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 oral hypoglycemic drugs • Know the side effects, contraindications of each class of oral hypoglycemic drugs.

3. Type II Diabetes 80-90% occurrence Over age 35 Pancreatic β-cells are not producing enough insulin Obesity is an important factor. Insulin resistance in peripheral tissues. Treated by oral hypoglycemic drugs.

4. Types II diabetes

5. Oral hypoglycemic drugs Insulin secretagogues Sulfonylurea drugs Meglitinides Insulin sensitizers Biguanides Thiazolidinediones

6. Others Alpha glucosidase inhibitors Gastrointestinal hormones Incretins (GLP-1) mimetics Dipeptidyl peptidase-4 (DPP-4) inhibitors

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

8. 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:

9. Insulin secretagogues (sulfonylureas) ↑ Hyperglycemia ↓ Blockade of ATP dependent K+channels ↓ Opening of voltage-dependent Ca++channels ↓ ↑ intracellular calcium in the beta cells ↓ ↑ Insulin release

10. Mechanisms of Insulin Release

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

12. 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.

13. 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:

14. First generation sulfonylureas

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

16. Glipizide, Glyburide, Glimepiride 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

17. SECOND GENERATION SULPHONYLUREAS

18. Unwanted Effects: 1. Hyperinsulinemia & Hypoglycemia: Less in tolbutamide. More in long acting sulfonylureas. More in old age, hepatic or renal diseases. 2. Weight gain due to increase in appetite

19. Meglitinides Repaglinide are rapidly acting insulin secretagogues

20. Mechanism of Action: Insulin secretagogue Mechanism of action is identical to sulfonylureas.

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: monotherapy or in combination with other oral hypoglycemic drugs Patients allergic to sulfur or sulfonylureas Uses of Meglitinides

23. Less incidence than sulfonylureas Hypoglycemia. Weight gain. Adverse effects of Meglitinides

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

25. Insulin sensitizers Biguanides e.g. Metformin

26. Increases peripheral glucose utilization(tissue glycolysis) Reduces insulin resistance. Inhibits hepatic gluconeogenesis. 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. overweight patients with type 2 diabetes (first-line therapy). Type II diabetesas monotherapy or in combination. Uses of metformin

29. Advantages of metformin No risk of hypoglycemia No weight gain Improvement of lipid profile Inexpensive

30. GIT disturbances: nausea, vomiting, diarrhea Lactic acidosis. Interference with vitamin B12 absorption (long term use). Metallic taste in the mouth Adverse effects of metformin

31. Renal disease. Liver disease. Alcoholism. Cardiopulmonary dysfunction. Pregnancy. Contraindications of metformin

32. Insulin sensitizersThiazolidinediones (glitazones) Pioglitazone

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

34. Pharmacokinetics of glitazones 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

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

36. Hepatotoxicity (liver function tests for 1st year of therapy). Fluid retention (Edema). Congestive heart failure Mild weight gain. Failure of estrogen-containing oral contraceptives Adverse effects of glitazones

37. -Glucosidase inhibitors Acarbose Miglitol

38. Reversible inhibitors of intestinal -glucosidases in intestinal brush border that are responsible for carbohydrate digestion. decrease carbohydrate digestion and glucose absorption in small intestine (lower postprandial glucose level). -Glucosidase inhibitors

39. Acarbose Given orally is not absorbed. Excreted in feces Taken just before meals. No hypoglycemia if used alone. -Glucosidase inhibitors

40. are effective alone in the earliest stages of impaired glucose tolerance are not recommended alone as therapy for moderate to severe hyperglycemia are most useful in combination with other oral hypoglycemic drugs or with insulin. Uses of -glucosidase inhibitors

41. GIT side effects: Flatulence, diarrhea, abdominal pain, bloating. Adverse effects

42. irritable bowel syndrome Inflammatory bowel disorders Intestinal obstruction. Contraindications of -glucosidase inhibitors

43. Incretins (GLP-1) mimetics • Incretins as GLP-1 (glucagon-like peptide-1). • Incretinsare hormones secreted from intestine in response to food, carried through circulation to beta cells. • Stimulate insulin secretion & decrease glucagon secretion.

44. Incretins Inactivated by dipeptidyl peptidase-4 (DPP-4).

45. Mechanism of action

46. Incretins mimeticsGLP-1 agonists e.g. Dulaglutide, Liraglutide, Albiglutide, Exenatide. Dulaglutide • is GLP-1 agonist. • given s.c. once a week. • Therapy of patients with type 2 diabetes who are not controlled with oral medicine.

47. Dulaglutide Adverse effects Nausea & vomiting (most common). Abdominal pain, decreased appetite & fatigue

48. Dipeptidyl peptidase-4 inhibitor (DPP- 4 inhibitors) e.g. Sitagliptin, vildagliptin Sitagliptin Inhibit DPP-4 enzyme thus increase incretin hormone (GLP-1). Orally Given once daily

49. Clinical uses Type II DM as an adjunct to diet & exercise as a monotherapy or in combination with other antidiabetic drugs. Adverse effects Nausea, abdominal pain, diarrhea

50. SUMMARY