Propylthiouracil

Propylthiouracil is an oral thionamide antithyroid medicine reserved for first-trimester pregnancy, thyroid storm, and patients who react to methimazole without having had a severe reaction. It blocks thyroid hormone synthesis and also reduces peripheral conversion of T4 to T3, which helps in storm. It needs dosing two or three times daily and carries a risk of severe liver injury, so it is not a first-line drug outside these uses.

Classification. Thionamide antithyroid agent. Tablets 50 mg and 100 mg (strengths vary by market).

Mechanism. Inhibits thyroid peroxidase, blocking iodination of tyrosine and coupling to form T3 and T4. At high doses it inhibits type 1 deiodinase, lowering T3 formation in tissues.

Pharmacodynamics. Free T4 falls within 2 to 4 weeks and the euthyroid state is reached at 6 to 8 weeks. Free T3 falls faster than with methimazole.

Pharmacokinetics. Bioavailability about 75%; 80 to 85% protein bound, so less crosses the placenta than methimazole. Half-life 1 to 2 hours, hence more frequent dosing. Metabolised in the liver by glucuronidation; excreted in urine.

Graves' disease and toxic nodular goitre, adults (second line, or first line in the first trimester).

• Initial dose 100 mg orally three times daily (300 mg daily); up to 150 mg three times daily in severe disease. Maximum 600 mg daily.
• Continue for 4 to 8 weeks until free T4 is normal, then reduce by 50 mg daily every 4 to 6 weeks to a maintenance of 50 mg two or three times daily.
• Equivalence: propylthiouracil 100 mg is about methimazole 5 to 10 mg.

Pregnancy, first trimester.

• Propylthiouracil 100 to 300 mg daily in 2 or 3 divided doses, with the lowest dose that keeps free T4 at the upper end of the reference range, checked every 2 to 4 weeks. At the start of the second trimester change to methimazole at the equivalent dose (propylthiouracil 100 mg to methimazole 5 to 10 mg), or continue propylthiouracil if liver risk is accepted.

Thyroid storm (emergency, critical care).

• Propylthiouracil 500 to 1000 mg orally or by nasogastric tube as a loading dose, then 250 mg every 4 hours (about 1000 to 1500 mg daily). Give potassium iodide or iodine solution at least 1 hour after the first dose, with a beta-blocker, a corticosteroid and supportive care.

Preparation for thyroidectomy or radioactive iodine (specialist).

• 100 mg three times daily until euthyroid, with a beta-blocker. For radioactive iodine, stop 5 to 7 days beforehand.

Children.

• Not advised because of severe liver failure; use only if methimazole cannot be used, at 5 to 7 mg/kg daily in 3 divided doses, directed by a paediatric endocrinologist.

Adjustments.

• Kidney: no change.
• Liver: avoid in liver disease; stop for any liver injury.
• Older adults: no change.
• Weight: dose by weight in children.

Contraindications. Previous severe reaction to propylthiouracil, methimazole or carbimazole; severe liver disease; children where methimazole is possible.

Major warnings.

• Severe liver injury and acute liver failure (about 1 in 10 000 adults, higher in children), sometimes needing transplant; can occur any time in the first 6 months and is unpredictable. Stop at once for jaundice, dark urine, pale stools, abdominal pain, anorexia or vomiting.
• Agranulocytosis (about 0.2 to 0.5%), usually in the first 3 months. Every patient is told to stop the drug and seek an urgent full blood count for sore throat, fever or mouth ulcers.
• Vasculitis, especially antineutrophil cytoplasmic antibody-positive disease with renal or lung involvement, more often than with methimazole.
• Teratogenicity is less than with methimazole, but a risk of malformations remains in the first trimester.

Other adverse effects. Rash, urticaria, arthralgia, fever, nausea, taste disturbance, hypothyroidism from over-treatment, hypoprothrombinaemia.

Major interactions.

• Warfarin: response falls as hyperthyroidism is corrected; propylthiouracil may also lower prothrombin; monitor INR.
• Digoxin levels rise as the patient becomes euthyroid.
• Beta-blocker and theophylline clearance fall as patients become euthyroid.
• Other drugs that suppress bone marrow or harm the liver: added risk.
• Iodine contrast and amiodarone alter response.

Special groups.

• Pregnancy: preferred in the first trimester; switch after the first trimester when liver risk makes this reasonable. Advise effective contraception in women of childbearing age.
• Breastfeeding: compatible at doses up to 300 mg daily, given in divided doses after feeds; monitor the infant for liver or blood signs.
• Children: avoid because of severe liver failure; use only if methimazole cannot be used.
• Older adults: lower doses; check for atrial fibrillation.
• Kidney impairment: no change; liver impairment: avoid.
• East Africa: often the only thionamide available in smaller facilities, so patients may be on it long term; counsel to stop it and return at once for yellow eyes, dark urine or fever, and arrange liver tests where possible.

Formulation and administration. Swallow tablets with water, two or three times daily at regular intervals, with or without food, in a consistent relation to meals.

Baseline. Full blood count with white cell differential, liver function tests (aminotransferases, bilirubin), TSH, free T4 and free T3, pregnancy test in women of childbearing age.

Monitoring.

• Free T4, free T3 and TSH every 4 to 6 weeks until stable, then every 2 to 3 months; adjust by free T4.
• Liver tests every 2 to 4 weeks for the first 6 months and with any symptom.
• Full blood count with any infection symptoms; routine counts do not predict agranulocytosis.
• Pregnancy test before starting and with any missed period.

Dose reduction and stopping. Reduce the dose once free T4 is normal. Stop with liver injury (aminotransferases over 3 times the upper limit, or any jaundice), agranulocytosis (neutrophils under 1.0 x 10^9/L), vasculitis, severe rash or at the end of the planned course. After liver injury never restart any thionamide.

Referral and escalation. Admit suspected liver failure, agranulocytosis or thyroid storm. Refer to endocrinology all pregnancy, children, relapse after a course, thyroid eye disease and any adverse reaction.