Oral hypoglycemic drugs
Prof. Mohammad Alhumayyd
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 oral hypoglycemic drugs
4. Know the side effects, contraindications of each class of
oral hypoglycemic drugs.
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.
Oral hypoglycemic drugs
Insulin secretagogues
 Sulfonylurea drugs
 Meglitinides
Insulin sensitizers
 Biguanides
 Thiazolidinediones
Others

Alpha glucosidase inhibitors

Gastrointestinal hormones:
Incretin(GLP-1) mimetics
Dipeptidyl peptidase-4 (DPP-4)
inhibitors
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 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.
Mechanisms of Insulin Release
Classification of sulfonylureas
First generation
second generation
Short
Intermediate
Long
acting
acting
acting
Tolbutamide Acetohexamide Chlorpropamide
Tolazamide
Short
Long
acting
acting
Glipizide
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 at
birth.

First generation sulfonylurea
Tolbutamid Acetohexamide
short-acting
intermediateacting
Tolazamide Chlorpropam
intermediatede
acting
long- acting
Absorption
Well
Well
Slow
Well
Metabolism
Yes
Yes
Yes
Yes
Metabolites
Inactive**
Active***
Active***
Inactive***
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 – 60hrs)
Urine
Urine
Urine
Urine
Half-life
Duration of
action
Excretion
**safe for old diabetic patients or pts with renal impairment.
***Pts with renal impairement can expect long t1/2.
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
SECOND GENERATION SULPHONYLUREA
Glipizide
Glibenclamide
(Glyburide)
Glimepiride
Absorption
Well reduced
by food
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
short
12 – 24 hrs
long
12 – 24 hrs
long
Divided doses
30 min before
meals
Single dose
Single dose
1 mg
Urine
Urine
Urine
Duration of
action
Doses
Excretion
Uses of sulfonylureas
• Type II diabetes:
monotherapy or in combination with other
antidiabetic drugs.
Unwanted Effects:
1. Hyperinsulinemia & Hypoglycemia
2. Weight gain due to increase in appetite
Meglitinides
E.g. Repaglinide
are rapidly acting insulin secretagogues
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 liver and excreted in bile.
 Taken just before each meal (3 times/day).

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.
Insulin sensitizers

Are drugs which increase the sensitivity of
target organs to insulin.
Include
 Biguanides(e.g. Metformin)
 Thiazolidinediones(e.g. Pioglitazone)
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.

Pharmacokinetics of metformin
orally.
 NOT bound to serum protein.
 NOT metabolized.
 t ½ 3 hours.
 Excreted unchanged in urine

Uses of metformin

overweight patients with type 2 diabetes, as
monotherapy or in combination with other
antidiabetics.
Advantages
No risk of hypoglycemia
 No weight gain
 Improvement of lipid profile
 Inexpensive

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

Contraindications of metformin
Renal disease.
 Liver disease.
 Alcoholism.
 Cardiopulmonary dysfunction.
 Pregnancy.

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 liver .
Excreted in urine 64% & bile
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

Adverse effects of Pioglitazone




Hepatotoxicity (liver function tests for 1st year
of therapy).
Fluid retention (Edema).
Congestive heart failure
Mild weight gain.
-Glucosidase inhibitors
E.g. Acarbose, Meglitol


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).
α-GLUCOSIDASE INHIBITORS (Contd.)
MECHANISM OF ACTION
Acarbose
Acarbos
e
Acarbose
32
α-GLUCOSIDASE INHIBITORS (Contd.)
MECHANISM OF ACTION
33
-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.
Adverse effects

GIT side effects: Flatulence, diarrhea,
abdominal pain.
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.
Incretins

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
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.
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
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
Mechanism of
action
SUMMARY
Class
Mechanism
Sulfonylureas
Tolbutamide
Meglitinides
repaglinide
Biguanides
Metformin
Thiazolidinediones
pioglitazone
Stimulates
insulin secretion
Site of
action
Main advantages
Main side
effects
Pancreatic
beta cells
• Effective
• Inexpensive
• Hypoglycemia
• Weight gain
Pancreatic
beta cells
Sulfa free
•Hypoglycemia
•Weight gain
Liver
Decreases
insulin
resistance
-Glucosidase
inhibitors
Acarbose
Inhibits
α-glucosidase
Incretins mimetics
Dulaglutide
Increase incretin
DPP-4 inhibitors
Sitagliptin
Inhibit incretin
breakdown
• mild weight loss
• No hypoglycemia
• GIT symptoms,
• Lactic acidosis
• Metallic taste
Hepatoxicity
Edema, mild
weight gain
Fat,
muscle
No hypoglycemia
GI tract
Low risk
•GI symptoms,
flatulence
Once/week, s.c.
Nausea & vomiting
GI tract
GI tract
Nausea &
abdominal pain