Anti diabetic drugs

1. Diabetes mellitus
•DM is characterized by elevated blood
sugar levels due to absolute or relative
lack of insulin.
•Type 1 diabetes - b-cell failure at outset
–Insulin dependent
•Type 2 diabetes - Gradual b-cell
deterioration
–Early stages: Diet and Oral agents
–Late-stage: Insulin therapy

2. Diabetes mellitus
•Glycosylated hemoglobin Hb-A1c :
It is used to monitor the plasma glucose
concentration over prolonged periods of
time (4-6 weeks).
•Insulin secretion is promoted by ↑ blood
glucose levels, amino acids, GI
hormones and by β-2 agonist.

3. Insulin
•Proinsulin is converted to insulin and C
peptide.
•Insulin is referred as the storage hormone
as it promotes anabolism and inhibits
catabolism of carbohydrates, fatty acids
and protein.
•In the absence of insulin, most tissues
cannot use glucose and fats/proteins are
broken down to provide energy.

4. Insulin
Mechanism of action :
•Insulin binds to insulin receptors on the
plasma membrane and activates
tyrosine kinase – primarily in adipose
tissue, liver and skeletal muscle.
•The Nerves, RBC’s, Kidney, and Lens of
the eye do not require insulin for
glucose transport.

5. Insulin
Liver :
•Insulin increase the storage of glucose as
glycogen in the liver.
•It inserts the GLUT-2 glucose transport
molecule in the cell membrane.
•It inhibits gluconeogenesis – thus
significantly ↓ glucose output by the liver.
•It decrease the protein catabolism.

7. Insulin
Muscle :
•Insulin stimulates the glycogen
synthesis and protein synthesis.
•Glucose transport into the cells is
facilitated by GLUT-4 into the cell
membrane.
•It inhibits the protein catabolism.

8. Insulin
Adipose tissue :
•Insulin facilitates the storage of
triglyceride by activating plasma
lipoprotein lipase and inhibiting
intracellular lipolysis.
•It increase the glucose uptake by
GLUT-4 insertion into the cell
membrane.

9. Insulin

10. Insulin
•Insulin is a 51 AA peptide
•Not active orally.
•Insulin is inactivated by insulinase found
mainly in liver and kidney.
•Dose reduced in renal insufficiency
•Sources of Insulin :
–Beef pancreas / Pork pancreas
–Human insulin: recombinant DNA origin

11. Insulin
Human Insulin :
•Do not contain measurable amounts of
proinsulin or contaminants.
•Diminished antibody
•Less allergic reactions
•Less lipodystrophy
•Preferred in gestational diabetes

12. Insulin
Insulin preparations :
•Rapid acting insulin :
Lispro, Aspart and Glulisine
•Short acting insulin:
Regular (crystalline)
•Intermediate acting insulin:
NPH (isophane) and Lente (insulin zinc)

•Long acting insulin:
Ultralente, Detimir and Glargine

13. Insulin Duration Route Features
Lispro 3 – 5 hrsI.V or S.C
Onset within 15
minutes
Regular
(crystalline)
7 – 10 hrsI.V or S.Ccommon
NPH
(Neutral protamine
hagedorn)
16 – 20 hrs S.C
NPH can mix
with regular
Ultralente24 – 30 hrsS.C Basal level
Insulin

14. Insulin

15. Insulin
Adverse effects of Insulin :
•Hypoglycemia
•Allergic reactions
•Lipodystrophy
•Others includes
–Seizures
–Coma

16. Oral Anti-diabetic drugs
Mechanisms to reduce blood sugar :
•Stimulation of pancreatic insulin release –
Sulfonylureas, Meglitinide
•Reduce the bio-synthesis of glucose in
liver – Biguanides (Metformin)
•Increase the sensitivity of target cells to
insulin -- Thiazolidinediones
•Retard the absorption of sugars from the
GI tract – Acarbose, Miglitol

18. Oral Anti-diabetic drugs
Sulfonylureas :
•First generation : Acetohexamide,
Chlorpropamide, Tolbutamide,
Tolazamide
•Second generation : Glipizide, Glyburide
– more potent, more efficacious and fewer
adverse effects.
•Third generation : Glimiperide

19. Sulfonylureas

20. Sulfonylureas
Dose
(mg)
Duration
(h)
First Generation
Tolbutamide (Orinase) 1000-1500 6-8
Chlorpropamide (Diabinese) 250-375 24-60
Tolazamide (Tolinase) 250-375 12-24
Second generation
Glipizide (Glucotrol) 10 10-24
Glyburide (Micronase)
(Glibenclamide)
Third generation
5 16-24
Glimepiride (Amaryl) 1-2 24

21. Oral Anti-diabetic drugs
Sulfonylureas : Adverse effects :
•Hypoglycemia
•Cholestatic jaundice
•Weight gain
•Cross placenta – fetal hypoglycemia.
•Chlorpropamide : It can cause water
retention by ↑ release of ADH (SIADH)
•Disulfiram-like reaction with alcohol.

22. Oral Anti-diabetic drugs
Repaglinide, Nateglinide :
•More rapidly acting insulin enhancers
and shorter duration than sulfonylurea.
•Hypoglycemia is the common adverse
effect.
•Less weight gain

23. Oral Anti-diabetic drugs
Repaglinide, Nateglinide
•The drug has minimal renal excretion
thus useful in patients with DM and
impaired renal function. 
•It is designed to be taken with each meal
to stimulate insulin release with meal.
If a meal is skipped, so is the repaglinide.

24. Oral Anti-diabetic drugs
Biguanides (Metformin):
•Inhibits gluconeogenesis.
•Does not promote insulin secretion.
•It increase the sensitivity of liver and
muscle to insulin.
•It causes modest weight loss.

25. Oral Anti-diabetic drugs
Metformin (Glucophage) :
•It does not cause hypoglycemia.
•It produces a significant ↓ TG and LDL,
and ↑HDL.
•There is a serious concern about lactic
acidosis especially in patients with kidney
disease.

26. Oral Anti-diabetic drugs
Thiazolidinediones
•Enhance glucose and lipid metabolism
through action on Peroxisome Proliferator
Activated Receptor (PPAR–γ)
•Enhance sensitivity to insulin in muscle
and fat by increasing the GLUT 4 glucose
transporters.
•E.g. ; Pioglitazone Actos,
Rosiglitazone Avandia

27. Anti-diabetic drugs
Thiazolidinediones :
•Beneficial effects on serum lipid; ↓TG
and ↑HDL.
•Troglitazone is associated with
hepatitis.
•Edema.

28. Anti-diabetic drugs
Alpha-Glucosidase Inhibitors:
•It inhibits -glucosidase which converts
dietary starch and complex
carbohydrates into simple sugars
•It reduces absorption of glucose after
meals.
•The main side effects includes
flatulence and diarrhea.
•Acarbose Acarbose (Glucobay)(Glucobay) , Miglitol , Miglitol (Glyset)(Glyset)

30. Anti-diabetic drugs
Glucagon like Peptide : GLP-1 analog :
Xenatide : (Byetta) :
•GLP is an incretin released from the small
intestine which increase the glucose
dependent insulin secretion.
•Xenatide suppress glucagon release and
reduce appetite
•It is administered by SC injection.

31. Anti-diabetic drugs
Glucagon like Peptide : GLP-1 analog : Xenatide : (Byetta) :

32. Anti-diabetic drugs
Dipeptidyl peptidase 4 (DPP-4) inhibitors: SITAGLIPTIN (januvia)
Xenatide
(Byetta) inj
Sitagliptin
(januvia)

33. Anti-diabetic drugs
•Sitagliptin (Januvia) is an oral anti-
diabetic drug.
•It inhibit the dipeptidyl peptidase 4 (DPP-
4), an enzyme which inactivates the
incretins GLP-1 and GIP, that are released
in response to a meal.
•It potentiates the secretion of insulin and
suppress the release of glucagon by the
pancreas.

34. Endocrine pancreas
Glucagon :
•It has positive inotropic action and
chronotropic action on the heart.
•It acts by stimulation of glucagon
receptors and not through beta 1
receptors.
•This is the basis for using glucagon in
beta blocker overdose.