Oral Hypoglycemic Agents Classification

Hypoglycemic Agents Introduction

Diabetes mellitus is a chronic metabolic disorder of multiple etiologies characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action or both. Diabetes mellitus may present with characteristic symptoms such as thirst, polyuria, blurring of vision and weight loss.

In its most severe forms, ketoacidosis or a non-ketotic hyperosmolar state may develop and lead to stupor, coma and finally to death. Often symptoms are not severe or may be absent and consequently hyperglycaemia sufficient to cause pathological and functional changes may be present for a long time before the diagnosis is made.

The long term effects of diabetes mellitus include progressive development of the specific complications of retinopathy with potential blindness, nephropathy that may lead to renal failure and/or neuropathy with risk of foot ulcers, amputation, joints and features of autonomic dysfunction, including sexual dysfunction. People with diabetes are at increased risk of cardiovascular, peripheral vascular and cerebro- vascular disease.

Classification of Diabetes Mellitus

Diabetes may be classified as

• Type 1 Diabetes mellitus
• Type 2 Diabetes mellitus
• Type 1.5 Diabetes mellitus
• Gestational Diabetes mellitus

Type 1 Diabetes Mellitus

It is also called as Insulin Dependent Diabetes Mellitus (IDDM) or Juvenile- onset diabetes. Type 1 diabetes develops when the body’s immune system destroys pancreatic ẞ cells, the only cells in the body that make the hormone insulin that regulates blood glucose. This form of diabetes usually strikes children and young adults, although disease onset can occur at any age.

Type 1 diabetes may account for 5% to 10% of all diagnosed cases of diabetes. Risk factors for Type 1 diabetes may include autoimmune, genetic and environmental factors.

Type 2 Diabetes Mellitus

It is also called as non-insulin-dependent diabetes mellitus (NIDDM) or adult- onset diabetes. Type 2 diabetes may account for about 90 to 95% of all diagnosed cases of diabetes. It usually begins as insulin resistance, a disorder in which the cells do not use insulin properly. As the need for insulin rises, the pancreas gradually loses its ability to produce insulin.

Type 2 diabetes is associated with older age, obesity, family history of diabetes, history of gestational diabetes, impaired glucose metabolism, physical inactivity and race or ethnicity. Type 2 diabetes is increasingly being diagnosed in children and adolescents.

Type 1.5 Diabetes Mellitus

Type 1.5 diabetes mellitus or Latent autoimmune diabetes in adults (LADA) is relatively a new type of diabetes mellitus. In this type the pancreas produces insulin but not sufficient to control or maintain the normal blood glucose level, so the body does not dramatically respond to insulin deficiency as do those with Type land so LADA is often initially diagnosed as Type 2 diabetes. The main difference between LADA and Type 2 is that, there is an autoimmune response present with LADA that is similar to that of Type 1. It means that there is a slow, progressive attack on B cells by protein antibody.

If oral hypoglycemic drugs are not responding well and characteristics of Type 1 diabetes is observed then it may be Type 1.5 diabetes. The only way to distinguish

Type 2 diabetes with LADA is to test for the presence of protein antibodies. Since LADA is more closely aligned with Type 1 diabetes, treatment is essentially the same as that of Type 1. Insulin therapy will eventually be needed, and it may be beneficial to start insulin before it is actually needed to preserve B-cell function for long time.

Gestational Diabetes mellitus

It is a condition in which women without previously diagnosed exhibit high blood glucose level during pregnancy. It is also more common among obese women and women with a family history of diabetes. During pregnancy, gestational diabetes requires treatment to normalize maternal blood glucose levels to avoid complications in the infant. After pregnancy, 5% to 10% of women with gestational diabetes are found to have Type 2 diabetes. Women who have had gestational diabetes have a 20 to 50% chance of developing diabetes in the next 5-10 years.

Insulin

Introduction

Peptides hormones are secreted by the pancreas occupy a central role in the regulation of metabolism of carbohydrates, lipids and amino acids. They are Insulin, Glucagon and Somatostatin. Insulin is the primary hormone which is responsible for controlling the storage and utilization of cellular nutrients. It activates the transport system and the intracellular utilization and storage of glucose, amino acids and fatty acids.

Insulin inhibits catabolic processes such as breakdown of glycogen, fat and protein, whereas the overall effect of insulin is hypoglycemic. The other pancreatic hormone Glucagon mobilize glucose from its stores and causes hyperglycaemia. The third pancreatic hormone Somatostatin, inhibit secretion of both Insulin and Glucagon.

Deficiency of effective insulin in the body causes a disease called diabetes mellitus (meaning in Greek is excessive thirst) which alters the metabolism of lipids, carbohydrates and proteins. This results in hyperglycaemia and glycosuria. Insulin was purified and crystallized by J.J.Abel in 1926. The amino acid sequence of the hormone was established by F.Sanger and the co-workers in 1955.

Its total synthesis was achieved by several groups in 1970’s. Hodgkin and co-workers established the three dimensional structure of Insulin. Recently the cloning of human Insulin gene and its transfer into bacteria Escherichia coli have been achieved, it is now produced by recombinant DNA technology.

Biosynthesis of Insulin

Insulin is synthesized by the B-cells of the islets of Langerhans of the pancreas (named after Paul Langerhans, 1869) from a precursor Proinsulin.

Once food enters the body, it immediately is detected and the insulin mRNA is translated as a single chain precursor called preproinsulin in the pancreas. By the removal of its single peptide during insertion into the endoplasmic reticulum, proinsulin is generated. Preproinsulin is the primary translation product of the insulin gene, composed of 110 amino acids. It is relatively inactive and has to be processed into proinsulin in order to eventually make the insulin hormone.

Proinsulin is a single polypeptide chain with 86 amino acids. The proteolytic conversion of proinsulin to insulin is accomplished by the removal of the Arg-Arg residue at 31 and 32 and Arg-Lys residue at the position 64 and 65 by the endopeptidase and thiol activated carbopeptidase-B like enzymes.

The action of the enzyme on proinsulin results in equimolar quantities of Insulin. Now the mature form of Insulin has been made into clusters of endocrine cells in islets of Langerhans. The extra C peptide and single peptide, which was clipped off, are packed in the Golgi into secretory granules to accumulate and be recycled in the cytoplasm. Once Insulin is properly made and the ẞ – cell is appropriately stimulated, Insulin is secreted from the cell into the blood.

Insulin consists of two peptide chains, A and B, which are connected by two disulphide bonds. The chain A composed of 21 amino acid residue and has one intra chain disulphide bond; the chain B has 30 amino acids. (Fig. 25.3)

There are some species specific differences in the amino acid sequence of insulin. Porcine insulin differs from human insulin only by the presence of alanine (Ala) instead of threonine as the last amino acid in the chain B and bovine insulin in addition has two more alteration in chain A, the threonine (Thr) and isoleucine (Ile) in 8 and 10 position are replaced by alanine and valine respectively.

Insulin circulates as monomer and only monomers will interact with insulin receptors. The insulin receptor is a large transmembrane glycoprotein composed of four subunits two identical a units with M, of about 130,000 dalton and two ẞ – units with Mr of 95,000 Dalton joined together by disulphide bond. The a-subunit is primarily responsible for binding insulin to receptor and ẞ – subunit possesses intrinsic protein kinase activity that is stimulated by insulin. The binding of the insulin to the receptor, may result in the generation of a soluble intracellular second messenger that may mediate the activation of enzymes like pyruvate dehydrogenase and glycogen synthetase.

X-ray diffraction studies show that, insulin occurs as a hexamer containing two zinc atoms. The dimer are first held by four hydrogen bonds and a hydrophobic bond along the ẞ sequence in the form of antiparallel ẞ – sheet. The dimer then binds by the interaction of the B14 – Ala, B17 – Leu and B18 Val residues. The core of the hexamer contains water. In the system, the hormones dissociates into monomers.

The crystal structure also reveals that, the two chains of the hormones form a highly ordered structure with several a-helical regions in both the chains. The carboxyl terminal portion of chain B and the carboxyl and amino residues of the chain A form the surface of the molecule which interact with the receptor.

The zinc – associated hexamer is a storage form of insulin in man. Insulin dimerizes at higher concentration found in pharmaceutical preparations. The detailed knowledge of three-dimensional structure of insulin led to the recognition that its biological activity resides in an area of molecule rather than in specific amino acid residues, just as dimerization and further association of the molecule also depends on an intact spatial structure.

Production of Insulin

Early commercial insulin were obtained by extraction from bovine or porcine or mixed bovine and porcine pancreases and purified by crystallization. Much of the insulin now produced has amino acid sequence identical to that of human insulin. Human insulin is obtained by the enzymatic modification from the porcine pancreas; it is also sometimes called as semi synthetic human insulin. The term human insulin is used for insulin produced by the chemical combination of A and B chains, which have been obtained from bacteria genetically modified by recombinant DNA technology. By using chromatographic procedure insulin is obtained in pure form.

Insulin Preparation

Many attempts have been made to prolong the duration of action of insulin. The water solubility of insulin in body fluids can be altered, so that it is slowly released. The solubility of insulin depends upon particle size (amorphous or crystalline) on zinc content and the nature of the buffer in which it is suspended. Amorphous insulin is the first form made available for clinical use.

Further purification resulted in crystalline commonly known as regular insulin. Regular insulin solutions are suspended in buffer solutions; neutral insulin has greater stability than acidic solution. A major disadvantage of regular insulin is its short duration of action, which necessitates its administration several times. Another way of prolonging the action was brought about by complexing with proteins from which is slowly released.

For example protamine (basic protein) insulin preparations, prolong the duration of action of insulin. Protamine zinc insulin suspension were even longer acting (36 hours) than protamine insulin. Protamine zinc insulin is a sterile buffered suspension of insulin in the form of a complex with suitable protamine and zinc chloride.

Isophane insulin suspension has quick onset and short duration than protamine insulin. It is also known as NPH; N indicates neutral pH, the P stands for protamine and H for Hegedron the developer of the product. It is prepared by careful control of protamine insulin ratio and the formation of crystalline entity containing stoichiometric amount of insulin and protamine.

By varying the amount of excess of zinc, by using an acetate buffer and adjusting the pH, two types to lente insulins are prepared. At high concentration of zinc, a microcrystalline form precipitates and is called ultralente. It has slower duration and longer onset of action than protamine zinc insulin. At relatively low zinc concentration, an amorphous form precipitates and is called semilente insulin.

The latter is more soluble and has quicker on set of action and shorter duration of action. Another type known as lente insulin is 70:30 mixture of ultralente and semilente insulin which has rapid onset of action and intermediate duration of action. Lente insulin is incompatible with protamine zinc insulin and NPH, because of different buffer system used in the preparation of this insulin.

Insulin in powder form should be stored in airtight containers protected from light. Storage at low temperature is also recommended. The injection is required to be stored in the refrigerator at 2° and 8° and not to be allowed to freeze.

Insulin is employed for the treatment of virtually all Type 1 and Type 2 diabetic patients. Insulin is destroyed in gastrointestinal tract and it must therefore be administered parenterally. Long term treatment relies on subcutaneous injection. For therapeutic purpose dose and concentration of insulin are expressed in units. It is recommended that every diabetic patient should carry an identification card or bracelet containing pertinent medical information; in addition some form of glucose should be carried for use if necessary.

Oral Hypoglycemic Agents Introduction

Oral hypoglycemic agents are the drugs that lower blood glucose levels and are effective orally. The main disadvantage of insulin and its preparations is that they must be given by injection or inhalation. Hence, orally active drugs have always been searched.

Oral Hypoglycemic Agents Classification

• Sulfonylureas.
• • First generation : eg. Carbutamide, Tolbutamide, Chlorpropamide, Tolazamide, Acetohexamide.
  • Second generation : eg. Glibenclamide, Glipizide, Gliclazide, Glimepiride.
• Biguanides : eg. Metformin, Phenformin, Buformin.
• Metaglinides : eg. Repaglinide, Nateglinide.
• Thiazolidinediones : eg. Pioglitazone.
• a – Glucosidase inhibitors : eg. Acarbose, Miglitol,Voglibose.
• Aldose reductase inhibitors : eg. Sorbinil, Epalrestat, Ranirestat.
• DPP-4 inhibitors : eg. Sitagliptin, Saxagliptin, Vildagliptin, Alogliptin.
• GLP-1 agonist : eg. Exenatide.
• Miscellaneous : eg. Ciglitazone, Linogliride, Pirogliride, Palmoxivate sodium.

Sulfonyl Urea

First Generation

The sulfonyl urea may be represented by the following general structure.

These are urea derivatives with an aryl sulfonyl group in the 1st position and an aliphatic group at the 3rd position. The R group on the aromatic ring primarily influences the duration of action of the compound.

The mechanism of action of the sulfonyl urea is to stimulate the release of insulin from the functioning B-cells of the intact pancreas. They also inhibit the secretion of glucagon.

Tolbutamide (Rastinone, Orinase)

It is a potassium channel blocker, stimulates the secretion of insulin by the pancreas. It has a short duration of action due to its fast metabolism hence safe for use in elderly diabetic.

ADR: Hypoglycemia, nausea and epigastric fullness.

Dose: 1to 2gm daily given either as a single dose with breakfast or more commonly in divided dose.

Use: It is an orally active hypoglycemic drug.

Chlorpropamide (Chloroformin)

Synthesis

It is a long-acting first generation sulfonyl urea derivative. It acts by increasing the secretion of insulin hence it is effective in patient have some pancreatic B-cell function.

ADR: Hypoglycemia, nausea and epigastric fullness.

Dose: 250mg as a single dose with breakfast and dose can be adjusted from 100 to 300mg to minimize hypoglycemia.

Use: An oral hypoglycemic agent with action and uses similar to Tolbutamide.

Second Generation

Glibenclamide (Daonil, Glinil, Glynase)

It is also known as Glyburide closely related to sulpha drugs. Its act by inhibiting ATP-sensitive potassium channel in pancreatic B-cells. This causes cell membrane depolarization results in an increase in intracellular calcium in the B-cells and subsequent stimulation in insulin release.

Synthesis

ADR: Hypoglycemia, cholestatic jaundice and agranulocytosis.

Dose: 2.5 to 5mg daily. Dose more than 10mg should be given in 2 divided doses.

Use: It is used to control hyperglycemia in Type 2 diabetes mellitus.

Glipizide (Diaglip, Dibizide)

It is an oral rapid and short acting antidiabetic drug from sulfonyl urea derivative. It acts by blocking potassium channel in the B-cells the cells remain depolarized which results in calcium influx. The increase in calcium will initiate more insulin release from ẞ-cells.

ADR: GI up sets, diarrhea, nausea and allergic skin reactions.

Dose: 2.5 to 5mg daily as a single dose.

Use: It is an orally active hypoglycemic drug.

Gliclazide (Glychek, Remicron MR)

ADR: GI disturbances, skin reactions and leucopenia.

Dose: 40 to 80mg daily gradually increased to 320mg daily if necessary.

Use: Similar to Tolbutamide.

Glimepiride (Novaride, Glimy)

ADR: Vomiting, GI pain and disturbances and pruritus.

Dose: 1to 2mg daily.

Use: It is used as an oral hypoglycemic agent in Type 2 diabetes mellitus.

Biguanides

Metformin (Riomet, Glumet)

Synthesis

ADR: Numb or cold feeling in arms and legs, muscle pain, weakness and lactic acidosis,

Dose: 500mg, 1 to 2 times daily.

Use: It is used to treat Type 2 diabetes with an advantage of weight reduction and absence of significant hypoglycemia.

Metaglinides

Meglitinides are non-sulfonyl urea oral hypoglycemic agents used in the management of Type 2 diabetes mellitus. They have rapid onset and short duration of action and these agents induces insulin release from functioning pancreatic B-cells.

Repaglinide (Regan, Repa)

ADR: Hypoglycemia, nausea, diarrhea and constipation.

Dose: Initial dose is 0.5mg, can be taken 15mts before a meal and maximum dose of 4mg.

Use: It is used as oral hypoglycemic agent in Type 2 diabetes mellitus.

Nateglinide (Glinate, Nds)

ADR: Back pain, dizziness and arthropathy.

Dose: 60 to 120mg three times a day prior to each meal.

Use: It is a novel drug in the management of Type 2 diabetes mellitus.

Thiazolidinones

Thiazolidinones are a new class of oral antidiabetic agents used for the treatment of NIDDM that enhances insulin sensitivity in peripheral tissues. In addition, they inhibit hepatic gluconeogenesis. These agents normalize glucose metabolism and reduce the amount of insulin needed to achieve glycemic control. They are effective in the presence of insulin.

Pioglitazone (Radizone, Pioglit. Pioglar)

ADR: Pharyngitis, edema, headache and upper respiratory tract infections.

Dose: 15 to 30mg/day increased in increments if necessary.

Use: It is used in the treatment of NIDDM.

Alpha-Glucosidase Inhibitors

It acts in the intestine to block the action of enzymes that are responsible for breaking down complex carbohydrate into simple sugars. The inhibitory properties of these agents are greatest for glycoamylase, followed by sucrose, maltose and dextrose respectively. They are used to establish greater glycemic control over hyperglycemia in type 2 diabetes mellitus, particularly with regard to postprandial hyperglycemia. They may be used as monotherapy in conjunction with an appropriate diabetic diet and exercise or they may be used in conjunction with other anti-diabetic drugs.

Acarbose (Diabose, Glucar)

It is a pseudo tetra saccharide containing an unsaturated cyclitol moiety. It inhibit enzyme glycoside hydrolases needed to digest carbohydrate specifically alpha- glucosidase enzyme in the brush border of the small intestines and pancreatic alpha- amylase.

ADR: Flatulence, abdominal pain, distension and diarrhea.

Dose: 25mg daily

Use: It is used to reduce sugar absorption in the gastro-intestinal tract and used as antidiabetic agent.

Miglitol (Migtor, Euglitol)

It acts by inhibiting the breakdown of complex carbohydrate into glucose. It is mainly used for establishing greater glycemic control by preventing the digestion of carbohydrate into monosaccharide which can be absorbed by the body.

ADR: Abdominal pain, diarrhea, flatulence and skin rash.

Dose: 25mg three times a day, to be taken at the start of each main meal.

Use: It is also used to reduce sugar absorption in the gastro-intestinal tract and used as antidiabetic agent.

Voglibose (Vocarb, Volix)

It acts by delaying the glucose absorption at the intestine level and thereby reduces the risk of cardiovascular complications and also preventing the sudden increase of glucose after a meal.

ADR: Flatulence, abdominal distension, diarrhea and skin reactions.

Dose: 200 to 300μg three times a day.

Use: It is a a-glucosidase inhibitor used for lowering post-prandial blood glucose levels in people with diabetes mellitus.

Aldose Reductase Inhibitors

In diabetic complications, the high concentration of glucose is converted to sorbitol by aldose reductase by the polyol pathway. Sorbitol is converted to fructose and these products accumulate in nerves, kidneys, retina, etc., Galactone is converted to galacitol which is not metabolized causes osmotic swelling. Aldose reducatase inhibitors interfere in the polyol pathway of sorbitol and fructose and thereby cause hypoglycemic efforts.

Sorbinil

ADR: It may cause eye, skin and respiratory tract irritation,

Dose: 250mg/day.

Use: It is used in the treatment of diabetic neuropathway.

Dipeptityl Peptidase – 4 (DPP – 4) inhibitors

DPP 4 inhibitors or gliptins are a class of oral hypoglycemic agents that block DPP 4. They can be used to treat Type 2 diabetes mellitus. It reduces glucagon and blood glucose level by increasing incretin level (GLP-1 and GIP), which inhibit glucagon release, which in turn increases insulin secretion there by decreases blood glucose level.

Sitagliptin (Januvia)

ADR: Stuffed or running nose, sore throat, head ache and diarrhea.

Dose: 100mg/day with or without food.

Use: It is used as an adjunct to improve glycemic control in adults with Type 2 diabetes mellitus.

Saxagliptin (Omglyza)

ADR: Stuffed or running nose, sore throat, head ache and burning urination.

Dose: 2.5mg or 5mg taken once daily with or without food.

Use: It is also used as an adjunct to improve glycemic control in adults with Type 2 diabetes mellitus.

Vildagliptin (Galvus)

ADR: Swelling of the hand, ankles or feet, weakness, dizziness and head ache.

Dose: 100mg/day, taken as two equal divided doses.

Use: It is used as an adjunct to improve glycemic control in adults with Type 2 diabetes mellitus.

Alogliptin (Nesina)

ADR: Head ache, dizziness, constipation, skin reactions and GI side effects.

Dose: 25mg/day.

Use: It is used as an adjunct to improve glycemic control in adults with Type 2 diabetes mellitus.

GLP-1 agonist

It belongs to the group of incretin mimetic usually administered as subcutaneous injection any time within 60minutes before the first and last meal of the day. Once weekly injection is also available.

Exenatide (Byetta)

It is a synthetic derivative of exendin-4 which is a hormone found in the saliva of the Gila monster. It acts by enhancing the glucose dependent insulin secretion by the pancreatic beta cell there by suppresses inappropriately elevated glucagon secretion and slows gastric emptying. It is a 39 amino acid peptide an insulin secretagogue with glucoregulatory effects.

ADR: Hypoglycemia, nausea, vomiting, diarrhea and weakness.

Dose: 5μg twice daily, one hr before meal.

Use: It is used as an adjunct to improve glycemic control with Type 2 diabetes mellitus.