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 of ATP-sensitive K channels which causes depolarization and opening of voltage- dependent calcium channels, which causes an increase in intracellular calcium in the beta cells, which stimulates insulin release. Mechanism of action of sulfonylureas:

8. Mechanisms of Insulin Release

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

10. 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.

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

12. First generation sulfonylureas

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

14. 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

15. Second generation sulfonylureas

16. Unwanted Effects: 1. Hyperinsulinemia & Hypoglycemia: Less in tolbutamide. More in old age, hepatic or renal diseases. 2. Weight gain due to increase in appetite 3. GIT upset.

17. CONTRAINDICATIONS: Hepatic impairment or renal insufficiency Pregnancy & lactation Type I diabetes

18. Meglitinides Repaglinide are rapidly acting insulin secretagogues

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

20. 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).

21. Type II diabetes: monotherapy or combined with metformin (better than monotherapy). Specific use in patients allergic to sulfur or sulfonylureas. Uses of Meglitinides

22. Hypoglycemia. Weight gain. Adverse effects of Meglitinides

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

24. Insulin sensitizers Biguanides Metformin

25. Does not require functioning B cells. Does not stimulate insulin release. Increases peripheral glucose utilization (tissueglycolysis). Inhibits hepatic gluconeogenesis. Impairs glucose absorption from GIT. Reduces plasma glucagon level. LDL &VLDL.  HDL Mechanism of action of metformin

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

27. Type II diabetes particular, in overweight and obese people (with insulin resistance). Advantages: No risk of hyperinsulinemia or hypoglycemia or weight gain (anorexia). Uses of metformin

28. 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

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

30. Insulin sensitizersThiazolidinediones (glitazones) Pioglitazone (Actos)

31. 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.

32. 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

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

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

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

36. -Glucosidase inhibitors Acarbose

37. 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

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

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

40. Uses effective alone in the earliest stages of impaired glucose tolerance. Combined with sulfonylurea in treatment of Type 2 diabetes to improve blood glucose control. Uses of -glucosidase inhibitors

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

42. Dipeptidyl peptidase-4 inhibitors Dipeptidyl peptidase-4 inhibitors (DPP- 4 inhibitors) e.g. Sitagliptin

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

44. Mechanism of action of 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.

45. Mechanism of action of DPP-4 inhibitors

46. Clinical uses Type 2 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.

47. SUMMARY