The document provides a comprehensive overview of oral hypoglycemic agents used in diabetes management, classifying them into categories such as secretagogues, sensitizers, and others. It details the mechanisms, pharmacokinetics, and side effects of different drug classes including sulfonylureas, biguanides like metformin, thiazolidinediones, and alpha-glucosidase inhibitors. Additionally, it discusses the roles of incretin mimetics and amylin analogues in enhancing insulin secretion and managing blood glucose levels.

1. ORAL HYPOGLYCEMIC
AGENTES
DIABETE MANAGEMENT

2. Classification of oral hypoglycemic
agents
1. Secretagogues
Sufonylureas
a. First generation
b. Second generation
Meglitinides
2. Sensitizers
Bioguanides
Thiazolidinediones

3. Classification of oral hypoglycemic agents
(cont)
3. Alpha-glucosidase inhibitors
4. Peptide analogues
Incretin mimetic
a. Glucagon-like peptide (GLP)
analogues and agonists
b. Gastric inhibitory peptide (GIP)
DPP-4 inhibitors
Amylin analogues

4. Chemical classification
 Sulphonylureas
 First generation: Tolbutamide, chlorpropamide,
acetohexamide, tolazamide
 Second generation: Glibenclamide, glipizide,
gliclazide, Glemipiride
 Biguanides: Phenformin, metformin
 Meglitinide Analogues: Repaglinide,
Nateglinide
 Thiazolidinediones: Rosiglitazone,
pioglitazone
 α–Glucosidase inhibitors: Acarbose, miglitol

5. Site of action of Oral Hypoglycemic Drugs

6. Mechanism of action of Sulfonylureas

7. Types of Sulfonylureas
Generation Agents Duration of action
First Tolbutamide 6-12 (hrs)
Chlorpropamide 60
Acetohexamide 12-24
Tolazamide 12-24
Second Glipizide 10-16
Glibenclamide 18-24
Glimepiride 18-24

8. Pharmacokinetic
Administered just before or along with
meal
Moderately protein bound (70-90%)
Metabolised in the liver; few are
metabolised to active metabolites
Low volume distribution
Few excreted unchanged in the urine

9. ADVERSE EFFECTS
Hypoglycemia:
long acting drugs dangerous (inadequate
diet, renal / hepatic diseases, other drug
administration)
GIT disturbances
Weight gain
Allergy : Jaundice with chlorpropamide
Thyroid dysfunction: tolbutamide reduces
iodine uptake.

10. DRUG INTERACTION
Antabuse like effect with alcohol
(especially with chlorpramide).
Enhancement
Highly protein binding drugs (salicylates)
increase the concentration.
Enzyme inhibitors (cimetidine,
chloramphenicol) increase the duration
of action.

11. DRUG INTERACTION
Inhibition
Enzyme inducers decrease the duration
of action.
Chronic alcoholism: hyperglycaemia.
Acute alcohol intake:
hypoglycaemia.
Corticosteroids, loop & thiazide diuretics,
oral contraceptives decrease insulin and
antagonise indirectly.
β-adrenergic drugs mask hypoglycemia.

12. MEGLITINIDE (GLINIDE)
 Secretion enhancer (insulin secretagogue)
 Mechanism similar to sulfonylureas but binding
may be at different site or receptor
 Rapid onset (should be taken immediately with
food or just before food)
 Metabolised in liver (caution: in liver dysfunction)
 Suitable to control postprandial hyperglycemia
uncontrollable with diet and exercise
 Substitute for sulfonylurea in case of allergy
 Repaglinide 0.25-0.4 mg, Nateglinide: 60-120 mg

13. Metformin (biguanides)
Mechanism
 Increase uptake and utilization of glucose
by skeletal muscle, which reduces the
insulin resistance
 Inhibition of hepatic and renal
gluconeogenesis, which decreases
hepatic glucose output predominantly
 Slow down the intestinal absorption of
glucose

14. Metformin (biguanides)
Mechanism
 Promote insulin-binding to its receptor
 Reduction in plasma glucacon level, does
not stimulate insulin, does not reduce
blood sugar in normal person
 Lowers LDL, VLDL and elevates HDL

15. Biguides (Metformin)
Partially absorbed, Partially metabolised
Duration: 8 hr; Taken with food
Dose: 500 mg bd (may be increased)
Metformin : Only oral anti-diabetic
approved in pregnancy
Side effects
Lactic acidosis (rare)
B-12 malabsorption

16. ACC = acetyl COA carboxylase
AMPK = adenosine mono phosphate kinase
SREPB = sterol regulatory expression binding
Protein

17. peroxisome proliferators-activated receptor γ

18. Thiazolidinediones (Glitazones)
Two types of PPARs - PPARα and PPARγ.
PPARα : ( TG but HDL)
PPARγ : insulin sensitizer
Thiazolidinediones + PPARγ
Transcription of several insulin responsive genes
Reverse the insulin resistance
Stimulate GLUT4 expression and translocation
Entry of glucose into muscle and fat is improved

20. Pioglitazone
 PPAR-α and PPAR-γ activity
 Absorbed within 2 hours of ingestion
 Food may delay uptake but total bioavailability
not affected
 Metabolized to active metabolites
 estrogen-containing oral contraceptives
metabolized by the same microsomal enzymes
 Once a day before meals (15 -30 mg)
 May be combined with metformin, sulfonylureas,
and insulin

21. ROSIGLITAZONE
 Predominantly on PPAR-γ
 Rapid absorption & high protein bound
 Other properties (kinetic & use) similar
Side effects (general)
 Fluid retention (weight gain), anemia,
headache, myalgia etc
 Not advisable in hepatic and CVS
complications
 Liver function test advisable

22. α-GLUCOSIDASES
 Starch, oligosaccharides and di-saccharides
monosaccharides for absorption
 Pancreatic α-amylase :sucrose, maltose,
glycoamylose, and dextrose
 α –glucosidases (intestinal brush ): lactose
 Acarbose & Miglitol cometitive inhibitor of α –
glucosidases and Pancreatic α-amylase (less)
 Miglitol: 6 times more potent against α-amylase
 postprandial digestion and absorption of starch
and disaccharides

23. α-GLUCOSIDASES
 Dose 25-100 mg (acarbose/miglitol) is taken at the
beginning of each meal.
 Minimally absorbed
 Produces flatulence, abdominal discomfort and
loose stool.

24. PEPTIDE ANALOGUES
Incretin Mimetics
 Incretins are insulin secretagogues
 GLP-1(Glucagon like peptide-1)liraglutide
 GIP (Gastric inhibitory peptide)
 Bind to GLP (incretin) receptors and increase
insulin release
 Exenatide: GLP-1 agonist is resistance to
degradation by DPP-4 and extends its half-life
 weight loss and gastrointestinal side effects

25. Dipeptidyl peptidase-4
 Dipeptidyl peptidase-4 degrades GLP-1
 Vildagliptin, sitagliptin, saxagliptin,
linagliptin : DPP-4 inhibitors
 prevents the action of DPP-4
 weight neutral and increased risk for
infection and headache

27. Insulin and Incretin

28. AMYLIN ANALOGUES
• Amylin, produced by pancreatic beta cells,
• Slows gastric emptying and suppress
glucagon
• Pramlintide is the amylin analogue
• SC inj. just before meal and it reduces
postprandial hyperglycemia
• Nausea, vomiting
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