Thionamides

Thionamides (carbimazole, methimazole or thiamazole, and propylthiouracil) are the first-line drugs to control hyperthyroidism from Graves disease and toxic nodular goitre. Carbimazole is a prodrug of methimazole; 10 mg of carbimazole is roughly equal to 6 mg of methimazole.

Mechanism. They inhibit thyroid peroxidase, blocking iodination of tyrosine residues and coupling to form T3 and T4. Propylthiouracil also inhibits peripheral conversion of T4 to T3. They also have a mild immunosuppressive effect in Graves disease.

Pharmacokinetics. Methimazole has a plasma half-life of 4 to 6 hours but long intrathyroidal action, so once daily dosing works. Propylthiouracil half-life is 1 to 2 hours, is heavily protein bound, and is given 2 to 3 times daily. Biochemical response takes 4 to 8 weeks.

Differences. Methimazole and carbimazole are preferred in most patients: once daily dosing, and less hepatotoxicity. Propylthiouracil carries a boxed warning for liver failure and is reserved for thyroid storm, the first trimester of pregnancy and intolerance of the other agents. Methimazole dose-related adverse effects are more common.

• Titration regimen: start at the usual doses in the table, reduce when free T4 normalises (4 to 6 weeks), and continue for 12 to 18 months.
• Block and replace: carbimazole 40 mg daily (or methimazole equivalent) with levothyroxine 50 to 150 micrograms daily for 6 months. This needs fewer visits but has a higher rate of adverse effects.
• Remission predictors: small goitre, mild disease, low TRAb at the end of treatment. Continue for longer or choose definitive therapy if TRAb remains high.
• Cross-reaction: a patient who develops agranulocytosis or severe reaction on one thionamide should not be switched to another.
• Pregnancy: propylthiouracil in the first trimester (carbimazole and methimazole cause embryopathy, including choanal atresia and aplasia cutis), then change to carbimazole or methimazole from the second trimester.
• Thyroid storm: propylthiouracil 500 to 1000 mg loading then 250 mg every 4 hours, or methimazole 60 to 80 mg daily.

Special groups. Breastfeeding: methimazole up to 20 to 30 mg daily and propylthiouracil up to 300 mg daily are acceptable. Children: methimazole 0.2 to 0.5 mg/kg daily, with propylthiouracil avoided. Older adults: usual doses, with early consideration of definitive therapy. Kidney impairment: no adjustment. Liver impairment: avoid propylthiouracil; use methimazole with close liver tests.

Adverse effects. Rash, urticaria and arthralgia (about 5%), agranulocytosis (0.2 to 0.5%, usually in the first 3 months), cholestatic hepatitis with methimazole, acute hepatocellular failure with propylthiouracil, ANCA-associated vasculitis with propylthiouracil, and altered taste.

Action thresholds. Stop for neutrophils under 1.0 x 10^9/L, jaundice, dark urine, or vasculitic symptoms. Do not rechallenge after agranulocytosis.

Interactions. Vitamin K antagonist and digoxin requirements change on becoming euthyroid. Iodine contrast and amiodarone alter response.

Monitoring. Baseline FBC, liver enzymes and TRAb; free T4 and T3 every 4 to 6 weeks until stable; every 3 to 4 months thereafter; liver enzymes with propylthiouracil every 2 to 4 weeks initially; FBC if symptoms of infection.

Referral and escalation. Agranulocytosis or severe hepatic reaction (emergency), pregnancy, relapse after a full course, orbitopathy, or need for definitive therapy.