Antithyroid Drugs - Endocrinal Drug

Antithyroid Drugs

Thioureylenes

The thioureylenes are compounds belonging to the family of thioamides, and the most important representative of the group is propylthiouracil (PTU). Other examples include methima-zole and carbimazole, which are organic thiourea antithyroid drugs included in the chemical class of mercaptoimidazolines. Carbimazole is a prodrug of methimazole. Carbimazole is rapidly and completely metabolised to methimazole in the body, with the antithyroid activity of carbimazole dependant upon this conversion to methimazole.

Antithyroid drugs inhibit the formation of thyroid hormones by interfering with the incorporation of iodine into tyrosyl resi-dues of thyroglobulin. They also inhibit the coupling of these iodotyrosyl residues to form iodothyronines by inhibiting the peroxidase enzyme.

In addition to blocking hormone synthesis, propylthiouracil (unlike other antithyroid drugs) inhibits the peripheral deiodin-ation of thyroxine to tri-iodothyronine.

Propylthiouracil, carbimazole, and methimazole are used in the management of hyperthyroidism including the treatment of Graves’ disease, thyroid storm, and in preparing individuals for thyroidectomy and as an adjunct to radioiodine therapy.

Adverse Effects

·              Agranulocytosis: Chronic ingestion of PTU, carbimazole, or methimazole has been reported to cause leukopenia, agranulocytosis, aplastic anaemia, eosinophilia, leukaemia, thrombocytopenia and hypoprothrombinaemia.

·              Hepatotoxicity: Chronic ingestion of PTU produces a characteristic hepatocellular or mixed cytotoxic-cholestatic hepatitis, believed to be a hypersensitivity reaction.

·              Arthralgia: Arthritis syndrome, which is rare, is generally transient, occurring within 2 months of initiation of therapy and resolving within 4 weeks of stopping therapy.

·              Following therapeutic use of carbimazole or methimazole, dizziness, paresthesias, and headache have been described occasionally.

·              Skin rashes may occur secondary to haematologic toxicity during chronic therapy.

·              Gastric upsets.

·              Methimazole therapy has uncommonly been reported to be related to the occurrence of T-lymphotropic virus type I-associated uveitis, with vitreous opacities and retinal vasculitis. The exact mechanism of this adverse reaction is unknown.

·              Reversible nephrotic syndrome has been observed in a very few patients during therapy with methimazole or carbimazole. It is likely that this is the result of a direct toxic effect on the glomerular basement membrane and epithelial podocytes.

·              Carbimazole hypersensitivity resulting in the development of antibodies to connective tissue or neural antigens in the cochlea has been reported. Hearing loss and tinnitus resulted.

Toxic Effects

·              Vomiting, headache, fever, arthralgia, pruritis and pancy- topenia.

·              Clinical signs/symptoms of overdose with carbimazole or methimazole may include manifestations of hypothy- roidism, including nausea and vomiting, constipation, headache, drowsiness, coldness, dry and puffy skin, muscle aches, and goitre. CNS depression and/or stimulation may occur. Hypothyroidism is unlikely to develop after a single acute overdose ingestion. Less frequently, overdose may result in hepatic enzyme changes or neuropathies.

·              Very little data are available on the effects of acute over- dose with propylthiouracil. Decreased T3 and elevated alkaline phosphatase levels were the only effects seen after a massive overdose in a young girl.

·              Chronic overdose may result in clinical hypothyroidism (nausea and vomiting, constipation, headache, drowsiness, coldness, dry and puffy skin, muscle aches). Propylthiouracil is transferred across the placenta and can induce goitre and hypothyroidism in the unborn. Hyperthyroidism may also occur as a compensatory mechanism. Infants of women with Graves’ disease who were treated with propylthiouracil may be either hypothyroid or hyperthyroid.

·              The administration of propylthiouracil to the mother from the 14th week of pregnancy or later has been of concern because of the possible development of goitre and mental retardation in the infant. Incidence of birth defects was not significantly higher in children of women who had been treated with propylthiouracil during pregnancy.

·              Methimazole crosses the placental membrane readily and can induce goitre and cretinism in the developing foetus. Congenital defects such as aplasia cutis (manifested by scalp defects), oesophageal atresia with tracheoesophageal fistula, and choanal atresia with absent/hypoplastic nipples have occurred rarely in infants exposed to methimazole in utero. Chronic ingestion of PTU, carbimazole or methimazole can result in a variety of immunologic-mediated adverse effects which are not expected to occur in overdose, including agranulocytosis, aplastic anaemia, vasculitis, lupus-like syndrome, and hepatitis. Fatal hepatic necrosis has been reported. Most adverse effects are dose-related and occur within the first 4 to 8 weeks of therapy.

·              Chronic propylthiouracil use has been linked with acute myeloblastic leukaemia in isolated cases.

Treatment

·              Symptomatic and supportive measures.

·              Alkaline phosphatase levels have been elevated in overdose cases involving PTU. Isoenzyme determination is recom- mended. Elevations in alkaline phosphatase do not neces- sarily reflect liver toxicity and may be related to increased bone or bile isoenzyme.

·              Monitor thyroid function tests and liver function in symp- tomatic patients.

·              Total and differential leukocyte counts should be performed in patients with suspected haematologic reactions. Agranulocytosis is usually reversible on discontinua-tion of therapy. Administration of recombinant humangranulocyte colony-stimulating factor may hasten recovery.Granulocyte-macrophage colony-stimulating factor(GM-CSF) and granulocyte colony-stimulating factor(G-CSF), or filgrastim, may be effective in acceleratingbone marrow recovery after carbimazole or methimazole therapy. Erythrocyte and platelet transfusions may be necessary. Treatment with these drugs has been shownto significantly shorten recovery time in patients withmethimazole-induced agranulocytosis.

·              Infection or fever in neutropenic patients should be treated aggressively with antibiotics. Cultures and sensitivities should be done. Appropriate broad-spectrum antibiotics should probably be initiated before culture results are  known. Adjust antibiotic regimen based on culture results.

·              Haemodialysis, peritoneal dialysis, forced diuresis, or char- coal haemoperfusion have not been shown to be beneficial  in overdose with these agents.known. Adjust antibiotic regimen based on culture results.