Hypoglycemic agents

Including oral hypoglycemic agents

1. Hypoglycemic Agents ASHISH M PHARM I YEAR PHARMACOLOGY

2. Hypoglycemic agents The drugs which are used to lower blood sugar are called hypoglycemic agents. They are used to treat diabetes mellitus. (Latin word mellitus means honey) Diabetes mellitus is characterized by persistent hyperglycemia , usually with glucosuria The lack or deficiency of insulin affects carbohydrate, protein and lipid metabolism. As a result the different symptoms (manifestations) observed are hyperglycemia , glucosuria , ketonaemia , ketonuria , hyperlipidemia , polyuria , polydipsia (increased thirst) etc.

3. Diabetes mellitus is divided into following types : Type 1 : Insulin-dependent diabetes mellitus (IDDM) . It is formerly called as 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 parcreatic disease or certain genetic syndrome or may be drug-induced .

4. Classification : Hypoglycaemic agents may be placed in 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

5. e)Alpha glucosidase inhibitors- E.g Acarbose , Miglitol F) Dipeptidyl peptidase (DPP4)- Sitagliptin g) Glucagon like peptide (GLP-1) analogoue Exenatide

6. INSULIN : It is a hormone produced by beta-cells of Islets of Langerhans of pancreas. It is a polypeptide containing 51 amino acids arranged in two chains namely A and B having 21 and 30 amino acids respectively. These two chains are connected by two disulphide bridges (~S~S-bonds of cysteine ) Source : Pancreas of pig or ox: Porcine insulin differs from human insulin in only one amino acid in 'B' chain. Bovine insulin differs from human insulin in two amino acids in ‘ A' chain and one amino acid in chain B. Human insulin is produced either by enzymatic modification of porcine insulin or by use of DNA recombinant technology in micro-organisms so that amino acid sequence is identical to that of human insulin.

7. Uses : It is used  1. to control diabetes mellitus (which is uncontrollable by diet alone) or to treat Insulin dependent diabetes mellitus. 2. to regulate carbohydrate metabolism. 3. to treat hyperkalaemia . 4. to treat severe ketoacidosis or diabetic coma Insulin exerts following action:- Decrease blood sugar level Increase oxidation of glucose Increase muscle glycogen Decreased Gluconeogenesis Decreased ketogenesis Increase Lipogenesis Increased protein synthesis

8. Induce glycogen synthesis - When glucose levels are high, insulin induces the formation of glycogen by the activation of the hexokinase enzyme, which adds a phosphates group in glucose, thus resulting in a molecule that cannot exit the cell. At the same time, insulin inhibits the enzyme glucose-6-phosphatase, which removes the phosphate group. These two enzymes are key for the formation of glycogen. Also, insulin activates the enzymes phosphofructokinase and glycogen synthase which are responsible of glycogen synthesis. Increased potassium uptake – forces cells synthesizing glycogen (a very spongy, "wet" substance, that increases the content of intracellular water, and its accompanying K+ ions) [58] to absorb potassium from the extracellular fluids; lack of insulin inhibits absorption. Insulin's increase in cellular potassium uptake lowers potassium levels in blood plasma. This possibly occurs via insulin-induced translocation of the Na+/K+- ATPase to the surface of skeletal muscle cells.[59][60]

9. Decreased gluconeogenesis and glycogenolysis – decreases production of glucose from noncarbohydrate substrates, primarily in the liver (the vast majority of endogenous insulin arriving at the liver never leaves the liver); increase of insulin causes glucose production by the liver from assorted substrates. Increased lipid synthesis – insulin forces fat cells to take in blood glucose, which is converted into triglycerides; decrease of insulin causes the reverse. Increased esterification of fatty acids – forces adipose tissue to make neutral fats (i.e., triglycerides) from fatty acids; decrease of insulin causes the reverse. Decreased lipolysis – forces reduction in conversion of fat cell lipid stores into blood fatty acids and glycerol; decrease of insulin causes the reverse. Decreased proteolysis – decreasing the breakdown of protein Increased amino acid uptake – forces cells to absorb circulating amino acids; decrease of insulin inhibits absorption. Arterial muscle tone – forces arterial wall muscle to relax, increasing blood flow, especially in microarteries ; decrease of insulin reduces flow by allowing these muscles to contract. Increase in the secretion of hydrochloric acid by parietal cells in the stomach. Decreased renal sodium excretion.

10. A. Sulfonylureas These agents are classified as insulin secretagogues , because they promote insulin release from the β cells of the pancreas. The primary drugs used today are tolbutamide and the secondgeneration derivatives, glyburide , glipizide , and glimepiride . Mechanism of action: 1 ) stimulation of insulin release from the β cells of the pancreas by blocking the ATP-dependent K+ channels, resulting in depolarization and Ca2+ influx 2) reduction in hepatic glucose production 3) increase in peripheral insulin sensitivity.

11. Pharmacokinetics: 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 Adverse Effects: Weight gain Hyperinsulinemia Hypoglycemia

12. B. Meglitinide analogs This class of agents includes repaglinide and nateglinide . Although they are not sulfonylureas , they have common actions . Mechanism of action: Their action is dependent on functioning pancreatic β 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.

13. Pharmacokinetics: These drugs are 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 . Weight gain is less of a problem with the meglitinides than with the sulfonylureas .

14. Biguanides Metformin ( glucophage ), the only currently available biguanide it increases glucose uptake and utilization by target tissues, thereby decreasing insulin resistance . Mechanism of action: reduction of hepatic glucose output, largely by inhibiting hepatic gluconeogenesis . Slowing intestinal absorption of sugars Improves peripheral glucose uptake and utilization. Metformin may be used alone or in combination with one of the other agents, as well as with insulin. Hypoglycemia has occurred when metformin was taken in combination.

15. Pharmacokinetics: Metformin is well absorbed orally, is not bound to serum proteins It is not metabolized Excretion is via the urine . Adverse effects: 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 .

16. Thiazolidinediones Troglitazone was the first of these to be approved for the treatment of Type 2 diabetic, but was withdrawn after a number of deaths due to hepatotoxicity were reported. Presently, two members of this class are available, pioglitazone and rosiglitazone . Mechanism of action: Exact mechanism by which the TZDs lower insulin resistance remains to be elucidated They are known to target the peroxisome proliferator -activated receptor-γ ( PPARγ )-α nuclear hormone receptor. Ligands for PPARγ 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.

17. Pharmacokinetics: Both pioglitazone and 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 feces. Rosiglitazone : The metabolites are primarily excreted in the urine.

18. α- glucosidase inhibitors Alpha- glucosidase inhibitors are oral antidiabetic drugs used for diabetes mellitus type 2 that work by preventing the digestion of carbohydrates (such as starch and table sugar ). Acarbose and miglitol are orally active drugs used for the treatment of patients with Type 2 diabetes . 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 membranebound α- 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, when used in combination with the sulfonylureas or with insulin, hypoglycemia may develop.

19. Dipeptidyl peptidase-4 inhibitor 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 . Mechanism of action: Sitagliptin inhibits the enzyme DPP-4, 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 inappropriate secretion of glucagon .