Oral hypoglycemic drugs
Prof. Hanan Hagar
Objectives
By the end of this lecture, students should be able to:
1. Classify different categories of oral hypoglycemic drugs.
2. Identify mechanism of action, pharmacokinetics and
pharmacodynamics of each class of oral hypoglycemic
drugs.
3. Identify the clinical uses of hypoglycemic drugs
4. Know the side effects, contraindications of each class of
oral hypoglycemic drugs.
Oral hypoglycemic drugs
1. Sulfonylurea drugs
2. Meglitinides
3. Biguanides
4. alpha-glucosidase inhibitors.
5. Thiazolidinediones.
6. Dipeptidyl peptidase-4 (DPP-4) inhibitors
Oral hypoglycemic drugs
Insulin secretagogues
 Sulfonylurea drugs
 Meglitinides
Insulin sensitizers
 Biguanides
 Thiazolidinediones
Others

Alpha glucosidase inhibitors

Gastrointestinal hormones
Insulin secretagogues
Are drugs which increase the amount of
insulin secreted by the pancreas
Include:
• Sulfonylureas
• Meglitinides
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.
Mechanism of action of sulfonylureas:
Glucose
Sulfonylureas
Meglitinides
Blockade of ATPsensitive K
channels
depolarization and opening of
voltage- dependent calcium
channels
Exocytosis &
insulin release
↑ in intracellular calcium in the beta
cells
Mechanisms of Insulin Release
Classification of sulfonylureas
First generation
Short
acting
Tolbutamide
Intermediate
acting
Acetohexamide
second generation
Long
acting
Chlorpropamide
Short
acting
Long
acting
Glipizide
Tolazamide
Glibenclamide
(Glyburide)
Glimepiride
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.
Pharmacokinetics of sulfonylureas:

Metabolized in liver

excreted in urine (elderly and renal disease)

Cross placenta, stimulate fetal β-cells to
release insulin → fetal hypoglycemia
First generation sulfonylureas
Tolbutamide Acetohexamide Tolazamide
short-acting intermediate- intermediate
-acting
acting
Chlorpropa
mide
longacting
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
Short
(6 – 8 hrs)
Intermediate
(12 – 20 hrs)
Intermediate
(12 – 18 hrs)
Long
( 20 – 60
hrs)
Urine
Urine
Urine
Urine
Duration of
action
Excretion
First generation sulfonylureas
Tolbutamide:
safe for old diabetic patients or patients
with renal impairment.
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
Second generation sulfonylureas
Glipizide
Glibenclamide
(Glyburide)
Glimepiride
Absorption
Well
Well
Well
Metabolism
Yes
Yes
Yes
Metabolites
Inactive
Inactive
Inactive
Half-life
2 – 4 hrs
Less than 3 hrs
5 - 9 hrs
10 – 16 hrs
12 – 24 hrs
12 – 24 hrs
short
long
long
Divided doses
30 min before
meals
Single dose
Single dose
Urine
Urine
Urine
Duration of
action
Doses
Excretion
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
CONTRAINDICATIONS:

Hepatic impairment or renal insufficiency

Pregnancy & lactation
Meglitinides
e.g. Repaglinide
are rapidly acting insulin secretagogues
Mechanism of Action:
Stimulate insulin release from functioning β
cells via blocking ATP-sensitive K-channels
resulting in calcium influx and insulin
exocytosis.
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).
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
Adverse effects of Meglitinides

Hypoglycemia.

Weight gain.
Insulin sensitizers

Are drugs which increase the sensitivity of
target organs to insulin.
Include
 Biguanides
 Thiazolidinediones (Glitazones)
Insulin sensitizers
Biguanides
e.g. Metformin
 Does not require functioning B cells.
 Does not stimulate insulin release.
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
Pharmacokinetics of metformin

orally.

Not bound to serum protein.

Not metabolized.

t ½ 3 hours.

Excreted unchanged in urine
Uses of metformin

Type II diabetes particularly in overweight
and obese people (with insulin resistance).
Advantages:
 No risk of hypoglycemia
 Mild weight loss (anorexia).
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.
Contraindications of metformin





Pregnancy.
Renal disease.
Liver disease.
Alcoholism.
Conditions predisposing to hypoxia as
cardiopulmonary dysfunction.
Insulin sensitizers
Thiazolidinediones (glitazones)

Pioglitazone (Actos)
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.
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
Uses of pioglitazone

Type II diabetes with insulin resistance.

Used either alone or combined with
sulfonylureas, biguanides.

No risk of hypoglycemia when used alone.
Adverse effects of pioglitazone

Hepatotoxicity ?? (liver function tests for
1st year of therapy).

Fluid retention (Edema).

Precipitate congestive heart failure

Mild weight gain.
Contraindications of pioglitazone

Congestive heart failure.

Pregnancy.

Lactating women

Significant liver disease.
-Glucosidase inhibitors

Acarbose
-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.
-Glucosidase inhibitors

Decrease postprandial hyperglycemia.

Taken just before meals.

No hypoglycemia if used alone.
Kinetics of -glucosidase inhibitors
Acarbose

Given orally, poorly absorbed.

Metabolized by intestinal bacteria.

Excreted in stool and urine.
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.
Adverse effects of -glucosidase inhibitors
GIT: Flatulence, diarrhea, abdominal pain
Dipeptidyl peptidase-4 inhibitors
DPP- 4 inhibitors e.g. Sitagliptin
(DPP- 4 inhibitors)
Sitagliptin

Orally

Given once daily

half life 8-14 h

Dose is reduced in pts with renal
impairment
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.
mechanism of action
of Sitagliptin
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.
SUMMARY
Class
Mechanism
Sulfonylureas
Tolbutamide
Glipizide
Glibenclamide
(glyburide)
Stimulating
insulin
production by
inhibiting the
KATP channel
Meglitinides
repaglinide
Stimulates
insulin
secretion
Site of
action
Main advantages
Pancreatic
beta cells
• Effective
• Inexpensive
Pancreatic
beta cells
Sulfa free
Biguanides
Metformin
Decreases
insulin
resistance
Liver
Thiazolidinedio
nes
pioglitazone
Decreases
insulin
resistance
Fat, muscle
-Glucosidase
inhibitors
Acarbose
Inhibits αglucosidase
GI tract
DPP-4 inhibitor
Sitagliptin
Increase
secretin
GI tract
Main side
effects
• Hypoglycemia
• Weight gain
• Allergy
•Hypoglycemia
•Weight gain
• mild
• GIT symptoms,
weight loss
• Lactic acidosis
• No hypoglycemia • Metallic taste
Hepatoxicity
Edema
Low risk
•GI symptoms,
flatulence