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.

Types of diabetes mellitus
Type I
due to autoimmune or viral diseases
Type II
due to obesity, genetic factors
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.
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
Insulin secretagogues
Sulfonylurea drugs
Meglitinide analogues
Insulin sensitizers
Biguanides
Thiazolidinediones
Oral hypoglycemic drugs
Others
Alpha glucosidase inhibitors
Dipeptidyl peptidase-4(DPP-4)
inhibitors
Insulin secretagogues
Are drugs which increase the amount of
insulin secreted by the pancreas

Include:
Sulfonylureas
Meglitinides

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
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:
Mechanisms of Insulin Release
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.

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
Tolbutamide:
safe for old diabetic patients or pts with
renal impairment.
First generation sulfonylureas
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
Type II diabetes:
monotherapy or in combination with other
antidiabetic drugs.

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

e.g. Repaglinide

Rapidly acting insulin secretagogues

Meglitinide analogues

Mechanism of Action:

Insulin secretagogue as sulfonylureas.
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.
Type II diabetes:
monotherapy or combined with other
antidiabetic drugs.

Patients allergic to sulfonylurea
Uses of Meglitinides

Hypoglycemia
Weight gain.
Adverse effects of Meglitinides
1. Biguanides, e.g. Metformin
2. Thiazolidinediones, e.g. pioglitazone

Insulin sensitizers

BIGUANIDES

E.g. Metformin

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
orally.
Not bound to serum protein.
Not metabolized.
t 3 hours.
Excreted unchanged in urine
Pharmacokinetics of metformin
Obese patients with type II diabetes
Monotherapy or in combination.
Advantages:
No risk of hyperinsulinemia or hypoglycemia
or weight gain (anorexia).
Uses of metformin
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
Pregnancy.
Renal disease.
Liver disease.
Alcoholism.
Heart failure

Contraindications of metformin
Insulin sensitizers
Thiazolidinediones (glitazones)
Pioglitazone


Mechanism of action
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 the liver
Excreted in urine 64% & bile
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
Hepatotoxicity ?? (liver function tests for
1st year of therapy).
Fluid retention (Edema).
Precipitate congestive heart failure
Mild weight gain.
Adverse effects of pioglitazone
E.g. Acarbose, Meglitol
Reversible inhibitors of intestinal -
glucosidases in intestinal brush border
responsible for degradation of
oligosaccharides to monosaccharides.



-Glucosidase inhibitors

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


-Glucosidase inhibitors

37
-GLUCOSIDASE INHIBITORS (Contd.)

MECHANISM OF ACTION
Acarbose
Given orally, poorly absorbed.
Metabolized by intestinal bacteria.
Excreted in stool and urine.



Kinetics of -glucosidase inhibitors

GIT: Flatulence, diarrhea, abdominal
pain.
No hypoglycemia if used alone.


Adverse effects of -glucosidase
inhibitors

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.
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).
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)

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



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.
Mechanism of
action
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