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1. Oral hypoglycemic drugs

2. Oral hypoglycemic drugs are medications designed to help manage high blood sugar
levels in individuals with diabetes when lifestyle changes such as diet and exercise
alone are insufficient. These drugs are taken by mouth and work through various
mechanisms to improve insulin sensitivity, increase insulin production, or reduce
glucose absorption in the intestines or its production by the liver. They are
primarily used in the treatment of type 2 diabetes, either alone or in combination with
other medications or insulin therapy, and are prescribed based on factors such as the
individual's medical history, glucose levels, and other health considerations. Regular
monitoring of blood sugar levels and ongoing medical supervision are essential when
using oral hypoglycemic drugs to optimize their effectiveness and minimize the risk
of side effects.

3. classification

4. Insulin secretagogues
Are drugs which increase the amount of insulin secreted by the
pancreas
Include:
• Sulfonylureas
• Meglitinides
•DPP-4 inhibitors

5.  Stimulate insulin release from functioning β cells by blocking of ATP-
sensitive K channels which causes depolarization and opening of
voltage- dependent calcium channels, which causes an increase in
intracellular calcium in the beta cells, which stimulates insulin release.
Mechanism of action of sulfonylureas:

6. Mechanism of Insulin Release

7. 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 (elderly and renal disease)
 Cross placenta, stimulate fetal β-cells to release insulin
→ fetal hypoglycemia at birth.

8. Tolbutamid
short-
acting
Acetohexamide
intermediate-
acting
Tolazamide
intermediate
-acting
Chlorpropam
ide
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 sulfonylureas

9. Tolbutamide:
safe for old diabetic patients or pts 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
First generation sulfonylureas

10. 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
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
Excretion Urine Urine Urine
Second generation sulfonylureas

11. Unwanted Effects:
1. Hyperinsulinemia & Hypoglycemia:
 Less in tolbutamide.
 More in old age, hepatic or renal diseases.
2. Weight gain due to increase in appetite
3. GIT upset.
CONTRAINDICATIONS:
 Hepatic impairment or renal insufficiency
 Pregnancy & lactation
 Type I diabetes

12. 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.
Meglitinides

13. 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).

14.  Type II diabetes:
monotherapy or combined with metformin
(better than monotherapy).
 Specific use in patients allergic to sulfur or sulfonylureas.
Adverse effects of Meglitinides
 Hypoglycemia.
 Weight gain.
Uses of Meglitinides

15. Mechanism of DDP-4 inhibitors
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.

16. Mechanism of action
of DPP-4 inhibitors

17. Clinical uses
Type 2 diabetes mellitus as a monotherapy or in combination with other
oral antidiabetic drugs when diet and exercise are not enough.
Orally
Given once daily
half life 8-14 h
Dose is reduced in pts with renal impairment
Adverse effects
Nausea, abdominal pain, diarrhea.

18.  Are drugs which increase the sensitivity of target organs to insulin.
Include
 Biguanides(AMPk activator)
AMPK stands for AMP-activated protein kinase. It's a crucial enzyme in cells
that functions as a metabolic master switch. AMPK is activated in response to
low energy levels, signaled by high levels of AMP compared to ATP. When
activated, AMPK promotes processes that generate energy (such as glucose
uptake and fatty acid oxidation) while inhibiting energy-consuming pathways
(such as protein and lipid synthesis).
Insulin sensitizers

19.  Does not require functioning β cells.
 Does not stimulate insulin release.
 Increases peripheral glucose utilization (tissue glycolysis).
 Inhibits hepatic gluconeogenesis.
 Impairs glucose absorption from GIT.
 Reduces plasma glucagon level.
– LDL &VLDL.
–  HDL
Mechanism of action of metformin

20.  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.
Adverse effects of metformin

21. Thiazolidinediones (glitazones)
Mechanism of action
Activate PPAR- (peroxisome proliferator-activated receptor -).
PPAR-gamma is a protein in our cells that helps control how our
bodies use and store fats and sugars. When activated, it improves
insulin sensitivity, making cells better at using glucose for energy.
– Decrease insulin resistance.
– Increase sensitivity of target tissues to insulin.
– Increase glucose uptake and utilization in muscle and adipose
tissue.

22. 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 sulfonylurea, biguanides.
 No risk of hypoglycemia when used alone.

23.  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.
Adverse effects of pioglitazone

24. Acorbose
 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.
 Decrease postprandial hyperglycemia.
 Taken just before meals.
 No hypoglycemia if used alone.
-Glucosidase inhibitors

25.  effective alone in the earliest stages of impaired glucose tolerance.
 Combined with sulfonylurea in treatment of Type 2 diabetes to
improve blood glucose control.
Kinetics of -glucosidase inhibitors
 Given orally, poorly absorbed.
 Metabolized by intestinal bacteria.
 Excreted in stool and urine.
Adverse effects
GIT: Flatulence, diarrhea, abdominal pain
Uses of -glucosidase inhibitors

26. An amylin analogue is a synthetic version of the hormone amylin, assisting in
blood sugar regulation by slowing glucose absorption and suppressing glucagon
secretion, commonly used in diabetes management to improve glycemic control.
Dopamine D2 receptor agonists, such as bromocriptine, are used in diabetes
management to improve glycemic control by modulating central nervous system
pathways involved in glucose metabolism, insulin sensitivity, and circadian
rhythm regulation. They work by enhancing dopamine signaling, which can lead
to decreased hepatic glucose production, improved insulin sensitivity, and
reduced postprandial hyperglycemia.

27. SGLT-2 inhibitors are a class of medications used in the treatment of type 2
diabetes. They work by blocking the sodium-glucose co-transporter 2 (SGLT-2)
in the kidneys, which is responsible for reabsorbing glucose back into the
bloodstream. By inhibiting this transporter, SGLT-2 inhibitors promote the
excretion of glucose in the urine, leading to lower blood sugar levels.
Additionally, they may also have other beneficial effects such as reducing blood
pressure and body weight.

28. SUMMARY
Class Mechanism Site of
action
Main advantages Main side
effects
Sulfonylureas
Tolbutamide
Glipizide
Glibenclamide
(glyburide)
Stimulating
insulin
production by
inhibiting the
KATP channel
Pancreatic
beta cells
• Effective
• Inexpensive
• Hypoglycemia
• Weight gain
Meglitinides
repaglinide
Stimulates
insulin
secretion
Pancreatic
beta cells
Sulfa free •Hypoglycemia
•Weight gain
Biguanides
Metformin
Decreases
insulin
resistance
Liver
• mild
weight loss
• No hypoglycemia
• GIT symptoms,
• Lactic acidosis
• Metallic taste
Thiazolidinedio
nes
pioglitazone
Decreases
insulin
resistance
Fat, muscle
Hepatoxicity
Edema
-Glucosidase
inhibitors
Acarbose
Inhibits α-
glucosidase
GI tract Low risk
•GI symptoms,
flatulence
DPP-4 inhibitor
Sitagliptin
Increase
secretin
GI tract