1. Dr. Sasan Zaeri (PharmD, PhD) Department of Pharmacology, BPUMS
Antidiabetic drugs
Dr. Sasan Zaeri (PharmD, PhD)
Department of Pharmacology, BPUMS

2. Diabetes mellitus (DM)
The most common metabolic disease
Chronic hyperglycemia
Biochemical
criteria
Normal
Prediabetic
Diabetic
FBS
< 100 mg/dL
mg/dL
>126 mg/dL
2-h GTT
<140 mg/dL
mg/dL
>200 mg/dL
Hb A1C
<5.6% %
>6.5%

3. Classification DM type I DM type II An autoimmune disease
Onset during childhood
Destruction of β-cells
Treatment with insulin
DM type II
A progressive disorder
Onset in adulthood
Insulin resistance + progressive destruction of β-cells
Early stages controlled with noninsulin antidiabetic drugs
Later stages often require addition of insulin to drug regimen

4. Antihyperglycemic Agents
Class
Available Agents
Insulin
Several forms
Sulfonylurea
Glibenclamide (glyburide), Gliclazide, Chlorpropamide
Biguanide
Metformin
Thiazolidinedione
Pioglitazone
α-Glucosidase inhibitors
Acarbose

5. Antihyperglycemic Mechanisms
Augment Insulin Supply
Enhance Insulin Action
Delay Carbohydrate Absorption
Insulins
Biguanides
α-Glucosidase inhibitors
Sulfonylureas
Thiazolidinediones

6. Insulin A small peptide hormone produced in the pancreas
Synthesis as prohormone proinsulin (86 aa)
Cleavage to insulin (51 aa) & C-peptide
Proinsulin & C-peptide have no physiologic actions

7. Insulin biological effects
Liver:
↑ Storage of glucose as glycogen
↓ Protein catabolism
Skeletal muscle:
↑ Glucose transport into muscle cells
↑ Glycogen synthesis and protein synthesis
Adipose tissue:
↑ Glucose transport into fat cells
↑ TG storage
↓ Intracellular lipolysis

8. Insulin indications
DM I
DM II
DM emergencies
Diabetic pregnant women

9. Insulin Preparations Different capacity to lower blood glucose.
Rapid acting
Short acting
Intermediate acting
Long acting

10. Extent and duration of action of various types of insulin
as indicated by the glucose infusion rates (mg/kg/min) required to maintain a constant glucose concentration. The durations of action shown are typical of an average dose of U/kg

11. Rapid-acting insulin Lispro, aspart, glulisine Onset: <15 min
Duration: 3-4 h
rapid onsets and early peaks of activity

12. Rapid-acting insulin Lispro, aspart, glulisine Indications:
control of postprandial glucose (immediately before a meal )
emergency treatment of uncomplicated diabetic ketoacidosis

13. Short-acting insulin
Regular
Onset: h
Duration: 4-6 h

14. Short-acting insulin Regular Indications:
emergencies of hyperglycemia (IV)
ordinary maintenance regimens (SC)
alone or mixed with intermediate preparations

15. Intermediate-acting insulin
Lente, Neutral Protamine Hagedorn (NPH)
Onset: 1-4 h
Duration : h

16. Intermediate-acting insulin
NPH insulin: exhibits a delayed onset and peak of action
NPH insulin is often combined with regular and rapid-acting insulins

17. INSULIN TACTICS Once daily NPH injection
6-23

18. INSULIN TACTICS Twice-daily Split NPH injection
Insulin Effect S B L S HS B
B=breakfast; L=lunch; S=supper; HS=bedtime
6-23

19. INSULIN TACTICS Twice-daily Split-mixed Regimens
Regular
NPH
Insulin Effect . B L S HS B
6-23

20. INSULIN TACTICS Multiple Daily Injections (MDI) NPH + Regular
NPH at AM and HS + Regular AC
NPH at HS + Regular AC
Regular
Regular
NPH
NPH
Insulin Effect
Insulin Effect B L S HS B B L S HS B
6-24

21. Long-acting insulin Glargine, Detemir, Ultralente
Gradual release pattern from injection site
Onset: 4 h
Duration: h

22. Long-acting insulin Glargine, Detemir, Ultralente Effects:
provide a peakless basal insulin level lasting more than 20 h
Indication:
control basal glucose levels without producing hypoglycemia

23. Glargine vs NPH Insulin(
6-34

24. Glargine insulin + Lispro insulin

25. Insulin side effects Hypoglycemia
Insulin induced immunologic complication
Injection pain
Weight Gain

26. Noninsulin antidiabetic drugs

27. Oral antidiabetic drugs
Insulin secretagogues (sulfonylureas)
Biguanide (metformin)
Thiazolidinediones (pioglitazone)
α-glucosidase inhibitors (acarbose)
Most commonly for TM II treatment

28. Major actions of oral antidiabetic drugs

29. SULFONYLUREAS

30. Sulfonylureas (SUs) Effects: Insulin secretagogues MOA:
Blockade of ATP-dependent K+ channels (KATP) in β-cells of pancreas→membrane depolarization → ↑release of insulin
Effects:
↑ Basal and postprandial insulin secretion
No effect in patients with non-functional pancreatic β cells

31. SUs

32. SUs 1st generation: 2nd generation: Tolbutamide, Chlorpropamide
Glibenclamide (Glyburide), Glipizide, Glimepiride
More potent
Use more commonly than the older
agents

33. SUs Side effects: Indication: DM II Dosing: Once or twice daily
Hypoglycemia
Weight gain

34. BIGUANIDES

35. Biguanides Metformin MOA:
↓hepatic glucose release
↓gluconeogenesis
Enhance peripheral glucose uptake & utilization
↑peripheral tissue sensitivity to insulin
Effects: Enhancement of insulin action, decrease weight
Depends upon:Presence of insulin
Metformin is a euglycemic agent
Slower action

36. Metformin Indications: Dosing: Two to three times daily Side effects:
DM II
Dosing: Two to three times daily
Side effects:
Nausea
↓appetite & weight loss
Lactic acidosis
diarrhea

37. ALPHA GLUCOSIDASE INHIBITORS

38. α-glucosidase inhibitors
MOA:
Carbohydrate analogs → α-glucosidase inhibition within the intestine → ↓glucose liberation → ↓intestinal glucose absorption → ↓(mild) blood glucose
Acarbose & Miglitol

39. α-glucosidase inhibitors
Effects:
Delays carbohydrate absorption
↓Postprandial hyperglycemia
No effect on fasting blood sugar and insulin release

40. α-glucosidase inhibitors indications
DM II
Prevent DM II in prediabetics
Must be taken just before a meal
Can be combined with other oral hypoglycemic agents
Dosing: Three times daily (with each meal)

41. α-glucosidase inhibitors side effects
Flatulence
Diarrhea
Abdominal pain

42. THIAZOLIDINEDIONES

43. Thiazolidinediones (glitazones)
Pioglitazone, Rosiglitazone

44. Pioglitazone MOA: Effects:
stimulation of nuclear receptors important for insulin action
peroxisome proliferator-activated receptor-gamma nuclear receptor (PPAR-γ receptor)
↑target tissue sensitivity to insulin
skeletal muscle and adipose tissues
Effects:
↑glucose uptake in muscle and adipose tissue
↓both fasting and postprandial hyperglycemia
Inhibition of hepatic gluconeogenesis (↓hepatic glucose output)
Change in lipid metabolism and the distribution of body fat
Shift of TG from non-adipose tissues to adipose tissue (↓serum TG)

45. Pioglitazone Indications: Dosing: Once daily Side effects: DM II
↓ risk of DM II in high-risk patients
Dosing: Once daily
Side effects:
Fluid retention
presents as mild anemia and edema
↑ risk of MI (Rosiglitazone)

46. Any question?