THYROCAB

(Carbimazole)

Carbimazole, the therapeutic action, resides in the active metabolite, Methimazole

Chemistry :

Carbimazole

C7H10N2O2S

2,3-Dihydro-3-methyl-2-thioxo-1H-imidazole-1-carboxylic acid ethyl ester

DIAGRAM

Pharmacology

Carbimazole anti-thyroid action depends entirely on conversion to Methimazole. After absorption Carbimazole is rapidly hydrolyzed and decarboxylated enzymatically in the blood stream to hits active metabolite, Methimazole.

Thyroid hormone synthesis

Thyroid gland absorbs iodide ions from the blood

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In the thyroid, iodide ions are converted to iodine by oxidation

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Tyrosine (from the thyroid gland) combines with iodine

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Formation at monoiodotyrosine (MIT and diiodotyrosine (DIT)

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Two DIT molecules combine to form T4 (Thyroxine)

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One DIT molecule and one MIT molecule combines to form T3 (Triiodothyronine)

� Methimazole interferes with thyroid hormone synthesis by inhibiting the incorporation of oxidized iodide into tyrosine residues in thyroglobulin.

� There is also evidence for blocking of the coupling reaction in which the mono- and diiodotyrosine are linked to form thyroid hormones.

� Methimazole may also have an immunosuppressive action through inhibition of the production of oxygen radicals in monocytes and reduction of antigen presentation to the antibody-producing lymphocytes. This influence is manifest in vivo by a reduction in circulating levels of anti-thyroglobulin and anti-TSH receptor antibodies.

� Unlike Propylthiouracil, Methimazole does not influence the peripheral conversion of thyroxine (T4) to triiodothyronine (T3).

Toxicology

Carbimazole does not have mutagenic potential and there is no evidence of carcinogenicity.

Clinical pharmacology

In the majority of patients presenting with hyperthyroidism, thyroid hormone levels are restored to normal after 3 4 weeks of treatment with carbimazole in a total daily dose of 10 30 mg.

Pharmacokinetics

The absorption of oral carbimazole is rapid and virtually complete but, in view of its rapid conversion to the active metabolite Methimazole, pharmacokinetic studies have been based on the measurement of Methimazole by HPLC. Peak levels of Methimazole of 0.2 1.0 µmol.occur 12 hr after 60 mg carbimazole orally. Plasma half-life is approximately 5 hr and is unaffected by thyroid status but is prolonged in both hepatic and renal disease. It has been suggested that in renal impairment the dose of carbimazole should be reduced, by 25% in patients with a GFR of 10 50 ml/min and by 50% when GFR is less than 10ml./min

Metabolism

Over 90% of orally administered carbimazole is excreted in the urine as either Methimazole or its metabolites, the remainder appearing in feces. There is 10% enterohepatic circulation. The metabolism of Methimazole is poorly understood but there is evidence that both the liver and thyroid are capable of oxidizing the drug to 3-methyl-2

Therapeutic use

Thyrocab is mainly used in:

1. Long-term control of hyperthyroidism of Graves' disease

2. Preparation of patients with hyperthyroidism for iodine-131 therapy or surgery

Temporary control of hyperthyroidism after iodine-131 therapy.

Indications:

1. Long-term control of hyperthyroidism of Graves' disease

The natural history of the hyperthyroidism of Graves' disease, the immunologically mediated form of hyperthyroidism, takes one of two forms.

• In about 70% there is a relapsing and remitting illness over many years with episodes of hyperthyroidism lasting several months.

• In the remainder, there is a single episode of hyperthyroidism lasting about 6 12 months followed by prolonged remission, although late relapse in this group after many years of euthyroidism is well recognized.

Current practice is to prescribe an anti-thyroid drug for 12 24 months. It follows that drug withdrawal will be associated with relapse of hyperthyroidism in the majority of patients, usually within the first year. Recurrent hyperthyroidism is normally an indication for iodine-131.

2. Preparation of patients with hyperthyroidism for iodine-131 surgery

It is well recognized that both iodine-131 therapy and partial thyroidectomy

may result in temporary exacerbation of hyperthyroidism arid are, therefore, associated with a small but finite risk of thyrotoxic crisis, especially in the elderly and in those with severe untreated disease.

Carbimazole may be prescribed at standard doses for a period of 6 weeks or until euthyroidism has been restored in patients due to undergo definite therapy, in order to lessen this risk. The use of a β-adrenoceptor antagonist alone or in combination with potassium iodide has also been successfully used as preparation for partial thyroidectomy.

3. Temporary control of hyperthyroidism after iodine. 131 therapy.

There is a delay of 6 8 weeks before hyperthyroidism is controlled by therapeutic iodine-131. If the thyrotoxicosis is of severe degree, symptoms are unlikely to be adequately controlled in the interim by a β-adrenoceptor antagonist. Carbimazole can be given in a dose of 10 30 mg daily, either as a single dose or in divided dosage, for-a period of 6 weeks starting a minimum of 48 h after the administration of the isotope.

Dosage:

Carbimazole is effective in the majority of patients if given as a single daily dose. The usual starting dose is 15 30mg daily for 4 to 6 weeks, reducing

at intervals of 4 to 6 weeks to a maintenance dose of 5 10 mg daily after approximately 3 months.

Reductions in dose are dictated by clinical response and by results of thyroid function tests. Serum thyroid hormone (thyroxine and triiodothyronine) and TSH should be measured at each review visit, every 6 8 weeks, and dosage adjusted to maintain levels in their respective normal ranges.

Block therapy

Treatment with carbimazole in a dose of 30 45 mg daily and after 4 weeks, when the patient is euthyroid, to continue the high dose, which effectively blocks thyroid hormone synthesis, but with the addition of replacement dosages of thyroxine (150 200 µg daily) or triiodothyronine (20 µg twice or three times daily). The advantage claimed for this regimen of less frequent review (i.e. every 3 6 months) is probably outweighed by poorer compliance when two drugs rather than one are prescribed.

Contraindications

1. Transient destructive forms of hyperthyroidism

In both sub-acute thyroiditis and post-partum painless thyroiditis, the hyperthyroidism is caused by the release of preformed thyroid hormones and is associated with a negligible iodine uptake. Carbimazole and related drugs are, therefore, ineffective. Fortunately, the hyperthyroidism is mild and transient, lasting 6 12 weeks, and can be controlled with β-adrenoceptor antagonists alone.

2. Hyperthyroidism resulting from nodular goiter

Unlike Graves' disease, the hyperthyroidism of nodular goiter is almost invariably permanent. Although carbimazole will control hyperthyroidism in the short term, relapse is inevitable after drug withdrawal. The most appropriate treatment is either iodine-131 or surgery.

Adverse reactions:

Potentially life-threatening effects

• The most serious adverse reaction is agranulocytosis which develops in 0.5% of patients treated with carbimazole.

Severe or irreversible adverse effects

� Rare: Cholestatic jaundice without evidence of hepatic necrosis, vasculitis and a Lupus like syndrome, nephrotic syndrome

Common adverse effect:

The most common are nausea, loss of taste, headache, Arthalgia, hair loss and skin rash. Adverse reaction may be self- limiting and do not necessarily require withdrawal of the drug.

Drug Interactions :

Increases sensitivity to warfarin has been observed in hyperthyroidism and careful control of dosage is required as the patient is rendered euthyroid.

Shelf life

Carbimazole tablets should be stored at room temperature. They are stable at a normal room temperature with a shelf life of 2 years.

Pack :

5 mg Bottle of 100 tablets

10 & 20 mg Bottle of 60 tablets.