Methimazole

Methimazole is the active thionamide antithyroid medicine and the first-choice drug for Graves' disease and toxic nodular hyperthyroidism outside the first trimester of pregnancy. It is given once daily, controls thyroid function over 4 to 8 weeks, and is used for long courses of 12 to 18 months or as preparation for radioactive iodine or surgery. The main risks are agranulocytosis, hepatotoxicity, pancreatitis and first-trimester teratogenicity.

Classification. Thionamide antithyroid agent; the active metabolite of carbimazole. Tablets 5 mg and 10 mg (strengths vary by market). Methimazole 6 mg is about equivalent to carbimazole 10 mg.

Mechanism. Inhibits thyroid peroxidase, blocking iodination of tyrosine and coupling to form T3 and T4. It does not block release of stored hormone, so the effect is delayed. It has a mild immunomodulatory action in Graves' disease and does not block peripheral conversion of T4 to T3.

Pharmacodynamics. Free T4 falls within 2 to 4 weeks and the euthyroid state is reached at 6 to 8 weeks. TSH can stay suppressed for months, so dose changes follow free T4.

Pharmacokinetics. Bioavailability about 90%; not protein bound; concentrated in the thyroid. Plasma half-life 5 to 6 hours, but the biological effect lasts over 24 hours, allowing a single daily dose. Metabolised in the liver; excreted in urine. Crosses the placenta and enters breast milk.

Graves' disease and toxic nodular goitre, adults (first line).

• Initial dose 10 to 30 mg orally once daily (5 to 10 mg in mild disease, 15 to 20 mg in moderate disease, 30 to 40 mg in severe disease). Maximum 40 mg daily for most patients.
• Continue the initial dose for 4 to 8 weeks until free T4 is normal, then reduce by 5 mg every 4 to 6 weeks to a maintenance of 2.5 to 10 mg once daily.
• Continue for 12 to 18 months in Graves' disease, then stop and monitor for relapse (about half relapse). Nodular disease is treated definitively (radioactive iodine or surgery) rather than with long-term thionamide.

Block and replace regimen (alternative).

• Methimazole 30 to 40 mg daily with levothyroxine 50 to 100 micrograms daily added once free T4 is normal, for 6 months. Mainly for fluctuating thyroid function; higher drug dose carries more adverse effects.

Preparation for thyroidectomy or radioactive iodine (specialist).

• 20 to 30 mg daily until euthyroid, with a beta-blocker for symptom control. For radioactive iodine, stop 5 to 7 days beforehand and restart 3 to 7 days after if needed. Surgery is done once euthyroid, often with a short course of potassium iodide.

Thyroid storm (emergency, critical care).

• Methimazole 20 mg orally or by nasogastric tube every 4 to 6 hours (propylthiouracil 200 mg every 6 hours is an alternative and also reduces T4 to T3 conversion). Give potassium iodide or iodine solution at least 1 hour after the first thionamide dose, with a beta-blocker, a corticosteroid and supportive care.

Children.

• Start 0.2 to 0.5 mg/kg daily in 1 to 3 divided doses, maximum 30 mg daily; reduce once euthyroid. Directed by a paediatric endocrinologist.

Adjustments.

• Kidney: no change.
• Liver: use caution and monitor; avoid in severe liver disease.
• Older adults: no change; lower doses suffice and a beta-blocker may be needed.
• Weight: dose by weight in children.

Contraindications. Previous severe adverse reaction to methimazole or carbimazole (agranulocytosis, severe hepatitis, pancreatitis); severe blood disorders; first trimester of pregnancy where an alternative exists.

Major warnings.

• Agranulocytosis (about 0.2 to 0.5%), usually in the first 3 months but any time; sudden and not predicted by routine counts. Every patient is told to stop the drug and seek an urgent full blood count if sore throat, fever, mouth ulcers or other infection appears.
• Teratogenicity: embryopathy (aplasia cutis, choanal and oesophageal atresia, facial and abdominal wall defects) with first-trimester use.
• Acute pancreatitis: stop and do not restart.
• Hepatotoxicity: cholestatic more often than hepatocellular, rarely severe.

Other adverse effects. Rash and pruritus (common, about 5%; antihistamine or change drug), arthralgia, nausea, taste disturbance, alopecia, vasculitis (including antineutrophil cytoplasmic antibody-positive), hypothyroidism from over-treatment, weight gain.

Major interactions.

• Warfarin: response falls as hyperthyroidism is corrected; monitor INR.
• Digoxin levels rise as the patient becomes euthyroid; monitor.
• Beta-blocker and theophylline clearance fall as patients become euthyroid; reduce the doses.
• Other drugs that suppress bone marrow (clozapine, carbamazepine, chemotherapy): added risk of neutropenia.
• Iodine contrast and amiodarone alter response.

Special groups.

• Pregnancy: avoid in the first trimester; propylthiouracil is preferred then, and women are switched back to methimazole after the first trimester when liver risk makes this reasonable. Use the lowest dose that keeps free T4 at the upper end of normal and check every 2 to 4 weeks. Advise effective contraception in women of childbearing age on treatment.
• Breastfeeding: compatible at doses up to 20 mg daily (carbimazole up to 30 mg daily), given as a single dose after a feed, with infant thyroid checks if the dose is higher.
• Children: specialist use; dose by weight (0.2 to 0.5 mg/kg daily).
• Older adults: lower doses; check for atrial fibrillation.
• Kidney and liver impairment: no kidney change; caution in liver disease.
• East Africa: Graves' disease is common, and iodine-deficient goitre regions have toxic nodular disease; radioactive iodine and surgery can be far from patients, so long courses are often needed, with adherence and clinic access the main barriers. Counsel on infection symptoms, since urgent blood counts may be hard to reach. Carbimazole is often the form stocked.

Formulation and administration. Swallow tablets with water, once daily at the same time, with or without food. A single morning dose is as effective as divided doses after the first weeks.

Baseline. Full blood count with white cell differential, liver function tests, TSH, free T4 and free T3, thyroid receptor antibodies where available, pregnancy test in women of childbearing age, ECG in older adults.

Monitoring.

• Free T4, free T3 and TSH every 4 to 6 weeks until stable, then every 2 to 3 months while on treatment; adjust the dose by free T4, since TSH lags.
• Full blood count and liver tests at baseline and with any infection symptoms; routine counts do not predict agranulocytosis.
• Liver tests periodically, and if jaundice, dark urine or pale stools appear.
• Pregnancy test before starting and with any missed period.

Dose reduction and stopping. Reduce the dose once free T4 is normal. Stop with agranulocytosis (neutrophils under 1.0 x 10^9/L, or under 1.5 x 10^9/L with symptoms), severe rash, hepatitis, pancreatitis, vasculitis or at the end of the planned course. Switch drug only after a mild reaction such as rash.

Referral and escalation. Admit suspected agranulocytosis for an urgent blood count, broad-spectrum antibiotics and haematology review. Admit thyroid storm. Refer to endocrinology all new Graves' disease, pregnancy, children, relapse after a course, thyroid eye disease and any adverse reaction.