Amiodarone - A New Look
At An Old Drug

Amiodarone is a benzofuran that was synthesized and tested as an anti-anginal agent in the 1960s. However, it was subsequently discovered to have anti-arrhythmic properties, and has been approved for this use in North America since 1986. It is now widely used as a broad spectrum antiarrhythmic, effective in atrial and ventricular arrhythmias, both as treatment and as prophylactic therapy. It is thought by many physicians to be the most effective anti-arrhythmic drug available today. However, its use is accompanied by a relatively high incidence of side effects, making it a somewhat complicated drug to use safely.

Clinical Indications For Amiodarone

Ventricular arrhythmias

The major indication for Amiodarone is in the treatment of sustained life-threatening ventricular arrhythmias, such as recurrent ventricular tachycardia and ventricular fibrillation. This beneficial effect may be seen even when other anti-arrhythmic agents have been unsuccessful. In the acute situation, when rapid anti-arrhythmic activity is required, intravenous Amiodarone is most useful. Close patient observation and dose adjustments are essential for optimal benefit without adverse effects. Hypotension and bradycardia are of most concern. Supplemental I.V. bolus doses can be used for breakthrough arrhythmias, however. The total daily dose should not exceed 2,000 mg.

Amiodarone has been used intravenously for as long as 3-6 weeks in patients who can not take oral medication. Once the patient stabilizes, there should be a switch to oral medication, assuming that a substrate for the ventricular arrhythmia has not been found and corrected.

Long-term oral Amiodarone for ventricular arrhythmias could be considered for patients with nonsustained ventricular tachycardia who have non-ischemic cardiac disease, ischemic patients with normal or near normal ejection fractions, and patients in whom an implantable defibrillator is not considered to be an option.

Atrial Arrhythmias:

Amiodarone is a very effective therapy for atrial arrhythmias. It slows the ventricular response at rest and with exercise in atrial flutter and atrial fibrillation, and often converts the arrhythmia to sinus rhythm. It can maintain sinus rhythm in patients with paroxysmal and in some cases, persistent arrhythmias. It is a most attractive drug for converting atrial fibrillation and maintaining sinus rhythm in patients with heart failure, in whom other anti-arrhythmic drugs are ineffective, and in fact dangerous. Amiodarone is also effective in atrial fibrillation and other atrial arrhythmias which are producing hemodynamic compromise in critically ill patients refractory to conventional therapy. In this situation intravenous Amiodarone can significantly slow the heart rate, without significant hemodynamic compromise, and in some cases may convert the arrhythmia.

Dosing Considerations

Suggested dosing for intravenous and oral therapies, both for atrial and ventricular arrhythmias, is outlined in the following Table 2.

*Due to it's unique pharmacokinetic profile, loading doses are necessary, and even with loading, clinically relevant effects may take several weeks to occur. Hence, one should not anticipate immediate results. Conversely, beneficial and adverse effects can last for weeks after drug withdrawal.

Electrophysiologic And ECG Effects Of Amiodarone

Amiodarone has several electrophysiological effects.

For the practicing clinician, these effects may manifest on the ECG as follows:

1. Slowing of the heart rate
2. Prolongation of the PR-interval
3. Prolongation of the QRS-duration
4. Prolongation of the QT-interval

Adverse Effects:

Adverse reactions due to Amiodarone are not unexpected given the drug's complicated pharmacologic features, and diverse effects. Because of its long half-life (averaging 100 days), Amiodarone organ toxicities are potentially more severe and difficult to manage than toxic reactions to other drugs with shorter half-lives. The adverse effects can be divided into those occurring early, and those occurring later.

Early Toxicity:

Late Toxicity:

Pulmonary:
This is the most feared and potentially serious adverse effect of Amiodarone. It can occur from 2-4 weeks up to 3 years after institution of therapy. It is best predicted in patients over the age of 65, and receiving maintenance doses of over 300 mg per day and is especially frequent in doses over 400 mg per day. At this dose level the incidence is between 3-5% of patients. Toxicity is usually manifested as dyspnea and predominantly cough, with symptoms mimicking heart failure, pulmonary infection, or interstitial lung disease. When toxicity is suspected, Amiodarone should be withdrawn. Corticosteroids are the treatment of choice in severe cases.

Cardiac
The majority of cardiac adverse effects are related to the electrophysiologic effects of Amiodarone, and include sinus bradycardia, AV-block, and marked QT-prolongation.

Central Nervous System
A tremor, which often manifests as a change in the quality of handwriting, is the most prominent adverse neurological effect. However, ataxia, dysequilibrium, and insomnia are not unusual. Less frequently, proximal truncal weakness or peripheral neuropathy can be observed.

Dermatological
Sun sensitivity and sunburn are quite common. After long-term use Amiodarone can cause a characteristic blue discoloration of the cheeks and nose. However, this effect is unusual and usually only occurs at high doses. Patients should be advised to stay out of direct sunlight and to wear maximum protection sunscreen.

Opthalmologic
All patients on Amiodarone develop corneal micro deposits, which can be seen on slit lamp examination, but which do not interfere with vision. Dry eyes, however, can occur for which artificial tears are helpful. With high doses in prolonged use, some patients develop visual disturbances described as halos around bright lights or blurring of vision at night. This often requires a dose reduction or discontinuation.

Thyroid
Amiodarone, because of its iodine content, can cause either hypo or hyper thyroidism. Biochemical hypothyroidism is relatively common, occurring in 20-25% of patients presenting as an asymptomatic elevation of TSH. Thyroid replacement therapy is often not necessary unless TSH values are above 20 units per litre. Of note, the level of T4 is not an accurate guide to thyroid hormone action for these patients. Hyperthyroidism is more unusual, and virtually always requires drug discontinuation. These patients should be referred to an endocrinologist, as the hyperthyroidism may be very resistant to treatment.

Hepatic
Amiodarone often causes asymptomatic elevations of AST and ALT, up to 2-3 times normal values. They usually response to dose reduction and may regress to normal spontaneously. Very rarely patients can develop hepatic necrosis and liver failure.

Other Adverse Effects
Patients occasionally develop a non-specific wasting syndrome with weight loss, malaise, and generalized weakness and fatigue. Improvement usually occurs with drug discontinuation.

Drug Interactions:

Since Amiodarone interferes with hepatic drug biotransformation, it potentially interacts with any drug that is eliminated by the liver. These drug interactions are one of the most important aspects of monitoring Amiodarone therapy. The drugs most commonly interacted with include: Warfarin, Digoxin, beta-blockers, calcium channel blockers which slow AV-node conduction, and other anti-arrhythmics.

The following table outlines potential drug interactions and suggested dose reductions:

Pre And Post Amiodarone Testing:

Because of the potential of adverse effects on various systems, baseline testing should be done if possible prior to patients receiving Amiodarone, and for specified periods thereafter. The following table outlines a suggested regimen:

Conclusion And Summary:

Amiodarone has emerged as one of the most effective drugs in terms of prevention of ventricular and atrial arrhythmias, and maintenance of sinus rhythm. However, this is a very complex drug which requires very close patient follow-up, attention to detail with regards to patients' symptoms, physical findings, and follow-up of pertinent laboratory results. Awareness of potential drug interactions is extremely important, especially with commonly used drugs in cardiac patients such as Warfarin, Digoxin, and beta-blockers.

The decision to use Amiodarone should be after a careful assessment of the potential benefits, the consideration of other available anti-arrhythmic agents, the use of the lowest effective dose for the particular rhythm disturbance being treated, and with the knowledge that frequent and detailed follow-up will be required.

- Bruce Josephson

Thanks to Dr. Leo Pereira, General Internist with special interest in Cardiology and Endocrinology, St. Martha's Regional Hospital in Antigonish, Nova Scotia, for reviewing the draft copy of this article.

References:

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5. Desai AD et al. Ann Intern Med 1997;127:294-303.
    
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