Chapter 37 Insulin and oral hypoglycemic agents

1. Chapter 37Insulin and oral hypoglycemic agents

2. diabetes mellitus Metabolic disorder of multiple etiology characterized by hyperglycemia with carbohydrates, fat, and protein metabolic alterations that result from a decrease in the circulating concentration of insulin (insulin deficiency) and a decrease in the response of peripheral tissues to insulin (insulin resistance).

3. Characteristics of DM • hyperglycemia • disturbance in metabolism of lipids, carbohydrates and proteins

4. Symptoms of diabetes • Polyuria (urinating frequently) • Polydipsia (very thirsty) • Continuous hunger • Weight loss

5. Other diabetes symptoms • Fatigue • Dry skin • Frequent infections • Feet ulceration • Loss of sensibility in inferior extremities (legs)

6. Classification of DM type Ⅰ DM (insulin-dependent diabetes mellitus, IDDM) type Ⅱ DM (non-insulin-dependent diabetes mellitus, NIDDM) Other type: secondery

7. Treatment and control • Medications • (insulin vs. hypoglycaemic agents) • Increase physical activity • at least walk for 30 min. most days • Appropriate diet • vegetables • fruit • low in fat and carbohydrates • Lifestyle changes

8. Classification of drugs (1) Insulin (2) Orally hypoglycemic agents Insulin sensitizers Sulfonylureas Biguanides Inhibitor of -glycosidase Chinese herbs

9. PART 1 insulin • Chemistry : small protein with a MW of 56 KD (in human) Two chains (A and B) • source : once from bovine and porcine pancreas, now by recombinant DNA techniques

10. Pharmacokinetics • will be degraded in the gastrointestinal tract if taken orally. • often administered by subcutaneous injection. • Half life:9-10 min • Elimination in liver and kindney

11. 胰岛素制剂及其作用时间

12. Pharmacological effects • The main effects of insulin are affecting metabolism of glucose, lipids and protein.

13. 1.Effects on glycometabolism (hypoglycemia) • Increase the synthesis and storage of glycogen • stimulating the uptake and metabolism of glucose by muscle and adipose tissue

14. Pharmacological effects 2.Effects on lipometabolism • inhibiting the hormone-sensitive lipase in adipose tissue→ inhibiting the hydrolysis of triglycerides • Increasing transfer of fatty acid →stimulates synthesis of fat

15. Pharmacological effects of insulin Pharmacological effects 3.Effects on protein metabolism (positive nitrogen balance) • stimulating amino acids uptake and protein synthesis • inhibiting protein degradation in muscle and other tissues

16. 4.Influence on kalium in blood Decrease kalium in blood 5.HR (heart rate), increase the contractility of myocardium, decrease renal blood flow [Mechanism of action]

18. Clinical uses • The goal is the normalization not only of blood glucose but also of all aspects of metabolism.

19. 1.IDDM :the only effective drug Patient with IDDM must rely on injected insulin daily in order to control hyperglycemia all his lifetime. The most common site of subcutaneous injection is abdomen.

20. 2.NIDDM :not adequately controlled by diet and oral hypoglycemic agents (Weight reduction, exercise and dietary modification can correct the hyperglycemia in some patients) • For NIDDM patients, the goal is to maintain blood glucose concentrations within normal limits and to prevent the development of long-term complications of the disease.

21. 3.DM associated with acute or serious complications: Ketoacidosis, hyperosmolar nonketotic coma 4.DM patients under stress conditions: serious infection, consumptive diseases, pregnancy, trauma, operation 5. Hyperkalemia and intracellular hypokalemia GIK: 10％GS1000ml＋I 20u＋Kcl3g ivdrip

22. Adverse reactions • 1.Hypoglycemia : most common may result from an inappropriately large dose of insulin or delayed food intake. Short effect agents: sweating, hunger, palpitations, tremor and anxiety, Long effect agents: neuroglycopenic symptoms (such as difficulty in concentrating, confusion, weakness, drowsiness, even loss of consciousness)

23. Adverse reactions • 2.Insulin allergy: The most frequent allergic manifestations are IgE-mediated local cutaneous reactions.

24. Adverse reactions • 3.Insulin Resistance Acute resistance: stress Chronic resistance: 1) AIRA (antiinsulin receptor autoantibody) 2) down regulation of receptor 3) dysfunction of glucose transfer 4. others

25. Preparations of insulin • Portable pen injection • Continuous subcutaneous insulin infusion devices (CSII, insulin pumps) • Inhaled insulin

26. Injection pen

28. 表42-1 胰岛素制剂比较 作用时间 分类 药物 给药途经 给药时间 Short-acting Regular iv 立即 0.5 2 急救 insulin sc 0.5 2-3 6-8 餐前半h.tid Neutral protamine 2-4 8-12 18-24 Hagedorn sc 2-4 6-10 12-18 Protamine zinc insulin 3-6 16-18 24-36 餐前1h.qd 开始 高峰 维持 餐前半h.tid 1-2次/日 sc Moderate -acting Globin zinc insulin 餐前半h.tid 1-2次/日 sc Long-acting

29. Part 2 Oral hypoglycemic agents Common characteristics • (1) Orally effective and convenient • (2) Slow and weak • (3) NIDDM

30. Ⅰ insulin sensitizer Rosiglitazone(罗格列酮) Englitazone (恩格列酮) Pioglitazone (吡格列酮) Troglitazone (曲格列酮) Ciglitazone （环格列酮）

31. Pharmacological action 1.Improve insulin resistance, lower hyperinsulinemia and hyperglycemia • Limosis and after-meal BS • Blood insulin and blood fatty acid • used in combination with other drugs • Low incidence of hypoglycemia

32. 2.Correct lipodystrophy ↓TG，↑TC and ↑HDL－C 3.Improve complication of NIDDM anti-atherosclerosis effect delay occurrence of albuminuria 4.Improve β-cell function

33. Mechanism （PPARγ )过氧化物酶增殖体受体γ Clinical use NIDDM and IR Adverse reaction general reaction heptic toxicity

34. Ⅱ.Sulfonylureas（磺酰脲类） • The first generation: Tolbutamide(甲苯磺丁脲), chlorpropamide(氯磺丙脲). • The second generation: glyburide(格列本脲), glipizide(格列吡嗪), gliquidone, glimepiride(格列美脲) • The third generation: gliclazide

35. pharmacokinetics • Absorption: P.O • Distribution: PPBR • Elimination: liver • Excretion:kidney

36. Pharmacological effects Hypoglycemic action: weaker than Insulin • (1)Increasing the release of Insulin from pancreatic βcell: • (2) Enhancing the sensitivity of target cell to insulin • ①Increasing the numbers of insulin receptors • ②Increasing the affinity of insulin receptors

37. (3) Decreasing the release of glucagons from pancreatic A cell by stimulating the release of somatostatin

38. 2.Antidiuretic action: chlorpropamide ↑secretion of ADH 3.Effects on coagulation ↓adhesion and agregation of PLT ↑synthesis of plasminogen ↓sensitivity of microvessel to CA

39. Clinical uses • 1.NIDDM • control hyperglycemia in NIDDM who can not achieve appropriate control with exercise and dietary modification alone. • (1)alone (2)plus insulin 2.Diabetes insipidus（尿崩症）

40. Adverse reactions 1. Hypoglycemia reactions 2. Gastrointestinal tract reactions: 3. Anaphylactic reaction 4.Hepatic damage

41. [Drugs interaction] 1.Some drugs increase actions of sulfonylureas (1)Aspirin.butazolidin.SNS.coumarins (2) Penicillin.probenecid（丙磺舒）. (3) Chloromycetin（氯霉素） (4) Alcohol

42. 2.Some drugs decrease actions of sulfonylureas Glucocorticoids. glucagon. adrenaline. thiazides dilantin

43. Ⅲ Biguanides • metformin • phenformin introduced in 1957 and were widely used. Phenformin was withdrawn in many countries during the 1970s because of an association with lactic acidosis. Metformin has been associated only rarely with that complications and has been widely used in Europe and Canada. It became available in the United States in 1995.

44. Pharmacological effects • 1.Hypoglycemic action: • (2) Slowing the absorption of glucose • (3) Promoting the use of glucose • (3) inhibiting release of glucagon • (1) Promoting the effects of insulin • 2.Regulating blood lipid • 3.Antiplatelet effects

45. Clinical uses • NIDDM patients with obesity Side effects • 1.gastrointestinal • 2.Ketonuria and acidemiaphenformin： lactic acidosis

46. Ⅳ α-glycosidase inhibitors • Acarbose（阿卡波糖，拜糖平） Mechanism of action :Inhibiting α-Glycosidase • (1)decreasing the formation of glucose • (2) slowing the absorption of glucose

47. Clinical uses used in combination with other oral anti-diabetic agents and/or insulin Side effects: 1.gastrointestinal reaction:60%,mal-absorption, flatulence, diarrhea, abdominal bloating 2.hypoglycemia: 3%

48. Ⅴ Other types agents: • Repaglinide • stimulating the pancreas to release insulin • Mimicking physiological secretion of insulin

49. The others • Chinese traditional medicine xiaokewan [Actions] 1.Absorption 2.Expansive action 3.Increase intestine peristalsis 4.Nourishing action [Uses]

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