Pharmacology

1. Treatment of Diabetes Mellitus
Dr. Salman Iftikhar
Department of Pharmacology

2. Diabetes Mellitus
• Type 1 (IDDM):
– Early onset
– Loss of pancreatic B cells  absolute
dependence on insulin
– Ketoacidosis – prone
• Type 2 (NIDDM)
– Usually adult onset
–  response to insulin
– Not Ketoacidosis – prone

3. Insulin

8. Oral antidiabetic Agents

9. Insulin sectretagouges

10. Sulfonylureas

12. Sulfonylureas
• Mechanism
– The acute action of sulfonylureas is to
block K+ channels  depolarization 
insulin release
• Effects of increased insulin
–  glucagon release from pancreatic  cells

13. Sulfonylureas
• Acetohexamide (active metabolite,  dose in
renal dysfunction)
• Tolbutamide (appropriate in renal
dysfunction)
• Chlorpropamide (long acting,
SIADH/disulfiram reaction)
• Glipizide ( dose in hepatic dysfunction)
• Glyburide (active metabolite,  dose in renal
dysfunction)

14. Sulfonylureas
• Adverse effects:
– Hypoglycemia
– Weight gain
– Hypersensitivity (possible cross allergy
with sulfonamides)
– Drug interactions mainly with first-
generation drugs  hypoglycemia with
cemetidine, insulin, sulfonamides,
salicylates

15. Meglitinide Drugs
• Repaglinide and nateglinide
– rapidly absorbed and promptly produce a
hypoglycemic effect of short duration
– Mechanism is same as sulfonylurea
compounds
– Taken before meals
– Used in combination with metformin but not
with other antidiabetics or insulin

16. Insulin Sensitizing Agents

17. Metformin
• “Euglycemic”,  postprandial glucose
levels but does not cause
hypoglycemia or weight gain
• May involve  tissue sensitivity to
insulin and/or  hepatic
gluconeogenesis
• Adverse effects: possible lactic
acidosis; gastrointestinal distress is
common

18. Thiazolidinediones
Pioglitazone & Rosiglitazone

19. • Mechanism:
– Bind to nuclear peroxisome proliferator-activating
receptors (PPARs) involved in transcription of
insulin responsive genes  sensitization of
tissues to insulin, plus  in hepatic
gluconeogenesis and triglycerides and  insulin
receptor numbers
– Adverse effects: less hypoglycemia than
sulfonylureas, but weight gain and edema reported
– pioglitazone may be associated with a slightly
increased risk of bladder cancer
– Increase the risk of osteoporosis and fractures in
older women

20. Acarbose
• No hypoglycemia
• Mechanisms: inhibits  glucosidase in
brush borders of small intestine  
formation of absorbable carbohydrate
  postprandial glucose   demand
for insulin
• Adverse effects: GI discomforts,
flatulence and diarrhea; recent
concerns over potential hepatotoxicity

21. New Drugs
Amylin Mimetic
Incretin Mimetics

22. PRAMLINTIDE
• Synthetic analog of amylin
• Injectable: modulates postprandial glucose
levels
• Suppresses glucagon release via
undetermined mechanisms, delays gastric
emptying, and has central nervous system-
mediated anorectic effects
• Administered in addition to insulin in those
who are unable to achieve their target
postprandial blood sugars

23. • Renal metabolism and excretion
• Always be injected by itself with a
separate syringe; it cannot be mixed
with insulin
• Adverse effects: hypoglycemia and
gastrointestinal symptoms including
nausea, vomiting, and anorexia.
PRAMLINTIDE

24. EXENATIDE
• A synthetic analog of glucagon-like-polypeptide 1
(GLP-1), exenatide is the first incretin therapy to
become available for the treatment of diabetes
• Approved as an injectable, adjunctive therapy in
persons with type 2 diabetes treated with metformin
or metformin plus sulfonylureas who still have
suboptimal glycemic control
• Multiple actions
– potentiation of glucose-mediated insulin secretion
– Suppression of postprandial glucagon release through as-
yet unknown mechanisms
– slowed gastric emptying, and a central loss of appetite
– The increased insulin secretion is speculated to be due in
part to an increase in beta-cell mass

25. • Adverse effects are nausea (about 44% of
users) and vomiting and diarrhea. The
nausea decreases with ongoing exenatide
usage
• Weight loss is reported in some users,
presumably because of the nausea and
anorectic effects. A serious and, in some
cases, fatal adverse effect of exenatide is
necrotizing and hemorrhagic pancreatitis.
• Safety issues, however, may deter future
use.
EXENATIDE

26. SITAGLIPTIN
• Inhibitor of dipeptidyl peptidase-4 (DPP-4), the enzyme
that degrades incretin and other GLP-1-like molecules
• Its major action is to increase circulating levels of GLP-
1 and GIP.

27. • Decreases postprandial glucose excursions
by increasing glucose-mediated insulin
secretion and decreasing glucagon levels
• Adverse effects include
– nasopharyngitis, upper respiratory infections, and
headaches. Rarely, severe allergic reactions
• Dosage should be reduced in patients with
renal impairment. Sitagliptin can be given as
monotherapy or combined with metformin or
Tzds.

28. BLOOD

29. • A patient takes nateglinide before each meal. Which
mechanism is responsible for the therapeutic effect of
this drug?
A. closing of potassium channels
B. slowed gastric emptying
C. inhibition of α-glucosidase
D. inhibition of DPP-4
E. insertion of glucose transporters in cell membranes