Of course. Here is a comprehensive, evidence-based drug monograph for Methimazole formatted as a complete blog post.
*Introduction
Methimazole is a first-line antithyroid agent belonging to the thioamide class. It is a cornerstone in the medical management of hyperthyroidism, particularly for Graves' disease. As a key component of the thyrostatic arsenal, methimazole works by inhibiting the synthesis of thyroid hormones, effectively bringing the hypermetabolic state under control. This monograph provides a detailed overview of its pharmacology, clinical use, and essential safety information for healthcare professionals and informed patients.
Mechanism of Action
Methimazole exerts its therapeutic effects through several mechanisms within the thyroid gland: * Inhibition of Thyroid Peroxidase: Its primary mechanism is the inhibition of the thyroid peroxidase enzyme. This enzyme is essential for the oxidation of iodide to iodine and the subsequent incorporation of iodine into tyrosine residues on thyroglobulin (organification). This effectively blocks the synthesis of the prohormone thyroxine (T4) and the active hormone triiodothyronine (T3). * Inhibition of Coupling: It also inhibits the coupling of iodotyrosines to form T4 and T3. * Immunosuppressive Effects: Methimazole may have mild immunosuppressive effects in Graves' disease, potentially reducing the levels of thyroid-stimulating immunoglobulins (TSI), though this is not its primary mode of action.
It is important to note that methimazole does not inactivate existing thyroid hormone stored in the colloid or circulating in the bloodstream. Therefore, its clinical effect is delayed until pre-formed hormones are metabolized, typically taking several weeks.
Indications
* Hyperthyroidism: Treatment of hyperthyroidism due to all causes, including: * Graves' disease (the most common indication) * Toxic nodular goiter (multinodular or solitary adenoma) * Thyroiditis (in selected cases) * Preoperative Preparation: To achieve a euthyroid state prior to thyroidectomy. * Adjunctive Therapy: As an adjunct to radioactive iodine therapy to hasten the normalization of thyroid function while waiting for the full effects of radiation.
Dosage and Administration
Route: Oral administration. Formulations: Available as 5 mg and 10 mg scored tablets. Standard Dosing:* Adults (Graves' Disease): The initial dose is typically 15-30 mg daily, administered in divided doses (e.g., every 8 or 12 hours). For mild disease, 5-10 mg daily may be sufficient. Once the patient is euthyroid (usually after 4-8 weeks), the dose is tapered to a maintenance dose of 5-15 mg daily, often given as a single dose. * "Block-and-Replace" Regimen: A higher dose (e.g., 30-40 mg daily) is used to completely block thyroid function, and levothyroxine is added for replacement. This strategy can stabilize hormone levels but is associated with a higher risk of adverse effects.
Special Populations:* Geriatric Patients: Initiate therapy at the lower end of the dosing range due to potentially increased sensitivity. * Pediatric Patients: Initial dose is 0.4 mg/kg/day administered in divided doses. Maintenance dose is approximately 0.2 mg/kg/day. * Renal Impairment: No specific dosage adjustment is recommended. * Hepatic Impairment: Use with extreme caution. Dose reduction may be necessary. It is contraindicated in patients with previous methimazole-induced severe hepatic injury. * Pregnancy: Use is contraindicated in the first trimester. Propylthiouracil (PTU) is the preferred agent in the first trimester due to a potentially lower risk of teratogenic effects (e.g., aplasia cutis). Methimazole may be considered after the first trimester if necessary, as PTU carries a higher risk of hepatotoxicity.
Pharmacokinetics
* Absorption: Rapidly and completely absorbed after oral administration. Bioavailability is approximately 93%. * Distribution: Distributed throughout the body with a volume of distribution of ~0.5 L/kg. It concentrates in the thyroid gland. * Metabolism: Primarily metabolized in the liver via glucuronidation. * Elimination: Excreted mainly in the urine as metabolites. The elimination half-life is relatively short (4-6 hours), but its clinical effect persists for much longer (24+ hours) due to its prolonged intrathyroidal duration of action, allowing for once-daily dosing in the maintenance phase. * Plasma Protein Binding: Not significantly bound to plasma proteins.
Contraindications
* Hypersensitivity to methimazole or any component of the formulation. * First trimester of pregnancy. * History of methimazole-induced agranulocytosis or severe bone marrow suppression. * Treatment of patients with previous methimazole-induced severe hepatic injury.
Warnings and Precautions
* Agranulocytosis: A rare (0.1-0.5%) but life-threatening adverse reaction characterized by a severe neutropenia. It typically occurs suddenly and is often idiosyncratic. Patients must be instructed to immediately report any signs of infection (e.g., fever, sore throat, mouth ulcers). * Hepatotoxicity: Can range from mild, asymptomatic transaminase elevation to acute liver failure, which can be fatal. Monitor liver function tests at baseline and periodically. * Vasculitis: ANCA-positive vasculitis has been reported, presenting with rash, arthralgia, and internal organ involvement. * Hypothyroidism: Overtreatment can lead to hypothyroidism. Monitor thyroid function tests regularly and adjust dose accordingly. * Pregnancy and Lactation: As noted, use is contraindicated in the first trimester. Methimazole is excreted in breast milk in low concentrations. Use with caution during lactation, monitoring the infant's thyroid function.
Drug Interactions
* Warfarin: Methimazole may potentiate the anticoagulant effect of warfarin by reducing the production of vitamin K-dependent clotting factors. Monitor INR closely. * Digoxin: Hyperthyroidism increases digoxin clearance. As methimazole corrects the hyperthyroid state, digoxin levels may rise, increasing the risk of toxicity. Monitor digoxin levels. * Theophylline: Similar to digoxin, clearance decreases as the patient becomes euthyroid, potentially increasing theophylline levels. * Beta-Blockers: Often used concomitantly for symptomatic control. The dose of beta-blockers may need to be reduced as hyperthyroidism is controlled. * Other Bone Marrow Suppressive Drugs: Concomitant use may increase the risk of agranulocytosis.
Adverse Effects
Common (>10%):* Maculopapular rash, urticaria * Arthralgia, myalgia * Gastrointestinal upset (nausea, vomiting, epigastric pain) * Hair loss * Taste disturbance
Serious but Rare:* Agranulocytosis (0.1-0.5%) * Hepatotoxicity (ranging from subclinical hepatitis to fulminant hepatic necrosis) * ANCA-positive vasculitis * Aplastic anemia, thrombocytopenia * Drug-induced lupus-like syndrome
Monitoring Parameters
* Thyroid Function: Monitor TSH, Free T4, and Free T3 every 4-6 weeks initially until euthyroid, then every 2-3 months during maintenance, and every 4-6 months once stable. * Complete Blood Count (CBC) with Differential: At baseline. Routine monitoring is not proven to prevent agranulocytosis due to its rapid onset. Patients must be educated to report febrile illness/sore throat immediately, at which point a CBC must be drawn. * Liver Function Tests (LFTs): At baseline and periodically during therapy. More frequently if symptoms of hepatitis (jaundice, dark urine, anorexia) occur. * Clinical Symptoms: Monitor for signs of hypothyroidism (fatigue, weight gain, cold intolerance) or continued hyperthyroidism.
Patient Education
* Adherence: Take the medication exactly as prescribed. Do not stop taking it without consulting your doctor. * Agranulocytosis Warning: Understand that this drug can rarely cause a serious drop in white blood cells. Contact your doctor immediately if you develop a fever, sore throat, mouth sores, or any signs of infection. * Hepatotoxicity Warning: Report any symptoms of liver problems, such as yellowing of the skin/eyes (jaundice), dark urine, severe fatigue, or abdominal pain. * Follow-up: Keep all scheduled laboratory and doctor appointments. This monitoring is crucial for your safety. * Pregnancy Planning: Inform your doctor immediately if you are pregnant, planning to become pregnant, or breastfeeding.
References
1. Ross, D. S., Burch, H. B., Cooper, D. S., et al. (2016). 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis. Thyroid, 26(10), 1343–1421. 2. Nakamura, H., Noh, J. Y., Itoh, K., et al. (2007). Comparison of methimazole and propylthiouracil in patients with hyperthyroidism caused by Graves' disease. The Journal of Clinical Endocrinology & Metabolism, 92(6), 2157–2162. 3. Cooper, D. S. (2005). Antithyroid drugs. The New England Journal of Medicine, 352(9), 905–917. 4. Drugdex® Micromedex Solutions. (2023). Methimazole. Truven Health Analytics, Inc. 5. Lexicomp Online®. (2023). Methimazole: Drug Information. UpToDate, Inc. 6. FDA Prescribing Information for Tapazole (Methimazole).