Benzylthiouracil/Carbimazole 2167 36. Masiukiewicz US, Burrow GN. Hyperthyroidism in pregnancy: ment if TSH levels are between 5 and 10 milliunits/litre Porphyria. Benzylthiouracil is considered to be unsafe in pa- diagnosis and treatment. Thyroid 1999; 9: 647–52. and goitre or antibodies (or both) are evident.7 tients with porphyria although there is conflicting experimental 37. Ogilvy-Stuart AL. Neonatal thyroid disorders. Arch Dis Child evidence of porphyrinogenicity. Fetal Neonatal Ed 2002; 87: F165–F171. Although titres of antithyroid antibodies may fall during 38. Char DH. Thyroid eye disease. Br J Ophthalmol 1996; 80: pregnancy, some patients may require progressive Preparations 922–6. 9,10 39. Fleck BW, Toft AD. Graves’ ophthalmopathy. BMJ 1990; 300: increases in levothyroxine dosage, and therefore it has Proprietary Preparations (details are given in Part 3) 1352–3. been recommended that thyroid function tests should be Fr.: Basdene. 40. Hart RH, Perros P. Glucocorticoids in the medical management performed in each trimester;1,2,4,11 some7,12 currently ad- of Graves’ ophthalmopathy. Minerva Endocrinol 2003; 28: 223–31. vocate monitoring every 6 to 8 weeks. The diagnosis of congenital hypothyroidism (neonatal Carbimazole (BAN, rINN) hypothyroidism) is now most commonly made on the ba- Hypothyroidism sis of screening programmes.13 Early treatment with ade- Carbimazol; Carbimazolum; Karbimatsoli; Karbimazol; Karbima- Hypothyroidism is the clinical syndrome resulting from quate doses of levothyroxine is required to minimise the zolas. Ethyl 3-methyl-2-thioxo-4-imidazoline-1-carboxylate. deficiency of thyroid hormones. It mainly affects women effects of hypothyroidism on mental and physical develop- Карбимазол and is more prevalent in the middle-aged and elderly. The ment. It should be started as soon as possible after birth and C7H10N2O2S = 186.2. symptoms of hypothyroidism may be due to general decel- should be reviewed regularly.13,14 However, it is generally CAS — 22232-54-8. eration of metabolism or to accumulation of mucopolysac- accepted that in those with more severe hypothyroidism at ATC — H03BB01. charide in the subcutaneous tissues and vocal cords. Com- diagnosis some small degree of deficit and incoordination ATC Vet — QH03BB01. mon clinical manifestations include weakness, fatigue, remains, although they should be mild enough to permit a lethargy, physical and mental slowness, and weight gain; normal life.15 puffy, nonpitted swelling of subcutaneous tissue often de- velops, particularly around the eyes. Menstrual disorders, Hypothyroid (myxoedema) coma is a medical emergen- N N O hyperlipidaemia, and constipation can occur and goitre cy requiring prompt treatment usually with liothyronine CH3 may develop despite associated cell destruction. given by intravenous injection because of its rapid action, H3C The term myxoedema is often reserved for severe or ad- although some centres use intravenous levothyroxine. Al- S O vanced hypothyroidism. In the most severely affected pa- ternatively, the nasogastric route may be used. Other treat- tients, progressive somnolence and torpor combine with ment includes intravenous hydrocortisone (because of the Pharmacopoeias. In Chin. and Eur. (see p.vii). cold intolerance and bradycardia to induce a state of coma likelihood of adrenocortical insufficiency) and intrave- Ph. Eur. 6.2 (Carbimazole). A white or yellowish-white crystal- nous fluids (to maintain plasma-glucose and electrolyte line powder. Slightly soluble in water; soluble in alcohol and in often known as ‘hypothyroid’ or ‘myxoedema coma’ (see acetone. below). concentrations). Respiratory function should be supported by assisted ventilation and oxygen. Hypothyroid coma In children, untreated hypothyroidism results in retarda- carries a poor prognosis, with mortality around 50% even Adverse Effects and Precautions tion of growth and mental development. Endemic cretin- with treatment. Adverse effects from carbimazole and other thiourea ism is a result of maternal, and hence fetal, iodine deficien- 1. Singer PA, et al. Treatment guidelines for patients with hyper- antithyroid drugs occur most frequently during the first cy and consequent lack of thyroid hormone production thyroidism and hypothyroidism. JAMA 1995; 273: 808–12. (see Iodine Deficiency Disorders, p.2170). Also available at: http://www.thyroid.org/professionals/ 8 weeks of treatment. The most common minor ad- publications/documents/GuidelinesHyperHypo_1995.pdf (ac- verse effects are nausea and vomiting, gastric discom- Hypothyroidism is usually primary, resulting from mal- cessed 18/05/05) fort, headache, arthralgia, skin rashes, and pruritus. function of the thyroid gland. In areas where iodine intake 2. Lindsay RS, Toft AD. Hypothyroidism. Lancet 1997; 349: is sufficient the commonest cause of hypothyroidism is 413–17. Correction. ibid.; 1023. Hair loss has also been reported. 3. Woeber KA. Update on the management of hyperthyroidism auto-immune lymphocytic thyroiditis of which there are and hypothyroidism. Arch Intern Med 2000; 160: 1067–71. Bone-marrow depression may occur and mild leucope- two major variants. In Hashimoto’s thyroiditis there is 4. Vanderpump MPJ, et al. Consensus statement for good practice nia is common. Rarely, agranulocytosis can develop, also goitre whereas in idiopathic or primary myxoede- and audit measures in the management of hypothyroidism and and is the most serious adverse reaction associated ma (atrophic thyroiditis) there is no thyroid enlargement. hyperthyroidism. BMJ 1996; 313: 539–44. 5. Toft AD. Thyroxine therapy. N Engl J Med 1994; 331: 174–80. with this class of drugs. Patients or their carers should Hypothyroidism can also be caused by either an excess or 6. Roberts CGP, Ladenson PW. Hypothyroidism. Lancet 2004; be told how to recognise such toxicity and should be a deficiency of iodine. An excess may result from intake of 363: 793–803. iodine or its salts or iodine-containing drugs such as amio- 7. AACE Thyroid Task Force. American Association of Clinical advised to seek immediate medical attention if mouth Endocrinologists medical guidelines for clinical practice for the ulcers or sore throat, fever, bruising, malaise, or non- darone. Drugs that decrease thyroid hormone synthesis evaluation and treatment of hyperthyroidism and hypothy- such as lithium can also be a cause of hypothyroidism. In roidism. Endocr Pract 2002; 8: 457–69. Also available at: specific illness develop. Full blood counts should be some patients hypothyroidism may be secondary to disor- http://www.aace.com/pub/pdf/guidelines/hypo_hyper.pdf (ac- performed, and treatment should be stopped immedi- cessed 07/04/06) ders of the hypothalamus or pituitary gland. 8. Surks MI, et al. Subclinical thyroid disease: scientific review ately if there is any clinical or laboratory evidence of The diagnosis of hypothyroidism is essentially clinical and guidelines for diagnosis and management. JAMA 2004; neutropenia. Aplastic anaemia or isolated thrombocy- but, given the non-specific nature of many of the symp- 291: 228–38. topenia have been reported rarely, as has hypopro- 1-3 9. Drake WM, Wood DF. Thyroid disease in pregnancy. Postgrad toms, biochemical tests are performed for confirmation. Med J 1998; 74: 583–6. thrombinaemia. A raised thyroid stimulating hormone (TSH) value and a 10. Alexander EK, et al. Timing and magnitude of increases in lev- There have been several reports of liver damage, most low free T or T concentration indicates primary hypothy- othyroxine requirements during pregnancy in women with hy- 4 3 pothyroidism. N Engl J Med 2004; 351: 241–9. commonly jaundice, in patients taking thiourea roidism. Protirelin and thyrotrophin have also been used 11. Girling JC. Thyroid disease in pregnancy. Hosp Med 2000; 61: antithyroid drugs; the drug should be withdrawn if for the differential diagnosis of hypothyroidism. 834–40. 12. Surks MI, et al. Subclinical thyroid disease: scientific review hepatic effects occur. Subclinical hypothyroidism is a condition in which there and guidelines for diagnosis and management. JAMA 2004; are normal concentrations of thyroid hormones, raised 291: 228–38. Other adverse effects sometimes observed with the concentrations of TSH, but no clinical symptoms. Patients 13. LaFranchi S. Congenital hypothyroidism: etiologies, diagnosis, thiourea antithyroid compounds include fever, a lupus- with subclinical hypothyroidism are at a greater risk of de- and management. Thyroid 1999; 9: 735–40. like syndrome, myopathy, vasculitis and nephritis, and 14. Hopwood NJ. Treatment of the infant with congenital hypothy- veloping clinical hypothyroidism if they also have thyroid roidism. J Pediatr 2002; 141: 752–4. taste disturbances. Creatine phosphokinase values antibodies against thyroid peroxidase/microsomal antigen, 15. Rovet JF. Congenital hypothyroidism: long term outcome. Thy- should be measured if patients experience myalgia. roid 1999; 9: 741–8. although the best strategy for identifying those at risk is not Excessive doses of antithyroid drugs may cause hy- yet known.2 pothyroidism and goitre. High doses in pregnancy may Hypothyroidism is readily treated by lifelong replace- result in fetal hypothyroidism and goitre (see Pregnan- ment therapy with levothyroxine.1,2,4-7 Although the thy- Benzylthiouracil cy, below). roid gland produces both T3 (liothyronine) and T4 (thyrox- Benciltiouracilo. 6-Benzyl-2,3-dihydro-2-thioxopyrimidin-4(1H)- ine), T3 is mainly produced by peripheral mono- one; 6-Benzyl-2-mercaptopyrimidin-4-ol; 6-Benzyl-2-thiouracil. An immune mechanism has been implicated in many of these reactions and cross-sensitivity between the deiodination of circulating T4 and it is therefore sufficient C11H10N2OS = 218.3. to give levothyroxine alone. There is no rationale for the CAS — 33086-27-0; 6336-50-1. thiourea antithyroid drugs may occur. use of combined preparations containing liothyronine and ATC — H03BA03. Breast feeding. The safety of breast feeding during maternal levothyroxine, or of dried thyroid hormone extracts, which ATC Vet — QH03BA03. treatment depends partly on how much drug is distributed into may lead to elevated serum concentrations of T3 and the breast milk. Thiourea antithyroid drugs may be used with thyrotoxic symptoms. Liothyronine may, however, be care in breast-feeding mothers; neonatal development and thy- used initially for its rapid onset of action in severe roid function of the infant should be closely monitored and the H hypothyroid states such as myxoedema coma (see below). N S lowest effective dose used. Initial checks should be made to ensure that thyroid Propylthiouracil has been preferred to carbimazole or thiamazole replacement treatment is restoring deficiencies in thyroid since it enters breast milk less readily.1-3 In a small study4 of hormone but not providing an excess. This is best done by NH breast-feeding mothers taking doses of propylthiouracil as high monitoring hormone concentrations and the goal of as 750 mg daily for Graves’ disease, no adverse effects were ob- replacement therapy is a normal TSH value, which is O served on the thyroid status of their infants. Thiamazole enters breast milk freely, with plasma to milk ratios generally associated with a normal or slightly elevated T4 3,5 value.2,5 of almost one. The infant’s intake of thiamazole after maternal Profile use of carbimazole (or thiamazole) might be greatly reduced by In subclinical hypothyroidism, treatment with levothyrox- 6 2-4,7,8 Benzylthiouracil is a thiourea antithyroid drug. It is given by discarding the breast milk produced 2 to 4 hours after a dose, ine is controversial. It has been recommended if anti- mouth in the treatment of hyperthyroidism (p.2165) in an initial since the highest concentration was found at this time. Two stud- bodies to thyroid peroxidase are present, or if TSH levels dose of 150 to 200 mg daily, reducing to a maintenance dose of ies found no adverse effects on thyroid function,7,8 thyroid hor- are above 10 milliunits/litre. Some also recommend treat- 100 mg daily; it is given in divided doses, preferably with food. mone levels,7 or physical and intellectual development, in breast- The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii) 2168 Thyroid and Antithyroid Drugs fed infants during up to 6 months7 to 1 year8 of maternal treat- 11. Naeye RL, Terrien CM. Hemorrhagic state after therapy with the production of antibodies to insulin, resulting in episodes of ment with thiamazole. Maximum maternal daily doses of 10 mg propylthiouracil. Am J Clin Pathol 1960; 34: 254–7. hypoglycaemia, has been associated with thiamazole9 and carbi- of thiamazole,3 15 mg of carbimazole, and 150 mg of 12. Gotta AW, et al. Prolonged intraoperative bleeding caused by mazole.10 9 propylthiouracil-induced hypoprothrombinemia. Anesthesiolo- propylthiouracil have been recommended, although thiamazole gy 1972; 37: 562–3. The thiourea antithyroid drugs all contain a thioamide group and 20 to 30 mg has been given to thyrotoxic lactating women for the 13. Ikeda S, Schweiss JF. Excessive blood loss during operation in cross-sensitivity between them might be expected. In particular, first month of a year of therapy with no observable adverse ef- the patient treated with propylthiouracil. Can Anaesth Soc J complete cross-reactivity may be expected between thiamazole 1982; 29: 477–80. fects on the thyroid function of their breast-fed infants.10 Despite and carbimazole since the latter is converted in vivo to thiama- stating that goitre has been associated with the use of carbima- Effects on the ears. Earache, high-frequency hearing loss, and zole, although one report11 suggests this is not necessarily the zole, the American Academy of Pediatrics considers the use of tinnitus in a patient with Graves’ disease were attributed to hy- case. Cross-sensitivity between propylthiouracil and all three drugs to be compatible with breast feeding.11 persensitivity to carbimazole;1 hearing loss, but not the tinnitus, carbimazole12 or thiamazole13 has been reported but the inci- 1. Kampmann JP, et al. Propylthiouracil in human milk: revision resolved when carbimazole was replaced with propylthiouracil. dence and clinical importance is not clear. Although it has been of a dogma. Lancet 1980; i: 736–8. 1. Hill D, et al. Hearing loss and tinnitus with carbimazole BMJ suggested that carbimazole or thiamazole may be substituted for 2. Johansen K, et al. Excretion of methimazole in human milk. Eur 1994; 309: 929. propylthiouracil in hypersensitive patients, it is safer to stop an- J Clin Pharmacol 1982; 23: 339–41. Effects on the kidneys. Glomerulonephritis associated with tithyroid drugs in such patients.12 3. Cooper DS. Antithyroid drugs: to breast-feed or not to breast- the development of antineutrophil cytoplasmic antibodies has 1. Bajaj S, et al. Antithyroid arthritis syndrome. J Rheumatol feed. Am J Obstet Gynecol 1987; 157: 234–5. been reported in patients receiving thiourea antithyroid drugs.1-5 1998; 25: 1235–9. 4. Momotani N, et al. Thyroid function in wholly breast-feeding 2. Kawachi Y, et al. ANCA-associated vasculitis and lupus-like infants whose mothers take high doses of propylthiouracil. Clin 1. Vogt BA, et al. Antineutrophil cytoplasmic autoantibody-posi- tive crescentic glomerulonephritis as a complication of treatment syndrome caused by methimazole. Clin Exp Dermatol 1995; 20: Endocrinol (Oxf) 2000; 53: 177–81. 345–7. with propylthiouracil in children. J Pediatr 1994; 124: 986–8. 5. Cooper DS, et al. Methimazole pharmacology in man: studies 3. Chastain MA, et al. Propylthiouracil hypersensitivity: report of using a newly developed radioimmunoassay for methimazole. J 2. D’Cruz D, et al. Antineutrophil cytoplasmic antibody-positive two patients with vasculitis and review of the literature. J Am Clin Endocrinol Metab 1984; 58: 473–9. crescentic glomerulonephritis associated with anti-thyroid drug Acad Dermatol 1999; 41: 757–64. treatment. Br J Rheumatol 1995; 34: 1090–1. 6. Rylance GW, et al. Carbimazole and breastfeeding. Lancet 4. Gunton JE, et al. Clinical case seminar: antithyroid drugs and 3. Yuasa S, et al. Antineutrophil cytoplasmic antibodies (ANCA)- antineutrophil cytoplasmic antibody positive vasculitis. A case 1987; i: 928. associated crescentic glomerulonephritis and propylthiouracil 7. Azizi F. Effect of methimazole treatment of maternal thyrotoxi- report and review of the literature. J Clin Endocrinol Metab therapy. Nephron 1996; 73: 701–3. 1999; 84: 13–16. cosis on thyroid function in breast-feeding infants. J Pediatr 4. Kudoh Y, et al. Propylthiouracil-induced rapidly progressive 1996; 128: 855–8. 5. Mathieu E, et al. Systemic adverse effect of antithyroid drugs. glomerulonephritis associated with antineutrophil cytoplasmic Clin Rheumatol 1999; 18: 66–8. 8. Azizi F, et al. Thyroid function and intellectual development of autoantibodies. Clin Nephrol 1997; 48: 41–3. 6. Dolman KM, et al. Vasculitis and antineutrophil cytoplasmic infants nursed by mothers taking methimazole. J Clin Endocri- 5. Prasad GVR, et al. Propylthiouracil-induced diffuse prolifera- autoantibodies associated with propylthiouracil therapy. Lancet nol Metab 2000; 85: 3233–8. tive lupus nephritis: review of immunological complications. J 1993; 342: 651–2. 9. Lamberg B-A, et al. Antithyroid treatment of maternal hyper- Am Soc Nephrol 1997; 8: 1205–10. 7. ten Holder SM, et al. Cutaneous and systemic manifestations of thyroidism during lactation. Clin Endocrinol (Oxf) 1984; 21: drug-induced vasculitis. Ann Pharmacother 2002; 36: 130–47. 81–7. Effects on the liver. Jaundice, usually cholestatic, has been re- 1-5 8. Van Kuyk M, et al. Methimazole-induced serum sickness. Acta 10. Azizi F, Hedayati M. Thyroid function in breast-fed infants ported with thiamazole and carbimazole. An immune-mediat- Clin Belg 1983; 38: 68–9. whose mothers take high doses of methimazole. J Endocrinol ed mechanism rather than a toxic reaction has been proposed. 9. Hakamata M, et al. Insulin autoimmune syndrome after the third Invest 2002; 25: 493–6. Hepatitis (sometimes progressing to cirrhosis6) and hepatic therapy with methimazole. Intern Med 1995; 34: 410–12. 11. American Academy of Pediatrics. The transfer of drugs and oth- necrosis have been associated with propylthiouracil,6-9 some- 10. Burden AC, Rosenthal FD. Methimazole and insulin autoim- mune syndrome. Lancet 1983; ii: 1311. er chemicals into human milk. Pediatrics 2001; 108: 776–89. times with fatal consequences.7,8 However, in one study10 almost Correction. ibid.; 1029. Also available at: 11. Kroll H, et al. Drug-dependent antibodies against the prodrug http://aappolicy.aappublications.org/cgi/content/full/ 30% of patients being treated with propylthiouracil developed carbimazole do not react with the metabolite thiamazole. Blood pediatrics%3b108/3/776 (accessed 18/05/05) asymptomatic liver changes (increased alanine aminotransferase 2001; 97: 2186–7. values). Dose reduction resulted in a return to normal values in 12. Smith A, et al. Cross sensitivity to antithyroid drugs. BMJ 1989; Effects on the blood. While leucopenia is considered to be a 13 of the 15 patients affected. 298: 1253. common adverse effect of the thiourea antithyroid drugs, occur- 13. De Weweire A, et al. Failure to control hyperthyroidism with a ring in up to a quarter of patients, it is usually mild and improves Despite reports of liver damage, propylthiouracil has been inves- thionamide after potassium perchlorate withdrawal in a patient as treatment continues.1 tigated in the treatment of patients with alcoholic liver disease with amiodarone associated thyrotoxicosis. J Endocrinol Invest (see p.2175). 1987; 10: 529. Agranulocytosis, a more serious hazard, is usually reported to 1. Becker CE, et al. Hepatitis from methimazole during adrenal 2 Pregnancy. Thiourea antithyroid drugs have been used success- affect 0.03% of patients in Europe, who are mostly treated with steroid therapy for malignant exophthalmos. JAMA 1968; 206: fully in pregnancy (see Hyperthyroidism, p.2165). carbimazole. However, the incidence has been reported to be 1787–9. Thiamazole (the metabolite of carbimazole) has been the drug higher (0.4%) in areas where thiamazole is used.3,4 Fatalities 2. Fischer MG, et al. Methimazole-induced jaundice. JAMA 1973; most frequently involved in the few reports of congenital have been reported.1,2,4,5 Although a direct toxic effect had been 223: 1028–9. 3. Blom H, et al. A case of carbimazole-induced intrahepatic defects following maternal use of such compounds. Several in- suggested, the agranulocytosis associated with the thiourea drugs cholestasis. Arch Intern Med 1985; 145: 1513–15. fants exposed to thiamazole in utero have been born with scalp is generally considered to be immunologically mediated.1,6 The 4. Schmidt G, et al. Methimazole-associated cholestatic liver inju- defects (aplasia cutis congenita—a localised absence of skin at onset of agranulocytosis is usually rapid and monitoring of the ry: case report and brief literature review. Hepatogastroenterol- birth)1,2 although hyperthyroidism itself may give rise to such blood count is not always of predictive value;3 routine monitor- ogy 1986; 33: 244–6. 5. Arab DM, et al. Severe cholestatic jaundice in uncomplicated defects.3 Individual cases of other congenital defects associated ing is not indicated.2 Agranulocytosis has occurred in patients hyperthyroidism treated with methimazole. J Clin Endocrinol with thiamazole have included choanal atresia (an upper respira- receiving propylthiouracil for a second time who had no such Metab 1995; 80: 1083–5. tory-tract defect), oesophageal atresia, and tracheo-oesophageal complications in their first course of therapy.7 There is limited 6. Özenírler S, et al. Propylthiouracil-induced hepatic damage. fistula3 but the incidence of congenital abnormalities is not evidence that agranulocytosis is more common at higher doses, Ann Pharmacother 1996; 30: 960–3. increased compared with the general population.4 Gastroschisis and in older patients. However, this has not been proved conclu- 7. Hanson JS. Propylthiouracil and hepatitis. Two cases and a re- view of the literature. Arch Intern Med 1984; 144: 994–6. (an abdominal wall defect) has been reported in an infant after sively.1 8. Limaye A, Ruffolo PR. Propylthiouracil-induced fatal hepatic maternal exposure to carbimazole.5 There have been some There have been some case reports of aplastic anaemia being necrosis. Am J Gastroenterol 1987; 82: 152–4. reports of neonates exposed to thiourea antithyroid drugs in utero 9. Ichiki Y, et al. Propylthiouracil-induced severe hepatitis: a case 6,7 produced by antithyroid drugs, but the excess risk associated report and review of the literature. J Gastroenterol 1998; 33: displaying signs of hypothyroidism including goitre. 6,8 with their use is considered to be very low and complete recov- 747–50. 1. Milham S. Scalp defects in infants of mothers treated for hyper- ery has been reported after withdrawal of the antithyroid drug. 10. Liaw Y-F, et al. Hepatic injury during propylthiouracil therapy thyroidism with methimazole or carbimazole during pregnancy. An immune mechanism has been implicated. in patients with hyperthyroidism. Ann Intern Med 1993; 118: Teratology 1985; 32: 321. 424–8. 9 2. Vogt T, et al. Aplasia cutis congenita after exposure to methima- Carbimazole has produced haemolytic anaemia. In this case zole: a causal relationship? Br J Dermatol 1995; 133: 994–6. the immune reaction was specific to carbimazole and could not Effects on the lungs. Diffuse interstitial pneumonitis occurred in 2 patients given propylthiouracil1 and a hypersensitivity reac- 3. Johnsson E, et al. Severe malformations in infant born to hyper- be demonstrated with thiamazole. thyroid woman on methimazole. Lancet 1997; 350: 1520. tion was suggested. Propylthiouracil was also implicated in 2 4. Wing DA, et al. A comparison of propylthiouracil versus methi- On very rare occasions patients taking propylthiouracil have ex- cases of alveolar haemorrhage associated with antineutrophil cy- 10-12 mazole in the treatment of hyperthyroidism in pregnancy. Am J perienced a reduction in prothrombin values and bleeding. In toplasmic antibody.2,3 Obstet Gynecol 1994; 170: 90–5. one patient bleeding was linked to propylthiouracil-induced 1. Miyazono K, et al. Propylthiouracil-induced diffuse interstitial 5. Guignon A-M, et al. Carbimazole-related gastroschisis. Ann 13 thrombocytopenia. pneumonitis. Arch Intern Med 1984; 144: 1764–5. Pharmacother 2003; 37: 829–31. 1. Bartalena L et al. Adverse effects of thyroid hormone prepara- 2. Ohtsuka M, et al. Propylthiouracil-induced alveolar haemor- 6. O’Doherty MJ, et al. Treating thyrotoxicosis in pregnant or po- tions and antithyroid drugs. Drug Safety 1996; 15: 53–63. rhage associated with antineutrophil cytoplasmic antibody. Eur tentially pregnant women. BMJ 1999; 318: 5–6. Respir J 1997; 10: 1405–7. 7. Masiukiewicz US, Barrow GN. Hyperthyroidism in pregnancy: 2. Committee on Safety of Medicines/Medicines Control Agency. diagnosis and treatment. Thyroid 1999; 9: 647–52. Reminder: agranulocytosis with antithyroid drugs. Current 3. Dhillon SS, et al. Diffuse alveolar hemorrhage and pulmonary Problems 1999; 25: 3. Also available at: http:// capillaritis due to propylthiouracil. Chest 1999; 116: 1485–8. www.mhra.gov.uk/home/idcplg?IdcService=GET_FILE& Effects on the muscles. Myositis with pain, weakness, and Pharmacokinetics dDocName=CON2023233&RevisionSelectionMethod= LatestReleased (accessed 17/05/06) increased creatine kinase concentrations has been reported with The pharmacokinetics of carbimazole and thiamazole carbimazole.1,2 This effect might be explained by ‘tissue hy- 3. Tajiri J, et al. Antithyroid drug-induced agranulocytosis: the 3 can be considered together since carbimazole is rapidly usefulness of routine white blood cell count monitoring. Arch pothyroidism’, and might respond to dosage reduction. and completely metabolised to thiamazole in the body. Intern Med 1990; 150: 621–4. 1. Page SR, Nussey SS. Myositis in association with carbimazole 4. Anonymous. Elaboration: drug-induced agranulocytosis–moni- therapy. Lancet 1989; i: 964. The antithyroid activity of carbimazole is dependent toring antithyroid treatment. Drug Ther Bull 1997; 35: 88. 2. Pasquier E, et al. Biopsy-proven myositis with microvasculitis in upon this conversion to thiamazole. 5. Anonymous. Drug-induced agranulocytosis. Drug Ther Bull association with carbimazole. Lancet 1991; 338: 1082–3. 1997; 35: 49–52. 3. O’Malley B. Carbimazole-induced cramps. Lancet 1989; i: Carbimazole and other thiourea antithyroid drugs are 6. International Agranulocytosis and Aplastic Anaemia Study. 1456. rapidly absorbed from the gastrointestinal tract with Risk of agranulocytosis and aplastic anaemia in relation to use Hypersensitivity. Many of the adverse effects associated with peak plasma concentrations occurring about 1 to 2 of antithyroid drugs. BMJ 1988; 297: 262–5. the thiourea antithyroid drugs appear to have an immune basis. hours after oral doses. 7. Shiran A, et al. Propylthiouracil-induced agranulocytosis in These effects may be associated with polyarthritis1 or hypersen- four patients previously treated with the drug. JAMA 1991; 266: 2-7 They are concentrated in the thyroid gland; since their 3129–30. sitivity vasculitis. The latter is sometimes severe and multisys- 8. Bishara J. Methimazole-induced aplastic anemia. Ann Pharma- temic, and fatalities have occurred. duration of action is more closely related to the intra- cother 1996; 30: 684. Hypersensitivity reactions may also be associated with the devel- thyroidal drug concentration than their plasma half-life, 9. Salama A, et al. Carbimazole-induced immune haemolytic opment of antineutrophil cytoplasmic antibodies (ANCA), or prolonged antithyroid activity results from single daily anaemia: role of drug-red blood cell complexes for immuniza- sometimes with a lupus-like syndrome with or without the pres- doses. Thiamazole is not bound to plasma proteins. tion. Br J Haematol 1988; 68: 479–82. ence of antinuclear antibodies.2,5 10. D’Angelo G, Le Gresley LP. Severe hypoprothrombinaemia af- Thiamazole has an elimination half-life from plasma of ter propylthiouracil therapy. Can Med Assoc J 1959; 81: Serum sickness with arthralgias and raised immunoglobulin M 479–81. (IgM) concentrations has been reported with thiamazole,8 and about 3 to 6 hours and is metabolised, probably by the Carbimazole/Iodine 2169 liver, and excreted in the urine. Less than 12% of a dose Preparations Iodine and iodides have variable effects on the thyroid of thiamazole may be excreted as unchanged drug. Proprietary Preparations (details are given in Part 3) (see below) and can produce goitre and hypothy- 3-Methyl-2-thiohydantoin has been identified as a Ital.: Bromotiren. roidism as well as hyperthyroidism (the Iod-Basedow metabolite of thiamazole. The elimination half-life Multi-ingredient: Ital.: Bromazolo. or Jod-Basedow phenomenon). Goitre and hypothy- may be increased in hepatic and renal impairment. roidism have also occurred in infants born to mothers Thiamazole crosses the placenta and is distributed into who had taken iodides during pregnancy. breast milk. Iodine Prolonged use may lead to a range of adverse effects, ◊ References to the pharmacokinetics of carbimazole and thiam- Iod; Iode; Iodium; Iodo; Iodum; Iyot; Jód; Jod; Jodas; Jodi; Jodum; often called ‘iodism’, some of which may again be due azole. Yo d o. to hypersensitivity. Adverse effects include metallic 1. Skellern GG, et al. The pharmacokinetics of methimazole after I = 253.80894. taste, increased salivation, burning or painful mouth; oral administration of carbimazole and methimazole, in hyper- 2 thyroid patients. Br J Clin Pharmacol 1980; 9: 137–43. CAS — 7553-56-2. there may be acute rhinitis, coryza-like symptoms, and 2. Kampmann JP, Hansen JM. Clinical pharmacokinetics of an- ATC — D08AG03. swelling and inflammation of the throat. Eyes may be tithyroid drugs. Clin Pharmacokinet 1981; 6: 401–28. ATC Vet — QD08AG03. irritated and swollen and there may be increased lach- 3. Jansson R, et al. Intrathyroidal concentrations of methimazole in patients with Graves’ disease. J Clin Endocrinol Metab 1983; Pharmacopoeias. In Chin., Eur. (see p.vii), Int., Jpn, US, and rymation. Pulmonary oedema, dyspnoea, and bronchi- 57: 129–32. Viet. tis may develop. Skin reactions include acneform or, 4. Cooper DS, et al. Methimazole pharmacology in man: studies . Greyish-violet, brittle plates or fine crys- using a newly developed radioimmunoassay for methimazole. J Ph. Eur. 6.2 (Iodine) more rarely, severe eruptions (iododerma). Other re- Clin Endocrinol Metab 1984; 58: 473–9. tals, with a metallic sheen. It is slowly volatile at room tempera- ported effects include depression, insomnia, impo- 5. Jansson R, et al. Pharmacokinetic properties and bioavailability ture. Very slightly soluble in water; soluble in alcohol; slightly tence, headache, and gastrointestinal disturbances, of methimazole. Clin Pharmacokinet 1985; 10: 443–50. soluble in glycerol; very soluble in concentrated solutions of io- dides. notably nausea, vomiting, and diarrhoea. Uses and Administration USP 31 (Iodine). Heavy, greyish-black plates or granules with a The symptoms of acute poisoning from ingestion of Carbimazole is a thiourea antithyroid drug that acts by metallic sheen and a characteristic odour. Soluble 1 in 3000 of iodine are mainly due to its corrosive effects on the gas- water, 1 in 13 of alcohol, 1 in 4 of carbon disulfide, and 1 in 80 trointestinal tract; a disagreeable metallic taste, vomit- blocking the production of thyroid hormones (see of glycerol; freely soluble in chloroform, in ether, and in carbon p.2165). It is used in the management of hyperthy- tetrachloride; soluble in solutions of iodides. Store in airtight ing, abdominal pain, and bloody diarrhoea occur. roidism (p.2165), including the treatment of Graves’ containers. Thirst and headache have been reported. Systemic tox- disease, the preparation of hyperthyroid patients for Incompatibility. With acetone, iodine forms a pungent irritat- icity may lead to shock, tachycardia, hypotension, fe- thyroidectomy, as an adjunct to radio-iodine therapy, ing compound. ver, metabolic acidosis and renal impairment. Death and in the treatment of thyroid storm. may be due to circulatory failure, oedema of the epi- Carbimazole is completely metabolised to thiamazole Potassium Iodate glottis resulting in asphyxia, aspiration pneumonia, or and it is this metabolite that is responsible for the Iodato potásico; Potasu jodan. pulmonary oedema. Oesophageal stricture may occur antithyroid activity of carbimazole. KIO3 = 214.0. if the patient survives the acute stage. Carbimazole is given orally in a typical initial dosage CAS — 7758-05-6. Victims of acute poisoning have been given copious of 15 to 40 mg daily, in divided doses; occasionally up Pharmacopoeias. In Br., Chin., and It. draughts of milk or starch mucilage; lavage should BP 2008 (Potassium Iodate). A white crystalline powder with a probably not be attempted, and certainly not unless the to 60 mg daily may be required. Control of symptoms slight odour. Slowly soluble in water; insoluble in alcohol. A 5% is usually achieved in 1 to 2 months. When the patient solution in water has a pH of 5.0 to 8.0. ingested iodine was in sufficiently dilute form not to is euthyroid the dose is gradually reduced to the small- produce gastrointestinal corrosion. Other possible oral est amount that will maintain the euthyroid state. Typ- Potassium Iodide treatments include activated charcoal or sodium thio- sulfate solution (usually as a 1% solution) to reduce io- ical maintenance doses are 5 to 15 mg daily, which Iodeto de Potássio; Ioduro potásico; Jodid draselný; Kalii Iodetum; may be given as a single daily dose. Kalii iodidum; Kalii Jodidum; Kalio jodidas; Kalium Iodatum; Kalium dine to the less toxic iodides. Treatment in children should be undertaken by a spe- Jodatum; Kaliumjodid; Kálium-jodid; Kaliumjodidi; Pot. Iod.; Po- Effects on the thyroid. Iodide may be isolated by the body cialist. The BNFC recommends an initial dose of tassii Iodidum; Potassium (Iodure de); Potassium, iodure de; from a variety of sources, including an iodine-rich diet, or some Potasu jodek; Potasyum Iyodür. disinfectants and drugs containing iodine (see also under Amio- 250 micrograms/kg three times daily for neonates and darone, p.1212). Although iodine is required for the production children up to 12 years of age. Children aged 12 to 18 KI = 166.0. CAS — 7681-11-0. of thyroid hormones, excessive quantities can cause hyperthy- years may be given 10 mg three times daily initially. ATC — R05CA02; S01XA04; V03AB21. roidism, or even paradoxical goitre and hypothyroidism. Doses are adjusted according to response; higher initial ATC Vet — QR05CA02; QS01XA04; QV03AB21. The normal daily requirement ranges from 100 to 300 micrograms.1,2 Quantities of 500 micrograms to 1 mg daily doses may be needed in thyrotoxic crisis. Pharmacopoeias. In Chin., Eur. (see p.vii), Int., Jpn, US, and probably have no untoward effects on thyroid function in most Viet. Carbimazole is also given orally in a dose of 20 to cases.2 When progressively larger doses are given there is an in- Ph. Eur. 6.2 (Potassium Iodide). A white or almost white powder 60 mg daily, with supplemental levothyroxine, as a itial rise in thyroid hormone production, but at still higher doses, or colourless crystals. Very soluble in water; soluble in alcohol; production decreases (the Wolff-Chaikoff effect). This effect is blocking-replacement regimen. freely soluble in glycerol. Protect from light. Either form of maintenance treatment is usually con- usually seen with doses of more than about 2 mg daily, but is USP 31 (Potassium Iodide). Hexahedral crystals, either transpar- normally transient, adaptation occurring on repeated dosage. In tinued for at least a year, and often for 18 months; up to ent and colourless or somewhat opaque and white, or a white, certain individuals a lack of adaptation produces a chronic inhi- 2 years of treatment may be required. granular powder. It is slightly hygroscopic. Soluble 1 in 0.7 of bition of thyroid hormone synthesis leading to goitre and water and 1 in 0.5 of boiling water, 1 in 22 of alcohol, and 1 in 2 hypothyroidism.1,2 Preparations of glycerol. Its solutions are neutral or alkaline to litmus. Excess iodine may also induce hyperthyroidism (the Iod-Base- BP 2008: Carbimazole Tablets. dow or Jod-Basedow phenomenon). Iodine-induced hyperthy- Proprietary Preparations (details are given in Part 3) Sodium Iodide roidism has been associated with iodine prophylaxis pro- Austral.: Neo-Mercazole; Austria: Carbistad; Denm.: Neo-Mercazole; Iodeto de Sódio; Ioduro sódico; Jodid sodný; Natrii Iodetum; grammes in developing countries.3 The highest incidence of Fin.: Tyr azol; Fr.: Neo-Mercazole; Ger.: Car; Neo-Thyreostat†; Gr.: Thy- rostat; Hong Kong: Cazole; India: Neo-Mercazole; Indon.: Neo-Merca- Natrii iodidum; Natrii Jodidum; Natrio jodidas; Natrium Iodatum; hyperthyroidism has been reported to occur 1 to 3 years after zole; Irl.: Neo-Mercazole; Malaysia: Camazol†; Norw.: Neo-Mercazole; Natriumjodid; Nátrium-jodid; Natriumjodidi; Sod. Iod.; Sodii Io- supplementation begins, with the incidence returning to normal 4 NZ: Neo-Mercazole; Philipp.: Neo-Mercazole; S.Afr.: Neo-Mercazole; didum; Sodium (Iodure de); Sodium, iodure de; Sodu jodek; So- within 3 to 10 years despite continued iodine exposure. Elderly Singapore: Camazol; Cazole†; Spain: Neo Tomizol; Switz.: Neo-Merca- dyum Iyodür. subjects and those with nodular goitres have been found to be at zole; UK: Neo-Mercazole. greatest risk. NaI = 149.9. CAS — 7681-82-5. To overcome any adverse effects on thyroid function as a result of iodine prophylaxis during pregnancy, WHO has issued Dibromotyrosine Pharmacopoeias. In Chin., Eur. (see p.vii), Jpn, and US. guidelines on the safe use of iodised oil during gestation.5,6 There Ph. Eur. 6.2 (Sodium Iodide). Colourless crystals or white or al- Dibromotirosina. 3,5-Dibromo-L-tyrosine. is some evidence that the use of iodine-containing antiseptics on most white, crystalline powder. It is hygroscopic. Very soluble in C H Br NO = 339.0. pregnant women and neonates may cause disturbances in thyroid 9 9 2 3 water; freely soluble in alcohol. Protect from light. function.7,8 CAS — 300-38-9. USP 31 (Sodium Iodide). Colourless, odourless crystals, or ATC — H03BX02. 1. Arthur JR, Beckett GJ. Thyroid function. Br Med Bull 1999; 55: white crystalline powder. It is deliquescent in moist air and de- ATC Vet — QH03BX02. 658–68. velops a brown tint upon decomposition. Soluble 1 in 0.6 of wa- 2. WHO. Iodine. In Trace elements in human nutrition and health. ter, 1 in 2 of alcohol, and 1 in 1 of glycerol. Store in airtight con- Geneva: WHO, 1996: 49–71. tainers. 3. Delange F, et al. Risks of iodine-induced hyperthyroidism after Br correction of iodine deficiency by iodized salt. Thyroid 1999; 9: 545–56. HO O OH Adverse Effects and Treatment 4. Fradkin JE, Wolff J. Iodide-induced thyrotoxicosis. Medicine Iodine and iodides, whether applied topically or given (Baltimore) 1983; 62: 1–20. 5. WHO. Safe use of iodized oil to prevent iodine deficiency in systemically, can give rise to hypersensitivity reactions pregnant women. Bull WHO 1996; 74: 1–3. Br NH2 which may include urticaria, angioedema, cutaneous 6. Delange F. Administration of iodized oil during pregnancy: a haemorrhage or purpuras, fever, arthralgia, lymphade- summary of the published evidence. Bull WHO 1996; 74: 101–8. 7. Linder N et al. Topical iodine-containing antiseptics and subclin- Profile nopathy, and eosinophilia. ical hypothyroidism in preterm infants. J Pediatr 1997; 131: Dibromotyrosine is an antithyroid drug used in the treatment of 434–9. hyperthyroidism (p.2165) in doses of 300 to 900 mg daily by Inhalation of iodine vapour is very irritating to mucous 8. Weber G et al. Neonatal transient hypothyroidism: aetiological mouth. membranes. study. Arch Dis Child Fetal Neonatal Ed 1998; 79: F70–2. The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)