Insulin & Oral Hypoglycemic Agents.

Pharmacology-2

Presented by;-
Mr. Tejas Mahendra Bhatia.
Third Year (Fifth Semester) B.Pharmacy,
Appasaheb Birnale College of Pharmacy, Sangli.
 CONTENTS:-
 Introduction to Diabetes Mellitus.
 INSULIN.
 Oral Hypoglycemic Agents.
 Introduction
 Diabetes Mellitus is a group of metabolic diseases
in which a person has high blood sugar levels,
either because,

 The pancreas do not produce enough INSULIN.

 Cells do not respond to INSULIN produced.

 The high blood sugar level produces classical
symptoms:-

POLYURIA
POLYDIPSIA
 Diagnosis for DM:-
 DM is diagnosed by :-

 Fasting blood glucose if exceeds 6.1-7.0

mmol.(126mg/dl).

 Postprandial glucose if exceeds

200mg/dl.

 HBA1C (glycosylated hemoglobin)

exceeds 6.5gm%.
 Types of DM:-
Type 1 DM.
 It results from the body’s failure to
produce insulin, and requires the person
to inject insulin or insulin pump.

 Is due to BETA CELLS destruction in pancreas.

 Is LESS COMMON.

 Is known as IDDM or JUVENILE diabetes.

 Treatment by INSULIN only.
 TYPE 2 DM:-
 Results from INSULIN RESISTANCE, a
condition in which cells fail to use insulin
properly. Sometimes combined with an
ABSOLUTE INSULIN DEFICIENCY.

 Moderate destruction in beta cells.

 MORE COMMON.

 Is known as NIDDM or Adult-Onset Diabetes.

 Treatment by orally active drugs or injection.

Difference Between TYPE 1 & TYPE 2
DM:-

Image Courtesy; ANA E-Learning

 OVER 90% CASES OF DIABETES are of
TYPE 2 DM.
 Causes may be:-
 Abnormality in Gluco Receptor of beta cells so
they respond at higher glucose levels.
 Reduced sensitivity of peripheral tissue to
insulin receptors.
 Excess RELEASE of HYPERGLYCEMIC
HORMONES (glucagon).
 Gestational Diabetes refers to onset of glucose
intolerance in women during pregnancy. It
excludes women who were diabetic before
 Pancreas:-

The pancreas is an organ located in the abdomen, The

pancreas has two main functions: an exocrine function
that helps in digestion and an endocrine function that
 Pancreas at a glance:-
 ALPHA CELLS:-
 Hormone:- GLUCAGON.
 Function:- Stimulates the conversion of stored
glycogen (stored in liver) to glucose.
 Stimulates GLYCOGENOLYSIS.
 Disorder:- Hypo secretion causes hypoglycemia.
 BETA CELLS:-
 Hormones:- INSULIN.
 Function:- Controls blood sugar level by signaling the
liver, muscle and fat cells to take in glucose from
blood and stimulates GLYCOGENESIS.
 Disorder:- Hypo secretion causes DM.
 DELTA CELLS:-
 Hormone:- SOMATOSTATIN.

 Function:- Suppresses release of INSULIN &

GLUCAGON.

 F CELLS:-
 Hormone:- Pancreatic Polypeptide.

 Function:- Inhibit the release of digestive secretions

of the pancreas.
 The external secretions of PANCREAS is
digestive in function, and ENDOCRINE
functions are performed by ISLETS OF
LANGERHANS.
 Islets of Langerhans:-Small, highly vascularized
masses of cells scattered throughout pancreas,
forming only 1-3 % of entire organ.
 Contains 4 types of secretary cells, viz ALPHA,
BETA, DELTA, F CELLS.
 Insulin secreting Beta cells are the most
numerous (70-80%)
 Alpha cells-20%
 Delta cells:- 4%
 F cells:- Less than 2%.
 INSULIN:-
 Discovered by BANTING & BEST.

 There are 51 AMINO ACID in an insulin

molecule.(ACTIVE FORM ONLY).

 TWO CHAIN POLYPEPTIDES.

Chain A:- has 21 Amino Acids.
Chain B:- has 30 Amino Acids.

BOTH CHAINS ARE CONNTECTED BY

DISULPHIDE BRIDGES. (P.Y GPAT).

 Isolated in 1921, used in treatment of DM in 1922.

 Polypeptide with MW of about 6000.

 A chain is ACIDIC & B chain is BASIC.

 Disulphide bridges are essential for biological

activity.

 Immediate precursor of insulin, PROINSULIN is

within the pancreatic beta cells in which A & B
chains are joined by connecting peptide (C-Peptide)
COMPOSED OF 31 AA.

 The pig(porcine) insulin closely resembles human

 Insulin is soluble in water, but undergoes molecular
aggregatation at extremes of pH 3.2 and 10).
 Such aggregations are also encouraged by presence of
Zinc which brings about crystallization of insulin.

 Isoelectric point:- 5.3

 Insoluble between pH 4 & 7.

 It can combine with proteins like globin and protamine,

whereby its activity is retained and duration of
action is prolonged.

 Recently human insulin has been successfully produced

through E.COLI by rDNA technology or by chemical
modification of pork insulin to replace AA that is different
 Glucose is the main stimulus for release of insulin from
BETA CELLS OF PANCREAS.

 Glucose stimulates GLUT-2 and inhibits ATP

sensitive Potassium channels: factors that are
responsible for depolarization of beta cells and
release of insulin.

 ALPHA 2 receptor stimulation inhibits insulin

secretion.
 Beta 2 Agonist and vagal stimulation enhances
insulin release.
 Somatostatin inhibits whereas glucagon stimulates
the release insulin.
 Insulin is synthesized from BETA CELLS of
pancreatic islets, from a precursor
preproinsulin.(110 AA)

 The connection or C PEPTIDE (35 AA) is split off

by proteolysis in GOLGI APPARATUS .

 Both insulin and C peptide are stored in granules

within the cells , C peptide is secreted in cells.

 Half life of insulin:- 4-6 minutes.

 Actions of Insulin:-
 CARBOHYDRATE METABOLISM
(By stimulating entry of glucose into cells by increasing
synthesis of glucose transporter 4 (GLUT-4)

 FAT METABOLISM

 PROTEIN METABOLISM
(Anabolic Effect).
 MODE OF ACTION_INSULIN:-
 Attachment of insulin molecule to a specific
insulin receptor on cell surface.

 Insulin lowers cAMP in some tissues by inhibiting

adenylate cyclase enzyme

 It also stimulates cyclic nucleotide

phosphodiesterase (enzyme destroying cAMP)
 Lowering cAMP contents of cells.

 Due to less cAMP in cells glycogen breakdown

decreases and glycogen synthesis increases.

 Facilitates potassium transport in cells.

ORAL HYPOGLYCAEMIC AGENTS:-
 ORAL HYPOGLYCAEMIC AGENTS:-
 These are agents used in the treatment of type 2
DM.
 These are classified into several groups based on
MOA or structures as follows:-
 1) ENHANCED INSULIN SECRETION:-
(Acts as potassium channel blockers causing
depolarization of beta cells)
A) Sulphonylurea:-
First generation: Chlorpropamide, Tolbutamide.
Second Generation:- Glipizide, Glibenclamide.(More
potent)
B) Meglitinides/Phenylalanine Analogues:-
Nateglinide
  2) OVERCOME INSULIN RESISTANCE:-
 A) Biguanides (AMPk Activator):-
 Metformin
 Phenformin.
 B) Thiazolidinediones:-
 Troglitazone
 Pioglitazone
 Rosiglitazone
 3) Retard Carbohydrates Absorption:-
 Alpha Glucosidase inhibitors:-
 Acarbose
 Voglibose
 Miglitol
  4) Miscellaneous Drugs:-
 A) Glucagon like peptide (GLP-1) agonist:-
 Exenatide
 Liraglutide.
 B) Dipeptidyl peptidase-4(DPP-4) inhibitors:-
 Sitagliptin
 Vildagliptin
 Saxagliptin
 C) Sodium Glucose Co-transporter-2 inhibitors:-
 Dapagliflozin
 Canagliflozin
 D) Amylin analogue:-
 Pramlintide.
 Sulfonylurea:-
 First Generation:-
 Tolbutamide.
 Chlorpropamide.
 Second Generation;- (4G’s )
 Glibenclamide
 Glipizide
 Glicazide
 Glimepiride
  SULFONYLUREA:-
 Chemically related to sulphonamides, but with no
antibacterial action.
 MODE OF ACTION:-
 Inhibits ATP sensitive Potassium channels and
causes DEPOLARIZATION of beta cells.

 This results in release of insulin.

 Effective only if 30% or more of beta cells in the

pancreas are functional.
 Effective in TYPE-2 DM only.
 Second Generation are more potent than first
generation drugs.
 All causes HYPOGLYCEMIA (maximum with
chlorpropamide).
 Chlorpropamide can cause dilution hyponatremia
(ADH like action), Cholestic jaundice, and dilsulfiram
like action.
 Gliclazide has additional ant platelets activity.
 Contraindicated in liver and kidney failure due to risk of
hypoglycemia.
 Tolbutamide is safest and is DOC in renal diseases due
to it’s shorter duration of action and is contraindicated in
pregnancy and lactation.
 Tolbutamide: Shortest Acting Sulfonylurea.
 T-Half:- 6-8 hours.
 Glycburide (Glibenclamide) has maximum
insulinotropic potency whereas tolbutamide has
least.
 MECHANISM OF ACTION:-
Drugs acts on the sulfonylurea receptor on
pancreatic beta cell membrane.

Inhibits ATP sensitive Potassium channels.

Causes depolarization of beta cells.

Enhance Calcium reflux.

Resulting in INSULIN SECRETION.

MOA FOR SU:-
  INTERACTION WITH OTHER DRUGS:-
 A) Drugs that enhance SU action:

 Displace from protein binding:-

 Phenylbutazone
 Sulfinpyrazone

 Inhibit Metabolism:-
 Sulfonamide.
 Warfarin.
 Acute alcohol intake (Also synergizes by causing
hypoglycemia).

 Synergizes or prolongs pharmacological action:

 Salicyclates, Propranolol, Sympatholytic
  Drugs that decrease SU action:-

 Induce Metabolism;-
 Phenobarbitone
 Phenytoin.
 Chronic Alccoholism.

 Opposite Action/Suppress Insulin Release:-

 Corticosteroid
 Thiazide
 Furosemide
 Oral Contraceptive.
  SIDE EFFECTS:-
 Severe Hypoglycaemia.
 Weight gain.
 Allergic skin reactions (rashes). (GPAT
P.Y)
 Bone Marrow Depression.
 Dilsulfiram like reactions. (CHLORPROPAMIDE)
 Chlolestatic jaundice.
 Teratogenic-Not safe during pregnancy.