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 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. 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.

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

5. Others
Alpha glucosidase inhibitors
Gastrointestinal hormones:
Incretin(GLP-1) mimetics
Dipeptidyl peptidase-4 (DPP-4)
inhibitors

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

8. Mechanisms of Insulin Release

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

12. Tolbutamid short-acting Tolazamide intermediate-acting
First generation sulfonylurea
Tolbutamid short-acting
Acetohexamide
intermediate-acting
Tolazamide intermediate-acting
Chlorpropamide
long- acting
Absorption
Well
Slow
Metabolism
Yes
Metabolites
Inactive**
Active***
Inactive***
Half-life
4 - 5 hrs
6 – 8 hrs
7 hrs
24 – 40 hrs
Duration of action
Short
(6 – 8 hrs)
Intermediate
(12 – 20 hrs)
Intermediate(12 – 18 hrs)
Long
( 20 – 60hrs)
Excretion
Urine
**safe for old diabetic patients or pts with renal impairment.
***Pts with renal impairement can expect long t1/2. .

13. Second generation sulfonylurea
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

14. SECOND GENERATION SULPHONYLUREA
Glipizide
Glibenclamide
(Glyburide)
Glimepiride
Absorption
Well reduced by food
Well
Metabolism
Yes
Metabolites
Inactive
Half-life
2 – 4 hrs
Less than 3 hrs
5 - 9 hrs
Duration of
action
10 – 16 hrs
short
12 – 24 hrs
long
Doses
Divided doses
30 min before meals
Single dose
1 mg
Excretion
Urine

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

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

17. Meglitinides E.g. Repaglinide are rapidly acting insulin secretagogues
Mechanism of Action
Insulin secretagogue as sulfonylureas.

18. 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).

19. Uses of Meglitinides Type II diabetes:
Monotherapy or in combination with other antidiabetic drugs
Patients allergic to sulfur or sulfonylureas
Adverse effects of Meglitinides
Hypoglycemia.
Weight gain.

20. Insulin sensitizers
Are drugs which increase the sensitivity of target organs to insulin.
Include
Biguanides(e.g. Metformin)
Thiazolidinediones(e.g. Pioglitazone)

21. Metformin(Glucophage)
Mechanism of action of metformin
Does not stimulate insulin release.
Increases liver,muscle&adipose tissues sensitivity toinsulin & increase peripheral glucose utilization.
Inhibits gluconeogenesis.
Impairsglucose absorption from GIT.

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

23. Uses of metformin
overweight patients with type 2 diabetes, as monotherapy or in combination with other antidiabetics.

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

25. Adverse effects of metformin
GIT disturbances: nausea, vomiting, diarrhea
Lactic acidosis(01/30,000- exclusive in renal failure)
Interference with vitamin B12 absorption (long term use).
Metallic taste in the mouth

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

27. Pioglitazone Mechanism of action
Increase sensitivity of target tissues to insulin.
Increase glucose uptake and utilization in muscle and adipose tissue.

28. 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

29. Uses of Pioglitazone Type II diabetes with insulin resistance.
Used either alone or in combination with other antidiabetics.
No risk of hypoglycemia when used alone

30. Adverse effects of Pioglitazone
Hepatotoxicity (liver function tests for 1st year
of therapy).
Fluid retention (Edema).
Congestive heart failure
Mild weight gain.

31. E.g. Acarbose, Meglitol -Glucosidase inhibitors
Reversible inhibitors of intestinal -glucosidases in the intestine responsible for degradation of oligosaccharides to monosaccharides.
decrease carbohydrate digestion and glucose absorption in small intestine (lower postprandial glucose level).

32. α-GLUCOSIDASE INHIBITORS (Contd.)
MECHANISM OF ACTION
Acarbose

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

34. Metabolized by intestinal bacteria Excreted in feces
-Glucosidase inhibitors
e.g. Acarbose
Given orally
Poorly absorbed.
Metabolized by intestinal bacteria
Excreted in feces
Taken just before meals.
No hypoglycemia if used alone.

35. GIT side effects: Flatulence, diarrhea, abdominal pain.
Adverse effects
GIT side effects: Flatulence, diarrhea, abdominal pain.

36. Incretin mimetics
Incretins are hormones secreted from intestine in response to food, carried through circulation to beta cells.
Stimulate insulin secretion & decrease in glucagon secretion.

37. Incretins E.g. Dulaglutide, Liraglutide, Albiglutide, Exenatide.
Incretins as:
GLP-1 (glucagon-like peptide-1).
E.g. Dulaglutide, Liraglutide, Albiglutide, Exenatide.
GLP-1Inactivated by dipeptidyl peptidase-4 (DPP-4).
DPP-4 Inhibitors:
E.g. Sitagliptin, vildagliptin

38. Glucagon- like peptide-1 agonists
E.g. Dulaglutide, Liraglutide, Albiglutide, Exenatide.
Dulaglutide
is glucagon-like peptide-1 (GLP-1) agonist.
given s.c. once a week.
Therapy of patients with type 2 diabetes who are not controlled with oral medicine.
Adverse effects
Nausea & vomiting (most common). Abdominal pain, decreased appetite & fatigue.

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

40. Clinical uses of sitaglibtin
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

41. Mechanism of action

42. SUMMARY Class Mechanism Site of action Main advantages
Main side effects
Sulfonylureas
Tolbutamide
Stimulates insulin secretion
Pancreatic beta cells
Effective
Inexpensive
Hypoglycemia
Weight gain
Meglitinides
repaglinide
Sulfa free
Biguanides
Metformin
Decreases insulin
resistance
Liver
mild weight loss
No hypoglycemia
GIT symptoms,
Lactic acidosis
Metallic taste
Thiazolidinediones
pioglitazone
Fat, muscle
Hepatoxicity
Edema, mild weight gain
-Glucosidase inhibitors
Acarbose
Inhibits α-glucosidase
GI tract
Low risk
GI symptoms, flatulence
Incretins mimetics
Dulaglutide
Increase incretin
Once/week, s.c.
Nausea & vomiting
DPP-4 inhibitors
Sitagliptin
Inhibit incretin breakdown
Nausea & abdominal pain