Anti-thyroid Drugs

Carbimazole and propylthiouracil inhibit synthesis of iodothyronine and thyroxine and are used in the treatment of hyperthyroidism.¹ The most commonly used antithyroid drug in the UK is carbimazole (its metabolite, methimazole, is used in Europe and North America) followed by propylthiouracil.

All people with hyperthyroidism should be referred to an endocrinologist:²

• If the person has no features of hyperthyroidism, treatment does not need to be initiated in primary care (can wait until patient seen by endocrinologist).
• If the person has features of hyperthyroidism, treatment may be initiated in primary care while waiting for the specialist assessment:
• Beta-blockers (propranolol 40mg three times a day) are first choice unless contraindicated. They reduce the risk of tachyarrhythmias and give symptomatic relief, e.g. for anxiety and tremor.
• Antithyroid drugs (carbimazole 20mg once a day) may be initiated at a low dose in primary care (only following discussion with an endocrinologist):
  • If beta-blockers are contraindicated.
  • In addition to beta-blockers if features of hyperthyroidism are marked.
• Treatment for pregnant or breastfeeding women, and for children should only be initiated by a specialist.

• Compliance is better with carbimazole because it is given once daily, whereas propylthiouracil needs to be given more frequently. Therefore carbimazole is preferred to propylthiouracil for most patients.
• Propylthiouracil also blocks peripheral conversion of thyroxine to tri-iodothyronine, which might make it the preferred drug in severe thyrotoxicosis or hyperthyroid storm.³
• Intolerance to carbimazole is an indication for using propylthiouracil, but there is a small degree of cross sensitivity.
• Pregnancy: both carbimazole and propylthiouracil cross the placenta. The lowest dose to control hyperthyroidism should be used. The required dosage for Graves' disease tends to fall during pregnancy.
• It is best to give propylthiouracil rather than carbimazole during breastfeeding because propylthiouracil is excreted in the milk to a lesser extent.

• Thyrotoxicosis - Carbimazole is effective as long term treatment in thyrotoxicosis or as preparation for surgical or radioactive iodine ablative therapy.
• Graves' disease - Antithyroid drugs are usually the treatment of choice for young people with this condition. Antithyroid drugs have no influence on the natural history of hyperthyroidism in Graves' disease.

Carbimazole is given for an arbitrary period of 18-24 months to identify people destined to have a single episode of hyperthyroidism, and who will remain in remission after the drug is stopped.

• Most patients feel better after 10-14 days and will be euthyroid at four to six weeks.
• Even after an 18 month course of antithyroid drugs, more than 50% of patients will relapse. Most of these will relapse in the first one or two years.

• Adverse effects occur in up to 7% of patients and usually present in the first 2 months of treatment. They are usually limited to minor adverse effects which include pruritus, urticarial or maculopapular rash, arthralgia, headache, GI upset or altered taste.
• The most serious complication of treatment is agranulocytosis, which occurs in 1 in 300-500 people and develops rapidly.
• Fever and arthralgias are minor side-effects but should prompt discontinuation of the drug since they might be indicative of more severe immunological side-effects.³

• Aplastic anaemia
• Thrombocytopenia
• Hepatitis (propylthiouracil)
• Cholestatic jaundice (carbimazole)
• SLE-like syndrome
• Hypoglycaemia (due to insulin antibodies, and seen most often in Japanese patients)

See individual drugs.

Antithyroid drugs can be given in two ways:

Titration

• Carbimazole is usually started in a dose of 10mg twice or three times daily initially (depending on the weight of patient) and then adjusted or stepped down according to clinical response and TFT results. TFT's usually normalize in a few weeks to months.
• TFT's are repeated every month and the dose altered according to the T4 level. TSH may remain suppressed for months despite the T4 coming into the normal range and is thus, unreliable.
• Once the patient is euthyroid the dose of carbimazole is reduced until the patient is on the lowest amount necessary to maintain the T4 and T3 within the normal range.
• Remission is usually achieved after 18-24 months. Attempts may then be made to stop carbimazole but continued monitoring for recurrence is required.

Block-replace regimens

• Fluctuation of thyroid hormone levels is much less of a problem than with the titration method. The same starting dosage of carbimazole or propylthiouracil is given but then levothyroxine is added to maintain euthyroidism.
• Levothyroxine 100 micrograms is usually needed around four weeks after starting the antithyroid drug when free T4 levels are near normal range.
• The dose of levothyroxine is adjusted based on free T4 levels, but the dose of antithyroid drug remains constant, usually 40mg daily for carbimazole.
• The six month Block-Replace regimen has been found to be as effective as 12 months of treatment.⁵
• The titration regimen must be continued for 18-24 months to achieve a remission rate of 40-50%. The same remission rate is achieved using the block-replace regimen for six months.
• Unless there is frequent monitoring of thyroid-hormone levels with the titration regimen, fluctuation of thyroid hormone levels is likely, but this is much less of a problem with the block-replace regimen.
• The Titration regime has fewer adverse effects than the Block-Replace regime.⁵

Continued thyroxine treatment following initial antithyroid therapy does not appear to provide any benefit in terms of recurrence of hyperthyroidism.⁵