Amiodarone revisited

Townsend Letter for Doctors and Patients,  May, 2006  by Guy. E. Abraham

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Amiodarone is an iodinated benzofuranic derivative containing 37.2% iodine by weight. Amiodarone is widely used in the management of cardiac arrhythmias. (1 and vide infra) The amiodarone molecule is deiodinated in vivo, resulting in urinary excretion of iodide in amounts equivalent to ten percent of the iodine ingested; that is, equivalent to 3.7% of amiodarone by weight. (2) With a maintenance dosage of 300 mg/day, the amount of iodine excreted daily is approximately 11 mg. In 15 patients on a maintenance dosage of 300 mg, studied by Rao et al., (2) the 24 hr. excretion of iodide amounted to 10-11 mg. No amiodarone nor its metabolite were detected in the urine samples, indicating that the iodide measured was the inorganic form.

With the assumption that urinary excretion of iodide is a good index of bioavailable iodine, (3) it was concluded that ten percent of the iodine covalently bound in amiodarone is bioavailable. However, there is some discrepancy in the published data on amiodarone. In two subjects ingesting 300 mg/day for 28 days, balance studies revealed that the amount of iodine retained by the body was 1.1 gm after 21 days and 1.6 gm after 28 days. (4) Further studies using iosotope dilution technique suggest that the body became saturated when a total of 2 gm iodine were retained. (4) A double peak of serum iodine levels was observed in some subjects, about eight hours apart, indicating an enterohepatic circulation. (5) The measurement of inorganic iodine in all the organs, fat tissues, and striated muscle of a patient who died following four years at 600 mg amiodarone/day confirmed that the iodine retained was the inorganic form. (4) The total body content was estimated at 2 gm. The largest quantities of inorganic iodine were present in fat tissues (700 mg) and striated muscle (650 mg). The largest concentrations were measured in the thyroid gland (1.16 mg/gm wet weight), followed by the liver (0.248 mg/gm); lungs (0.082 mg/gm); the adrenal glands (0.076 mg/gm); and the heart (0.05 mg/gm). Every organ evaluated, including the skin, contained significant amounts of inorganic iodine.

In the balance studies, the amount of inorganic iodine retained was 1.1 gm after 21 days and 1.6 gm after 28 days of amiodarone therapy at 300 mg/day. The average daily amount of iodine retained in the body would be 1.1 gm/21 days = 55 mg, and 1.6 gm/28 days = 57 mg. Amiodarone contains 37.2% iodine, that is, 110 mg iodine per daily dose. Therefore, 50% of the total iodine ingested was retained by the body, and ten percent was excreted in the urine.

Urinary iodine level is not a good index of bioavailable iodine. An iodine/iodide loading test recently developed by the author to evaluate whole body sufficiency for iodine, revealed that average mean values of 20% to 25% of the ingested dose of iodine/iodide were excreted in the 24 hr. urine collection, when the subjects ingested 12.5 to 37.5 mg of elemental iodine from a tablet form of Lugol solution. (6) Using a daily amount of 50 mg elemental iodine for three months, the mean percent of dose ingested that was recovered in the urine averaged 40% prior to supplementation; 60% after one month; 75% after two months; and 90% after three months of supplementation. An excretion of 90% or more was considered evidence of whole body sufficiency for iodine. (6) The estimated total amount of iodine retained after three months of supplementation, when whole body sufficiency for iodine was achieved, was 1.5 gm elemental iodine. (7) That amount is very close to 1.6 gm iodine retained by the subject after 28 days of amiodarone therapy at 300 mg/day. Since the maximum response to amiodarone occurs following one month at 300 mg amiodarone/day, this is evidence that the active principle in amiodarone is the iodine released and that whole body sufficiency for iodine is required to achieve a positive response in patients with cardiac arrhythmias.

Similar to the double peak of serum iodide levels observed in patients on amiodarone, (5) a double peak of urinary excretion of iodide (Table 1) was obtained in a subject following 50 mg elemental iodine, who collected each void sample separately. The first peak occurred in the second sample collected two to five hours after ingestion of iodine, and the second peak in the sixth sample collected 11-13 hours following ingestions of iodine, approximately eight hours apart. This is evidence that ingested inorganic iodine undergoes an enterohepatic circulation. This could explain the large concentration of iodine measured in the liver. (4)

Based on the concept of orthoiodosupplementation, the daily intake of iodine required for whole body sufficiency ranged from 100 to 400 times the RDA. (6) A critical evaluation of the published data on amiodarone combined with the concept of orthoiodosupplementation strongly suggests that cardiac arrhythmias are manifestations of iodine deficiency. Since magnesium supplementation is effective in preventing lethal arrhythmias in acute myocardial infarction, (8) orthoiodosupplementation combined with magnesium therapy would be expected to result in a better response, without the severe and common side effects of amiodarone. (9)