1. Chapter 42 Insulin and oral hypoglycemic drugs

2. 正常人糖尿病尿崩症

3. Different forms of diabetes mellitus

4. Complications of diabetes mellitus §Acute complications § Diabetic ketoacidosis § Hyperosmotic nonketotic coma §Chronic complications § Cardiovascular diseases § Renal damage § Retinal damage § Nerve degeneration § Infection § Myopathy § etc.

5. A. Insulin and its enhancers

6. Structure of insulin

7. A. Insulin and its enhancers Insulin 1. Pharmacological effects (1) Carbohydrate metabolism: reducing blood glucose levels by gycogenolysis , glycogen synthesis , gluconeogenesis  (ketone badies  ) (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 Interacting with insulin receptor

9. Structure of insulin

13. 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, pshychiatric disorders A. Insulin and its enhancers

14. 3. Preparations Properties Properties Preparations PreparationsOnsetPaekDuration Fast-acting Regular insulin 0.5 - 1h 2-3h 6-8 h Intermmediate- acting Neutral protamine hagedorn 2-4h6-10h 12-18 h Long-acting Protamine zinc insulin suspension 3-6h6-10h 24-36 h A. Insulin and its enhancers

15. 4. Adverse effects (1) Hypersensitivity: treated with H 1 receptor antagonist, glucocorticoids (2) Hypoglycemia: adrenaline secretion (sweeting, hunger, weakenss, tachycardia, blurred vision, headache, etc.), treated with 50% glucose (3) Insulin resistance: acute, chronic (4) Lipoatrophy and lipohypertrophy A. Insulin and its enhancers

16. Insulin action enhancers Thiazolidinediones (TDs) 噻唑烷酮类化合物 Rosiglitazone 罗格列酮 Rosiglitazone 罗格列酮 Pioglitazone 吡格列酮 Pioglitazone 吡格列酮 Troglitazone 曲格列酮 Troglitazone 曲格列酮 A. Insulin and its enhancers

17. Rosiglitazone罗格列酮 Pioglitazone Pioglitazone吡格列酮

18. Insulin action enhancers 1. Pharmacological effects Selective agonists for nuclear peroxisome proliferator-activated receptor-  (PPAR , 过氧化物酶 增殖体激活受体  ), increasing glucose transport into muscle and adipose tissue. Selective agonists for nuclear peroxisome proliferator-activated receptor-  (PPAR , 过氧化物酶 增殖体激活受体  ), increasing glucose transport into muscle and adipose tissue. (1) Lowering insulin resistance (2) Lipid metabolism regulation: TG, free fatty acid  (3) Antihypertensive effects A. Insulin and its enhancers

19. 2. Clinical uses used for treatment of insulin-resistant diabetic patients or type 2 patients used for treatment of insulin-resistant diabetic patients or type 2 patients 3. Adverse effects Edema, headache, myalgia, GI reactions, hepatic damage (troglitazone) A. Insulin and its enhancers

20. B. Oral hypoglycemic drugs SulfonylureasBiguanides  -Glucosidase inhibitors Others

21. B. Oral hypoglycemic drugs Sulfonylureas 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 Gliclazide 格列齐特 ( 达美康 )

23. B. Oral hypoglycemic drugs 1. Pharmacological effects Blocking K + channel: Ca 2+ inflow , insulin release , Stimulating insulin secretion Increasing insulin sensitivity (long-term use)

24. B. Oral hypoglycemic drugs 2. Clinical uses (1) Insulin-indenpedent diabetic patients (type 2): alone or combined with insulin (2) Diabetes insipidus ( 尿崩症 ) : Chlorpropamide ( 氯磺丙脲 ): antiuretic hormone (ADH) 

25. B. Oral hypoglycemic drugs 3. Adverse effects (1) GI reactions (2) CNS reactions (3) Hypoglycemia: especially in elderly, hepatic or renal insufficiencies (4) Others: leukopenia, cholestatic jaundice, hepatic damage

26. B. Oral hypoglycemic drugs 4. Drug interactions (1) Potentiation of hypoglycemic effects replacement in plasma protein binding: salicylic acid, sulfates, indomethacin, penicillin, warfarin, etc. replacement in plasma protein binding: salicylic acid, sulfates, indomethacin, penicillin, warfarin, etc. inhibition of hepatic microsomal enzymes: chloramphenicol, warfaren inhibition of hepatic microsomal enzymes: chloramphenicol, warfaren (2) Attenuation of hypoglycemic effects induction of hepatic microsomal enzymes: phenytoin, phenobarbital, etc. induction of hepatic microsomal enzymes: phenytoin, phenobarbital, etc. interactions in pharmacodynamics: glucagon, thiazides, etc. interactions in pharmacodynamics: glucagon, thiazides, etc.

27. B. Oral hypoglycemic drugs Biguanides Metformin 二甲双胍 Metformin 二甲双胍 Phenformin 苯乙双胍 Phenformin 苯乙双胍

28. B. Oral hypoglycemic drugs 1. Pharmacilogical effects increasing glucose uptake in fat tissues and anaerobic glycolysis in skeletal muscles increasing glucose uptake in fat tissues and anaerobic glycolysis in skeletal muscles decreasing glucose absorption in gut and glucagon release decreasing glucose absorption in gut and glucagon release 2. Clinical uses 2. Clinical uses mild insulin-independent patients with obesity mild insulin-independent patients with obesity 3. Adverse effects severe lactic acidosis, malabsorption of vitamin B 12 and folic acid severe lactic acidosis, malabsorption of vitamin B 12 and folic acid

29. B. Oral hypoglycemic drugs  -Glucosidase inhibitors Acarbose 阿卡波糖 Acarbose 阿卡波糖 Reducing intestinal absorption of starch ( 淀粉 ), dextrin ( 糊精 ), and disaccharides ( 二糖 ) by inhibiting the action of intestinal brush border  -glucosidase

30. B. Oral hypoglycemic drugs Others Repaglinide 瑞格列奈 Repaglinide 瑞格列奈 Oral insulin secretagogue