ANTI-DIABETIC DRUGS. Introduction According to WHO, around 100 million of people are patients of diabetes in the world. Diabetes deaths are likely to.

ANTI-DIABETIC DRUGS

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.

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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 metabollism 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. 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.

GDM: Gestational Diabetes Mellitus.

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 B cells at a low basal rate and at much higher stimulated rate in response to a variety of stimuli, especially glucose.

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

1) Short acting* Soluble insulin* Regular insullin* Natural insulin

2) Intermediate acting : * Isophan insuln* Insulin zinc

3) Long acting : * Crystalline insulin

Pharmacokynetics of insulin

Route of administration : Subcuteneous, IV, IM.(orally insulin is digested because it is protein in nature).

Adsorption : slow in subcuteneous. Metabolism : Liver 60%, Kidney 40%. Plasma half life : 3 – 9 minutes. Excretion : Urine.

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.

*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 e. i. 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

Sulfonyl urea derivatives

Biguinide derivatives

Fast acting(5-12 hours)

Long acting(24-36 hours)

Intermediate acting

(12-24 hours)

Oral Hypoglycaemic Agents

Classification

A) Sulfonylureas

1.First generation sulfonylureas:

- Tolbutamide

- Chlorpropamide

- Acetohexamide

2.Second generation sulfonylureas:

-Glibenclamide

-glipizide

-glicazide

B) Biguanides– Metformine– Phenformine– Buformine

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-R2R1 SO2 –NH-CO-NH-R2

SAR of Sulfonylureas

Activity and potency of sulfonylureas change with introducing of new group or substituents to the basic structure of sulfonylureas called SAR of sulfonylureas.

R1 SO2 –NH-CO-NH-R2

R1 R2

Tolbutamide CH3 C4H9

Chlorpropamide Cl C3H7

Acetohexamide CH3

GlyburideCl

OCH3

CONH-(CH2)2

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.

Sulfonylureas

Bind and decrease K+ entry of Beta cell

Produce depolarisation

Increase Ca+ ion entry

Insulin release from Beta cell

Anti- diabetic action

Pharmacokynetics

Route of administration : Oral. Absorbtion : Absorbed well from the gut with

food. Distribution : 99% protein bound, can cross

placenta. Metabolism : Liver. Excretion : Urine.

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

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.

Dosage and Administration

Drugs Given dose Maximum effective dose Administration

Tolbutamide 500mg 3000mg with or immediately after food

Tolazamide 100-250mg 1000mg with food

Chlorpropomide 100-200mg 750mg with food

Glyburide 2.5-5mg 20mg with food

Biguanides

Chemistry :

N-C-NH-C-NH2.HCLCH3

CH3

NH NH

N,N-dimethyl imidodi-carbanimidic diamide HCl

Mechanism of action

1. Biguanides Directly stimulate glycolysis in peripheral tissues with increased glucose removal from blood.

2. Reduce blood glucose level by reducing hepatic gluco-neogenesis.

3. Reduce intestinal glucose absorption. 4. Enhancement of insulin receptor binding.

Pharmacokynetics

Route of administration : Oral. Absorption : Small intestine. Metabolism : Does not bound to plasma

protein. Excretion : Excreted unchanged in urine. Plasma half life : About 2 hours.

Indication

IDDM, NIDDM

Obese person with NIDDM not controlled sulfonylureas.

Secondary failure with sulfonylureas.

Adverse effect

GIT upset : Nausea, vomiting, abdominal discomfort, diarrhoea, fatigue, hypoglycemia.

Lactic acidosis (rare but fatal toxic effect).

Cotraindication

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.