1. Graves’ hyperthyroidism and anti-thyroid drugs By 蔡文欽

2. Case The patient is a 77 years female with history of hypertension with regular treatment for many years. She suffered from poor appetite, body weight loss, diarrhea, sweating, insomnia, palpitation, weakness, anxiety and hand tremor difficult swallow function for two months. She went to our OPD and was admitted for further evaluation and management.

3. PE Conscious:clear Skin: warm and moist HEENT: no protrudent eye; fine air Neck: no palpable mass Heart: tachycardia; RHB. Limbs: proximal weakness; edema(+); tremor(+)

5. Treatment PTU(50mg/tab) 2# BID Propranolol 2# TID

6. Graves' disease Patient with biochemically confirmed thyrotoxicosis, diffuse goiter on palpation, ophthalmopathy, positive TPO antibodies, and often a personal or family history of autoimmune disorders.

7. Introduction Thionamides, a sulfhydryl group and a thiourea moiety within a heterocyclic structure Propylthiouracil (PTU, 6-propyl-2-thiouracil). Methimazole (1-methyl-2-mercaptoimidazole); in US, Asia and Europe. Carbimazle (analogue of methimazole); in UK. Inhibit TPO-mediated iodination

8. Introduction Propylthiouracil block the conversion of T4  T3 within the thyroid and in peripheral tissues Immunosuppressive effects  TRAb, intracellular adhesion molecule, IL-2 and IL-6 receptors.

13. clinical pharmacology Rapid GI absorbtion. No dosed adjustment in children, elderly, liver disease or renal failure. PTU  T 1/2 : 90mins  80-90% bound to albumin Methimazole  T 1/2 : 6hrs  Free form

14. clinical use of drugs Primary treatment for hyperthyroidism or as preparative therapy before radiotherapy or surgery. Weighed against the risks and benefits of the more definitive therapy, such as radioiodine and surgery.  Ophthalmopathy, pregnancy and most children and adolescents. Randomized trial comparing antithyroid drugs, radioiodine, and surgery  patient satisfaction was more than 90 percent for all three,  Lowest medical costs in ATD.

15. choice of drugs oncedaily in methimazole; better adherence and rapid improvement in T3 and T4 than PTU. PTU (300 mg daily)  $408 /year Methimazole (15 mg daily, $360; or 30 mg daily, $720). Side-effect profiles of the two drugs  methimazole. PTU is preferred during pregnancy.

16. practical considerations methimazole vs PTU  1:10; underestimate  10mg  85%; 40mg  92% after six weeks Follow-up every 4-6 weeks  2-3 months after 3-6 months; then 4-6 months

17. Remission Less remission if more severe degrees of hyperthyroidism, large goiters, high TRAb or a high T3/T4 after course of drug treatment. High relapse if depression, paranoia and problem of daily life. Poor clinical or biochemical predictor in 300 patients study. TRAb(+) after treatment  relapse; normal  relapse(30-50%). Duration and dose vs relapse. 12 to 18 months is recommended.

18. Discontinuation of drug treatment Stopped or tapered after 12 to 18 ms except children and adolescents. Relapse after 3-6 ms; 50-60%. Pregnancy  postpartum relapse or thyroiditis. ↑Failure rate of radioiodine in PTU.

21. Minor side effect Dose-related in methimazole. Cross-reactivity  50%. Arthragia  antithyroid arthritis syndrome.

22. Major side effect Agranulocytosis(90 days; 0.35% vs 0.37%)  Autoimmune process; ANCA. 1000-1500.  Fever and sore throat; stop drugs and G-CSF.  Pseudomonas aeruginosa. Hepatotoxicity(0.1-0.2%)  Hepatocellular injury in PTU and cholestatsis in methimazole Vasculitis (PTU>methimazole)  Lupus; self-limited  Steroid or cyclophosphamide; H/D.

23. Use of antithyroid drugs during pregnancy and lactation Congenital anomalies, esp aplasia cutis while methimazole (1/2000 births). Methimazole embryopathy; 2/241 vs. 1/2500 to 1/10,000 (esophageal atresia and choanal atresia). No increase in other studies. Class D (risk of fetal hypothyroidism). No risk in breast milk