Oral hypoglycemic drugs are used only in the treatment of type 2 diabetes which is a disorder involving resistance to secreted insulin. Type 1 diabetes involves a lack of insulin and requires insulin for treatment. There are now four classes of hypoglycemic drugs:

1. Prof. Amol B Deore
MVP’s Institute of Pharmaceutical Sciences, Nashik
(INDIA)

2. Diabetes
 Diabetes mellitus: it is a metabolic disorder characterized
by deficiency of insulin or insulin resistance which leads
to hyperglycemia.
 Diabetes mellitus type 1 is a disease caused by the lack of
insulin. Insulin must be used in Type I, which must be
injected.
 Diabetes mellitus type 2 is a disease of insulin resistance
by cells. Type 2 diabetes mellitus is the most common
type in worldwide.

5. Management
Treatments include:
 (1) Agents that increase the amount of insulin secreted
by the pancreas,
 (2) Agents that increase the sensitivity of target organs
to insulin, and
 (3) Agents that decrease the rate at which glucose is
absorbed from the GIT tract.

6. INSULIN
 Parenteral Insulin preparations
Conventional insulin: bovine insulin, porcine insulin

7. HUMAN INSULIN PREPARATIONS
Type Preparation
Duration
of action
Time of injection
Fast acting 1. Regular Insulin injection
2. Prompt Insulin Zinc
suspension (SEMILENTE)
3. Insulin Lispro
4. Insulin aspart
5-7 hrs Before breakfast
Intermediate
acting
1. Isophane Insulin
suspension (NPH insulin)
2. Insulin Zinc suspension
(LENTE)
3. Globin Zinc Insulin
injection
18-24 hrs Before breakfast
Long acting 1. Protamine Zinc Insulin
suspension (PZI)
2. Extended Zinc Insulin
suspension (ULTRLENTE)
24-36 hrs At breakfast

8. Mechanism of action

9. Pharmacological action

12. EFFECT ON LIVER:
 Increase protein synthesis
 Inhibits glycogenolysis
 Inhibits conversion of fatty acids and amino acids to
keto acids
 Inhibits conversion of amino acids to glucose
 Promotes glucose storage as glycogen (induces
glucokinase and glycogen synthase, inhibits
phosphorylase)
 Increases triglyceride synthesis and very low density
lipoprotein formation

13. EFFECT ON SKELETAL MUSCLE:
 Increased protein synthesis
 Increases amino acid transport (uptake)
 Increases ribosomal protein synthesis
 Increased glycogen synthesis
 Increases glucose transport (uptake)
 Induces glycogen synthase and inhibits phosphorylase

14. EFFECT ON ADIPOSE TISSUE:
 Increased triglyceride storage
 Increased lipogenesis
 Decreased lipolysis
 Lipoprotein lipase is induced and activated by insulin
to hydrolyze triglycerides from
 lipoproteins

15. ROUTE OF ADMINISTRATION
 Insulin is usually taken as subcutaneous injections
by single-use syringes with needles, an insulin pump,
or by repeated-use insulin pens with needles.

16. Insulin in not given orally. Why?
 Insulin is a high molecular weight polypeptide
hormone secreted from pancreatic Beta cells of Islets
of Langerhans.
 If Insulin is administered orally in diabetes, then it is
inactivated by the gastric enzyme Pepsin in stomach
and corboxypeptidase enzyme in small intestine.
 Hence very little fraction of Insulin enter in to systemic
blood circulation for producing hypoglycemic action
with low bioavailability.
 Therefore Insulin should not be given orally. It must
be given subcutaneously.

17. ADVERSE DRUG REACTION
 Hypoglycemia: may be due to insulin over dosage, failure to
eat
 Insulin Allergy: Insulin allergy, immediate type
hypersensitivity, is a rare condition characterized by local or
systemic urticaria, Lymphadenopathy. In severe cases,
anaphylaxis shock.
 Redness at injection site, atrophy of adipose tissue
(lipodystrophy)
 Insulin Resistance: Insulin antibodies will lead to insulin
resistance
 Lipodystrophy at Injection Sites: Injection of older insulin
preparations sometimes led to atrophy of subcutaneous fatty
tissue at the site of injection.
 Insulin presbyopia: difficulty or loss of accommodation,
patient can see near objects but failed to see far away objects.
 Insulin neuropathy
 Obesity: due to insulin therapy without dietary restriction

18. ORAL HYPOGLYCEMIC AGENTS
 These are the drugs used in the management of
diabetes mellitus type 2. All are administered orally
and are thus also called oral hypoglycemic agents.

19. INSULIN SECRETOGOGUES
 Sulfonylureas: Glyburide, Glimepiride, Glipizide,
Glibenclamide, Tolbutamide, chlorpropamide,
acetohexamide
 Meglitinides: Repaglinide, Nateglinide
INSULIN SENSITIZERS
 Biguanides: Metformin, Phenformin, Buformin
 Thiazolidinediones: Pioglitazone, Rosiglitazone
MISCELANEOUS
 Alpha glucosidase inhibitors: Acarbose, Miglitol,
Voglibose
 Gliptins: Vildagliptin, Sitagliptin, Septagliptin,
Saxagliptin, Alogliptin, Linagliptin

20. SULFONYLUREAS
 Ex. Glyburide, Glimepiride, Glipizide, Glibenclamide,
Tolbutamide, chlorpropamide, acetohexamide

21. Mechanism
 They increase the sensitivity of Beta-cells towards glucose,
enabling them to increase insulin release at every glucose
level.
 These drugs probably act on sulphonylureas receptors on the
cell membrane of Beta cells. These receptors are linked to
ATP sensitive K+ channels on the cell membrane.
Sulphonylureas bind to their receptors leads to closing off
ATP-sensitive K+ channels and promote depolarization
(decreased repolarization) of the Beta-cell membrane. This
produces Ca++ influx resulting in insulin release from Beta
cells by degranulation. Hence they are insulin
secretagogues.
 They also inhibit hepatic gluconeogenesis and
glycogenolysis.
 They increase insulin sensitivity of insulin receptors in the
peripheral tissues such as skeletal muscles and liver.

22. They work best with patients over 40 years old who have had
diabetes mellitus for under ten years. They cannot be used with
type I DM. They can be safely used with metformin or
Thiazolidinediones.
Adverse drug reactions
 Sulfonylureas may cause hypoglycemic reactions,
including coma, particularly in elderly patients with
impaired hepatic or renal function who are taking longer-
acting sulfonylureas.
 Allergic skin reactions
 Bone marrow depression: leukopenia,
thrombocytopenia, agranulocytosis
 Teratogenicity, embryopathy
 jaundice
 Intolerance to alcohol

23. BIGUANIDES
e.g. Metformin, Phenformin, Buformin
 They act by stimulating peripheral utilization (uptake)
of glucose by skeletal muscles, liver cells and
adipocytes (fat cells)
 Increase insulin sensitivity of insulin receptors of
skeletal muscles and liver
 inhibit hepatic gluconeogenesis
 reduce intestinal absorption of glucose
 they lower blood glucose level in absence of
functioning pancreas (endogenous insulin) hence may
use in Type-1 DM (IDDM)
 They are used in NIDDM who are obese or where
sulphonylureas are not effective alone.

24. Adverse drug reactions
 Metallic taste, anorexia, weight loss, nausea,
abdominal discomfort, diarrhea, lethargy, muscular
weakness
 Anaphylaxis reactions rarely
 Ketoneuria and lactic acidosis

25. THIAZOLIDINEDIONES
Ex. pioglitazone, rosiglitazone
 Thiazolidinediones principally act by increasing
insulin sensitivity (lowering insulin resistance) in
peripheral tissues—and thus are effective only when
insulin is present
 Decrease hepatic glucose production
(gluconeogenesis)
 Thiazolidinediones increase glucose transport
(uptake) into muscle and adipose tissue by enhancing
the synthesis and translocation of specific forms of the
glucose transporters.
 The thiazolidinediones also activate genes that
regulate fatty acid metabolism in peripheral tissue.

26. Differentiate between sulfonylureas
and biguanides
SULFONYLUREA BIGUANIDES
1) Ex. Glyburide, Glimepiride,
Glipizide, Glibenclamide,
Tolbutamide
Ex. Metformin, Phenformin,
Buformin
1) -Stimulating pancreatic Beta cells
for insulin release (secretion) by
degranulation of Beta cells)
-Inhibit hepatic glycogenolysis
-inhibit hepatic gluconeogenesis
- decrease insulin resistance
-Increase insulin sensitivity of
insulin receptors of skeletal muscles
and liver
-inhibit hepatic gluconeogenesis
-reduce intestinal absorption of
glucose
1) No action on peripheral glucose
utilization (uptake)
Increase peripheral glucose
utilization (uptake) by the skeletal
muscle and liver
1) They are insulin secretagogues They are Insulin sensitizers

27. 1) Sulfonylureas are useful only
in
Type II diabetes with
patients over 40 years
Most commonly used agent for
type II diabetes in children and
teenagers
1) Never used in type 1 diabetic
patient
Phenformin may be used in Type
1 diabetes patients in
combination with Insulin
1) Weight gain in patients Weight loss, anorexia in patients
1) No effect on effect on LDL
cholesterol
Good effect on LDL cholesterol
1) Sulfonylureas are
contraindicated in breast
feeding mother
Biguanides are contraindicated in
cardiovascular disorders
1) Increased risk of hypoglycemia low risk of hypoglycemia as
compared to alternatives
1) lower risk of gastrointestinal
problems
increased risk of gastrointestinal
problems