Oral hypoglycemic drugs

1. Oral hypoglycemic drugs Prof. Hanan Hagar

2. Objectives By the end of this lecture, students should be able to: • Classify different categories of oral hypoglycemic drugs. • Identify mechanism of action, pharmacokinetics and pharmacodynamics of each class of oral hypoglycemic drugs. • Identify the clinical uses of hypoglycemic drugs • Know the side effects, contraindications of each class of oral hypoglycemic drugs.

3. Oral hypoglycemic drugs 1. Sulfonylurea drugs 2. Meglitinides 3. Biguanides 4. alpha-glucosidase inhibitors. 5. Thiazolidinediones. 6. Dipeptidyl peptidase-4 (DPP-4) inhibitors

4. Oral hypoglycemic drugs Insulinsecretagogues Sulfonylurea drugs Meglitinides Insulinsensitizers Biguanides Thiazolidinediones

5. Others Alpha glucosidase inhibitors Gastrointestinal hormones

6. Insulin secretagogues • Are drugs which increase the amount of insulin secreted by the pancreas • Include: • Sulfonylureas • Meglitinides

7. Stimulate insulin release from functioning B cells by blocking ATP-sensitive K+ channels which causes depolarization and opening of voltage- dependent Ca 2+ channels, which causes an increase in intracellular calcium in the beta cells and stimulates insulin release. Mechanism of action of sulfonylureas:

8. Mechanism of action of sulfonylureas:

9. Mechanisms of Insulin Release

10. Long acting Short acting Intermediate acting Classification of sulfonylureas First generation second generation Short acting Long acting Glipizide Tolbutamide Acetohexamide Tolazamide Chlorpropamide Glibenclamide (Glyburide) Glimepiride

11. Pharmacokinetics of sulfonylureas: Orally, well absorbed. Reach peak concentration after 2-4 hr. All are highly bound to plasma proteins. Duration of action is variable. Second generation has longer duration than first generation.

12. Metabolized in liver excreted in urine (elderly and renal disease) Cross placenta, stimulate fetal β-cells to release insulin → fetal hypoglycemia Pharmacokinetics of sulfonylureas:

13. First generation sulfonylureas

14. Tolbutamide: safe for old diabetic patients or patients with renal impairment. First generation sulfonylureas

15. Glipizide - glyburide (Glibenclamide) More potent than first generation Have longer duration of action. Less frequency of administration Have fewer adverse effects Have fewer drug interactions Second generation sulfonylureas

16. Second generation sulfonylureas

17. Unwanted Effects: Hyperinsulinemia & Hypoglycemia: Less in tolbutamide. More in old age, hepatic or renal diseases. Weight gain due to increase in appetite GIT upset. Allergic reactions in pts sensitive to sulfa drugs

18. CONTRAINDICATIONS: Hepatic impairment or renal insufficiency Pregnancy & lactation

19. Meglitinides e.g. Repaglinide are rapidly acting insulin secretagogues

20. Mechanism of Action: Stimulate insulin release from functioning β cells via blocking ATP-sensitive K-channels resulting in calcium influx and insulin exocytosis.

21. Pharmacokinetics of meglitinides Orally, well absorbed. Very fast onset of action, peak 1 h. short duration of action (4 h). Metabolized in liver and excreted in bile. Taken just before each meal (3 times/day).

22. Type II diabetes Specific use in patients allergic to sulfur containing drugs e.g. sulfonylureas. Can be used as monotherapy or combined with metformin Uses of Meglitinides

23. Hypoglycemia. Weight gain. Adverse effects of Meglitinides

24. Insulin sensitizers • Are drugs which increase the sensitivity of target organs to insulin. Include • Biguanides • Thiazolidinediones (Glitazones)

25. Insulin sensitizers Biguanides • e.g. Metformin • Does not require functioning B cells. • Does not stimulate insulin release.

26. Decrease insulin resistance. Increases peripheral glucose utilization (tissueglycolysis). Inhibits hepatic gluconeogenesis. Impairs glucose absorption from GIT. LDL , VLDL &  HDL Mechanism of action of metformin

27. orally. Not bound to serum protein. Not metabolized. t ½ 3 hours. Excreted unchanged in urine Pharmacokinetics of metformin

28. Type II diabetes particularly in overweight and obese people (with insulin resistance). Advantages: No risk of hypoglycemia Mild weight loss (anorexia). Uses of metformin

29. GIT disturbances: nausea, vomiting, diarrhea Long term use interferes with vitamin B12 absorption. Lactic acidosis: in patients with renal, liver, pulmonary or cardiac diseases. Metallic taste in the mouth. Adverse effects of metformin

30. Pregnancy. Renal disease. Liver disease. Alcoholism. Conditions predisposing to hypoxia as cardiopulmonary dysfunction. Contraindications of metformin

31. Insulin sensitizersThiazolidinediones (glitazones) Pioglitazone (Actos)

32. Mechanism of action Activate PPAR- (peroxisome proliferator-activated receptor -). Decrease insulin resistance. Increase sensitivity of target tissues to insulin. Increase glucose uptake and utilization in muscle and adipose tissue.

33. Pharmacokinetics of pioglitazone Orally (once daily dose) Highly bound to plasma albumins (99%) Slow onset of activity Half life 3-4 h Metabolized in liver Excreted in urine 64% & bile

34. Type II diabetes with insulin resistance. Used either alone or combined with sulfonylureas, biguanides. No risk of hypoglycemia when used alone. Uses of pioglitazone

35. Hepatotoxicity ?? (liver function tests for 1st year of therapy). Fluid retention (Edema). Precipitate congestive heart failure Mild weight gain. Adverse effects of pioglitazone

36. Contraindications of pioglitazone Congestive heart failure. Pregnancy. Lactating women Significant liver disease.

37. -Glucosidase inhibitors Acarbose

38. Are reversible inhibitors of intestinal -glucosidases in intestinal brush border that are responsible for carbohydrate digestion. decrease carbohydrate digestion and glucose absorption in small intestine. -Glucosidase inhibitors

39. Decrease postprandial hyperglycemia. Taken just before meals. No hypoglycemia if used alone. -Glucosidase inhibitors

40. Acarbose Given orally, poorly absorbed. Metabolized by intestinal bacteria. Excreted in stool and urine. Kinetics of -glucosidase inhibitors

41. Effective alone in the earliest stages of impaired glucose tolerance. Can be combined with sulfonylurea in the treatment of Type 2 diabetes to improve blood glucose control. Uses of -glucosidase inhibitors

42. GIT: Flatulence, diarrhea, abdominal pain Adverse effects of -glucosidase inhibitors

43. Dipeptidyl peptidase-4 inhibitors DPP- 4 inhibitors e.g. Sitagliptin

44. (DPP- 4 inhibitors) Sitagliptin • Orally • Given once daily • half life 8-14 h • Dose is reduced in pts with renal impairment

45. Mechanism of action of sitagliptin Sitagliptin inhibits DPP-4 enzyme, which metabolizes the naturally occurring incretin hormones thus increase incretin secretion (gastrointestinal hormones secreted in response to food). Incretin hormones decreases blood glucose level by : Increasing insulin secretion Decreasing glucagon secretion.

46. mechanism of action of Sitagliptin

47. Clinical uses • Type II diabetes mellitus as a monotherapy or in combination with other oral antidiabetic drugs when diet and exercise are not enough. Adverse effects • Nausea, abdominal pain, diarrhea.

48. SUMMARY