INSULIN AND ORAL HYPOGLYCEMIC AGENTS

DIABETES Diabetes Insipidus (DI) Diabetes Mellitus (DM)

Metabolic disorder –

Hyperglycemia

Glycosuria

Hyperlipemia

Negative nitrogen balance

Ketonaemia

Pathological changes

- Thickening of capillary basement membrane- Increase in vessel wall matrix- Cellular proliferation

- Complications

- Early atherosclerosis- Retinopathy- Neuropathy

Types of DM

Type I insulin dependent diabetes mellitus(IDDM), juvenile onset diabetes mellitus.

Type IA(autoimmune) Type IB(idiopathic)

Type II noninsulin dependent diabetes mellitus(NIDDM), maturity onset diabetes mellitus

Insulin

Two chain polypeptide- 51 amino acid

A- chain- 21 amino acids B-chain- 30 amino acids

Regulation of Insulin Secretion Chemical Hormonal Neural

ACTION OF INSULIN

Carbohydrate

Protein

Fat metabolism

Mechanism of action Tyrosin kinase receptor

Fate of insulinOrally- degraded in g.i.t

i.v- metabolised in liver

Types of insulin preprationsConventional Highly purified

According to purification method

Single peak insulin Monocomponent insulins

HUMAN INSULINS

rDNA technology in E.coli

Enzymatic modification of porcine insulin

Indication of Human insulin Insulin resistance Allergy to conventional preprations Injection site lipodystrophy Short term use of insulin in diabetics During pregnancy

Reactions of insulin Hypoglycaemia Local reactions Allergy Edema

Drug interactions

USES OF INSULINDMDiabetic ketoacidosis(Diabetic Coma)

Insulin lack

Hyperglycaemia Ketosis

GlycosuriaAcidosis ketonuria Impairment of

glucose entry into brain

Loss of electrolytes

Intracellular K+

depletion

Loss of fixed cations in urine

Loss of water

Hyperosmolarity of bloodIntracellulardehydration

Osmotic diuresisVomiting

Hyperventilation

Dehydration

Hypotension,Shock,tachycardia

Impairment of consciousness

Hyperosmolar (Non ketotic hyperglycaemia)

Insulin Resistance Acute

Chronic

Infection,trauma,surgery,emotional stressketoacidosis

Conventional preprations

ORAL HYPOGLYCAEMIC DRUGS

Drugs lower the blood glucose level

Effective orally

Sulfonyl Ureas

Biguanides

Meglitinide Analogues

First generationTolbutamidechlorpropamide

Second generationGlibenclamide(glyburide)GlipizideGliclazideGlimepiride

PhenforminMetformin

RepaglinideNateglinide

Thiazolidinediones Rosiglitazone Pioglitazone

α-Glucosidase Inhibitors Acarbose Miglitol

SULFONYLUREAS

These agents promote the release of insulin from β-cells (secretogogues);

Mechanism: These agents require functioning β-cells, they

stimulate release by blocking ATP-sensitive K+ channels resulting in depolarization with Ca+2 influx which promotes insulin secretion.

They also reduce glucagon secretion and increase the binding of insulin to target tissues.

They may also increase the number of insulin receptors

BIGUANIDES (Insulin Sensitizers) work by improving insulin target cell response; the

biguanides & thiazolidinediones.

Biguanides: it increases glucose uptake and utilization by target

tissues

Mechanism: Metformin reduces plasma glucose levels by inhibiting

hepatic gluconeogenesis. It also slows the intestinal absorption of sugars. It also

reduces hyperlipidemia (↓LDL & VLDL cholesterol and ↑ HDL).

It is the only oral hypoglycemic shown to reduce cardiovascular mortality.

THIAZOLIDINEDIONES (Glitazones)

These agents are insulin sensitizers, they do not promote insulin secretion from β-cells but insulin is necessary for them to be effective

Mechanism of Action:

These agents act through the activation of peroxisome proliferator-activated receptor-γ (PPAR-γ).

Agents binding to PPAR-γ result in increased insulin sensitivity is adipocytes, hepatocytes and skeletal muscle.

Accumulation of subcutaneous fat occurs with these agents.

MEGLITINIDE ANALOGUES

Mechanism: These agents bind to ATP sensitive K+channels like

sulfonylureas acting in a similar fashion to promote insulin secretion however their onset and duration of action are much shorter.

They are particularly effective at mimicking the prandial & post-prandial release of insulin.

α-Glucosidase Inhibitors

oligosaccharides monosaccharides

Acarbose also inhibits pancreatic amylase.

hydrolyses

Glucagon

Single chain polypeptide- 29 amino acid

MW- 3500

Regulation ↑ glucose levelFFA and ketone bodies

Action- opposite to insulin(hormone of fuel mobilization)Secretion ↑ during fasting

MOAActivates adenylyl cyclase ↓ ↑cAMP

USES-hypoglycaemia due to insulin or oral hypoglycaemics-cardiogenic shock-diagnosis of pheochromocytoma

Liver Fat cells heart