Carbimazole and the Thioamide/Thioureylene family

The antithyroidal drugs Carbimazole, Methimazole and Propylthiouracil all contain a thioamide group which is essential for antithyroid action.

Carbimazole, which is converted to Methimazole in the body is widely used in the UK.

[Treatment]

Action

• Decreases output of thyroid hormones from thyroid leading to a gradual reduction in symptoms.

• BMR and pulse rate return to normal over 3-4 weeks as stores of hormones must be used up first.
• Prevent hormone synthesis by blocking thyroid peroxidase catalysed reactions, hence I2 and thyroglobulin do not complex and MIT and DIT are not formed.
• They also block the coupling of iodotyrosines.
• Propylthiouracil also reduces the de-iodination of T4 to T3. Methimazole does this to a much lesser extent.
• There is little evidence that the bulging eyes typified by Grave's disease are cured by Thioamides.

Pharmokinetics

• All thioamides are taken orally.

Carbimazole and Methimazole

• Carbimazole is rapidly converted to Methimazole, which is pharmacologically active.
  • Methimazole is distributed throughout the body water and has a plasma half life of 6-15 hours, there is concentration in the thyroid.
• Most is absorbed into the body but the time taken to be absorbed is variable.
• 65-70% is excreted in 48 Hours
• Despite the short plasma half life only small doses need be given as the drug accumulates in the thyroid.
  • A single 30-40 mg dose can exert an antithyroid effect for 24 hours. Thus in mild to moderate cases a single daily dose may be taken.
  • 3-4 Weeks are required for the drug to take effect as the thyroid may have large stores of hormone which must be depleted.

Propylthiouracil

• Propylthiouracil is rapidly absorbed, reaching peak levels after about 1 hour.

• About 50-80% are available for use in the body due to incomplete absorption and break down by the liver.
• There is, again, some accumulation in the thyroid.
• Most of the ingested dose is excreted by the kidneys in 24 hours as inactive glucuronide.
• Propylthiouracil may acts more rapidly as it inhibits conversion of T4 to T3.
  • As a single 100 mg dose can inhibit 60% of iodine complexation for 7 hours the drug can be taken at six hourly intervals.

Typical treatment pattern

• Initially a large dose of Propylthiouracil is administered. This will be 100-150 mg every six hours. This is used in preference to Methimazole as it has a faster antithyroidal effect.
• On responding to this treatment the dose ill be reduced. Often the patient is placed on 30-40 mg of Methimazole daily. Methimazole is preferred as is exerts its effect for a longer time than Propylthiouracil.
• Once the condition is under control the dose will be reduced to a maintenance dose of 5-15 mg of Methimazole. It is at this point that the side effects become rare and the immune system can recover.
• If at anytime the immune system becomes compromised treatment is stopped and antibiotics administered.

Toxicity

• All thioamides cross the Placental barrier and appear in the milk. They are concentrated by the foetal thyroid.
• Propylthiouracil is the preferred drug as this is more strongly bound to plasma protein and thus crosses the placenta less readily. It is also not secreted in sufficient quantities to rule out breast feeding.

• Adverse reactions occur in 3-12% of patients, normally early on in the treatment.
• Most commonly a maculopapular pruritic rash (coloured, raised patches, itchy) and possibly fever
• More rare adverse reactions are:
  • Urticarial rash (itchy rash with individual swellings that rapidly appear and disappear)
  • Vasculitis (Patchy inflammation of the walls of a blood vessel. Can lead to skin rashes, arthritis, pupura and kidney failure.)
  • Arthralgia (pain in joint with no sign of swelling).
  • Lupus like reaction (red scaly rash caused by inflammation of connective tissue).
    • Cholestatic jaundice (failure of normal amounts of bile to reach the intestine resulting in obstructive jaundice. Causes dark urine, pale faeces, and usually itching).
    • Hypoprothrombinemia (reduction in clotting factor prothrombin in blood resulting in an increased tendency to bleed).
  • Lymphadenopathy (Diseased lymph nodes)
  • Polyserositis (Inflammation of the membranes that line the chest, abdomen and joint with the accumulation of fluids in the cavities. If complicated by the infiltration of major organs by a glycoprotein the disease usually proves fatal).
• The most serious complication is agranulocytosis, this is the acute shortage of eosinophils. It occurs in 0.3-0.6% of patients. The risk is increased in those over 40, and those on high doses of Methimazole. The result is normally reversed soon after ceasing to take the drug. Antibiotic treatment may be necessary to treat resultant infections. There is a 50 % cross sensitivity between Methimazole and Propylthiouracil; thus switching drugs is not recommended.

© 1996 Iain Chambers