ANTI-DIABETIC DRUGS

By
Gunjan Kalyani, M. Pharm.
Assistant Professor
Columbia Institute of Pharmacy
Raipur 493111, Chhattisgarh, India
Mobile: +91-8349204583
Mail ID: [email protected]

Former Research Fellow

National Center for Natural Resources (NCNR)
Pt. Ravishankar Shukla University, Raipur 492010, India
 Introduction
• According to WHO, around 100 million of people are
patients of diabetes in the world.
• Diabetes deaths are likely to increase by more than 50%
in the next 10 years without urgent action.
 Diabetes will be a primary killer
WHO and IDF indicates that 3.2 million deaths happen for
diabetes in each year.
In the world about 6 deaths occur in every minutes for
. diabetes. Diabetes a primary cause of kidney failure, blindness,
and amputations and so why it said that, in next 25 years
diabetes will be the one primary killer.
 Diabetes
• Definition from WHO:
Diabetes mellitus is a metabolic disorder of multiple etiology
which is characterized by chronic hyperglycemia with
disturbance of carbohydrate, fat and protein metabolism
resulting from defects of insulin secretion, insulin action or
both.
 Effect of diabetes
• long term damage.
• Dysfunction.
• Failure of different organ.
 Causes
• Impaired glucose intake by skeletal muscle.
• Impaired glycogenesis.
• Impaired hepatic output of glucose.
• Impaired input of glucose.
 Symptoms of diabetes
Classical symptoms are-
Thirst
Polyuria
Weight loss
Blurred vision
But in severe form –
Develop ketoacidosis because of fat breaking.
Non ketonic hyperosmolar state will increase. This will lead to
coma, if untreated it leads to death.
 Classification of Diabetes
• Diabetes Mellitus (DM) is classified as –
1) Type-1 Diabetes Mellitus
2) Type-2 Diabetes Mellitus
 Type-1 Diabetes Mellitus
 Insulin Dependent Diabetes Mellitus or Juvenile Diabetes. It
results from pancreatic Beta cell destruction and severe in
insulin deficiency.
It occurs mostly in Juvenile but occasionally at adults, specially
the non-obese.
 Type-2 Diabetes Mellitus
Non-Insulin Dependent Diabetes Mellitus, occurs in adult. It is
characterized by tissue resistance to the action of insulin combined
with a relative deficiency of insulin.
Type 2 diabetes is a lifelong disease that prevents your body from
using insulin the right way. People with type 2 diabetes are said to
have insulin resistance.
Although insulin is produced by Beta cell it is inadequate to
overcome the resistance and blood glucose rises.
 Some other types
MRDM: Malnutrition Related Diabetes Mellitus.
Malnutrition-related diabetes mellitus (MRDM) is a rare type
of diabetes associated with long term malnutrition. This type
of diabetes is characterized by insulinopenia, insulin resistance,
hyperglycemia and failure of the beta-cells in the pancreas
GDM: Gestational Diabetes Mellitus.
Gestational diabetes mellitus (GDM) is defined as any degree of
glucose intolerance with onset or first recognition during pregnancy
(1). The definition applies whether insulin or only diet modification is
used for treatment and whether or not the condition persists after
pregnancy.
 Treatment
Many complications of diabetes can be prevented or delayed
through effective management.

This includes –
Healthy diets.
Physical activity.
Avoidance of over weights and obesity.
Not smoking.
 Treatment
• Diabetes therapy is not only about lowering glucose level but
also about the overall complications such as blood pressure
and blood lipids. This requires life long care and management.

• People with type 2 diabetes often require oral drugs and

sometimes insulin is used to control their blood levels.
 Treatment
• People with type 1 diabetes require insulin to survive.
 Insulin
• Insulin is a small protein which contains two chains (A and B)
linked by disulfide bridges.
• Insulin is released from pancreatic Beta cells at a low basal rate
and at much higher stimulated rate in response to a variety of
stimuli, especially glucose.
Structure of Insulin
 Chemistry of insulin
It consists of two open poly-peptide chains (A and B). There
are 21 amino acids in chain A and 30 amino acids in B chain.

Two chains are inter-linked by a di – sulfide bridge.

There is an additional disulfide bridge between the 6th and 11th

amino acid residues of the A chain. Breaking the di – sulfide
bridge, inactive insulin.

It is protein in nature. It’s MW is 5800.

 Classification of insulin
Short acting
* Soluble insulin
* Regular insulin
* Natural insulin
Intermediate acting :
* Isophan insulin
* Insulin zinc
Long acting :
* Crystalline insulin
 Hyperglycemia
• Hyperglycemia is a condition in which blood sugar increases above the normal level,
i.e. above 120mg per 100ml.
• When the blood sugar level exceeds the renal threshold, sugar appears in the urine.
• It mainly occurs due to the Impaired glucose intake by skeletal muscle.

Note:
The renal threshold is the concentration of a substance dissolved in the blood above
which the kidneys begin to remove it into the urine
*Impaired glycogenesis.
*Impaired hepatic output of glucose.
*Impaired input of glucose.
 Hypoglycemia
• Hypoglycemia is a condition in which blood sugar decreases
below the normal level, below 40mg per 100ml.
• The symptoms –
* Sweating
* Anxiety
* Dizziness
* Headache
* Weakness
* Fall in blood pressure.
 Hypoglycemic agent
• Hypoglycemic agents are the agents which used in the
treatment and prevention of diabetes mellitus.
• They are capable of reducing blood sugar level.
 Glycosuria
• It is the condition when the glucose reuptake by the kidney is
impaired.
• In this condition blood glucose level exceeds 80mg glucose per
100ml of blood.
 Classification of Hypoglycemic agents

Hypoglycemic
agent

Parenteral Oral

Intermediate
Fast acting Long acting Sulfonyl urea Biguinide
acting
(5-12 hours) (24-36 hours) derivatives derivatives
(12-24 hours)
 Oral Hypoglycemic Classification
Insulin Insulin
Secretagogues Sensitizers

I. Sulfonylureas III. Biguanides

II. Meglitinide IV. Thiazolidinediones

analogs

V.α-Glucosidase
Inhibitors
 Sulfonylureas
Mechanism of action
A. Increase release of insulin
B. Decrease production of glucose in the liver
C. Increase the number of insulin receptors
D. Effective only if have functioning beta cells
• Side effect is hypoglycemia and weight gain
• These drugs include glibenclamide, glipizide, and
glimepiride .
 Sulfonyl urea
Chemistry
Sulfonylureas are chemically related with sulfonamide structure.
The compounds are aryl-sulfonyl-ureas with substitution on the
benzene and urea group.
The basic structure is-

R1 SO2 –NH-CO-NH-R2
 SAR of Sulfonylureas
A. R1 and R2 should be lipohililc in character for their action.
B. Para position of R1 substitution with halogens, alkyl groups and
methylthio increases the hypoglycaemic activity.
C. R1 substitution at Para position with larger substituents are more
potent because R1 substituents are distant from sulphonamide
nitrogen which helps in binding with receptor and increases the
activity.
D. N alkyl substitution makes more active compound at R2.

R1 SO2 –NH-CO-NH-R2
 Mechanism of action
• The main action of sulfonylureas is to stimulate the Beta cells
of islets of langerhans, causing insulin secretion and thus
reducing plasma glucose.
• High affinity receptors for sulfonylureas are present on the K-
ATP channels in Beta cell plasma membrane and the binding
of various sulfonylureas parallels their potency in stimulating
insulin release.
 Mechanism of action
Sulfonylureas
Bind and decrease K+ entry of Beta cell
Produce depolarisation
Increase Ca+ ion entry
Insulin release from Beta cell
Anti- diabetic action
 Mechanism of action
• Indications : NIDDM (except in overwieght diabetes)
• Adverse effects : Hypoglycemia, Hypersensitivity, Nausea,
Vomiting, Bone marrow depression, Diarrhoea, abdominal
discomfort.
 Contraindications
• Diabetes in pregnancy.
• Known allergy to drug.
• IDDM.
• After surgery.
• Severe renal insufficiency and hepatic failure.
• Elderly patient with impaired renal function.
 Drug interactions
• There are some drugs which potentiates the actions of
sulfonylureas i. e. increase hypoglycemic activity. They are –
* NSAIDs
* Alcohol
* Coumarin
* Antibacterial agents
* Antifungal agents
 Drug interactions
• Also there are some drugs which antagonises the action of
sulfonylureas i. e. decrease hypoglycemic activity. They are –
* Thiazide
* Frusemide
* Thyroid hormone
* Corticosteroids
* Oral contraceptives.
 Examples R1 R2
Tolbutamide CH3 C4H9

Chlorpropamide Cl C3H7

Acetohexamide CH3

Glyburide Cl
CONH-(CH2)2
OCH3
 Meglitinides
Nateglinide and repaglinide are nonsulfonylureas that lower
blood sugar by stimulating pancreatic secretion of insulin
In contrast to the sulfonylureas, the meglitinides have a rapid
onset and a short duration of action
They are categorized as postprandial glucose regulators
Monotherapy or in combination with metformin
Should be taken 1 to 30 minutes before a meal
Side effects hypoglycemia and weight gain
 Biguanides
Mechanism of action
increases the use of glucose by muscle and fat cells, decreases
hepatic glucose production, and decreases intestinal absorption of
glucose
Does not cause hypoglycemia
May be used alone or in combination
Side effects include GIT disturbance and lactic acidosis
Contraindicated in liver or renal impairment. Can result in lactic
acidosis.
This group include metformin
 Biguanides
• Chemistry :

N,N-dimethyl imidodi-carbanimidic diamide

 Mechanism of action
A. Biguanides Directly stimulate glycolysis in peripheral tissues
with increased glucose removal from blood.
B. Reduce blood glucose level by reducing hepatic gluco-
neogenesis.
C. Reduce intestinal glucose absorption.
D. Enhancement of insulin receptor binding.
 Adverse effect
• GIT upset: Nausea, vomiting, abdominal discomfort, diarrhoea,
fatigue, hypoglycemia.
• Lactic acidosis (rare but fatal toxic effect).
 Contraindication
• Renal insufficiency.
• Hypoxic condition.
• Pulmonary insufficiency.
• Hepatic insufficiency.
 Drug interaction
With insulin, does not show any action.
With sulfonylureas, show effective action when a single drug
has proved to be ineffective.
Cimetidine increases the absorption of Metformin and
decreases the renal clearance.
 Thiazolidinediones
Mechanism of action
Decrease insulin resistance. Through binding with PPAR lead to
regulation adipocyte production and secretion of fatty acids as well
as glucose metabolism, resulting in increased insulin sensitivity in
adipose tissue, liver, and skeletal muscle
Side effects include weight gain, headache and anemia
Contraindicated in patients with liver disease and acute MI
May be used as monotherapy or in combination with insulin,
metformin or a sulfonylurea
These drugs include Pioglitazone and rosiglitazone
 Alpha glucosidase Inhibitors
• Include acarbose and miglitol
• Mechanism of action: inhibit alpha-glucosidase enzymes in GI
tract. Delays absorption of complex CHO and simple sugars
• Can be combined therapy with sulfonylurea
• Contraindicated in malabsorption, severe renal impairment
• Side effects include bloating and diarrhea
Synthesis of Tolbutamide
 Structures

Tolbutamide Chlorpropamide

Glipizide Glimepiride
 Structures

Metformin

Rosiglitazone Pioglitazone
 Structures

Repaglinide Nateglinide

Acarbose Voglibose