Methimazole☆

Methimazole☆ BL Furman, Strathclyde Institute of Pharmacy & Biomedical Sciences, Glasgow, UK ã 2017 Elsevier Inc. All rights reserved.

Introduction Basic Chemistry Human Pharmacokinetics Targets-Pharmacodynamics Therapeutics Indications Adverse Effects Agent-Agent Interactions Pre-Clinical Research References

Name of the clinical form Related names

Chemical names CAS number

1 1 2 2 2 2 2 2 3 3

Methimazole Source: EMTREE Methimazole; Tapazole (trade); basolan; danantizol; favistan; frentirox; mercaptizol; 2 mercapto 1 methylimidazole; mercazole; mercazolyl; metazolo; methimazol; methirit; methothyrin; methothyrine; 1 methyl 2 imidazolethiol; 1 methylimidazole 2 thiol; methylmercaptoimidazol; 1 methyl 2 mercapto imidazole; 1 methyl 2mercaptoimidazole; methylmercaptoimidazole; methymazole; metimazole; metizol; metothyrin; n methyl 2 thioimidazole; strumazole; tapazole; thacapzol; thycapsol; thycapzol; thymidazole; tiamazole; thiamazole; 1 methyl 2 mercaptoimidazole; strumazol 1-methylimidazole-2-thiol 60-56-0

Introduction Methimazole is one of several thioamide drugs used in the treatment of hyperthyroidism. It inhibits the thyroid peroxidases (TPO) that catalyze the iodination of tyrosine residues in thyroglobulin and the oxidative coupling of iodinated tyrosines. Inhibition of iodination is competitively antagonized by iodide at low drug concentrations, but not at higher drug concentrations (Taurog, 1976). It has been suggested that it also reduces the autoimmunity that underlies Graves’ disease. This is on the basis that successful treatment is associated with suppression of thyroid receptor autoantibodies (Peakman et al., 1989). It is still unclear if methimazole has an immunomodulatory function or if the fall in circulating thyroid stimulating antibodies is secondary to a reduction in thyroid activity. Methimazole is the active metabolite of carbimazole, from which it is rapidly converted. Methimazole is the main antithyroid agent used in the United States, whereas carbimazole is used in Europe and in the UK.

Basic Chemistry

Chemical structure Structure

Chemical formula Properties Physical properties Molecular weight Solubility

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C4 H6 N2 S Methimazole is a white to pale buff crystalline powder, with a faint, characteristic odor. It should be protected from light (Parfitt, 1999). 114.171 Methimazole is soluble in water (1 part to 5 parts of water), ethanol (1 part to 5 parts of ethanol) and chloroform (1 part to 4.55 parts of chloroform). It is slightly soluble in ether (1 part to 125 parts of ether) (Parfitt, 1999).

Change History: January 2016. BL Furman updated abstract, added keywords, updated the text to the entire article, and added new references.

Reference Module in Biomedical Sciences

http://dx.doi.org/10.1016/B978-0-12-801238-3.98053-X

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Methimazole

Human Pharmacokinetics Methimazole is rapidly absorbed from the gastrointestinal tract and shows high bioavailability after oral administration ( 93%). Peak values are observed 1–2 h after administration and it has an elimination half-life of 4.9–5.7 h in normal and thyrotoxic subjects (Jansson et al., 1985; Parfitt, 1999). The elimination half-life was unaffected by renal insufficiency, but this was prolonged in patients with hepatic failure (Jansson et al., 1985).

Targets-Pharmacodynamics Methimazole inhibits thyroid peroxidase enzymes. Target Name(s)

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Peroxidase enzymes

Therapeutics Methimazole is used in the United States for the treatment of hyperthyroidism, including that due to Graves’ disease. It may be used alone, the dose being titrated according to clinical response and the circulating concentrations of free thyroid hormones (T3 and T4). Alternatively, in the treatment of Graves’ disease, some use a “block and replace” regime where large doses of methimazole are given continuously, in an attempt to exert an immunosuppressive effect, along with thyroxine to prevent iatrogenic hypothyroidism. However, there is no evidence that the use of large doses of methimazole (40 mg daily for 1 year) along with thyroxine is more effective than a lower dose (10 mg daily) (Reinwein et al., 1993). Improvement is usually seen in 1–3 weeks and the symptoms are usually under control by 1–2 months of commencing therapy (Parfitt, 1999).

Indications

Dosage

Value

Units

Prep. and route of admin.

15–60

mg

tablets, p.o.

Reference

Comments Methimazole can be given either in divided doses or as a single daily dose.

Adverse Effects In most cases, adverse effects are minor and transient (eg, nausea, vomiting, gastric discomfort, skin rash, itching, mild leucopenia). The major adverse effects appear to have an immune origin and include bone marrow depression that can lead to agranulocytosis, which is the most dangerous effect, occurring in 0.1–0.5% of patients (Bartalena et al., 1996). Patients are therefore told to obtain immediate medical attention if they develop sore throats, mouth ulcers, fever, bruising, or non-specific illness. Meyer-Gessner and others (Meyer-Gessner et al., 1994) suggested that agranulocytosis occurs almost exclusively during the first 10 weeks of treatment and is probably related to the drug dose. There are several case-reports suggesting that recombinant human granulocyte colonystimulating factor (rhG-CSF) shortens the recovery time in patients with methimazole-induced agranulocytosis. Other major adverse effects (aplastic anemia, thrombocytopenia, lupus erythematosus-like syndrome, vasculitis,) are exceedingly rare. Hepatotoxicity is another rare, but acknowledged, adverse effect (Woeber, 2002). The drug may be teratogenic (Di Gianantonio et al., 2001). Choanal as well as esophageal atresia may have a higher incidence than expected in fetuses exposed to methimazole between 3 and 7 gestational weeks. Until further data are available, where antithyroid drugs are needed to treat thyrotoxicosis in pregnancy or in women who plan to become pregnant, propylthiouracil should be used, as it is may be safer for use during the fertile period (Laurberg and Andersen, 2014). The apparent reduced teratogenicity of propylthiouracil relative to carbimazole and methimazole may reflect its lower use. The hepatotoxicity of propylthiouracil is well established.

Agent-Agent Interactions

Agent name None

Mode of interaction

Methimazole

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Pre-Clinical Research Methimazole can be used experimentally to produce hypothyroidism in the rat. It can be administered in the drinking water and 0.003% was found in one study to produce reduction of serum T4 and T3 concentrations and 50% depression of protein bound iodine at 1 week to 1 month of treatment (Cooper et al., 1984). 0.03% methimazole in the drinking water for 4 weeks reduced serum free T4 concentrations from 29.6  1.2 pmol L 1 to 2.4  0.3 pmol L 1 (Zhang et al., 2002).

References Journal Citations Bartalena L, Bogazzi F, and Martino E (1996) Adverse effects of thyroid hormone preparations and antithyroid drugs. Drug Safety 15(1): 53–63. Cooper DS, Kieffer JD, Saxe V, Mover H, Maloof F, and Ridgway EC (1984) Methimazole pharmacology in the rat: Studies using a newly developed radioimmunoassay for methimazole. Endocrinology 114(3): 786–793. Di Gianantonio E, Schaefer C, Mastroiacovo PP, Cournot MP, Benedicenti F, Reuvers M, Occupati B, Robert E, Bellemin B, Addis A, Arnon J, and Clementi M (2001) Adverse effects of prenatal methimazole exposure. Teratology 64(5): 262–266. Jansson R, Lindstrom B, and Dahlberg PA (1985) Pharmacokinetic properties and bioavailability of methimazole. Clinical Pharmacokinetics 10(5): 443–450. Laurberg P and Andersen SL (2014) Therapy of endocrine disease: Antithyroid drug use in early pregnancy and birth defects: Time windows of relative safety and high risk? European Journal of Endocrinology 171(1): R13–R20. Meyer-Gessner M, Benker G, Lederbogen S, Olbricht T, and Reinwein D (1994) Antithyroid drug-induced agranulocytosis: Clinical experience with ten patients treated at one institution and review of the literature. Journal of Endocrinological Investigation 17(1): 29–36. Peakman M, Hussain M, Cundy T, and Vergani D (1989) Increased activated T-lymphocytes and normal thyrotropin receptor antibody levels in Graves’ disease in long-term remission. Journal of Clinical & Laboratory Immunology 30(1): 1–5. Reinwein D, Benker G, Lazarus JH, and Alexander WD (1993) A prospective randomized trial of antithyroid drug dose in Graves’ disease therapy. European Multicenter Study Group on Antithyroid Drug Treatment. The Journal of Clinical Endocrinology and Metabolism 76(6): 1516–1521. Taurog A (1976) The mechanism of action of the thioureylene antithyroid drugs. Endocrinology 98(4): 1031–1046. Woeber KA (2002) Methimazole-induced hepatotoxicity. Endocrine Practice 8(3): 222–224. Zhang L, Parratt JR, Beastall GH, Pyne NJ, and Furman BL (2002) Streptozotocin diabetes protects against arrhythmias in rat isolated hearts: Role of hypothyroidism. European Journal of Pharmacology 435(2–3): 269–276. Book Citations Parfitt K (1999) Martindale: The complete drug reference, 32 edn. London: Pharmaceutical Press.