2. Diabetes mellitus
• Diabetes mellitus is a metabolic disease
associated with a high level of blood sugar and
as a rule, disturbance of carbohydrate, lipid
and protein metabolism.
3. • Diabetes is classified into two types.
• Insulin dependent (type I), in which there is
suppression of endogenous insulin production by
the organism itself and insulin-independent (type II),
which results either because of insufficient insulin
production or because of breakdown of insulin
receptors, which is usually a result of other
problems in the organism.
4. Diabetes mellitus
• Type I
– “Childhood” diabetes
– Loss of pancreatic β cells
– Decreased insulin
– Destruction of β cells
• Type II
– “Adult” diabetes
– Defective signal reception in insulin pathway
– Decreased insulin
• Both cause hyperglycemia, glycosuria, lipid
breakdown because tissues are deficient in
glucose, ketone bodies
5. Diabetes Mellitus
• This is a disease caused by elevated glucose
levels
• 2 Types of diabetes:
Type I diabetes (10% of cases)
–Develops suddenly, usually before age 15.
–Caused by inadequate production of insulin
because T cell-mediated autoimmune
response destroys beta cells.
–Controlled by insulin injections.
6. Type II diabetes
(90% of cases)
–Usually occurs after age 40 and in obese
individuals, but genetics, aging and peripheral
insulin resistance also.
–Insulin levels are normal or elevated but there is
either a decrease in number of insulin receptors
or the cells cannot take it up.
–Controlled by dietary changes and regular
exercise.
7. Diabetes mellitus
• Drugs used for lowering the glucose level in the
blood are called hypoglycemic agents.
• Likewise, substances that raise the level of
glucose in the blood are called hyperglycemic
agents.
• Changes in the level of glucose in the blood can
be caused by various reasons, the primary cause
being Diabetes mellitus.
8. • Insulin and other hypoglycemic agents are
used to treat Diabetes mellitus.
10. Insulin
• Used in Type I
• Sometimes used in Type II
• Must be administered parenterally
• Other forms in clinical trials
• Made from pork, beef-pork,
biosynthetic human or analogue
10
14. 14
Sulfonylureas (Oral Hypoglycemic drugs)
Tolbutamide Acetohexamide
Tolazamide
Chlorpropamide Glipizide
Glyburide
(Glibenclami
de)
Glimepiride
Short
acting
First generation
Intermediate
acting
Long
acting
Long
acting
Short
acting
Second generation
15. 15
Drugs other than Sulfonylurea
Metformin
Biguanides α-Glucosidase
Inhibitors
Thiazolidinediones
Acarbose Rosiglitazone
Pioglitazone
Repaglinide
Nateglinide
Meglitinides
17. Glipizide
• Synonyms of this drug are Glybinis, Minidiab,
Glucotrol and others.
• Glipizide: 1-cyclohexyl-3-[[p-[2-(5-
methylpyrazincarboxamido)ethyl]phenyl]
sulfonyl]urea
18. Glipizide
• Glipizide is generally prepared by the reaction of
sulfonamides with isocyanates followed by
condensation.
19. Synthesis of Glipizide
• 6-methylpyrazincarboxylic acid is initially reacted with
thionyl chloride, resulting in the corresponding chloride,
which undergoes further action with
4-(2-aminoethyl) benzene sulfonamide, forming the
corresponding amide 26.2.12.
• The resulting sulfonamide is reacted in a traditional
scheme with cyclohexyl isocyanate, forming the desired
glipizide (26.2.13)
21. Glipizide MOA
• This drug belongs to the second-generation
sulfonylurea derivatives.
• Like all of the other oral hypoglycemic drugs
examined, it is a β-cell stimulant in pancreas; but on
the other hand, it increases the sensitivity to insulin,
the degree to which it binds with target cells.
• At the same time, it differs in that it is easier to
tolerate.
22. • The hypoglycemic effect sets in at significantly
lower doses than with first-generation drugs.
23. Uses of glipizide
• It is used for type II diabetes mellitus of in a
single dose given 15 to 30 minutes prior to
breakfast.
24. Adverse effects of Glipizide
• It causes GIT disturbances like anorexia, heart
burn and vomiting.
• It may lead to obesity due to increase in
appetite.
• Mild and dose-dependent Metallic taste also
occurs.
25. Biguanides
• As early in 1918, guanidine was found to lower
blood sugar, but it is highly toxic.
• Exploration of this eventually led to Phenformin.
• Biguanides have been used in NIDDM patients as
adjuncts in insulin therapy and they are active
only in patients with some endogenous insulin
secretion.
26. Biguanides
• Biguanides might better be called antidiabetic
agents than hypoglycemic agents because
they have relatively little effect in normal
individuals.
27. Biguanides
• Biguanides have no effect on β-cells.
• Phenformin causes lactic acidosis and
therefore, has been withdrawn from U.S.A, GI
disturbances are also reported.
28.
29. Synthesis of Metformin
• Equimolar amounts of dimethylamine and 2-
cyanoguanidine are dissolved in toluene with
cooling to make a concentrated solution, and
an equimolar amount of hydrogen chloride is
slowly added. The mixture begins to boil on its
own and after cooling, metformin
hydrochloride precipitates with a 96% yield.
31. MOA of Metformin
• The exact mechanism of action remains
uncertain, the biguanides normalise blood
glucose levels by several proposed mechanisms.
• These including
➢Reduction in GIT absorption of glucose
➢Stimulation of anaerobic glycolysis
➢Inhibition of gluconeogenesis
32. ➢Stimulation of tissue glucose uptake and
increasing insulin-receptor binding.
• Of these its ability to reduce hepatic glucose
production is thought to be the most important.
33. Uses of Metformin
• It is comparatively safer than Phenformin.
• It is recommended for maturity onset diabetes
responding inadequately to dietary treatment
like phenformin, particularly in the obese
34. 34
BIGUANIDES
SIDE EFFECTS
1. Metallic taste in the mouth
2. Gastrointestinal (anorexia, nausea, vomiting,
diarrhea, abdominal discomfort)
3. Vitamin B 12 deficiency (prolonged use)
4. Lactic acidosis (exclusive in renal & hepatic failure)
