Thyroid hormones and antithyroid drugs

1. Thyroid hormones and antithyroid drugs Huifang Tang Email: tanghuifang@zju.edu.cn

2. Metabolism of thyroid hormones 1.Uptake of iodide 2.Oxidation of iodide (peroxidase) and iodination and coupling of tyrosine 3. Formation of thyroxine (T4) and triiodothyronine (T3) from iodotyrosine 4.Secretion of thyroid hormones (proteolytic enzymes) 5.Regulation by thyroid stimulating hormone (TSH), T4, T3

4. Formation of thyroxine (T4) and triiodothyronine (T3) from iodotyrosine

5. Different forms of thyroid hormones

6. Action of thyroid hormones:interaction with their receptors in the nuclei

7. Regulation of Thyroid hormone

8. 1. Normalizing growth and development 2. Promoting body metabolism Body temperature; energy levels, ect. 3. Enhancing sympathetic activity 4. Cardiovascular Effects Pharmacology of thyroid hormones

9. Hyperthyroidism: antithyroid drugs: thiourea derivatives iodine and iodides  receptor antagonists surgery radioiodines: 131I, 125I Hypothyroidism: thyroid hormones iodine and iodides Therapeutic drugs on thyroid function

10. 1. Treatment of hypothyroidism A. thyroid hormones Hypothyroidism Cretinism（呆小病） Myxedema（粘液性水肿）

11. Common signs and symptoms Cretinism:a situation induced by a insufficiency of thyroid hormone at birth and during minority, execute growth, twined facial features, increased tongue and mental detainment Adult: Fatigue, weakness, weight gain or increased difficulty, losing weight, cold intolerance Coarse, dry hair, dry and rough pale skin, hair loss Muscle cramps and frequent muscle aches Constipation(便秘) Depression, irritability Memory loss Abnormal menstrual cycles, decreased libido A. thyroid hormones

12. Myxedema describes a specific form of cutaneous and dermal edema secondary to increased deposition of connective tissues, as seen in various forms of hypothyroidism A.thyroid hormones

13. Etiology PRIMARY HYPOTHYROIDISM Hoshimoto’s thyroiditis-most common Irradiation of thyroid Surgical removal Late stage invasive fibrous thyroiditis Iodine deficiency Drug therapy (Lithium) Infiltrative Diseases: Sarcoidosis, Amyloidosis Scleroderma, Hemochromatosis A. thyroid hormones

14. SECONDARY HYPOTHYROIDISM 5% of cases. Pituitary or hypothalamic neoplasm. Congenital hypopituitarism. Pituitary necrosis (Sheehan’s syndrome) A. thyroid hormones

15. Diagnosis In Primary Hypothyroidism TSH is high. Free thyroid hormone are depressed. In Secondary Hypothyroidism Both TSH and free thyroid hormones are low. A. thyroid hormones

16. Thyroid Hormone Replacement Levothyroxine(左甲状腺素) can cause increases in resting heart rate and blood pressure So replacement should start at low doses in older and patients at risk for cardiovascular compromise Myxedema Coma Below normal temperature, decreased breathing, low blood pressure, low blood sugar, unresponsiveness Hydrocortisone, T3 A. thyroid hormones

17. 2. Simple goiter (单纯性甲状腺肿) Supply iodide--iodide deficiency Thyroid hormones Surgry--nodule A.thyroid hormones simple goiter

18. B. Antithyroid drugs

19. Hyperthyroidism

20. Thyroid crisis clinical features Exacerbation of features of hyperthyroidism- hyperpyrexia. May be extreme (>39oC) and is generally considered essential to diagnosis. - confusion, fits, coma, muscle weakness. Very common. - arrhythmias, cardiac failure. Decreasing pulse rate and BP with the development of shock are associated with poor prognosis- vomiting, diarrhoea. Occasionally jaundice: associated with poor prognosis- hyperkalaemia relatively common (15%) but rarely a problem in itself- rarely apathetic hyperthyroidism (usually elderly patients) may present in crisis with features of profound exhaustion, hyporeflexia, severe myopathy, marked weight loss and hypotension

21. How To Diagnose Hyperthyroidism TSH – expect this to be low Free T4 – expect to be high Nuclear thyroid scintigraphy I131 uptake and scan – expect iodine uptake to increased TSH-receptor stimulating autoantibody levels (TSI levels, 甲状腺刺激性免疫球蛋白)

22. antithyroid drugs:thiourea derivatives iodine and iodides  receptor antagonists radioiodines:131I, 125I surgery Therapeutic drugs for Hyperthyroidism

23. Thiourea derivatives Propylthiouracil 丙硫氧嘧啶 Methimazole (tapazole) 甲巯咪唑 Carbimazole 卡比马唑 Iodine and iodides  Receptor antagonists Radioiodide(131I) B. Antithyroid drugs

24. B. Antithyroid drugs Thiourea derivatives 甲巯咪唑Thiamazole 丙硫氧嘧啶（PTU） 卡比马唑

25. thyroid peroxidase (TPO) Mechanism of inhibition of thyroid hormone synthesis by thiaureas

26. Thiourea derivatives 1. Pharmacological effects (1) Inhibiting the formation of thyroid hormones by interfering with iodination:inhibiting peroxidation, then the iodination and coupling Symptom relieving: 2-3 weeks Basic metabolic rate returning: 1～2 months (2) Inibiting peripheral deiodination of T4: T4 T3 (propylthiouracil) (3) Decrease the carbohydrate metabolism mediated by β-receptor (4) Immunosuppress action, decrease TSI B. Antithyroid drugs

27. Physiological process Absorption： easy to be absorbed when taken orally. Thiouracil is the most fast to be absorbed. Imidazole is absorbed slowly. The bioavailability is 80％ The plasma protein binding rate is 75%. T1/2: 2h. T1/2 of tapazole is 4.7h. Distribution：organs generally all over the body and can pass the placenta. The concentration in lacto is about 3 times as in blood. Metabolism：Mainly in liver , fast . 60％ are destroyed in vivo，the rest are eliminated by urine in a conjugative form. Carbimazole functions after turning into tapazole in vivo. B. Antithyroid drugs

28. 3. Clinical uses (1) Non-operative therapy of hyperthyroidism:latent period (2) Preoperative therapy of hyperthyroidism:combined with iodide (3) Thyrotoxic crisis:combined with larger dose of iodide, propylthiouracil B. Antithyroid drugs

29. 4. Adverse effects (1) agranulocytosis (0.3%-0.6%) (2) Hypersensitivity (3) GI reactions (4) Goiter Caution: periodic inspection of hemogram. The medication shoule be stopped if the symptoms as pharyngalgia, fever occur. Female during lactation period, thyroid cancer patients and nodular goiter with hyperthyroidism are forbidden to take. B. Antithyroid drugs

30. Iodine and iodides 1. Pharmacological effects (1) Small doses:simple goiter (2) Larger doses:inhibiting the release of thyroid hormones (proteolysis ) and synthesis After iodide use, the thyroid vascularity is reduced, and the gland becomes much firmer, the cells become smaller( (inhibiting TSH release). After two week use, I uptake is inhibited, hyperthyroidism. So not treat hyperthyroidism along. B. Antithyroid drugs

31. Wolff-Chaikoff效应 Mechanism of iodides

32. 2. Clinical uses (1) Small doses: simple goiter Add 1/10000~1/100000 potassium iodide or sodium iodide to salt could prevent the desease. Early stage potassium iodide (10mg) or Lugol’s solution (0.1ml or 0.5 ml/d) Lugol’s solution: 5% iodine and 10% potaasium iodide (2) Larger doses: Preoperative therapy of hyperthyroidism: Lugol’s solution combined with thiourea derivatives (for 2 weeks) Thyrotoxic crisis: combined with thiourea derivatives (propylthiouracil) B. Antithyroid drugs

33. 3. Adverse effects (1) Acute effects:hypersensitivity, angioedema, swelling of the larynx (2) Chronic intoxication (iodism) (3) Thyroid dysfunction:exacerbation of hyperthyroidism, goiter B. Antithyroid drugs

34. Receptor antagonists 1. Pharmacological effects (1) Heart: 1 block (2) CNS: relieving anxiety (3) Presynaptic 2 receptor: NE release  (4) Inhibiting the conversion of T4 to T3 2. Clinical uses Adjuvant therapeutic drug B. Antithyroid drugs

35. Radioiodedes 131I, 125I, 123I 1. Pharmacological effects 131I is rapidly absorbed, concentrated by the thyroid, and into storage follicles. Its effects depends on emission of β-rays and a penetration range of 500-2000μm, the thyroid was destructed within a few weeks after administration. B. Antithyroid drugs

36. Radioiodine 131I, 125I, 123I 2. Clinical uses Hyperthyroidism in long course, and other drugs can not control the symptom. Diagnosis. ( ray generated by 131I accounts for 1％ and can be detected in vitro . It is usually used in the examination of thyroid iodine uptaking function ) iodine uptake rate high when hyperthyroid , time of iodine uptake peak antelocation; iodine uptake rate low when hypothyroid , time of iodine uptake peak retroposition B. Antithyroid drugs

37. Radioiodine 131I, 125I, 123I 3. Adverse effects Hypothyroidism. Radioactive iodine should not be administered to pregnant women or nursing mothers, since it cross the placenta and is excreted in breast milk. B. Antithyroid drugs

38. Therapeutic drugs on thyroid function Hyperthyroidism: antithyroid drugs: thiourea derivatives ( Propylthiouracil 丙硫氧嘧啶 Methimazole (tapazole) 甲巯咪唑 Carbimazole 卡比马唑) iodine and iodides  receptor antagonists surgery radioiodines: 131I, 125I Hypothyroidism: thyroid hormones iodine and iodides Summary

40. (conti.)