Pharmacology and toxicity of thionamides
- Douglas S Ross, MD
Douglas S Ross, MD
- Section Editor — Thyroid Disease
- Professor of Medicine
- Harvard Medical School
Thionamide compounds were found in 1943 to inhibit thyroid hormone synthesis. They are actively transported into the thyroid gland where they inhibit both the organification of iodine to tyrosine residues in thyroglobulin and the coupling of iodotyrosines (figure 1) .
The pharmacology and toxicity of propylthiouracil (PTU) and methimazole will be reviewed here. Specific issues related to their use in the treatment of Graves' disease are discussed separately. (See "Thionamides in the treatment of Graves' disease".)
Propylthiouracil (PTU) and methimazole are the thionamide drugs available in the United States. Carbimazole is a third option available in some European and Asian countries. Methimazole and carbimazole are interchangeable because carbimazole is completely metabolized to methimazole. The carbimazole dose required to yield an equivalent dose of methimazole is approximately 40 percent higher.
PTU, but not methimazole, inhibits the 5'-monodeiodinase that converts thyroxine (T4) to triiodothyronine (T3) in extrathyroidal tissue. However, methimazole has several important pharmacokinetic advantages over PTU:
●The serum half-life of methimazole is four to six hours, whereas that of PTU is 75 minutes.
- Cooper DS. Antithyroid drugs. N Engl J Med 2005; 352:905.
- Okamura K, Ikenoue H, Shiroozu A, et al. Reevaluation of the effects of methylmercaptoimidazole and propylthiouracil in patients with Graves' hyperthyroidism. J Clin Endocrinol Metab 1987; 65:719.
- Rivkees SA, Szarfman A. Dissimilar hepatotoxicity profiles of propylthiouracil and methimazole in children. J Clin Endocrinol Metab 2010; 95:3260.
- Cooper DS, Rivkees SA. Putting propylthiouracil in perspective. J Clin Endocrinol Metab 2009; 94:1881.
- Bahn RS, Burch HS, Cooper DS, et al. The Role of Propylthiouracil in the Management of Graves' Disease in Adults: report of a meeting jointly sponsored by the American Thyroid Association and the Food and Drug Administration. Thyroid 2009; 19:673.
- Sundaresh V, Brito JP, Wang Z, et al. Comparative effectiveness of therapies for Graves' hyperthyroidism: a systematic review and network meta-analysis. J Clin Endocrinol Metab 2013; 98:3671.
- Otsuka F, Noh JY, Chino T, et al. Hepatotoxicity and cutaneous reactions after antithyroid drug administration. Clin Endocrinol (Oxf) 2012; 77:310.
- Ross DS, Burch HB, Cooper DS, et al. 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis. Thyroid 2016; 26:1343.
- Andersohn F, Konzen C, Garbe E. Systematic review: agranulocytosis induced by nonchemotherapy drugs. Ann Intern Med 2007; 146:657.
- Watanabe N, Narimatsu H, Noh JY, et al. Antithyroid drug-induced hematopoietic damage: a retrospective cohort study of agranulocytosis and pancytopenia involving 50,385 patients with Graves' disease. J Clin Endocrinol Metab 2012; 97:E49.
- Nakamura H, Miyauchi A, Miyawaki N, Imagawa J. Analysis of 754 cases of antithyroid drug-induced agranulocytosis over 30 years in Japan. J Clin Endocrinol Metab 2013; 98:4776.
- Andersen SL, Olsen J, Laurberg P. Antithyroid Drug Side Effects in the Population and in Pregnancy. J Clin Endocrinol Metab 2016; 101:1606.
- van Staa TP, Boulton F, Cooper C, et al. Neutropenia and agranulocytosis in England and Wales: incidence and risk factors. Am J Hematol 2003; 72:248.
- Cooper DS, Goldminz D, Levin AA, et al. Agranulocytosis associated with antithyroid drugs. Effects of patient age and drug dose. Ann Intern Med 1983; 98:26.
- Takata K, Kubota S, Fukata S, et al. Methimazole-induced agranulocytosis in patients with Graves' disease is more frequent with an initial dose of 30 mg daily than with 15 mg daily. Thyroid 2009; 19:559.
- Pearce SH. Spontaneous reporting of adverse reactions to carbimazole and propylthiouracil in the UK. Clin Endocrinol (Oxf) 2004; 61:589.
- Tamai H, Takaichi Y, Morita T, et al. Methimazole-induced agranulocytosis in Japanese patients with Graves' disease. Clin Endocrinol (Oxf) 1989; 30:525.
- Tajiri J, Noguchi S, Murakami T, Murakami N. Antithyroid drug-induced agranulocytosis. The usefulness of routine white blood cell count monitoring. Arch Intern Med 1990; 150:621.
- Balkin MS, Buchholtz M, Ortiz J, Green AJ. Propylthiouracil (PTU)-induced agranulocytosis treated with recombinant human granulocyte colony-stimulating factor (G-CSF). Thyroid 1993; 3:305.
- Fukata S, Kuma K, Sugawara M. Granulocyte colony-stimulating factor (G-CSF) does not improve recovery from antithyroid drug-induced agranulocytosis: a prospective study. Thyroid 1999; 9:29.
- Andrès E, Kurtz JE, Perrin AE, et al. Haematopoietic growth factor in antithyroid-drug-induced agranulocytosis. QJM 2001; 94:423.
- Andrès E, Zimmer J, Mecili M, et al. Clinical presentation and management of drug-induced agranulocytosis. Expert Rev Hematol 2011; 4:143.
- Thomas D, Moisidis A, Tsiakalos A, et al. Antithyroid drug-induced aplastic anemia. Thyroid 2008; 18:1043.
- Liaw YF, Huang MJ, Fan KD, et al. Hepatic injury during propylthiouracil therapy in patients with hyperthyroidism. A cohort study. Ann Intern Med 1993; 118:424.
- Williams KV, Nayak S, Becker D, et al. Fifty years of experience with propylthiouracil-associated hepatotoxicity: what have we learned? J Clin Endocrinol Metab 1997; 82:1727.
- Arab DM, Malatjalian DA, Rittmaster RS. Severe cholestatic jaundice in uncomplicated hyperthyroidism treated with methimazole. J Clin Endocrinol Metab 1995; 80:1083.
- Yang J, Li LF, Xu Q, et al. Analysis of 90 cases of antithyroid drug-induced severe hepatotoxicity over 13 years in China. Thyroid 2015; 25:278.
- Wang MT, Lee WJ, Huang TY, et al. Antithyroid drug-related hepatotoxicity in hyperthyroidism patients: a population-based cohort study. Br J Clin Pharmacol 2014; 78:619.
- FDA Drug Safety Communication: New Boxed Warning on severe liver injury with propylthiouracil, April 2010. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm209023.htm (Accessed on April 22, 2010).
- Balavoine AS, Glinoer D, Dubucquoi S, Wémeau JL. Antineutrophil Cytoplasmic Antibody-Positive Small-Vessel Vasculitis Associated with Antithyroid Drug Therapy: How Significant Is the Clinical Problem? Thyroid 2015; 25:1273.
- Yang M, Qu H, Deng HC. Acute pancreatitis induced by methimazole in a patient with Graves' disease. Thyroid 2012; 22:94.
- Roh E, Kim YA, Ku EJ, et al. Two cases of methimazole-induced insulin autoimmune syndrome in graves' disease. Endocrinol Metab (Seoul) 2013; 28:55.
- TOXICITIES AND THEIR MANAGEMENT
- Common, minor side effects
- Potential teratogenicity
- Rare but serious adverse effects
- - Agranulocytosis
- - Hepatotoxicity
- - ANCA-positive vasculitis
- - Pancreatitis
- - Insulin autoimmune syndrome
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