Continuing Education Activity

Methimazole affects the production of thyroid hormone and is useful in treating conditions related to thyroid hormone, especially thyrotoxicosis. Thus, it is considered a thyroid blocking agent. This activity reviews methimazole's indications, interactions, adverse effects, and other pharmacodynamic and pharmacokinetic factors. In addition, it highlights the role of the interprofessional team in improving care for patients receiving methimazole for conditions where it has an indicated therapeutic value.

Objectives:

• Identify the mechanism of action of methimazole.
• Describe the adverse effects of methimazole.
• Review the toxicity of methimazole.
• Outline interprofessional team strategies for improving care coordination and communication to advance methimazole and improve outcomes.

Indications

FDA-approved Indications

• Patients with Graves disease[1]
• Patients with toxic multinodular goiter who are poor candidates for surgery or radioactive iodine therapy[2]
• To alleviate symptoms of hyperthyroidism in preparation for thyroidectomy or radioactive iodine therapy.[3]

Non-FDA-approved Indications

• Thyrotoxicosis/thyroid storm[3]

Mechanism of Action

Methimazole (MMI) is an anti-thyroid drug that belongs to drug class thionamides. The primary mechanism of action of methimazole is to block thyroid hormone production 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).[4]

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 the reduction of immune molecules like intracellular adhesion molecule 1, soluble interleukin 2, and anti-thyrotropin receptor antibody over time, thus alleviating immune-related hyperthyroid issues.[5] Whether or not the improvements in the patient profile are due to this or the improvement of thyroid function remains unclear.

However, this drug does not affect 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 is available as oral tablets in 5 mg and 10 mg strengths. The starting dose is between 20 to 40 mg per day, depending upon the severity of the disease.[6]

• 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. It has the added benefit of needing fewer thyroid function tests (TFTs) for monitoring, but with a slightly increased side effect frequency.[7][8]

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.[6]
• 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.
• Pregnant Women: It is classified as Pregnancy Category D medicine. Fetal harm is reported when methimazole is administered to a pregnant woman. If the woman becomes pregnant while taking methimazole or when methimazole is used during pregnancy, the patient should be counseled on the potential risk to the fetus.[9] In addition, prescribe alternative treatments for hyperthyroidism while pregnancy as congenital disabilities are reported in babies with maternal use of methimazole.
• Breastfeeding Women: As per manufacturer recommendations, methimazole is excreted in breastmilk when lactating women are administered methimazole, and hence postpartum patients receiving methimazole should not breastfeed their babies. Some experts recommend methimazole as the antithyroid drug of choice in nursing mothers compared to alternative agents. Maternal methimazole use does not affect intellectual development or thyroid function in breastfed infants with a maximum daily dose of 20 mg. To minimize the infant exposure, advise the patient to Take methimazole right after nursing or wait for 3 - 4 hours before nursing. The American Thyroid Association recommends monitoring infants for appropriate development and growth during routine health and wellness evaluations. Routine assessment of serum thyroid function in the child is not recommended. The infant should be watched for signs of infection as rare idiosyncratic reactions (e.g., agranulocytosis) might occur. In addition, monitor the infant's complete blood count and differential if there is a suspicion of a drug-induced blood dyscrasia.[10]

Adverse Effects

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

Serious adverse effects:

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.[11]
• Regular monitoring of granulocyte count is considered useless by most experts.
• Fever and sore throat are the most common presenting features of agranulocytosis. Therefore, 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.

Hepatotoxicity 

• The hepatic toxicity of methimazole is more of a cholestatic process than allergic hepatitis seen in propylthiouracil and recovers slowly after discontinuing the drug.[6]

Teratogenicity 

• Methimazole can cross the placental membrane readily due to its insignificant protein binding. During the organogenesis phase, it causes immense fetal adverse effects, especially when administered in the first trimester. Possible congenital disabilities seen in infants born to mothers who received methimazole during pregnancy include goiter, cretinism, aplasia cutis, umbilical abnormalities, facial dysmorphism, esophageal atresia, craniofacial defects, and choanal atresia.[12][13]
• Propylthiouracil is the preferred antithyroid drug during pregnancy, especially for the first trimester, since the incidence of congenital anomalies is much less than methimazole.[14] Clinicians should attempt to use the lowest effective dose, and if continuous monitoring shows the need for increased drug dosage, surgery is a consideration.

Hypothyroidism 

• Methimazole can cause hypothyroidism.[6] Therefore it is crucial to monitor T3 T4 levels in the serum, to adjust the dose to maintain a euthyroid state. In addition, since it crosses the placenta readily, it is capable of causing hypothyroidism and cretinism in newborns.

Drug Interactions

• The anti-vitamin-K activity of methimazole might increase the activity of oral anticoagulants.
• Hyperthyroidism can increase the clearance of beta-blockers. Therefore, dose reduction of beta-blockers might be required when a patient with hyperthyroidism reaches a euthyroid state.
• Dose reduction of digoxin might be required when a patient with hyperthyroidism reaches a euthyroid state.
• Theophylline level increases when hyperthyroid patients on a stable theophylline regimen become euthyroid; a reduced dose of theophylline may be needed.

Contraindications

• Methimazole is contraindicated if there is hypersensitivity to the drug or any of its components.
• It is relatively contraindicated during pregnancy.[15]

Monitoring

• The dose of methimazole is titrated based on the thyroid hormone level and clinical status of patients.[6]
• 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.[16]
• MMI is known to cause hypoprothrombinemia and bleeding. Monitor prothrombin time for such patients, especially before surgery.[17]
• Both propylthiouracil and methimazole appear in low concentrations in breast milk but do not influence the infant's 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 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 research has observed no significant adverse outcomes. 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.[10]
• Thyroid function tests are necessary at regular intervals if 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.[18]

• 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 a drug overdose, initiate supportive therapy as per the patient's condition. Consider the possibility of multiple drug overdose and drug-drug interactions. Ensure patient's airway, support ventilation, and hemodynamic stability. Monitor for serum electrolytes, blood gases, and patient's vitals. Consider giving activated charcoal to decrease the absorption of the medicine from the stomach before it reaches peak plasma concentration.

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 treating hyperthyroidism (mainly for Graves disease). However, 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 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 to the healthcare team. Nursing can verify medication compliance along with the pharmacist, as well as observe for any adverse effects. It is essential to communicate openly with all interprofessional team members to improve patient safety and better patient outcomes associated with methimazole use.[Level V]