oral hypoglycemic drugs

1. Oral hypoglycemic
drugs
Dr Reham ellisy
Assistant lecturer pharmacology
department

2. Oral hypoglycemic
1_Insulin secretagogues
Drugs that bind to sulfonylurea receptors (K+ATP channel modulators)
They include
A) sulfonylureas
1- First generation e.g.tolbutamide,chloropropamide
2-Second generation e. g. Glibenclamide, glimepride, glipizide,
gliclazide.
B) Non sulfonylurea (meglitinides) :e.g.repaglinide&nateglinide

3. Oral hypoglycemic
2-Insulin sensitizers:
A) Biguanides e.g.metformin
B)Thiazolidendiones e.g:rosiglitazone&pioglitazone
3-Drugs that affect absorption of glucose from intestine :
alpha-glucosidase inhibitors:acarbose& miglitol.
new antidiabetics:
4-Glucagon like peptide -1(GLP-1)agonists (incretin like)
:e.g.exendin_4(exenatide) &liraglutide
5-Dipeptidy peptidase inhibitors(DPP_4 inhibitors):
E. G. Sitagliptin, saxagliptin. And vildagliptin.
6-Amylin analogue:pramlintide.
7-Sodium glucose co transporters2 inhibitors.

4. 1-Secretagogues
A)Sulfonylurea
Members
• First generation
1-Tolbutamide.
2-Acetohexamide.
3-Chlorpropamide.
• Second generation
1-Glibenclamide(glyburide)
2-Glipizide :30 min b meal.
3-Gliclazide(diamicron)
4-Glimepride(amaryl)

5. Sulfonylureas
• Mechanism of action
1-Bind to(SUR)-close
k channel-depolarization
Ca dependent exocytosis of
insulin
2-↓glucagon release
3-↓gluconeogenesis

6. Pharmacokinetic
1-Absorption :food and hypoglycemia decrease absorption.
2- Distribution :high bound to p.p (90_99%)-pass bbb-pass placeta.
3-Metabolism:in liver by HME
4-Excretion :kidney
• Therapeutic uses
1. Type 2 diabetes mellitus (NIDDM).after failure diet & exercise.
2. Chlorpropamide:central diabetes insipidus.

7. Sulfonylurea drug interactions
Decrease action of sulfonyl
((hyper glycemia
Enhance action of sulfonyl (hypoglycemia)
1-Counter regulatory hormones:
oral contraceptives,glucagon,
.corticosteroids
1-Displace from protein binding:
salicylates,sulfonamides.
2-HME inducers:Phenobarbitone, phenytoin,
Rifampicin.
2-HME inhibitors : Cimetidine ketoconazole,
Chloramphenicol,MAO-inhibitors.
3-Suppress insulin release:
Thiazides , furosemide, diazoxide,phenytoin
Verapamil.
B2 agonist increase glycogenolysis.
3-Synergise with or prolong
pharmacodynamic action:
Salicylates , alcohol. Propranolol.

8. Side effects(sulfonylureas)
1-Hypoglycemia :esp overdose,elder,hepatic,renal.
2-weight gain:Appetite center stimulation.
3-Allergy.
4-Bone marrow inhibition.Chloropropamide.
5-Cholestatic jaundice chloropropamide -CNS manifestation.
6-↑coronary heart disease esp first genereation.
7-Edema due to antiduritic effect. chloropropamide
8-Failure of response.
9-GIT upset.
10 –Teratogenic& fetal hypoglycemia.

9. B) Non sulfonylureas (insulin secretagogues) -
Meglitinides
• Members: Repaglinide , Nateglinide
• Structurally different from sulfonylureas.
• Mechanism of action as sulfonylurea.
• Rapid onset-short duration-used orally(preprandial uses).
• Metabolism in liver-adjust in hepatic insufficiency
• Side effects: hypoglycemia
• Secondry failure

10. Meglitinides (mechanism of action)

11. 2-Insulin sensitizers
A-(Biguanides)
• Metformin
• Euglycemic-not hypoglycemic
• MOA:Inhibit mitochondrial complex 1
• ATP↓&AMP↑→↑ AMP-dependent
Protein kinase(AMPK)
1-↑Fatty acid oxidation.
2-↑Glucose uptake,
3-↑Anaerobic glycolysis.
4-↑ Insulin sensitivity.
5- ↓Lipogenesis & ↓ Gluconeogenesis.
6- ↓Glucagon release.
7-↓Intestinal glucose absorption.

12. Biguanides
Kinetics
• Not bound to P.P
• Drug transported by (OCT1)to liver &sk muscle
• Eliminated by kidney unchanged by (OCT2)
Therapeutic uses:
1-Monotherapy&combination with oral hypo in type 2 DM
2-Reduce the risk of diabetes in high risk pts
3-Treatment of infertility in women with PCO.
improve ovulation,menstrual cyclicity ,reduce androgen.

13. Biguanide side effects
1-Gastrointestinal :nusea, vomiting , diarrhea and abdominal cramps.
2-Metallic taste.
3-Lactic acidosis: presence of concurrent illness as sepsis,mycordial
infarction,heart failure and renal failure.
4- Vit B12 malabsorption
5-Drug interaction: cimetidine, furosemide and nifedipine.(How?)

14. B-PPARᵧ Activators (Thiazolidinediones)
• Pioglitazone,rosiglitazone,troglitazone.
• Mechanism of action: bind to PPARᵧ present in muscle,fat,liver.

15. Thiazolidinediones
• Therapeutic uses:
-Alone or with sulfonylurea-or metformin –or insulin.the combination has
advantage of not causing hypoglycemia.
• Side effects:
1-weight gain &oedema .Macular oedema.
2-Increased risk of heart failure.
3-Hepatotoxic,teratogenicity.
4-Rosiglitazone ↑ risk of myocardial ischemia.
5-Increased risk of osteoprosis and bone fracture.
6-Pioglitazone ↑risk of cancer bladder.

16. 3-Alpha glucosidase inhibitors
Mechanism of action:

17. 3-Alpha glucosidase inhibitors
• Examples : acarbose , miglitol.orally taken
• Slow absorbtion of carbohydrates
• Best one decrease post prandial plasma glucose
• Side effects:
1. Malabsorption,↓absorption of metformin (cannot combined with it )
2. Flatulence
3. Diarrhea
4. Don’t stimulate insulin release,don’t induce hypoglycemia.

18. 4-Glucagon like peptide -1(GLP-1)agonists
• Mechanism of action :

19. (GLP-1)Incretin like
• Exenatide-liraglutide.
• Given SC.
• Used in combination with metformin or sulfonylurea.
• Side effects:
1. Nusea,vomiting.
2. Weight loss
3. Acute pancreatitis
4. Hypoglycemia esp with
sulfonylurea

20. 5-DIPEPTIDYL PEPTIDASE-4 inhibitors
• Mechanism of action:

21. DPP-4 INHIBITORS
• Sitaglitin,saxagliptin.
• Used orally.
• Used as montherapy or in combination with metformin.
• Side effects:
1. Headache
2. Nasopharyngitis
3. Upper respiratory drug infections

22. 6-PRAMLINTIDE
Mechanism of action:

23. PRAMLINTIDE
• Amylin analogue.
• Binds to amylin receptors → reduction of glucagon release
Delay gastric emptying & satiety.
• Used SC prior to meals.
• Used adjunct therapy to insulin in type 1&type 2 diabetes.
• Side effects:
1. Nusea
2. Hypoglycemia especially with insulin.

24. 9-Sodium-glucose co-transporter 2 inhibitors
• Canagliflozin,dapagliflozin,empagliflozin.
• used orally in type 2 DM.
• Side effects:
1-↑Incidence of genital &
Urinary infections.
2-Osmotic diuresis →
Intravascular volumeDepletion
&hypotension
Contraindicated with low GFR