Category:Antithyroid agents

An antithyroid agent is a medicine that reduces the production or peripheral action of thyroid hormone, used to treat hyperthyroidism. The category contains the two thionamide medicines that block the thyroid synthesis pathway (methimazole and propylthiouracil), the radioactive iodine isotope I-131 that destroys the thyroid gland by beta-radiation, and the adjunctive medicines that control symptoms or block peripheral conversion of thyroxine to triiodothyronine while the primary treatment takes effect (beta-blockers; iodine; corticosteroids in thyroid storm).

The pharmacological history of antithyroid medicine began at the Mayo Clinic in the 1940s. The American physiologist Edwin Astwood at Harvard reported in 1943 that thiourea and the related thiouracil inhibited thyroid hormone synthesis and produced clinical improvement in thyrotoxic patients; the toxicity of thiourea limited its clinical use, but propylthiouracil (PTU), introduced shortly afterwards, became the standard medical treatment for Graves' disease thyrotoxicosis and for toxic multinodular goiter.^[1] Methimazole (carbimazole's active metabolite; carbimazole used in Europe, methimazole in the U.S.) was developed in 1949 and gradually replaced PTU as first-line for most indications, on the basis of its longer half-life (six hours versus one hour), once-daily dosing convenience, and lower hepatotoxicity profile.

The thionamides act by inhibiting thyroid peroxidase, the enzyme responsible for iodination of tyrosine residues on thyroglobulin and for the coupling of iodotyrosines to form thyroxine (T4) and triiodothyronine (T3) within the thyroid follicular lumen. Propylthiouracil has the additional peripheral action of inhibiting type 1 5'-deiodinase, the enzyme that converts T4 to the more active T3 in peripheral tissues, which gives it a small but real clinical advantage in the management of severe thyrotoxicosis and thyroid storm. The disadvantage of PTU is its three-times-daily dosing, its higher hepatotoxicity (rare but devastating fulminant hepatic failure including in children, which led to a 2010 FDA boxed warning restricting first-line use to the first trimester of pregnancy and to thyroid storm), and its higher rate of ANCA-associated vasculitis.

The contemporary clinical positioning is well-established. Methimazole is first-line for nonpregnant adult Graves' disease and for toxic multinodular goiter; propylthiouracil is reserved for the first trimester of pregnancy (where methimazole has been associated with aplasia cutis and a small but real choanal-atresia signal), for thyroid storm (where its peripheral T4-to-T3 inhibition is useful), and for the rare patient intolerant of methimazole. The titration is to clinical and biochemical euthyroidism, with dose reduction over 12 to 18 months and a trial of withdrawal at approximately 18 months; approximately 40 percent of Graves' patients achieve sustained remission after a single course, with the remainder requiring continued thionamide therapy or definitive treatment (radioactive iodine or thyroidectomy).

Radioactive iodine (I-131) is administered as a single oral dose calculated to deliver approximately 100 to 200 microcuries per gram of estimated thyroid weight, the cells of which concentrate iodine via the sodium-iodide symporter (NIS) and are destroyed by the beta-radiation from the captured isotope. The treatment was developed by Saul Hertz and Arthur Roberts at the Massachusetts General Hospital and the MIT cyclotron facility in the early 1940s; their first clinical use of I-131 for hyperthyroidism was on 31 March 1941, making it the first therapeutic use of an artificially produced radionuclide.^[2] Radioactive iodine is the most common definitive treatment for Graves' disease in the United States; the European preference is more often for thionamide therapy first with surgery as backup. The post-treatment hypothyroidism is essentially inevitable and is treated with lifelong levothyroxine replacement (described under thyroid hormones).

The adjunctive antithyroid medicines complete the category. The beta-blocker propranolol controls the tachycardia, tremor, and anxiety of severe hyperthyroidism within hours and is added to thionamide therapy at presentation. Stable iodine (potassium iodide as saturated solution SSKI or as Lugol's solution) blocks thyroid hormone release acutely by the Wolff-Chaikoff effect; it is given for 7 to 14 days before thyroid surgery to reduce gland vascularity, and intravenously in thyroid storm. Lithium has historical use as a thyroid-hormone-release inhibitor in selected refractory thyroid storm or in radioactive-iodine-rejection cases; its narrow therapeutic window limits routine use. Corticosteroids (intravenous hydrocortisone or oral prednisone) block peripheral T4-to-T3 conversion and are used in thyroid storm and in the rare amiodarone-induced thyrotoxicosis. Cholestyramine binds enterohepatically recirculated thyroid hormones and accelerates their elimination in selected severe cases.

Two specific clinical scenarios deserve mention. Thyroid storm (severe decompensated thyrotoxicosis with hyperpyrexia, tachyarrhythmia, encephalopathy) is treated with high-dose intravenous propranolol or esmolol, intravenous propylthiouracil, intravenous corticosteroid, and stable iodine (after the first thionamide dose to avoid loading the gland with substrate); supportive care for fever, fluid balance, and arrhythmia is foundational. Amiodarone-induced thyrotoxicosis (described under antiarrhythmics) is managed by methimazole, corticosteroids, and (in type II destructive thyroiditis variant) thyroidectomy if medically uncontrolled; the underlying amiodarone may be continued in selected cases because its withdrawal does not rapidly reverse the thyrotoxicosis.

By mechanism:

• Thionamides (inhibit thyroid peroxidase):
  • Methimazole (Tapazole; first-line for most adult indications)
  • Carbimazole (European preference; metabolised to methimazole in vivo)
  • Propylthiouracil (PTU; first-trimester pregnancy, thyroid storm, methimazole intolerance)
• Radioactive iodine:
  • I-131 (sodium iodide oral capsule; definitive ablative treatment for Graves' disease, toxic adenoma, toxic multinodular goiter, residual thyroid cancer after thyroidectomy)
• Inhibitors of thyroid hormone release:
  • Stable iodine: potassium iodide as SSKI, Lugol's solution; intravenous sodium iodide
  • Lithium carbonate (historical, selected refractory use)
• Symptomatic adjuncts:
  • Beta-blockers (cross-indexed): propranolol, atenolol, metoprolol, esmolol (intravenous for thyroid storm)
• Peripheral T4-to-T3 conversion inhibitors (in thyroid storm):
  • Corticosteroids (hydrocortisone IV, prednisone PO)
  • Propylthiouracil (in addition to its primary thyroid-peroxidase action)
  • Propranolol (small effect)
  • Iopanoic acid and ipodate (radiographic contrast agents with antithyroid effect; largely unavailable in the U.S.)
• Bile-acid sequestrants (cross-indexed; accelerate thyroid hormone elimination):
  • Cholestyramine

The boundary of this category is "medicine that reduces thyroid hormone production, release, or action, used to treat hyperthyroidism." The thyroid hormones (levothyroxine, liothyronine, desiccated thyroid extract) are the opposite-direction medicines and are collected under thyroid hormones separately, although they are used in this category's patients after definitive treatment with radioactive iodine or thyroidectomy. The medicines used for Hashimoto thyroiditis (largely just levothyroxine; selected use of selenium with weak evidence) are not antithyroid agents and are listed under thyroid hormones. The medicines used for Graves' ophthalmopathy (intravenous methylprednisolone, teprotumumab, orbital irradiation, surgical decompression) are listed under their primary mechanism classes; teprotumumab (Tepezza, Horizon 2020), an IGF-1 receptor antagonist, is the first medicine specifically approved for thyroid eye disease.

This category page is an encyclopedia article about its subject. The actual index of medicines belonging to the category is generated automatically by the wiki engine, from category-membership declarations on the individual medicine pages, and appears at the foot of the page below the references.