurrence of atrial fibrillation (successful in up to 80% of patients).[Nolan et al, Pharmacotherapy 1998 Nov-Dec;18(6 Pt 2):127S-137S ]

   • Amiodarone is as good as propafenone for the termination of chronic atrial fibrillation (worked in about 50%). [ J Am Coll Cardiol 1999 Mar 15;33(4):966-71 ] See also [ Am J Cardiol 1999 Jan 1;83(1):58-61 ], and for acute AF [ Pacing Clin Electrophysiol 1998 Nov;21(11 Pt 2):2475-9], although it acts more slowly. Other studies have also found that conversion of acute AF takes time with amiodarone, being no better than placebo up to 8 hours [ Pacing Clin Electrophysiol 1998 Nov;21(11 Pt 2):2470-4 ] {I would increase the infusion rate!}

• USP DI 1990 10ed. Vol 1A pp174-178;
• Avery's Drug Treatment. Speigth TM(ed) 3ed 1987. ISBN 0 86471 024 0. ADIS Press
• Merck Index 11 ed 1989. Budavari S et al. Merck & CO. ISBN 911910-28-X
• Drug Interactions. 2ed. Stockley I. Blackwell Scientific. 1991. ISBN 0-632-02713-4
• Jessurun GAJ et al, Amiodarone-Induced Pulmonary Toxicity. Drug Safety 1998 18.5 339-44.