Oral Hypogylcaemic Drugs

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Chapter: Medicinal Chemistry : Oral Hypogylcaemic Drugs

Diabetes mellitus is a metabolic disorder characterized by hyperglycaemia, glycosuria, hyperlipidemia, negative nitrogen balance, and ketonaemia.


Oral Hypogylcaemic Drugs


Diabetes mellitus is a metabolic disorder characterized by hyperglycaemia, glycosuria, hyperlipidemia, negative nitrogen balance, and ketonaemia. Most patients can be classified, clinically, as having either type I diabetes mellitus (insulin dependent diabetes mellitus (IDDM) or type II noninsulin dependent diabetes mellitus (NIDDM). The incidence of each type of diabetes varies widely throughout the world. In the United States, about 5% to 10% of the diabetic patients have type I diabetes mellitus, with an incidence of 17 per 100,000 found in United Kingdom. The vast majority of diabetic patients have type II diabetes mellitus.

Type I diabetes is also called juvenile onset diabetes mellitus. There is β-cell destruction in the pancreatic islets of langerhans. Majority of the cases are due to autoimmune (type I A) antibodies that destroy β cells, are detectable in blood, but some are idiopathic (type I B) no β (beta) cell antibody is found. In all type I cases, circulating insulin levels are low or very low and ketosis may occur. Genetic predisposition is also a cause for this condition.

Type II diabetes is also called maturity onset diabetes mellitus. There is no loss or moderate reduction in the β cell mass, insulin in circulation levels is low and generally has a late onset of disease after middle age. This may be due to an abnormality in the glucoreceptors of β cells, therefore, they respond at higher glucose concentrations or at relative β cell deficiency. The reduced sensitivity of peripheral tissues to insulin and reduction in the number of insulin receptors are a consequence for producing diabetes. When glucagons exceed a normal amount, it produces hypoglycaemia. The insulin is secreted by the β cells of langerhans, synthesized by a single chain precursor of 110 amino acid preproinsulin. After translocation through the membrane of rough endoplasmic reticulum, the 24 amino acid N-terminal peptide of preproinsulin is rapidly cleared off to form proinsulin. Here, the molecules folds and the disulphide bonds  are formed. In the conversion of proinsulin to insulin in the Golgi complex, four basic amino acids and the remaining connector or C peptide are removed by proteolysis. This gives rise to two peptide chains (A and B) of insulin molecules, which contains one intrasubunit and two intersubunits disulphide bonds. The A chain consists of 21 amino acids and B with 30 amino acids and molecular mass is about 5734 daltons.

The regulatory factors of insulin secretion are chemical, hormonal, and neural. Chemical regulation depends upon the glucose entry in to the β cells by glucose transport. Once, after the entry of glucose and its phosphorylation by glucokinase, glucoreceptor activation indirectly inhibits the adenosine triphosphate (ATP) sensitive potassium channels and increases intracellular calcium, which triggers the exocytic release of insulin. Hormonal change in corticosteroids modify the release of insulin. Insulin inhibits glucagon secretion and glucagons increase the insulin secretion.

The neural control is mediated by α2 and β2 receptors. Stimulation of α2 receptor decreases the insulin release and stimulation of β2 receptors increases insulin release. Cholinergic stimulation increases the insulin secretion.

Hypoglycaemic drugs are agents, which decrease the blood sugar level. Oral hypoglycaemic agents must be distinguished from more hypoglycaemic drugs, such as salicylates, which are too toxic for clinical use in doses that effectively lower the blood sugar. An ideal antidiabetic drug should be nontoxic and correct the basic metabolic defects in diabetics, in addition to lowering the blood sugar.

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