Methimazole

Article Author:
Gauri Singh
Article Editor:
Ricardo Correa
Updated:
8/4/2019 12:40:03 AM
PubMed Link:
Methimazole

Indications

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.

Mechanism of Action

The chief mechanism of action of methimazole is to block the production of thyroid hormone from the thyroid gland. It interferes with the step that causes 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.

Administration

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 8 hourly doses.
  • 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.

Adverse Effects

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 anti-thyroid drug during pregnancy, especially for the first trimester since the incidence of congenital anomalies with it is much less as compared to methimazole.[8] It is attempted 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. 

Contraindications

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

Monitoring

  • Patients receiving MMI should be closely monitored and cautioned to immediately report any signs of illness, especially fever, sore throat, malaise, headache. If so, obtain total and differential cell counts and look for any evidence of agranulocytosis. Extra care is necessary for patients who receive additional drugs that could potentially cause agranulocytosis.[9]
  • MMI is known to cause hypoprothrombinemia and bleeding. Monitor prothrombin time for such patients, especially before surgery.[10]
  • Both propylthiouracil and methimazole appear in low concentrations in the breast milk but do not influence the infant thyroid function, and breastfeeding is permissible on moderate doses of these agents. Those with elevated antibody levels need assessment for fetal and neonatal thyroid dysfunction. On ultrasound features of fetal thyroid dysfunction include growth restriction, advanced bone age, goiter, or cardiac failure. According to the guidelines of the American Thyroid Association (ATA), low to moderate doses of MMI (i.e., 20 to 30 mg/day) can and should be used during lactation, since no significant adverse outcomes have been observed. It also recommends regular monitoring of the infant's thyroid function, and that lactating mothers take their thyroid medication in divided doses, preferably immediately following a feeding.[11]
  • Thyroid function tests are necessary at regular intervals, in case any dosing adjustments are needed.
  • Any patient who gets pregnant or intends to get pregnant while on any anti-thyroid medication should immediately report to their doctor for a change of therapy.

Toxicity

The common symptoms of methimazole overdosage are nausea, vomiting, epigastric discomfort, fever, joint pain, itching, body ache, and swelling.

  • Agranulocytosis or aplastic anemia can also occur in hours to days.
  • Less commonly, hepatitis, nephrotic syndrome, nerve damage, dermatitis, and stimulation or depression of the nervous system can occur.
  • The median lethal dose or the level of methimazole in the body associated with toxicity and/or death is still unknown.

Treatment

In cases of a drug overdose, initiate supportive therapy as per the patient's condition.

Enhancing Healthcare Team Outcomes

Physicians, nurses, and pharmacists in many parts of the world continue to use methimazole because of its effectiveness, and low cost for treatment of hyperthyroidism (mainly for Graves disease).

It is essential to know the side effects of methimazole, particularly severe drug allergy when taken with multiple medications, and side effects with the use of any thioamide medication in general. Furthermore, it is imperative to counsel the patient about the rare side effects like agranulocytosis or liver failure before starting the medication. 

In general, methimazole prescribing should be from an endocrinologist, with patient monitoring by the primary care provider and nurse practitioner. Dose changes must not occur without first consulting with the endocrinologist. The pharmacist should verify all dosing, perform mediation reconciliation, and report any concerns back to the healthcare team. Nursing can verify medication compliance along with the pharmacist, as well as observe for any adverse effects. Only with open communication with members of the interprofessional team can the outcomes be improved and the adverse effects of the drug reduced. [Level V]


References

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[2] Sonnet E,Massart C,Gibassier J,Allannic H,Maugendre D, Longitudinal study of soluble intercellular adhesion molecule-1 (ICAM-1) in sera of patients with Graves' disease. Journal of endocrinological investigation. 1999 Jun;     [PubMed PMID: 10435852]
[3] Edmonds CJ,Tellez M, Treatment of Graves' disease by carbimazole: high dose with thyroxine compared to titration dose. European journal of endocrinology. 1994 Aug;     [PubMed PMID: 8075780]
[4] Benker G,Reinwein D,Kahaly G,Tegler L,Alexander WD,Fassbinder J,Hirche H, Is there a methimazole dose effect on remission rate in Graves' disease? Results from a long-term prospective study. The European Multicentre Trial Group of the Treatment of Hyperthyroidism with Antithyroid Drugs. Clinical endocrinology. 1998 Oct;     [PubMed PMID: 9876342]
[5] Takata K,Kubota S,Fukata S,Kudo T,Nishihara E,Ito M,Amino N,Miyauchi A, 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 : official journal of the American Thyroid Association. 2009 Jun;     [PubMed PMID: 19445623]
[6] Mandel SJ,Cooper DS, The use of antithyroid drugs in pregnancy and lactation. The Journal of clinical endocrinology and metabolism. 2001 Jun;     [PubMed PMID: 11397822]
[7] Barbero P,Valdez R,Rodríguez H,Tiscornia C,Mansilla E,Allons A,Coll S,Liascovich R, Choanal atresia associated with maternal hyperthyroidism treated with methimazole: a case-control study. American journal of medical genetics. Part A. 2008 Sep 15;     [PubMed PMID: 18698631]
[8] Abalovich M,Amino N,Barbour LA,Cobin RH,De Groot LJ,Glinoer D,Mandel SJ,Stagnaro-Green A, Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society Clinical Practice Guideline. The Journal of clinical endocrinology and metabolism. 2007 Aug;     [PubMed PMID: 17948378]
[9] Vicente N,Cardoso L,Barros L,Carrilho F, Antithyroid Drug-Induced Agranulocytosis: State of the Art on Diagnosis and Management. Drugs in R     [PubMed PMID: 28105610]
[10] Lipsky JJ,Gallego MO, Mechanism of thioamide antithyroid drug associated hypoprothrombinemia. Drug metabolism and drug interactions. 1988;     [PubMed PMID: 2482800]
[11] Methimazole 2006;     [PubMed PMID: 30000083]