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
Insulin secretagogues
Sulfonylurea drugs
Meglitinides
Insulin sensitizers
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. Mechanism of action of sulfonylureas:
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.

8. Mechanism of action of sulfonylureas:
Glucose
Sulfonylureas
Meglitinides
Blockade of ATP-sensitive K channels
depolarization and opening of voltage- dependent calcium channels
↑ in intracellular calcium in the beta cells
Exocytosis &
insulin release

9. Mechanisms of Insulin Release

10. Classification of sulfonylureas
First generation
second generation
Short
acting
Intermediate
Long
Long
acting
Short
Tolbutamide
Glipizide
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. Pharmacokinetics of sulfonylureas:
Metabolized in liver
excreted in urine (elderly and renal disease)
Cross placenta, stimulate fetal β-cells to release insulin → fetal hypoglycemia

13. Tolbutamide short-acting Tolazamide intermediate-acting
First generation sulfonylureas
Tolbutamide short-acting
Acetohexamide
intermediate-acting
Tolazamide intermediate-acting
Chlorpropamide
long- acting
Absorption
Well
Slow
Metabolism
Yes
Metabolites
Inactive
Active
Half-life
4 - 5 hrs
6 – 8 hrs
7 hrs
24 – 40 hrs
Duration of action
Short
(6 – 8 hrs)
Intermediate
(12 – 20 hrs)
(12 – 18 hrs)
Long
( 20 – 60 hrs)
Excretion
Urine

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

15. Second generation sulfonylureas
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

16. Second generation sulfonylureas
Glipizide
Glibenclamide
(Glyburide)
Glimepiride
Absorption
Well
Metabolism
Yes
Metabolites
Inactive
Half-life
2 – 4 hrs
Less than 3 hrs
5 - 9 hrs
Duration of
action
10 – 16 hrs
12 – 24 hrs
short
long
Doses
Divided doses
30 min before meals
Single dose
Excretion
Urine

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

23. Adverse effects of Meglitinides
Hypoglycemia.
Weight gain.

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

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

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

29. Adverse effects of metformin
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.

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

31. Insulin sensitizers Thiazolidinediones (glitazones)
Pioglitazone (Actos)

32. Activate PPAR- (peroxisome proliferator-activated receptor -).
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. Uses of pioglitazone Type II diabetes with insulin resistance.
Used either alone or combined with sulfonylureas, biguanides.
No risk of hypoglycemia when used alone.

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

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

37. -Glucosidase inhibitors
Acarbose

38. -Glucosidase inhibitors
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.

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

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

41. Uses of -glucosidase inhibitors
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.

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

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 Class Mechanism Site of action Main advantages
Main side effects
Sulfonylureas
Tolbutamide
Glipizide
Glibenclamide
(glyburide)
Stimulating insulin production by inhibiting the KATP channel
Pancreatic beta cells
Effective
Inexpensive
Hypoglycemia
Weight gain
Allergy
Meglitinides
repaglinide
Stimulates insulin secretion
Sulfa free
Biguanides
Metformin
Decreases insulin resistance
Liver
mild
weight loss
No hypoglycemia
GIT symptoms,
Lactic acidosis
Metallic taste
Thiazolidinediones
pioglitazone
Decreases insulin
resistance
Fat, muscle
Hepatoxicity
Edema
-Glucosidase inhibitors
Acarbose
Inhibits α-glucosidase
GI tract
Low risk
GI symptoms, flatulence
DPP-4 inhibitor
Sitagliptin
Increase secretin