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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
Tolbutamide Acetohexamide
Tolazamide
Chlorpropamide Glipizide
Glyburide
(Glibenclamide)
Glimepiride
First generation
Long
acting
Short
acting
second generation
Short
acting
Intermediate
acting
Long
acting

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 Well Slow Well
Metabolism Yes Yes Yes Yes
Metabolites Inactive Active 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 – 60
hrs)
Excretion Urine Urine Urine Urine
First generation sulfonylurea

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

15. Glipizide Glibenclamide
(Glyburide)
Glimepiride
Absorption Well Well Well
Metabolism Yes Yes Yes
Metabolites Inactive Moderate activity Moderate activity
Half-life 2 – 4 hrs Less than 3 hrs 5 - 9 hrs
Duration of 10 – 16 hrs 12 – 24 hrs 12 – 24 hrs
action short long long
Doses Divided doses
30 min before
meals
Single dose Single dose
1 mg
Excretion Urine Urine Urine
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 B12
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