1. Thyroid hormones and antithyroid drugs Dept of Pharmacology Shi-Hong Zhang (张世红) shzhang713@zju.edu.cn

2. Thyroid gland Front view

3. 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

6. Hyperthyroidism 颤抖 心慌，心脏肥大 腱反射亢进 多食、腹泻、消瘦 甲状腺肿大，突眼，情绪激动

7. cretinism (呆小症) Hypothyroidism simple goiter (单纯性甲状腺肿) 瘿

10. Therapeutic drugs on thyroid dysfunction • Hyperthyroidism: • antithyroid drugs: thiourea derivatives 硫脲类 iodine and iodides 碘和碘化物 receptor antagonists Radioiodines 放射性碘:131I • Hypothyroidism: • thyroid hormones • iodine and iodides

12. Antithyroid drugs Thiourea derivatives 丙硫氧嘧啶 甲巯咪唑 卡比马唑

13. Antithyroid drugs 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) Inhibiting peripheral deiodination of T4: T4 T3 (propylthiouracil 丙硫氧嘧啶)

14. Antithyroid drugs Thiourea derivatives 1. Pharmacological effects (3) Inhibiting glucose metabolism by down-regulating βreceptor (4) Immunosuppression: TSI↓

15. Mechanism of inhibition of thyroid hormone synthesis by thioureas: Thioureas are oxidized by oxidized thyroid peroxidase (TPO)

16. Thiourea derivatives 2. 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 3. Adverse effects (1) Agranulocytosis (0.2%) (2) Hypersensitivity (3) GI reactions (5) Goitrogenic action (goiter): TSH↑

17. Antithyroid drugs 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.

18. Mechanism of iodides

19. Antithyroid drugs 2. Clinical uses (1) Simple goiter (2) Preoperative therapy of hyperthyroidism:combined with thiourea derivatives (2) Thyrotoxic crisis:combined with thiourea derivatives (propylthiouracil) Lugol’s solution 卢戈氏液: 5% iodine and 10% potassium iodide

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

21. Antithyroid drugs Radioiodines • 131I, 125I, 123I • Destroying thyroid tissue: βray • Careful use for hyperthyroidism and differentiated thyroid carcinoma • Radioactive iodine uptake test

22. Antithyroid drugs  receptor antagonists 1. Pharmacological effects (1) Heart: 1 block (2) CNS: relieving anxiety (3) Presynaptic 2 receptor: NE release  2. Clinical uses Adjuvant therapeutic drug

23. Pancreatic hormones & antidiabetic drugs

24. 胰高血糖素 胰岛素 生长抑素

25. Overview of Glucose Regulation by insulin Glucose absorption lipolysis Insulin secretion lipogenesis Persistent Hepatic Glucose Output Glucose disposal Glycogenesis Amended from Dinneen SF. Diabetes Med. 1997;14(suppl 3):S19-24.

26. Different forms of diabetes mellitus

27. prediabetic metabolic syndrome “Beta-cell failure”

29. Complications of diabetes mellitus • Acute complications • Diabetic ketoacidosis (酮症酸中毒) • Hyperosmotic nonketotic coma(高渗性非酮症性昏迷） • Chronic complications • Cardiovascular diseases • Renal damage • Retinal damage • Nerve degeneration • Infection • Myopathy • etc.

31. Pharmacological therapy • Insulin • Oral hypoglycemic drugs • Insulin secretagogues (促胰岛素分泌药): • Sulfonylureas 磺酰脲类 • Meglitinides (Non-SU)格列奈类 • GLP-1 agonists and DPP-4 inhibitors • Insulin sensitizers胰岛素增敏剂: • Thiazolidinediones (TDs，噻唑烷二酮类) • Biguanides 双胍类 • α-glucosidase inhibitors α-葡萄糖苷酶抑制剂 • Amylin analogue胰淀粉样多肽类似物 • Aldose reductase inhibitor 醛糖还原酶

32. A. Insulin

33. Frederick Sanger (1918- )

34. A. Insulin 1. Pharmacological effects (1) Carbohydrate metabolism:reducing blood glucose levels by glycogenolysis , glycogen synthesis , gluconeogenesis  (ketone bodies ), glucose transport . (2) lipid metabolism:fat synthesis , lipolysis , plasma free fatty acids  (3) Protein metabolism:active transport of amino acids , incorporation of amino acids into protein , protein catabolism  (4) Mechanism of insulin actions Interacting with insulin receptor

36. A. Insulin 2. Clinical uses (1) Insulin-dependent patients with diabetes mellitus (type 1 diabetes mellitus) (2) Insulin-independent patients:failure to other drugs (3) Diabetic complications:diabetic ketoacidosis (酮症酸中毒), hyperosmotic nonketotic coma（高渗性非酮症性昏迷） (4) Critical situations of diabetic patients:fever, severe infection, pregnancy, trauma, operation (5) Others:promotion of K+ uptake into the cells

37. A. Insulin • 3. Preparations • Fast-acting insulin • Regular insulin 正规胰岛素 • Monocomponent insulin 单组分胰岛素 • Start working 0.5-1h after injection, reach peak 2-4h, and last 5-7h.

38. A. Insulin • 3. Preparations • Intermediate-acting insulin • Neurtral protamine hagedorn (NPH) 中性精蛋白锌胰岛素 • Isophane insulin 低精蛋白锌胰岛素 • Globin zinc insulin 珠蛋白锌胰岛素 • Start working 1-1.5h after injection, reach peak 8-12h, and last 24h.

39. A. Insulin • 3. Preparations • Long-acting insulin • Protamine zinc insulin(PZI) 鱼精蛋白锌胰岛素 • Start working 4-8h after injection, reach peak 14-20h, and last 24-36h.

40. A. Insulin • 3. Preparations • Mixed insulin • Human insulin isophane 低精蛋白锌胰岛素+ • Human insulin 人胰岛素 • Start working 0.5h after injection, reach peak 2-12h, and last 16-24h.

41. A. Insulin • 3. Preparations • Fast-acting insulin analogs • Insulin aspart 门冬胰岛素 • Insulin lispro 赖脯胰岛素 • Start working 5-15 minutes after injection, reach peak at 1h, and last ~4 hours.

42. A. Insulin • 3. Preparations • Super-long acting insulin analogs • Insulin glargine 甘精胰岛素 • Onsets 1-2 h after injection and continues to work for as long as 24 hours. • Used to treat type 1 or type 2 diabetes mellitus. • Less soluble than native human insulin at physiological pH, and precipitates in skin following subcutaneous injection, resulting in delayed absorption.

44. For patients who eat meals out, may consider use of an insulin pen. Most insulins now available as pen

45. Insulin Pump and Glucose Monitoring Insulin Pump – “Open Loop” Patient sets basal infusion rate and superimposed boluses Continuous Glucose Monitor “Closed Loop” insulin pump system is ultimate goal: infusion rate adjusted based on input from continuous glucose monitor.

46. A. Insulin 4. Adverse effects (1) Hypersensitivity: treated with H1 receptor antagonist, glucocorticoids (2) Hypoglycemia:adrenaline secretion (sweating, hunger, weakness, tachycardia, blurred vision, headache, etc.), treated with 50% glucose (3) Insulin resistance: acute, chronic (4) Lipoatrophy and lipohypertrophy (5) Weight gain (6) Refractive errors (7) Edema

47. B. Oral hypoglycemic drugs • Insulin secretagogues （促胰岛素分泌药）: • Sulfonylureas 磺酰脲类 • Meglitinides (Non-SU)格列奈类(苯丙胺酸衍生物) • GLP-1 agonists and DPP-4 inhibitors • Insulin sensitizers胰岛素增敏剂: • Thiazolidinediones (TDs，噻唑烷二酮类) • Biguanides 双胍类 • α-glucosidase inhibitors α-葡萄糖苷酶抑制剂 • Amylin analogue胰淀粉样多肽类似物 • Aldose reductase inhibitor 醛糖还原酶

48. B. Oral hypoglycemic drugs Sulfonylureas（磺酰脲类） Tolbutamide (D860) 甲苯磺丁脲 Chlorpropamide 氯磺丙脲 Glibenclamide 格列本脲 (优降糖) Glipizide 格列吡嗪（美吡达） Gliclazide 格列齐特 (达美康)

49. Sulfonylureas 1. Pharmacological effects 1) Increase insulin release: blocking ATP sensitive K+ channel,Ca2+ inflow 

50. Sulfonylureas 1. Pharmacological effects 2) Increase receptor affinity to insulin (long-term use) 3) Promote glucose uses 4) Increase sensitivity of βcells to glucose 5) Anti-uretic effect (Chlorpropamide 氯磺丙脲) 6) Anti-platelet effect (Gliclazide格列齐特)