- Email: [email protected]
Antithyroid Drugs
Antithyroid Drugs Anthony D. Toft Royal Infirmary, Edinburgh, United Kingdom
Glossary Graves’ disease The most common cause of hyperthyroidism, accounting for approximately 75% of cases and resulting from the inappropriate production of thyrotropin-receptor antibodies, which stimulate the thyroid gland to secrete excessive quantities of thyroxine and triiodothyronine. hyperthyroidism (thyrotoxicosis) The clinical condition arising from sustained raised concentrations of thyroxine and/or triiodothyronine in the circulation. With rare exceptions (e.g., thyrotropin-secreting pituitary tumor), serum thyrotropin concentrations are low. thionamides A group of antithyroid drugs comprising carbimazole, its active metabolite, methimazole, and propylthiouracil. Their main action is to inhibit the iodination of tyrosyl residues in thyroglobulin, one of the early stages of thyroid hormone synthesis.
T
he antithyroid drugs are principally used in the management of hyperthyroidism of Graves’ disease. The antithyroid drugs carbimazole, methimazole, and propylthiouracil are heterocyclic compounds known as thionamides that contain a thiourylene group.
INTRODUCTION Carbimazole (CBZ) is immediately metabolized in serum to methimazole (MMI), and it has been calculated that 10 mg of CBZ yields 6 mg of MMI. All the antithyroid drugs are rapidly and almost completely absorbed from the gastrointestinal tract, with peak serum concentrations at 1 or 2 h. Antithyroid drugs are actively transported into the thyroid, where they inhibit the synthesis of triiodothyronine (T3) and thyroxine (T4), principally by interfering with the iodination of tyrosine by serving as preferential substrate for the iodinating intermediate of thyroid peroxidase. Oxidized iodine is thus diverted from the tyrosyl iodination sites in thyroglobulin. The iodinated antithyroid
Encyclopedia of Endocrine Diseases, Volume 1. ß 2004 Elsevier Inc. All rights reserved.
drugs are desulfurated and further oxidized to inactive metabolites. In addition, propylthiouracil (PTU) inhibits T4 to T3 conversion, but this is of little clinical significance other than perhaps in the management of thyrotoxic crisis, when it is important to lower the raised serum T3 concentration as quickly as possible. There is also evidence that the thionamides have an immunosuppressive action, but any effect is shortlived because patients with Graves’ hyperthyroidism frequently relapse after drug withdrawal. Historically, CBZ has been the drug of choice in the United Kingdom, but MMI has been the drug of choice in all other areas of the world. PTU is also widely employed in the Americas but elsewhere tends to be restricted to use during pregnancy and breastfeeding and in patients who have reacted adversely to CBZ or MMI.
PHILOSOPHY OF TREATMENT OF GRAVES’ DISEASE Each of the treatments for Graves’ disease is effective but none is perfect, and the conclusions of Hershman and colleagues in the 1960s remain valid today, namely that the experience with antithyroid drugs, thyroidectomy, and radioiodine have not provided clear-cut criteria that can be used to select the best treatment for individual patients. A course of antithyroid drugs is appropriate for the minority of patients in whom a single episode of hyperthyroidism is followed by prolonged remission (30%). The majority, however, have a relapsing and remitting course over many years, and efforts to predict the natural history of the hyperthyroidism in most patients at diagnosis, using biochemical and immunological markers, have proved disappointing. On a group basis, a small goiter, a low serum concentration of thyrotropin-receptor antibodies (TRAbs), and older age favor remission after a course of antithyroid drugs, whereas the risk of relapse in a young male with severe hyperthyroidism and a large vascular goiter is so high that most would advocate surgery as the primary treatment. Similarly, a
261
262 patient with a high concentration of TRAbs, significant ophthalmopathy, and pretibial myxoedema at the end of a course of antithyroid drugs is unlikely to remain in remission for very long. Because of the difficulty in determining the future pattern of the hyperthyroidism, treatment remains empirical and is inevitably influenced by the prejudices of the physician and the patient and by the expertise locally available, such as provided by nuclear medicine facilities and an experienced thyroid surgeon. Management varies from center to center and between countries such that the preferred treatment of a 43-year-old female presenting with hyperthyroidism of moderate severity who did not plan further pregnancy was antithyroid drugs (77%) by European physicians but iodine-131 (69%) by their North American counterparts. There was an even greater contrast in choice of therapy when the index case was that of a 19-year-old female. One-third of physicians in the United States regarded iodine-131 as most appropriate, whereas only 4% of physicians in Europe thought it was most appropriate. Frustration caused by the failure to target antithyroid therapy more specifically and by the gradual acceptance that iodine-131 is neither carcinogenic nor teratogenic has led to a move during the 10 years since the previously discussed survey was performed to advocate the more liberal use of radioactive iodine, irrespective of age. However, there remain anxieties among the public about irradiation in general. Antithyroid drugs are not normally indicated in the treatment of toxic nodular goiter, unless they are used to render the patient euthyroid prior to surgery since recurrence of hyperthyroidism is invariable after drug withdrawal. There is no role for antithyroid drugs in subacute or postpartum thyroiditis, in which the thyrotoxicosis is due to the release of preformed thyroid hormones.
Antithyroid Drugs
Long-term treatment with antithyroid drugs is appropriate, however, in patients with underlying autonomous thyroid function (Graves’ disease or nodular goiter) in whom hyperthyroidism has been precipitated by amiodarone and in whom chronic treatment with the antidysrhythmic drug is planned because iodine-131 is likely to be ineffective.
DOSAGE Methimazole is available as 5- and 10-mg tablets and CBZ as 5- and 20-mg tablets. The initial dose is 20–30 and 30–40 mg daily, respectively, depending on the severity of the hyperthyroidism (Fig. 1). Once-daily dosage is appropriate in all but the most severely thyrotoxic patients, who benefit from a twice-daily regimen. After 3 or 4 weeks, the dose of MMI can be reduced to 10–20 mg daily and that of CBZ to 20–30 mg daily. Further adjustment should be made on the basis of measurements of serum concentrations of T3, T4, and thyroid-stimulating hormone (TSH) until a maintenance dose of 5 and 5–15 mg of MMI or CBZ, respectively, is achieved. Some patients can be maintained on as little as 5 mg CBZ on alternate days and, although this may a homeopathic dose, will promptly relapse if the drug is stopped. Patients begin to feel an improvement after 10–14 days. Initial changes in drug
DURATION OF TREATMENT The conventional period of antithyroid drug therapy is best viewed as a method by which those destined to have a single short-lived episode of hyperthyroidism are identified and destructive therapy with iodine-131 or surgery avoided. Remission rates vary slightly, depending on the iodine status of the population, but approximately 50% remain in remission after 2 years of follow-up. The percentage is significantly less after only 6 months of treatment and is not improved by prolonging therapy for up to 3 years. Relapse can occur at any stage but is most common in the first 2 years.
Figure 1 Mean SE serum-free T4 concentrations during the first 10 weeks of treatment of hyperthyroidism of Graves’ disease with either 20 mg (open circles) or 40 mg (closed circles) of CBZ daily. Although patients in both groups were clinically euthyroid by week 10, there seems little point in delaying the reversal of thyrotoxicosis by using the lower dose in the absence of evidence that adverse effects of the thionamides are dose related. Adapted from Page et al. (1996).
p0055
263
Antithyroid Drugs
dosage should be based on thyroid hormone concentrations because delayed recovery of thyrotropes, previously exposed to high levels of T3 and T4 in the serum, may result in an inappropriately low serum TSH concentration. After 10–12 weeks of treatment, serum TSH is the best guide for adjustment of the dose, with high and low concentrations indicating excessive and inadequate therapy, respectively. PTU is available as 50-mg tablets and the starting dose is 100–150 mg three times daily, reflecting its shorter half-life. The maintenance dose is 50–150 mg daily.
Block-and-Replace Therapy In this regime, the antithyroid drug is continued at the high initial dose after the patient is euthyroid, and hypothyroidism is avoided in the long-term by adding thyroxine at a dose of 100–150 mg daily. The dose of thyroxine, but not that of the antithyroid drug, is adjusted to maintain serum TSH at the lower reference range. This combination has long been thought to be beneficial for patients with significant ophthalmopathy, presumably by avoiding hypothyroidism and possibly also due to the immunosuppressive action of the high-dose thionamide. It is also of value for those with so-called “brittle thyrotoxicosis,” often attributed to poor compliance but now known in some patients to be due to fluctuating concentrations and activities of TRAbs. Remission rates are not improved by standard block-and-replace therapy. Claims that a negligible relapse rate can be achieved by following block-and-replace therapy for 18 months with thyroxine alone for up to an additional 3 years, thereby “putting the thyroid to rest,” reducing antigen release and TRAb concentrations, have not been substantiated.
ADVERSE REACTIONS The adverse effects of antithyroid drugs can occur at any time but almost always do so within 3–6 weeks of starting treatment. There is some cross-sensitivity between CBZ or MMI and PTU. Although it is common practice to change to the alternative antithyroid drug in the event of a minor adverse reaction, such as a skin rash, opinion is divided over whether the development of agranulocytosis is an absolute contraindication to further drug therapy.
Life-Threatening Reaction The most serious adverse reaction is agranulocytosis, which develops in 0.2–0.5% of patients.
Agranulocytosis is characterized by fever, systemic upset, oropharyngeal bacterial infection, and a granulocyte count of less than 0.25 109/liter. The onset is sudden, and the consensus is that routine monitoring of the white blood cell count serves no purpose. Patients should simply be instructed to contact their medical practitioner immediately in the event of developing a sore throat or mouth ulceration. After stopping antithyroid drug therapy, the white blood cell count returns to normal within 1–3 weeks, during which time the affected patient should be isolated and treated with broad-spectrum antibiotics. Recovery of the white blood cell count may be hastened by the use of granulocyte colony-stimulating factor, but its value in patients with the most profound reduction in granulocyte count (< 0.1 109/liter) is unclear. Mild leukopenia with a relative lymphocytosis is common in Graves’ disease and is not a contraindication to the use of antithyroid drugs.
Other Reactions The most common reactions are nausea, loss of taste, headache, and hair loss, which may be self-limiting and do not necessarily require drug withdrawal. The most troublesome is a skin rash, which is usually urticarial and affects 1 to 2% of patients. A migratory polyarthritis may occur alone or in association with the rash and resolves within 4 weeks of stopping treatment. Much rarer adverse effects include cholestatic jaundice, vasculitis (almost exclusively in patients taking PTU, which may be associated with anti-neutrophil cytoplasmic antibody), a lupus-like syndrome, and the nephrotic syndrome.
ADJUNCT TO TREATMENT WITH IODINE-131 Iodine-131 requires approximately 6–8 weeks to be effective, and during this latent period hyperthyroidism may be exacerbated, with an increase in morbidity and even mortality in those with severe thyrotoxicosis and associated cardiovascular disease. For this reason, it is not uncommon not only to render the patient euthyroid before radioiodine treatment but also to continue the antithyroid drug for 6 weeks. The thionamides confer on the thyroid a degree of radioresistance. Unless PTU or MMI (CBZ) is stopped for at least 15 and 2 days, respectively, before and for a similar period after iodine-131 therapy, the cure rate, defined as abolishing hyperthyroidism, is reduced. If it is not clinically possible to discontinue PTU for such a prolonged period in relation to iodine-131 therapy, the dose of isotope should be increased by at least 25%.
264
ANTITHYROID DRUGS IN PREGNANCY Maternal hyperthyroidism in pregnancy is usually due to Graves’ disease. TRAb crosses the placenta and if the mother is thyrotoxic, it must be assumed that the fetus is similarly affected. Before effective treatment was available, the fetal death rate was as high as 50%. Fortunately, antithyroid drugs also cross the placenta and by careful monitoring of maternal thyroid function, normal fetal development can be achieved, even though cord blood may show evidence of overtreatment. Like other organ-specific autoimmune diseases, Graves’ hyperthyroidism tends to improve or even remit during pregnancy. A small dose of antithyroid drug, such as 5 mg MMI daily, will maintain free T4 and TSH concentrations in the reference ranges. It is good clinical practice to examine the mother every 4 weeks during pregnancy and to stop the antithyroid drug 4 weeks before the expected date of delivery to avoid any possibility of fetal hypothyroidism when brain development is at a maximum. There is evidence that maternal hypothyroidism may cause subtly impaired neuropsychological development in the subsequent offspring. Apart from meticulous control of maternal thyroid function during pregnancy, it is wise for thyrotoxic patients not to become pregnant until stable normal thyroid function has been achieved. Measurement of the thyrotropin-receptor antibody concentration in maternal serum during the last examination before delivery may be helpful because a high level is a predictor of neonatal thyrotoxicosis. Since thyroid hormones cross the placenta relatively poorly, the block-and-replace regime is not recommended during pregnancy.
Methimazole (CBZ) or Propylthiouracil? Aplasia cutis congenita (ACC) is a rare disorder of the skin, usually affecting the scalp and less than 3 cm in diameter, that has been reported in a small number of
Appetite see Hunter and Satiation
Antithyroid Drugs
neonates whose mothers received MMI during pregnancy. ACC has not been reported in association with PTU, which is widely used in North America, and some believe that PTU is the drug of choice during pregnancy or for those planning pregnancy. The consensus, however, is that there is insufficient evidence to establish a direct causal relationship between ACC and MMI. Because MMI (CBZ) and PTU are equally effective in controlling Graves’ hyperthyroidism during pregnancy, it makes sense to use the preparation with which one has most experience. If hyperthyroidism recurs after delivery, is due to Graves’ disease and not postpartum thyroiditis, and the mother wishes to breast-feed, PTU is the drug of choice because it is transferred to the milk one-tenth as much as the other thionamides.
See Also the Following Articles Graves’ Disease . Graves’ Disease, Hyperthyroidism in . Hyperthyroidism, Subclinical . Iodine, Radioactive . Thyroid Disease, Epidemiology of . Thyroid Function Tests . TSH Receptor (Thyrotropin Receptor)
Further Reading Hancock, L. D., Tuttle, R. M., LeMar, H., Bauman, J., and Patience, T. (1997). The effect of propylthiouracil on subsequent radioactive iodine therapy in Graves’ disease. Clin. Endocrinol. 47, 425–430. Hershman, J. M., Givens, J. R., Cassidy, C. E., and Astwood, E. B. (1966). Long-term outcome of hyperthyroidism treated with antithyroid drugs. J. Clin. Endocrinol. Metab. 26, 803–807. McIver, B., Rae, P., Beckett, G., Wilkinson, E., Gold, A., and Toft, A. (1996). Lack of effect of thyroxine in patients with Graves’ hyperthyroidism who are treated with an antithyroid drug. N. Engl. J. Med. 334, 220–224. Mestman, J. H. (1998). Hyperthyroidism in pregnancy. Endocrinol. Metab. Clin. North Am. 27, 127–149. Page, S. R., Sheard, C. E., Herbert, M., Hopton, M., and Jeffcoate, W. J. (1996). A comparison of 20 or 40 mg per day of carbimazole in the initial treatment of hyperthyroidism. Clin. Endocrinol. 45, 511–515.
Glossary Graves’ disease The most common cause of hyperthyroidism, accounting for approximately 75% of cases and resulting from the inappropriate production of thyrotropin-receptor antibodies, which stimulate the thyroid gland to secrete excessive quantities of thyroxine and triiodothyronine. hyperthyroidism (thyrotoxicosis) The clinical condition arising from sustained raised concentrations of thyroxine and/or triiodothyronine in the circulation. With rare exceptions (e.g., thyrotropin-secreting pituitary tumor), serum thyrotropin concentrations are low. thionamides A group of antithyroid drugs comprising carbimazole, its active metabolite, methimazole, and propylthiouracil. Their main action is to inhibit the iodination of tyrosyl residues in thyroglobulin, one of the early stages of thyroid hormone synthesis.
T
he antithyroid drugs are principally used in the management of hyperthyroidism of Graves’ disease. The antithyroid drugs carbimazole, methimazole, and propylthiouracil are heterocyclic compounds known as thionamides that contain a thiourylene group.
INTRODUCTION Carbimazole (CBZ) is immediately metabolized in serum to methimazole (MMI), and it has been calculated that 10 mg of CBZ yields 6 mg of MMI. All the antithyroid drugs are rapidly and almost completely absorbed from the gastrointestinal tract, with peak serum concentrations at 1 or 2 h. Antithyroid drugs are actively transported into the thyroid, where they inhibit the synthesis of triiodothyronine (T3) and thyroxine (T4), principally by interfering with the iodination of tyrosine by serving as preferential substrate for the iodinating intermediate of thyroid peroxidase. Oxidized iodine is thus diverted from the tyrosyl iodination sites in thyroglobulin. The iodinated antithyroid
Encyclopedia of Endocrine Diseases, Volume 1. ß 2004 Elsevier Inc. All rights reserved.
drugs are desulfurated and further oxidized to inactive metabolites. In addition, propylthiouracil (PTU) inhibits T4 to T3 conversion, but this is of little clinical significance other than perhaps in the management of thyrotoxic crisis, when it is important to lower the raised serum T3 concentration as quickly as possible. There is also evidence that the thionamides have an immunosuppressive action, but any effect is shortlived because patients with Graves’ hyperthyroidism frequently relapse after drug withdrawal. Historically, CBZ has been the drug of choice in the United Kingdom, but MMI has been the drug of choice in all other areas of the world. PTU is also widely employed in the Americas but elsewhere tends to be restricted to use during pregnancy and breastfeeding and in patients who have reacted adversely to CBZ or MMI.
PHILOSOPHY OF TREATMENT OF GRAVES’ DISEASE Each of the treatments for Graves’ disease is effective but none is perfect, and the conclusions of Hershman and colleagues in the 1960s remain valid today, namely that the experience with antithyroid drugs, thyroidectomy, and radioiodine have not provided clear-cut criteria that can be used to select the best treatment for individual patients. A course of antithyroid drugs is appropriate for the minority of patients in whom a single episode of hyperthyroidism is followed by prolonged remission (30%). The majority, however, have a relapsing and remitting course over many years, and efforts to predict the natural history of the hyperthyroidism in most patients at diagnosis, using biochemical and immunological markers, have proved disappointing. On a group basis, a small goiter, a low serum concentration of thyrotropin-receptor antibodies (TRAbs), and older age favor remission after a course of antithyroid drugs, whereas the risk of relapse in a young male with severe hyperthyroidism and a large vascular goiter is so high that most would advocate surgery as the primary treatment. Similarly, a
261
262 patient with a high concentration of TRAbs, significant ophthalmopathy, and pretibial myxoedema at the end of a course of antithyroid drugs is unlikely to remain in remission for very long. Because of the difficulty in determining the future pattern of the hyperthyroidism, treatment remains empirical and is inevitably influenced by the prejudices of the physician and the patient and by the expertise locally available, such as provided by nuclear medicine facilities and an experienced thyroid surgeon. Management varies from center to center and between countries such that the preferred treatment of a 43-year-old female presenting with hyperthyroidism of moderate severity who did not plan further pregnancy was antithyroid drugs (77%) by European physicians but iodine-131 (69%) by their North American counterparts. There was an even greater contrast in choice of therapy when the index case was that of a 19-year-old female. One-third of physicians in the United States regarded iodine-131 as most appropriate, whereas only 4% of physicians in Europe thought it was most appropriate. Frustration caused by the failure to target antithyroid therapy more specifically and by the gradual acceptance that iodine-131 is neither carcinogenic nor teratogenic has led to a move during the 10 years since the previously discussed survey was performed to advocate the more liberal use of radioactive iodine, irrespective of age. However, there remain anxieties among the public about irradiation in general. Antithyroid drugs are not normally indicated in the treatment of toxic nodular goiter, unless they are used to render the patient euthyroid prior to surgery since recurrence of hyperthyroidism is invariable after drug withdrawal. There is no role for antithyroid drugs in subacute or postpartum thyroiditis, in which the thyrotoxicosis is due to the release of preformed thyroid hormones.
Antithyroid Drugs
Long-term treatment with antithyroid drugs is appropriate, however, in patients with underlying autonomous thyroid function (Graves’ disease or nodular goiter) in whom hyperthyroidism has been precipitated by amiodarone and in whom chronic treatment with the antidysrhythmic drug is planned because iodine-131 is likely to be ineffective.
DOSAGE Methimazole is available as 5- and 10-mg tablets and CBZ as 5- and 20-mg tablets. The initial dose is 20–30 and 30–40 mg daily, respectively, depending on the severity of the hyperthyroidism (Fig. 1). Once-daily dosage is appropriate in all but the most severely thyrotoxic patients, who benefit from a twice-daily regimen. After 3 or 4 weeks, the dose of MMI can be reduced to 10–20 mg daily and that of CBZ to 20–30 mg daily. Further adjustment should be made on the basis of measurements of serum concentrations of T3, T4, and thyroid-stimulating hormone (TSH) until a maintenance dose of 5 and 5–15 mg of MMI or CBZ, respectively, is achieved. Some patients can be maintained on as little as 5 mg CBZ on alternate days and, although this may a homeopathic dose, will promptly relapse if the drug is stopped. Patients begin to feel an improvement after 10–14 days. Initial changes in drug
DURATION OF TREATMENT The conventional period of antithyroid drug therapy is best viewed as a method by which those destined to have a single short-lived episode of hyperthyroidism are identified and destructive therapy with iodine-131 or surgery avoided. Remission rates vary slightly, depending on the iodine status of the population, but approximately 50% remain in remission after 2 years of follow-up. The percentage is significantly less after only 6 months of treatment and is not improved by prolonging therapy for up to 3 years. Relapse can occur at any stage but is most common in the first 2 years.
Figure 1 Mean SE serum-free T4 concentrations during the first 10 weeks of treatment of hyperthyroidism of Graves’ disease with either 20 mg (open circles) or 40 mg (closed circles) of CBZ daily. Although patients in both groups were clinically euthyroid by week 10, there seems little point in delaying the reversal of thyrotoxicosis by using the lower dose in the absence of evidence that adverse effects of the thionamides are dose related. Adapted from Page et al. (1996).
p0055
263
Antithyroid Drugs
dosage should be based on thyroid hormone concentrations because delayed recovery of thyrotropes, previously exposed to high levels of T3 and T4 in the serum, may result in an inappropriately low serum TSH concentration. After 10–12 weeks of treatment, serum TSH is the best guide for adjustment of the dose, with high and low concentrations indicating excessive and inadequate therapy, respectively. PTU is available as 50-mg tablets and the starting dose is 100–150 mg three times daily, reflecting its shorter half-life. The maintenance dose is 50–150 mg daily.
Block-and-Replace Therapy In this regime, the antithyroid drug is continued at the high initial dose after the patient is euthyroid, and hypothyroidism is avoided in the long-term by adding thyroxine at a dose of 100–150 mg daily. The dose of thyroxine, but not that of the antithyroid drug, is adjusted to maintain serum TSH at the lower reference range. This combination has long been thought to be beneficial for patients with significant ophthalmopathy, presumably by avoiding hypothyroidism and possibly also due to the immunosuppressive action of the high-dose thionamide. It is also of value for those with so-called “brittle thyrotoxicosis,” often attributed to poor compliance but now known in some patients to be due to fluctuating concentrations and activities of TRAbs. Remission rates are not improved by standard block-and-replace therapy. Claims that a negligible relapse rate can be achieved by following block-and-replace therapy for 18 months with thyroxine alone for up to an additional 3 years, thereby “putting the thyroid to rest,” reducing antigen release and TRAb concentrations, have not been substantiated.
ADVERSE REACTIONS The adverse effects of antithyroid drugs can occur at any time but almost always do so within 3–6 weeks of starting treatment. There is some cross-sensitivity between CBZ or MMI and PTU. Although it is common practice to change to the alternative antithyroid drug in the event of a minor adverse reaction, such as a skin rash, opinion is divided over whether the development of agranulocytosis is an absolute contraindication to further drug therapy.
Life-Threatening Reaction The most serious adverse reaction is agranulocytosis, which develops in 0.2–0.5% of patients.
Agranulocytosis is characterized by fever, systemic upset, oropharyngeal bacterial infection, and a granulocyte count of less than 0.25 109/liter. The onset is sudden, and the consensus is that routine monitoring of the white blood cell count serves no purpose. Patients should simply be instructed to contact their medical practitioner immediately in the event of developing a sore throat or mouth ulceration. After stopping antithyroid drug therapy, the white blood cell count returns to normal within 1–3 weeks, during which time the affected patient should be isolated and treated with broad-spectrum antibiotics. Recovery of the white blood cell count may be hastened by the use of granulocyte colony-stimulating factor, but its value in patients with the most profound reduction in granulocyte count (< 0.1 109/liter) is unclear. Mild leukopenia with a relative lymphocytosis is common in Graves’ disease and is not a contraindication to the use of antithyroid drugs.
Other Reactions The most common reactions are nausea, loss of taste, headache, and hair loss, which may be self-limiting and do not necessarily require drug withdrawal. The most troublesome is a skin rash, which is usually urticarial and affects 1 to 2% of patients. A migratory polyarthritis may occur alone or in association with the rash and resolves within 4 weeks of stopping treatment. Much rarer adverse effects include cholestatic jaundice, vasculitis (almost exclusively in patients taking PTU, which may be associated with anti-neutrophil cytoplasmic antibody), a lupus-like syndrome, and the nephrotic syndrome.
ADJUNCT TO TREATMENT WITH IODINE-131 Iodine-131 requires approximately 6–8 weeks to be effective, and during this latent period hyperthyroidism may be exacerbated, with an increase in morbidity and even mortality in those with severe thyrotoxicosis and associated cardiovascular disease. For this reason, it is not uncommon not only to render the patient euthyroid before radioiodine treatment but also to continue the antithyroid drug for 6 weeks. The thionamides confer on the thyroid a degree of radioresistance. Unless PTU or MMI (CBZ) is stopped for at least 15 and 2 days, respectively, before and for a similar period after iodine-131 therapy, the cure rate, defined as abolishing hyperthyroidism, is reduced. If it is not clinically possible to discontinue PTU for such a prolonged period in relation to iodine-131 therapy, the dose of isotope should be increased by at least 25%.
264
ANTITHYROID DRUGS IN PREGNANCY Maternal hyperthyroidism in pregnancy is usually due to Graves’ disease. TRAb crosses the placenta and if the mother is thyrotoxic, it must be assumed that the fetus is similarly affected. Before effective treatment was available, the fetal death rate was as high as 50%. Fortunately, antithyroid drugs also cross the placenta and by careful monitoring of maternal thyroid function, normal fetal development can be achieved, even though cord blood may show evidence of overtreatment. Like other organ-specific autoimmune diseases, Graves’ hyperthyroidism tends to improve or even remit during pregnancy. A small dose of antithyroid drug, such as 5 mg MMI daily, will maintain free T4 and TSH concentrations in the reference ranges. It is good clinical practice to examine the mother every 4 weeks during pregnancy and to stop the antithyroid drug 4 weeks before the expected date of delivery to avoid any possibility of fetal hypothyroidism when brain development is at a maximum. There is evidence that maternal hypothyroidism may cause subtly impaired neuropsychological development in the subsequent offspring. Apart from meticulous control of maternal thyroid function during pregnancy, it is wise for thyrotoxic patients not to become pregnant until stable normal thyroid function has been achieved. Measurement of the thyrotropin-receptor antibody concentration in maternal serum during the last examination before delivery may be helpful because a high level is a predictor of neonatal thyrotoxicosis. Since thyroid hormones cross the placenta relatively poorly, the block-and-replace regime is not recommended during pregnancy.
Methimazole (CBZ) or Propylthiouracil? Aplasia cutis congenita (ACC) is a rare disorder of the skin, usually affecting the scalp and less than 3 cm in diameter, that has been reported in a small number of
Appetite see Hunter and Satiation
Antithyroid Drugs
neonates whose mothers received MMI during pregnancy. ACC has not been reported in association with PTU, which is widely used in North America, and some believe that PTU is the drug of choice during pregnancy or for those planning pregnancy. The consensus, however, is that there is insufficient evidence to establish a direct causal relationship between ACC and MMI. Because MMI (CBZ) and PTU are equally effective in controlling Graves’ hyperthyroidism during pregnancy, it makes sense to use the preparation with which one has most experience. If hyperthyroidism recurs after delivery, is due to Graves’ disease and not postpartum thyroiditis, and the mother wishes to breast-feed, PTU is the drug of choice because it is transferred to the milk one-tenth as much as the other thionamides.
See Also the Following Articles Graves’ Disease . Graves’ Disease, Hyperthyroidism in . Hyperthyroidism, Subclinical . Iodine, Radioactive . Thyroid Disease, Epidemiology of . Thyroid Function Tests . TSH Receptor (Thyrotropin Receptor)
Further Reading Hancock, L. D., Tuttle, R. M., LeMar, H., Bauman, J., and Patience, T. (1997). The effect of propylthiouracil on subsequent radioactive iodine therapy in Graves’ disease. Clin. Endocrinol. 47, 425–430. Hershman, J. M., Givens, J. R., Cassidy, C. E., and Astwood, E. B. (1966). Long-term outcome of hyperthyroidism treated with antithyroid drugs. J. Clin. Endocrinol. Metab. 26, 803–807. McIver, B., Rae, P., Beckett, G., Wilkinson, E., Gold, A., and Toft, A. (1996). Lack of effect of thyroxine in patients with Graves’ hyperthyroidism who are treated with an antithyroid drug. N. Engl. J. Med. 334, 220–224. Mestman, J. H. (1998). Hyperthyroidism in pregnancy. Endocrinol. Metab. Clin. North Am. 27, 127–149. Page, S. R., Sheard, C. E., Herbert, M., Hopton, M., and Jeffcoate, W. J. (1996). A comparison of 20 or 40 mg per day of carbimazole in the initial treatment of hyperthyroidism. Clin. Endocrinol. 45, 511–515.