oral. hypoglycemic agents.pptx

oral. hypoglycemic agents.pptx

• 1.
  Content  Introduction  Diabetes Types of diabetes  Insulin  Biosynthesis of Insulin and Mechanism of action  Classification of oral hypoglycaemic agent  Mechanism of action of oral hypoglycaemic agent  Pharmacokinetics of oral hypoglycaemic agent  Adverse effect of oral hypoglycaemic agent
• 2.
  Hypoglycaemic agent  Thedrugs which are used to lower blood sugar are called hypoglycaemic agents. They are used to treat diabetes mellitus. (Latin word mellitus means honey)  Diabetes mellitus is characterized by persistent hyperglycemia, usually with glycosuria  The lack or deficiency of insulin affects carbohydrate, protein, and lipid metabolism. As a result, the different symptoms (manifestations) observed are hyperglycemia, glucosuria, ketonemia, ketonuria, hyperlipidemia, polyuria, polydipsia (increased thirst), etc.
• 3.
  Diabetes  Diabetes describesa group of metabolic diseases in which the person has high blood glucose (blood sugar), either because insulin production is inadequate, or because the body's cells do not respond properly to insulin, or both.
• 4.
  Types of DiabetesMellitus  Diabetes mellitus is divided into the following types :  Type 1: Insulin-dependent diabetes mellitus (IDDM). It is formerly called Juvenile - onset as it develops generally in youth. Insulin is essential to treat this type as patients have little or no endogenous insulin.  Type 2 : Non-insulin-dependent diabetes mellitus (NIDDM). It is formerly called as adult-onset or maturity-onset diabetes as it develops in middle ages or in elderly patients who are often obese. It is treated by dietary modification or by use of oral hypoglycaemic agents and in certain cases by insulin.  Type 3: Malnutrition-related diabetes mellitus (MRDM).  Type 4: Secondary diabetes. It is due to certain pancreatic disease or certain genetic syndrome or may be drug-induced.
• 5.
  Insulin  Insulin isa peptide hormone, produced by beta cells of the pancreas, and is central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, skeletal muscles, and fat tissue to absorb glucose from the blood. In the liver and skeletal muscles, glucose is stored as glycogen, and in fat cells (adipocytes) it is stored as triglycerides.  When control of insulin levels fails, diabetes mellitus can result. As a consequence, insulin is used medically to treat some forms of diabetes mellitus.
• 6.
  BIOSYNTHESIS OF INSULIN Insulin is synthesized as a large precursor polypeptide chain the pre-pro insulin. It has 109 amino acids. It is rapidly converted to pro-insulin in the endoplasmic reticulum by removal of the leader sequence of 23 amino acid residues.  The proinsulin with 86 amino acids is transported to the Golgi apparatus where it is cleaved by protease. The site-specific cleavage is done by an enzyme named "prohormone convertase 1 and 2" The C-peptide or connecting peptide with 33 amino acids is removed. (The number of amino acids in C peptide may vary according to species). Now insulin has 53 amino acids: the extra two amino acids are removed by carboxypeptidase H and insulin with 51 amino acids is thus formed.
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  MECHANISM OF ACTION: Insulin acts on specific receptors located on the cell membrane of practically every cell, but their density depends on the cell type: liver and fat cells are very rich.  The insulin receptor is a receptor tyrosine kinase  (RTK) which is a heterotetrameric glycoprotein consisting of 2 extracellular a and 2 transmembranes B subunits linked together by disulfide bonds, orienting across the cell membrane as a heterodimer  It is oriented across the cell membrane as a heterodimer.  The A subunits carry insulin binding sites, while the B subunits have tyrosine kinase activity.
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  Classification of HypoglycaemicAgent  Hypoglycaemic agents may be placed in the following groups: 1. Hormones: Insulin and its preparation. 2. Oral hypoglycaemic agents or synthetic hypoglycemic agents (a) Sulphonylureas 1. First generation:- chlorpropamide, tolbutamide, Acetohexamide 2. Second Generation :-glibenclamide, Glipizide, Glimepiride (b) Biguanides e. g. Phenformin, metformin. (c) Meglitinides: Repaglinide, Nateglinide (d) Thiazolidinediones - Rosiglitazone, Pioglitazone
• 11.
  (e) Alpha glucosidaseinhibitors- E.g Acarbose,Miglitol (f) Dipeptidyl peptidase (DPP4)- Sitagliptin g) Glucagon like peptide (GLP-1) analogue Exenatide
• 12.
  (A)Sulfonylureas  These agentsare classified as insulin secretagogues because they promote insulin release from the B cells of the pancreas. The primary drugs used today are tolbutamide and the second-generation derivatives, glyburide, glipizide, and glimepiride. Mechanism of action:  stimulation of insulin release from the B cells of the pancreas by blocking the ATP-dependent K* channels, resulting in depolarization and Ca2+ influx.  reduction in hepatic glucose production  increase in peripheral insulin sensitivity.
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  Pharmacokinetic  Given orally,these drugs bind to serum proteins  Metabolized by the liver  Excreted by the liver or kidney  Tolbutamide has the shortest duration of action (6-12 hours), whereas the second-generation agents last about 24 hours
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  Adverse effect  Weightgain  Hyperinsulinemia  Hypoglycaemia  These drugs should be used with caution in patients with hepatic or renal insufficiency because delayed excretion of the drug resulting in its accumulation-may cause hypoglycemia.  Renal impairment is a particular problem in the case of those agents that are metabolized to active compounds, such as glyburide.  Glyburide has minimal transfer across the placenta and may be a reasonably safe alternative to insulin therapy for diabetes in pregnancy.
• 16.
  (B)Biguanides  Metformin (Glucophage),the only currently available biguanide  it increases glucose uptake and utilization by target tissues, thereby decreasing insulin resistance.  Requires insulin for its action, but it does not promote insulin secretion.  Hyperinsulinemia is not a problem. Thus, the risk of hypoglycemia is far less than that with sulfonylureas.
• 17.
  Mechanism of action reduction of hepatic glucose output, largely by inhibiting hepatic gluconeogenesis.  Slowing intestinal absorption of sugars  Improves peripheral glucose uptake and utilisation.  Metformin may be used alone or in combination with one of the or in other agents, as well as with insulin.  Hypoglycaemia has occurred when metformin was taken in combination.
• 18.
  Pharmacokinetics:  Metformin iswell absorbed orally, and is not bound to serum proteins  It is not metabolized  Excretion is via urine. Adverse effects:  These are largely gastrointestinal.  Contraindicated in diabetics with renal and/or hepatic disease, acute myocardial infarction, severe infection, or diabetic ketoacidosis.  It should be used with caution in patients greater than 80 years of age or in those with a history of congestive heart failure or alcohol abuse.  Long-term use may interfere with vitamin B12 absorption.
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  (C) Meglitinides  Meglitinidesare secretagogues like sulfonylureas, although not structurally related. They induce insulin secretion from pancreas, with a different mechanism of action from sulfonylureas. There are three available drugs: repaglinide, nateglinide, and mitiglinide.  This class of agents includes repaglinide and nateglinide. Although they are not sulfonylureas, they have common actions.
• 20.
  Mechanism of action: Their action is dependent on functioning pancreatic B cells.  They bind to a distinct site on the sulfonylurea receptor of ATP-sensitive potassium channels, thereby initiating a series of reactions culminating in the release of insulin.  However, in contrast to the sulfonylureas, the meglitinides have a rapid onset and a short duration of action.  They are are categorized as postprandial glucose regulators.  Meglitinides should not be used in combination with sulfonylureas due to overlapping mechanisms of action.
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  Pharmacokinetics:  These drugsare well absorbed orally after being taken 1 to 30 minutes before meals.  Both meglitinides are metabolized to inactive products by CYP3A4 in the liver.  Excreted through the bile. Adverse Effects:  Incidence of hypoglycemia is lower than that of the sulfonylureas. Repaglinide has been reported to cause severe hypoglycemia in patients who are also taking the lipid-lowering drug gemfibrozil.  Weight gain is less of a problem with the meglitinides than with the sulfonylureas.
• 22.
  (D) Thiazolidinediones  Anothergroup of agents that are insulin sensitizers is the thiazolidinediones (TZDs) or, more familiarly the glitazones.  Although insulin is required for their action, these drugs do not promote its release from the pancreatic B cell thus, hyperinsulinemia does not result.  Troglitazone was the first of these to be approved for the treatment of Type 2 diabetes but was withdrawn after a number of deaths due to hepatotoxicity were reported. Presently, two members of this class are available, pioglitazone and rosiglitazone.
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   Mechanism ofaction:  The exact mechanism by which the TZDs lower insulin resistance remains to be elucidated  They are known to target the peroxisome proliferator-activated receptor- (PPARy)-a nuclear hormone receptor. Ligands for PPARy regulate adipocyte production and secretion of fatty acids as well as glucose metabolism, resulting in increased insulin sensitivity in adipose tissue, liver, and skeletal muscle.
• 24.
  Pharmacokinetics:  Both pioglitazoneand rosiglitazone are absorbed very well after oral administration and are extensively bound to serum albumin.  Both undergo extensive metabolism by different cytochrome P450 isozymes.  Pioglitazone: Renal elimination is negligible, with the majority of the active drug and metabolites excreted in the bile and eliminated in the faces.  Rosiglitazone: The metabolites are primarily excreted in the urine.
• 25.
  Adverse Effects:  Veryfew cases of liver toxicity have been reported with rosiglitazone or pioglitazone.  Weight increase can occur, possibly through the ability of TZDs to increase subcutaneous fat or due to fluid retention.  Glitazones have been associated with osteopenia and increased fracture risk.  Other adverse effects include headache and anemia.
• 26.
  (E) Alpha-glucosidase inhibitor Alpha-glucosidase inhibitors are oral anti-diabetic drugs used for diabetes mellitus type 2 that work by preventing the digestion of carbohydrates (such as starch and table sugar). Carbohydrates are normally converted into simple sugars (monosaccharides), which can be absorbed through the intestine.  Hence, alpha-glucosidase inhibitors reduce the impact of carbohydrates on blood sugar.  Acarbose and miglitol are orally active drugs used for the treatment of patients with Type 2 diabetes.
• 27.
  Mechanism of action: These drugs are taken at the beginning of meals. They act by delaying the digestion of carbohydrates, thereby resulting in lower postprandial glucose levels. Both drugs exert their effects by reversibly inhibiting membrane-bound a-glucosidase in the intestinal brush border. This enzyme iS responsible for the hydrolysis of oligosaccharides to glucose and other sugars.  Consequently, the postprandial rise of blood glucose is blunted. Unlike the other oral hypoglycemic agents, these drugs do not stimulate insulin release, nor do they increase insulin action in target tissues.  Thus, as monotherapy, they do not cause hypoglycemia. However, used in combination with the sulfonylurea or with insulin, hypoglycemia may develop.
• 28.
  Pharmacokinetics:  Acarbose ispoorly absorbed.  It is metabolized primarily by intestinal bacteria, and some of the metabolites are absorbed and excreted into the urine. On the other hand, miglitol is very well absorbed but has no systemic effects. It is excreted unchanged by the kidney. Adverse effects:  The major side effects are flatulence, diarrhea, and abdominal cramping. Patients with inflammatory bowel disease, colonic ulceration, or intestinal obstruction should not use these drugs.
• 29.
  (F) Dipeptidyl Peptidase-4Inhibitor  DPP-4 inhibitors or gliptins, are a class of oral hypoglycemics that block DPP-4. They can be used to treat diabetes mellitus type 2  The first agent of the class - sitagliptin – was approved by the FDA in 2006.  Glucagon increases blood glucose levels, and DPP-4 inhibitors reduce glucagon and blood glucose levels. The mechanism of DPP-4 inhibitors is to increase incretin levels (GLP-1 and GIP), which inhibit glucagon release, which in turn increases insulin secretion, decreases gastric emptying, and decreases blood glucose levels.  Sitagliptin is an orally active dipeptidyl peptidase-IV (DPP-IV) inhibitor used for the treatment of patients with Type 2 diabetes. Other agents in this category are currently in development.
• 30.
  Mechanism of action: Sitagliptin inhibits the enzyme DPP, IV, which is responsible for the inactivation of incretin hormones, such as glucagon-like peptide-1 (GLP-1). Prolonging the activity of incretin hormones results in increased insulin release in response to meals and a reduction in the inappropriate secretion of glucagon. Sitagliptin may be used as  mono-therapy or in combination with sulfonylurea, metformin or glitazone.
• 31.
  Pharmacokinetics:  Sitagliptin iswell absorbed after oral administration. Food does not affect the extent of absorption. The majority of sitagliptin is excreted unchanged in the urine. Dosage adjustments are recommended for patients with renal dysfunction. Adverse Effects:  In general, sitagliptin is well tolerated, with the most common adverse effects being nasopharyngitis and headache. Rates of hypoglycemia are comparable to those with a placebo when sitagliptin is used as monotherapy or in combination with metformin or pioglitazone.