The strange life of amiodarone
Amiodarone is the most effective, and certainly the strangest, antiarrhythmic drug ever developed. (Antiarrhythmic drugs are used to treat heart rhythm disturbances. Click here for a quick review of heart rhythm disturbances.) Anyone being treated with amiodarone should understand the idiosyncrasies - and the risks - associated with this highly effective drug.
The strange history of amiodarone in the U.S.
Amiodarone was developed in Belgium in the 1960s as a drug for treating angina, and was quickly released for marketing in most countries except the United States. Doctors noticed that, in their patients placed on amiodarone, heart arrhythmias greatly diminished. Clinicians quickly began using the drug to treat cardiac arrhythmias of all sorts. Within a few years, word began filtering into the United States - amiodarone was a unique antiarrhythmic drug that was said to "always work, and had no side effects." Both of these assertions, of course, proved false.
In the late 1970s, American doctors began obtaining amiodarone from Canada and Europe to use in their patients with life-threatening arrhythmias who did not respond to any other drugs. The FDA sanctioned this activity on a limited basis, but the drug seemed so effective that literally hundreds of American electrophysiologists were soon obtaining the drug (one way or another) and by the mid 1980's tens of thousands of Americans were receiving the drug. The Americans, as a group, studied the effects of amiodarone somewhat more rigorously than their overseas colleages, and here's what they found: Amiodarone was indeed far more effective at suppressing arrhythmias than any other drug they had ever seen, but it produces a bizarre series of side effects that doctors around the world seemed to have "missed." By the mid 1980s, the FDA was essentially forced to release amiodarone for marketing in the U.S. - the foreign manufacturers of the drug threatened to cut off the American supply (having supplied free drug to thousands and thousands of Americans for more than 5 years,) and the American doctors impressed on the FDA what a medical disaster that would produce. So, unlike any other drug in modern history, amiodarone became FDA approved without rigorous, FDA-approved randomized clinical trials. The true breadth of amiodarone-induced side effects took more than a decade to uncover.
Why amiodarone is a strange drug
Amiodarone has several characteristics that make it unique.
First, the drug takes weeks to achieve its maximum effectiveness. This is because amiodarone is stored in most of the tissues of the body, and to "load" the body with the drug, all the tissues need to be saturated. The typical "loading" regimen of amiodarone, therefore, is to use very large doses for a week or two, then taper the dosage over the next month or so. It is not unusual to give patients 1200 or 1600 mg per day at first, and then maintain them on as little as 100 or 200 mg per day chronically.
Second, amiodarone leaves the body very, very slowly. It is not excreted (like most drugs) by the liver or the kidneys. It is lost when amiodarone-containing human cells are lost - such as skin cells or cells from the GI tract, which are shed by the millions each day. Thus, if it is decided that one needs to stop amiodarone, the drug remains in the body in measurable quantities for months and months. The "half life" of the drug, in contrast to most other drugs, is measured in weeks instead of hours.
Third, because amiodarone is stored in many different kinds of tissues, it can produce side effects affecting many different organs. Some of these side effects take months or years to develop, so it is never true that one can stop being vigilant.
Fourth, amiodarone works through many different mechanisms, unlike most drugs. It fits into two separate categories of antiarrhythmic drugs (Class I and Class III, for what it's worth); it acts as a beta blocker; it acts as a calcium blocker; it acts to dilate blood vessels; and it often acts to "block" the effect of thyroid horomone.
The strange side effects of amiodarone
One reason the side effects of amiodarone were not spotted for years was that they often take weeks or months to develop (unlike side effects from typical antiarrhythmic drugs, that usually appear within days). Also, the kinds of side effects produced by amiodarone are not the kind that heart doctors typically expect with antiarrhythmic drugs. In any case, it took more than a decade for many European doctors to admit (even after the American medical literature became saturated with articles) that they had been missing some rather remarkable side effects.
Amiodarone commonly causes deposits to form on the cornea of the eyes - in fact, this occurs in virtually every one taking the drug. These deposits often cause no visual disturbances, but not infrequently patients complain of "halo-vision," where looking at bright lights at night is like looking at the moon on a foggy evening.
Amiodarone can cause a very disfiguring blue-grey discoloration of the skin, generally in areas of sun exposure, and that gradually worsens over a period of years. It is not clear that this "smurf syndrome" clears up when the drug is stopped. In younger patients this side effect can be devastating.
Amiodarone often sensitizes the skin to sunlight, so that even trivial exposure can cause a fairly nasty sunburn. People taking amiodarone must often cover the body completely when going out during the summer, especially in hot, humid climates.
Each amiodarone molecule contains four iodine atoms - so a typical dose of amiodarone provides far more iodine to the body than is needed. It is thought to be the iodine that mediates the thyroid side effects of amiodarone. The more common of these is hypothyroidism - low thyroid. This, fortunately, is relatively easy to treat with thyroid medication. But some patients develop hyperthyroidism - high thyroid - and this can be a real problem and a real challenge to treat. (They hyperthyroidism often does not respond to the "typical" treatment used for this problem.)
Amidoarone can cause liver toxicity, so liver enzymes need to be monitored periodically.
The most serious side effect of amiodarone is pulmonary toxicity - lung disease. This comes in two flavors. Amiodarone can produce an acute pulmonary syndrome that looks and acts just like typical pneumonia - sudden onset of cough and shortness of breath. This condition usually improves rapidly once amiodarone is stopped. It can occur within days of beginning amiodarone. The second flavor is more insidious - it is a gradual, unnoticeable, "stiffening" of the lungs that both the doctor and patient can overlook until finally severe, probably irreversible lung damage is done. This problem can occur years after the drug is begun, or as early as a few months after beginning amiodarone.
When should amiodarone be used?
If Satan were going to develop an antiarrhythmic drug, he would make one that suppressed arrhythmias very well (so people would want to use it,) had none of the typical side effects, but that had a host of atypical, relatively subtle, but ultimately dangerous side effects that doctors were likely to overlook. He might not be satisfied with amiodarone, but would likely consider it a pretty good first approximation.
Amiodarone should be used for arrhythmias that are life-threatening or that are very disruptive to one's life, and for which there are no other reasonable therapies. Despite its drawbacks the drug has helped tens of thousands of patients, and has restored them to a nearly normal life. When used appropriately, amiodarone can be a major benefit.
But because of the potential toxicity its use should be limited. No doctor should blithely prescribe the drug, but should do so with reluctance, realizing that he/she is exposing the patient to long-term risks. The doctor should, by prescribing the drug, be committing him/herself to being a long-term partner of the patient. He/she should carefully coach the patient on what problems to look for, and together they should be ever vigilant for the side effects of the drug.