Pharmacotherapy Newsletter

Volume 1, Issue 2, 01/25/2009

Question

How can amiodarone (Cordarone®) cause hypothyroidism and is it relevant?

Answer

It is common to see some patients with high-risk or life-threatening ventricular arrhythmias and atrial fibrillation to be put on the antiarrhythmic, amiodarone (Cordarone®).^1,2  When amiodarone is given to a euthyroid (normal thyroid function) patient, the normal physiologic process for the formation of the thyroid hormones, thyroxin (T4) and 3,5,3'-triiodothyronine (T3), can be affected.  The following are the generalized steps of thyroid hormone production: thyroid releasing hormone (TRH) is secreted from the hypothalamus to stimulate the anterior pituitary gland to release thyroid stimulating hormone (TSH); the TSH then travels to the thyroid gland where it causes the increased production of thyroglobulin and the enzyme, thyroid peroxidase; iodide ingested from food or water enters into the thyroid follicular cell via the Na/I cotransporter; once the iodide is inside the thyroid follicle cell it is transported into the follicular lumen via the pendrin transporter.  The iodide is oxidized by thyroid peroxidase into iodine where it then iodinates the tyrosine residues within the thyroglobulin to form both monoiodotyrosine and diiodotyrosine, which then are used to make the T4 and T3; this newly produced T4 and T3 then undergo proteolysis and exocytosis for secretion and recycling.  So then how does amiodarone affect this process?

Amiodarone's influence on the production and secretion of T4 and T3 occurs by several mechanisms.  Most importantly, each 200 mg tablet of amiodarone contains 74.4 mg (37.3%) of iodine by weight with 10% (7.4mg) per day being released as free iodine.³  This is about a 50-fold greater amount than the daily recommended iodine intake which is known to be only 0.15 mg (150mcg) per day in adults.⁴  This increase in  iodine concentrations is known to  reduce blood flow into the thyroid gland (see 1 in diagram), inhibit the organification, or iodination, of the tyrosine residues on thyroglobulin molecule (see 2 in diagram), and decreases the release of thyroid hormones possibly due to an inhibition of thyroglobulin proteolysis (see 3 in diagram; last step in process for the release of T3 and T4).^5,6  While not directly related to the development of hypothyroidism, amiodarone has been known to antagonize T3-induced gene expression at the tissue level  which may play another role for amiodarone's effect in treating cardiac conditions.⁷  The combination of these events can result in sub-clinical and clinical hypothyroidism.^2,8