Methimazole (MMI) is an anti-thyroid drug that belongs to drug class thionamides; the FDA approved uses of which include:

• Patients with Graves disease
• Patients with toxic multinodular goiter who are poor candidates for surgery or radioactive iodine therapy
• To ameliorate symptoms of hyperthyroidism in preparation for thyroidectomy or radioactive iodine therapy.

The non-FDA approved use of MMI includes treating thyrotoxicosis/thyroid storm.

The primary mechanism of action of methimazole is to block the production of thyroid hormone from the thyroid gland. It interferes with the step that causes the iodination of tyrosine residues in thyroglobulin, mediated by the enzyme thyroid peroxidase, thus preventing the synthesis of thyroxine (T4) and triiodothyronine(T3).[1] An additional mechanism is by inhibiting the iodotyrosyl residues from the coupling. Methimazole may also interfere with the oxidation of the iodide ion and iodotyrosyl groups. Eventually, thyroglobulin gets depleted, and circulating thyroid hormone levels decrease. It may also help to control diseases by affecting the overall immune system. Various studies show that reduction of immune molecules like intracellular adhesion molecule 1, soluble interleukin 2, and anti-thyrotropin receptor antibody over time, thus ameliorating immune-related hyperthyroid issues.[2] Whether or not the improvements in the patient profile are due to this, or because of improvement of thyroid function, remains unclear.

However, there is no effect of this drug on the existing thyroxine (T4) and triiodothyronine (T3) in the circulation or stored in the thyroid gland. Similarly, there have been no observations of alterations in the effectiveness of exogenously administered thyroid hormones.

Methimazole administration is via the oral route. The starting dose is between 20 to 40 mg per day, depending upon the severity.

• The daily dose gets divided into three doses every 8 hours.
• As per the "titration regimen," the high starting dose is then tapered after 4 to 8 weeks. A maintenance dose of 5 to 20 mg follows after almost 4 to 6 months of therapy, which continues for an extra 12 to 18 months.
• As per the "block–replace regimen," a high dose of antithyroid drugs is maintained, but with levothyroxine therapy to maintain a euthyroid state; this has the added benefit of needing fewer thyroid function tests (TFTs) for monitoring, but with a slightly increased side effect frequency.[3][4]

The treatment of thyroid storm includes a starting dose of 60 to 80 mg/day orally until achieving control, also given at 8-hour intervals. Adjust the subsequent doses and duration of treatment as per patient response.

Methimazole has a narrow therapeutic window. Therefore it is essential to note the maximally allowed dosage :

• Adults:40 mg/day orally; up to 60 mg/day in severe disease.
• Geriatric:40 mg/day orally; up to 60 mg/day in severe disease.
• Adolescents: Maintenance doses rarely exceed 30 mg/day orally; 1 mg/kg/day orally in severe hyperthyroidism. Patients who have attained full growth, doses may approach adult dosing.
• Children: Maintenance doses rarely exceed 30 mg/day orally, or 1 mg/kg/day if severe hyperthyroidism.
• Infants:1 mg/kg/day if severe hyperthyroidism.

The side effects of methimazole are mostly dose-related. The minor ones like (most commonly) hives and itching, improve with anti-histaminic medications or by discontinuing the drug.

Serious adverse effects include:

(1) Agranulocytosis

• The cut-off criterion for it is an absolute granulocyte count of less than 500 per mL.
• It most frequently occurs in the first three months of starting therapy but can occur even after a year or more of exposure, or during repeated exposures when treating a relapse.[5]
• Regular monitoring of granulocyte count is considered useless by most experts.
• Fever and sore throat are the most common presenting features of agranulocytosis. All patients should get verbal and written instruction regarding the importance of getting an urgent white cell count if these symptoms arise for confirming the absence of this complication for continued antithyroid drug therapy.
• Stop methimazole if the count is less than 1000 per ml. Treat fever or any apparent infections with intravenous antibiotics.
  • IV granulocyte colony-stimulating factor is known to reduce the length of hospitalization and recovery time. 
• Propylthiouracil (PTU) and methimazole have cross-reactivity for agranulocytosis, so avoid using the former in such patients.

(2) Hepatotoxicity 

• The hepatic toxicity of methimazole is more of a cholestatic process, as compared to allergic hepatitis seen in propylthiouracil, and recovers slowly after discontinuing the drug.

(3) Teratogenicity 

• Methimazole can cross the placental membrane readily due to its insignificant protein binding. It causes immense fetal adverse effects, especially when administered in thefirst trimester, during the organogenesis phase. Possible congenital disabilities seen in infants born to mothers who received methimazole during pregnancy include aplasia cutis, umbilical abnormalities, facial dysmorphism, esophageal atresia, craniofacial defects, and choanal atresia.[6][7]
• Propylthiouracil is the preferred antithyroid drug during pregnancy, especially for the first trimester since the incidence of congenital anomalies with it is much less as compared to methimazole.[8] Clinicians should attempt to use the lowest effective dose, and if continuous monitoring shows the need for increased drug dosage, surgery is a consideration.

(4) Hypothyroidism 

• Methimazole can cause hypothyroidism. Therefore it is crucial to monitor T3, T4 levels in the serum, to adjust the dose to maintain a euthyroid state. Since it crosses the placenta readily, it is capable of causing hypothyroidism and cretinism in newborns. 

Methimazole is contraindicated if there is hypersensitivity to the drug or any of its components.