Antithyroid Drugs

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Introduction. use for more than half a centurythe treatment of choice for most young people with Graves' disease. Mechanism of Action . simple molecules :thionamides, contain a sulfhydryl group and a thiourea moiety within a heterocyclic structure Propylthiouracil and methimazole: United StatesMethimazole: Europe and AsiaCarbimazole: United Kingdom actively concentrated by thyroid gland against a concentration gradient.inhibit thyroid hormone synthesis by interfering with thyroid peroxid30777

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Antithyroid Drugs

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1. Antithyroid Drugs New England Medical Journal David S. Cooper, M.D March 3, 2005 Number 9 Volume 352:905-917 by R4 ??? .

2. Introduction use for more than half a century the treatment of choice for most young people with Graves' disease

3. Mechanism of Action simple molecules :thionamides, contain a sulfhydryl group and a thiourea moiety within a heterocyclic structure Propylthiouracil and methimazole: United States Methimazole: Europe and Asia Carbimazole: United Kingdom actively concentrated by thyroid gland against a concentration gradient. inhibit thyroid hormone synthesis by interfering with thyroid peroxidase–mediated iodination of tyrosine residues in thyroglobulin

7. Mechanism of Action-2 PTU block the conversion of T4 to T3 within the thyroid and in peripheral tissues immunosuppressive effects: 1) antithyrotropin-receptor antibodies 2) intracellular adhesion molecule 1 3) soluble interleukin-2 and interleukin-6 receptors decrease with time may induce apoptosis of intrathyroidal lymphocytes, and decrease HLA class II expression ?circulating suppressor T cells ? helper T cells, natural killer cells and activated intrathyroidal T cells

9. Mechanism of Action-3 analyses of animal data and human studies suggested that changes in the immune system may not be predicated solely on changes in thyroid function.

10. Clinical Pharmacology rapidly absorbed from GI tract peak within one to two hours Serum levels have little to do with antithyroid effects, which typically last from 12 to 24 hours for PTU methimazole ? long duration ?once-daily Methimazole is essentially free in serum, whereas 80 to 90 percent of PTU is bound to albumin

11. Clinical Pharmacology -2 doses do not need to be altered in children ,elderly, renal failure and liver disease, although the clearance of methimazole (but not PTU) may be decreased.

12. Clinical Use of Drugs two ways: primary treatment for hyperthyroidism or preparative therapy before radiotherapy or surgery Graves' disease, "remission“ is possible. (euthyroid for one year after cessation) not primary therapy for toxic multinodular goiters and solitary autonomous nodules, because spontaneous remissions rarely occur

13. Clinical Use of Drugs-2 primary treatment in pregnant and most children and adolescents preferable in severe Graves' eye disease radioiodine therapy has been associated with worsening ophthalmopathy

15. Clinical Use of Drugs-3 antithyroid drugs, radioiodine, and surgery :patient satisfaction > 90% costs lowest : drug also used to normalize thyroid function before the administration of radioiodine, caused by a rise in stimulating antithyrotropin-receptor antibodies

16. Choice of Drugs methimazole>PTU, by better adherence and more rapid improvement in T3 and T4, and side-effect propylthiouracil : during pregnancy.

17. Practical Considerations starting dose of methimazole : 15 to 30 mg qd, PTU : 300 mg daily tid many patients can be controlled with smaller doses of methimazole, suggesting that the accepted potency ratio of 10:1 for methimazole as compared with PTU is underestimated . if methimazole is overly aggressive iatrogenic hypothyroidism with relatively mild hyperthyroidism may result

18. Practical Considerations-2 follow-up every four to six weeks, until thyroid function is stable or the patient becomes euthyroid Maintenance : 5 to 10 mg of methimazole or 100 to 200 mg of PTU daily. hypothyroidism or goiter can develop if the dose is not decreased appropriately

19. Practical Considerations-3 After the first three to six months, follow-up intervals can be increased to every two to three months and then every four to six months. Serum TSH levels remain suppressed for weeks or even months, despite a normalization of thyroid hormone levels, so a test of TSH is a poor early measure

20. Practical Considerations-4 patients sometimes continue to have elevated serum T3 levels despite normal or even low T4 or FT4, ?increase, not decrease, the antithyroid drug dose

21. Low Remission severe hyperthyroidism large goiters T3-to-T4 ratio >20 higher baseline levels of antithyrotropin-receptor antibodies

22. Remission-2 age, sex, and smoking Ophthalmopathy duration of symptoms before diagnosis risk factors for relapse ?depression, hypochondriasis, paranoia, mental fatigue after an average of three years of antithyroid-drug therapy

23. Remission-3 TSHR at the end of a course of treatment predictive value -->positive : relapse often However, even those patients whose antibody titers have normalized have a fairly high rate of relapse (30 to 50 percent)

24. Remission-4 Since immunosuppressive effects, a higher dose or longer treatment duration might enhance the chances of remission. prospective trials >4y follow-up do not indicate that treatment for >1 year has any effect on relapse rates treatment for 12 to 18 months is the usual practice

25. Remission-5 a Japanese study showed that a combination of an antithyroid drug plus thyroxine for 1year, followed by thyroxine alone for 3 years, decreased the relapse rate significantly

26. Discontinuation of Drug Treatment children and adolescents, are often for many years, relapse is increased in normal FT4 and T3 but suppressed TSH. Relapse usually occurs within the first three to six months after medication is stopped

27. Discontinuation of Drug Treatment-2 overall recurrence rate 50 to 60 percent. About 75 percent of women in remission who become pregnant will have a postpartum relapse of Graves' disease or the development of postpartum thyroiditis.

28. Discontinuation of Drug Treatment-3 When used before radioiodine therapy, PTU (but not methimazole), increases the failure rate of the radioactive iodine This "radioprotective" effect of PTU may be related to its ability to neutralize iodinated free radicals produced by radiation exposure, can be overcome by increasing the radioiodine dose.

29. Side Effects methimazole are dose-related, (PTU less clear ) cutaneous reactions (usually urticaria or macular rashes), arthralgia, and GI upset 5% of patients, with equal frequency for both drugs

30. Side Effects-2 cross-reactivity between the two agents may be as high as 50 percent. the use of the alternative antithyroid drug is contraindicated arthralgias, should prompt drug discontinuation, : may be a harbinger of a severe transient migratory polyarthritis known as "the antithyroid arthritis syndrome”

31. Side Effects-3 Agranulocytosis an absolute granulocyte count of less than 500 per cubic millimeter 0.37 % in PTU and 0.35 % methimazole must be distinguished from the transient, mild granulocytopenia (<1500 per cubic millimeter) in Graves' disease, African descent, and occasionally in patients treated with antithyroid drugs. baseline differential white-cell count

32. Side Effects-4 Agranulocytosis Occur within 90 days of treatment, but can occur >1 year greater in older patients A higher rate of death can develop after a prior uneventful course, a relapse and a second course of therapy.

33. Side Effects-5 Fever and sore throat are the most common sepsis :very rapid onset of fever, chills, and prostration Pseudomonas aeruginosa most common G-CSF may shorten the time to recovery and length of hospitalization

34. Side Effects-6 Hepatotoxicity 0.1 to 0.2 % 30 % with normal baseline GPT treated with PTU, transient increases ranging from 1.1 to 6 times normal —resolve while therapy is continued. asymptomatic elevations in GPT occur frequently in untreated patients with hyperthyroidism and are not predictive of further increases after PTU therapy.

35. Side Effects-7 The average duration of PTU therapy before the onset of hepatotoxicity is approximately three months allergic hepatitis Pathology: submassive or massive hepatic necrosis case fatality rate of 25 to 50 % Liver transplantation may be required

36. Side Effects-8 methimazole and carbimazole are typical of a cholestatic process alternative agent could be used cautiously

37. Side Effects-8 Vasculitis PTU >methimazole drug-induced lupus perinuclear antineutrophil cytoplasmic antibodies, antimyeloperoxidase antineutrophil cytoplasmic antibodies. Mechanism: PTU can react with myeloperoxidase to form reactive intermediates ?promote autoimmune inflammation

38. Side Effects-9 Vasculitis acute renal dysfunction, arthritis, skin ulcerations, vasculitic rash, and upper and lower respiratory symptoms, including sinusitis and hemoptysis. Although resolves after drug cessation, high-dose glucocorticoid or cyclophosphamide in severe cases short-term hemodialysis

40. Pregnancy and Lactation Thyrotoxicosis occurs in 1 /1000 to 2000 pregnancies an antithyroid drug should be started at the time of diagnosis PTU in North America because cross the placenta minimally as compared with methimazole However, recent studies suggest that PTU does, in fact, cross the placenta

41. Pregnancy and Lactation-2 congenital anomalies with methimazole, particularly aplasia cutis, (single or multiple lesions of 0.5 to 3 cm at the vertex or occipital of scalp) very rare "methimazole embryopathy," ?choanal or esophageal atresia. 2 of 241 children of women exposed to methimazole, (spontaneous rate of 1 in 2500 to 1 in 10,000 for esophageal atresia and choanal atresia, respectively).

42. Pregnancy and Lactation-3 If allergy to PTU, methimazole can be substituted class D agents (i.e., drugs with strong evidence of risk to the fetus) If the maternal FT4 level is maintained at or slightly above the upper limit of normal, the risk of fetal hypothyroidism is negligible.

43. Pregnancy and Lactation-4 By the third trimester, approximately 30 % of women can discontinue therapy and still remain euthyroid For nursing mothers, both drugs are considered safe

44. Thyroid Storm PTU preferred : inhibit conversion of T4 to T3, (but no evidence that it is more efficacious than methimazole) A high dose of either drug should be used, 60 to 120 mg of methimazole 600 to 1200 mg of PTU per day in divided doses

45. Thyroid Storm-2 A CBC/DC obtained immediately and discontinued if granulocyte count <1000 per cubic millimeter

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