1. Oral hypoglycemic drugs Prof. Mohammad Alhumayyd

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 oral hypoglycemic drugs.  Identify the clinical uses of hypoglycemic drugs  Know the side effects, contraindications of each class of oral hypoglycemic drugs.

3. Types of diabetes mellitus Type I due to autoimmune or viral diseases Type II due to obesity, genetic factors

4. Pts with Type 11 diabetes have two physiological defects: 1. Abnormal insulin secretion. 2. Resistance to insulin action in target tissues associated with decreased number of insulin receptors.

5. Drugs used for treatment of Type-2 diabetes 1. Sulfonylurea drugs 2. Meglitinide analogues 3. Biguanides 4. Thiazolidinediones. 5.Alpha-glucosidase inhibitors. 6. Dipeptidyl peptidase-4(DPP-4) inhibitors

6. Insulin secretagogues Sulfonylurea drugs Meglitinide analogues Insulin sensitizers Biguanides Thiazolidinediones Oral hypoglycemic drugs

7. Others Alpha glucosidase inhibitors Dipeptidyl peptidase-4(DPP-4) inhibitors

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

9. Classification of sulfonylureas TolbutamideAcetohexamideTolazamideChlorpropamideGlipizide Glyburide(Glibenclamide)Glimepiride First generation LongactingShort acting acting second generation Short acting actingIntermediateacting Longacting

10. Stimulate insulin release from functioning B cells by blocking of ATP-sensitive K channels resulting in depolarization and calcium influx(Hence, not effective in totally insulin-deficient pts” type-1). Potentiation of insulin action on target tissues. Reduction of serum glucagon concentration. Mechanism of action of sulfonylureas:

11. Mechanisms of Insulin Release

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. Metabolized in liver excreted in urine Cross placenta, stimulate fetal B cells to release insulin → hypoglycemia at birth.

13. Tolbutamid short- acting Acetohexamide intermediate- acting Tolazamide intermediate -acting Chlorpropa mide long- acting Absorption Well SlowWell Metabolism Yes Metabolites InactiveActive Inactive Half-life 4 - 5 hrs6 – 8 hrs7 hrs24 – 40 hrs Duration of action Short (6 – 8 hrs) Intermediate (12 – 20 hrs) Intermediate (12 – 18 hrs) Long ( 20 – 60 hrs) Excretion Urine First generation sulfonylurea

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

15. GlipizideGlibenclamide (Glyburide) Glimepiride AbsorptionWell MetabolismYes MetabolitesInactiveModerate activity Half-life2 – 4 hrsLess than 3 hrs5 - 9 hrs Duration of10 – 16 hrs12 – 24 hrs actionshortlong DosesDivided doses 30 min before meals Single dose 1 mg ExcretionUrine SECOND GENERATION SULPHONYLUREA

16. Type II diabetes: monotherapy or in combination with other antidiabetic drugs. Uses of sulfonylureas

17. Unwanted Effects: 1. Hyperinsulinemia & Hypoglycemia: 2. Weight gain due to increase in appetite

18. e.g. Repaglinide Rapidly acting insulin secretagogues Meglitinide analogues

19. Mechanism of Action: Insulin secretagogue as sulfonylureas.

20. Pharmacokinetics of Meglitinides Orally, well absorbed. Very fast onset of action, peak 1 h. short duration of action (4 h). Metabolized in the liver & excreted in bile.

21. Type II diabetes: monotherapy or combined with other antidiabetic drugs. Patients allergic to sulfonylurea Uses of Meglitinides

22. Hypoglycemia Weight gain. Adverse effects of Meglitinides

23. 1. Biguanides, e.g. Metformin 2. Thiazolidinediones, e.g. pioglitazone Insulin sensitizers

24. BIGUANIDES E.g. Metformin

25. Does not stimulate insulin release. Increases liver,muscle &adipose tissues sensitivity to insulin & increase peripheral glucose utilization. Inhibits gluconeogenesis. Impairs glucose absorption from GIT. 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. Obese patients with type II diabetes Monotherapy or in combination. Advantages: No risk of hyperinsulinemia or hypoglycemia or weight gain (anorexia). Uses of metformin

28. Metallic taste in the mouth GIT disturbances: nausea, vomiting, diarrhea Lactic acidosis Long term use interferes with vitamin B 12 absorption. Adverse effects of metformin

29. Pregnancy. Renal disease. Liver disease. Alcoholism. Heart failure Contraindications of metformin

30. Insulin sensitizers Thiazolidinediones (glitazones) Pioglitazone

31. Mechanism of action – 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 the liver – Excreted in urine 64% & bile

33. 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 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. E.g. Acarbose, Meglitol Reversible inhibitors of intestinal  - glucosidases in intestinal brush border responsible for degradation of oligosaccharides to monosaccharides.  -Glucosidase inhibitors

36. decrease carbohydrate digestion and absorption in small intestine. Decrease postprandial hyperglycemia. Taken just before meals. No hypoglycemia if used alone.  -Glucosidase inhibitors

37. 37 α-GLUCOSIDASE INHIBITORS (Contd.) MECHANISM OF ACTION

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

39. GIT: Flatulence, diarrhea, abdominal pain. No hypoglycemia if used alone. Adverse effects of  -glucosidase inhibitors

40. Incretin mimetics e.g. Exenatide(GLP-1) Incretins are GI hormones secreted in response to food, carried through circulation to the beta cells to stimulate insulin secretion & decrease glucagon secretion.

43. Incretins Two main Incretin hormones: – GLP-1 (glucagon-like peptide-1) – GIP (gastric inhibitory peptide or glucose- dependent insulinotropic peptide) Both are inactivated by dipeptidyl peptidase-4 (DPP-4).

44. Incretin mimetics Exenatide is glucagon-like peptide-1 (GLP-1) agonist. given s.c. once or twice daily Therapy of patients with type 2 diabetes who are not controlled with oral medicine. Adverse efects Nausea & vomiting(most common)

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

46. Mechanism of action of sitagliptin Inhibit DPP-4 enzyme and leads to an increase in incretin hormones level. This results in an increase in insulin secretion & decrease in glucagon secretion.

47. Mechanism of action

48. Clinical uses Type 2 DM as an adjunct to diet & exercise as a monotherapy or in combination with other antidiabetic drugs. Adverse effects Nausea, abdominal pain, diarrhea Nasopharyngitis