BY Y. Chandravadana Associate proffesor Krishna teja pharmacy college Tirupati.

Transcription

1 BY Y. Chandravadana Associate proffesor Krishna teja pharmacy college Tirupati.

2 DEFINITION : A syndrome of disordered metabolism due to a combination of hereditary and environmental causes. CLASSIFICATION: TYPE 1 Lack of insulin. TYPE 2 Cells resistance to insulin SIGNS AND SYMPTOMS : Very thristy Feeling tired Using the toilet often to urinate Constant hunger High level of glucose in urie and in fasting blood.

3 ACUTE Diabetic ketoacidosis(dka) Non ketotic hyperosmolar coma CHRONIC Microvascular disease: impotence and poor wound healing ATHEROSCLEROSIS:strokes,coronary heart disease Renal failure retinal damage nerve damage Infective disease: tuberculosis

4 TYPE1: Insulin must be injected or inhaled TYPE2: Food control, exercise, medicines (1) Agents which increase insulin secretion (2) Agents which increase the sensitivity of target organs to insulin; (3) Agents which decrease glucose absorption (4) Insulin needed for patients with serious complications or an emergency

5 Chemistry: 51 aa aaranged in two chains (A & B ) linked by disulfide bridges. Secretion: by betacells in pancreatic islet. Degradation: liver and kidney Endogenous: liver (60%) and kidney (35%- 40%) Exogenous: liver (35%-40%) and kidney (60%) T1/2 in plasma: 3-5 min

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7 A Polypeptide hormone with two peptide chains that are connected by disulfide bonds. Synthesized as a precursor (pro-insulin) that undergoes proteolytic cleavage to form insulin and C peptide, both of which are secreted by the beta cells of the pancreas triggered by high blood glucose. Insulin and glucagon regulate blood glucose levels. ACTIONS: Controls intermediary metabolism, having actions on liver, muscle and fat. Conserves fuel by facilitating the uptake and storage of glucose, amino acids and fats after a meal.

8 Pro insulin is converted to insulin and C peptide. Insulin is referred as the storage hormone as it promotes anabolism and inhibits catabolism of carbohydrates,fatty acids and protein. In the absence of insulin,most tissues cannot use glucose and fats/proteins are broken down to provide energy.

9 Human insulin is produced by recombinant DNA technology using special strains of Escherichia coli or yeast that have been genetically altered to contain the gene for human insulin. MOA: Acts on insulin receptors on liver cells, fat cells and stimulates glucose transport across membrane by ATP dependent transporters like GLUT 4 and GLUT 1.

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11 1)SUGAR METABOLISM : Stimulates glucose uptake and use by cells; inhibits glyconeogenesis blood sugar 2)FATTY METABOLISM : Improves fatty acids and transportation and fat anabolism ; inhibits fat catabolism and fatty acid and acetone body generation. 3)PROTEIN METABOLISM : Improves a transportation and protein anabolism ; inhibits protein catabolism and a utilization in liver.

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13 LIVER: Insulin increases the storage of glucose as glycogen in the liver. It inserts the GLUT-2 glucose transport molecule in the cell membrane. It inhibits gluconeogenesis thus significantly in glucose output by the liver. It decrease the protein catebolism.

14 ADIPOSE TISSUE: Insulin facilitates he storage of triglyceride by activating plasma lipoprotein lipase and inhibiting intracellular lipolysis. It increase the glucose uptake by GLUT 4 insertion into the cell membrane.

15 Hydrolysis of the disulfide linkage between A and B chains. 60%liver, 40%kidney(endogenous insulin) 60%kidney, 40%liver(exogenous insulin) Half-life 5-7min (endogenous insulin) Delayed release form (injected one) Category B (not teratogenic) Usual places for injection : upper arm, front and side parts the thighs and the abdomen. Not to inject in the same place (rotate). Should be stored in refrigerator and warm up to room temperature before use. Must be used within 30 days.

16 INSULIN SYRINGES : Prefilled disposible syringes with regular or modified insulin. PEN DEVICES : Fountain pen like ; insulin cartridges. INHALED INSULIN : Fine powder delivered through nebulizer, rapid absorption. INSULIN PUMPS : Portable infusion devices connected to subcutaneously placed cannula (continuous insulin infusion). INSULIN PATCH-PEN : A small (two inches long, one inch wide and 1/4inch thick) plastic deviceis designed to a warm on the skin like a bandage.

17 IMPLANTABLE PUMPS : Electromechanical mechanism regulates insulin delivery from percutaneously refillable reservoir. Mechanism pumps, fluorocarbon propellants and osmotic pumps are also being developed. OTHER ROUTES: -Oral(liposome/impermeable polymer coating) -Rectal -Nasal -Intra-peritoneal

18 (1)Ultra-short acting (2)Short-acting(regular) (3)Intra mediate-acting (4)Long-acting

19 Uses Physical characteristics Chemical structure Route & time of administration Short-acting (regular) insulins e.g. Humulin R, Novolin R Designed to control postprandial hyperglycemia & to treat emergency diabetic ketoacidosis Clear solution at neutral ph Hexameric analogue S.C min before meal I.V. in emergency (e.g. diabetic ketoacidosis) Ultra-Short acting insulins e.g. Lispro, aspart, glulisine Similar to regular insulin but designed to overcome the limitations of regular insulin Clear solution at neutral ph Monomeric analogue S.C. 5 min (no more than 15 min) before meal I.V. in emergency (e.g. diabetic ketoacidosis) Onset of action min ( S.C ) Peak serum levels 2 4 hr 0 15 min ( S.C ) min Duration of action 6 8 hr 3 4 hr Usual administration 2 3 times/day or more 2 3 times / day or more 19

20 RAPID ACTING INSULIN: Lispro, Aspart and Glulisine SHORT ACTING INSULIN: Regular(crystalline) INTERMEDIATE ACTING INSULIN: NPH(isophane) and Lente(insulin zinc) LONG ACTING INSULIN: Ultralente, detimir and Glargine.

21 INSULIN DURATION ROUTE FEATURES Lispro 3-5hrs L.V/S.C Onset within 15mins Regular 7-10hrs L.V/S.V Common NPH 16-20hrs S.C NPH can (neutral mix with protamine regular Hagadorm) Ultralenta 24-30hrs S.V Basal level

22 Classification Sulfonylureas Thiazolidinediones Biguanides α-glucosidase inhibitors Meglitinides 22

23 Mechanism to reduce blood sugar : Stimulation of pancreatic insulin release sulfonylureas, meglitinide. Reduce the bio synthesis of glucose in liver-biguanides (melformin). Increase the sensitivity of target cells to insulinthiazolidinediones. Retard the absorption of sugars from the GIT(gastro intestinal tract)-acarbose,miglitol.

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25 Representative Drugs 1st generation: tolbutamide chlorpropamide tolazamide 2nd generation: glybenclamide glyburide glipizide glymepride 3rd generation: glyclazipe 25

26 MECHANISM OF ACTION OF SULPHONYLUREAS 1) Release of insulin from β-cells 2) Reduction of serum glucagon concentration 3) Potentiation of insulin action on target tissues 26

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28 Hypoglycemic mechanism 1. Rapid mechanism: stimulation of insulin secretion Sulfonylurea receptor in β-cell membrane activated ATP-sensitive K + -channel inhibited Cellular membrane depolarized Ca 2+ entry via voltage-dependent Ca 2+ channel Insulin release 2. Long term profit involved mechanism 1Inhibition of glucagon secretion by pancreas α cells; 2Ameliorating insulin resistance 3 Increase insulin receptor number & the affinity to insulin 28

29 Pharmacological effects 1. Hypoglycemic effect 2. Antidiuretic effect chlorpropamide & glybenclamide 3. Antiplatelete-aggregation effect glyclazipe 29

30 Sulfonylureas First generation Done(mg) Duration(h) Tolbutamide(orinase) Chloropropamide(Diabinese) Tolazamide(Tolinase) Second generation Glipizide (glucotrol) Glyburide (micronase) (glibenclamide) Thrid generation Glimepiride (Amaryl)

31 SIDE EFFECTS OF SULPHONYLUREAS 1) Nausea, vomiting, abdominal pain, diarrhea 2) Hypoglycaemia 3) Dilutional hyponatraemia & water intoxication (Chlorpropamide) 4) Disulfiram-like reaction with alcohol (Chlorpropamide) 5) Weight gain 31

32 SIDE EFFECTS OF SULPHONYLUREAS (contd.) 6) Blood dyscrasias (not common; less than 1% of patients) - Agranulocytosis - Haemolytic anaemia - Thrombocytopenia 7) Cholestatic obstructive jaundice (uncommon) 8) Dermatitis (Mild) 9) Muscle weakness, headache, vertigo (not common) 10) Increased cardio-vascular mortality with longterm use?? 32

33 Pharmacokinetics : These drugs are well absorbed orally after being taken 1-30min before meals. Both maglitinides are metabolized to inactive products by CYP3A4 in the liver. Excreted through the bile.

34 c Their action is dependent on functioning pancreatic beta-cells They bind to a distinct site on the sulfonylurea receptor of ATP-sensitive potassium channel. There by initiating a series of reactions culminating in the release of insulin. However in contrast to the sulfonylurease, the meglitinides have a rapid onset and ashort duration of action. They are categorized as postprandial glucose regulators. Meglitinides should not be used in combination with sulfonyureas due to overlapping mechanisms of action.

35 Drugs other than Sulfonylurea Meglitinides Biguanides α-glucosidase Inhibitors Thiazolidinediones Repaglinide Nateglinide Metformin Acarbose Rosiglitazone Pioglitazone 35

36 Two classes of oral agents-the biguanides and thiazolidinediones improve insulin action. These agents lower blood sugar by improving target cell responseto insulin without increasing pancreatic insulin secretion. They address the core problem in type II diabetes-insulin resistance.

37 BIGUANIDES (Contd.) MECHANISM OF ACTION 1. Increase peripheral glucose utilization 2. Inhibits gluconeogenesis 3. Impaired absorption of glucose from the gut 37

38 BIGUANIDES (Contd.) SIDE EFFECTS 1. Metallic taste in the mouth 2. Gastrointestinal (anorexia, nausea, vomiting, diarrhea, abdominal discomfort) 3. Vitamin B 12 deficiency (prolonged use) 4. Lactic acidosis ( rare 01/ 30,000-exclusive in renal & hepatic failure) 38

39 Metformin (glucophage), the only currently available biguanide. It increases glucose up take and utilization by target tissues,there by decreasing insulin resistance. Requires insulin for its action,but it does not promote insulin reaction. Hyper insulinemia is not a problem. Thus, the risk of hypoglycemia is far less than that with sulfonylureas.

40 BIGUANIDES (Metformin): Inhibits gluconeogenesis. Does not promote insulin secretion. It increase the sensitivity of liver and muscle to insulin. It causes modest weight loss.

41 BIGUANIDES (Contd.) CONTRAINDICATIONS 1. Hepatic impairment 2. Renal impairment 3. Alcoholism 4. Heart failure 41

42 Representative Drugs rosiglitazone pioglitazone troglitazone ciglitazone Pharmacological effects Improving function of pancreas β cells Ameliorating insulin resistance Ameliorating fat metabolic disorder Preventing and treating type 2 diabetes mellitus and their cardiovascular complications 42

43 Mechanism (possible) Peroxisome proliferator-activated receptor-γ(ppar-γ) activated Nuclear genes involved in glucose & lipid metabolism and adipocyte differentiation activated Clinical use Insulin resistance & type 2 diabetes mellitus Adverse reactions Troglitazone occasionally induces hepatic injury 43

44 MECHANISM OF ACTION: Exact mechanism by which thetzds lower insulin resistance remains to be elucidated. They are known to target the peroxisome proliferate-activated receptor-y(ppary)-alpha nuclear hormone receptor. Ligands for PPARy regulate adipo-cyte production and secretion of fatty acid as well as glucose metabolism, resulting in increased insulin sensitivity in adipose tissue, liver and skeletal muscle.

45 PHARMACOKINETICS: Both pioglitazone are absorbed very well after oral administration and are extensively bound to serum albumin. Both under go extensive metabolism by different cytochrome P450 isozymes. PIOGLITAZONE: Renal elimination is negligible, with the majority inactive drug and metabolites excreted in the bite and eliminated in the feces. ROSIGLITAZONE: The metabolites are primarily excreted in the urine.

46 THIAZOLIDINEDIONE DERIVATIVES (Contd.) PHARMACOKINETICS - 99% absorbed - Metabolized by liver - 99% of drug binds to plasma proteins - Half-life 3 4 h - Eliminated via the urine 64% and feces 23% 46

47 THIAZOLIDINEDIONE DERIVATIVES (Contd.) INDICATIONS Type 11 diabetes alone or in combination with metformin or sulfonylurea or insulin in patients resistant to insulin treatment. 47

48 ADVERSE EFFECTS: Very few 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 asteopenia and increased fracture risk. Other adverse effects include headache and anemia.

49 α-glucosidase INHIBITORS (Contd.) MECHANISM OF ACTION Inhibits intestinal alpha-glucosidases and delays carbohydrate absorption, reducing postprandial increase in blood glucose 49

50 α-glucosidase INHIBITORS (Contd.) SIDE EFFECTS Flatulence Loose stool or diarrhea Abdominal pain Alone does not cause hypoglycemia 50

51 Alpha glucosidase inhibitors are oral antidiabetics drugs used for diabetes mellitus type2 that work by preventing the digestion of carbohydrates(such as starch and table sugar). Carbohydrates are normally converted into simple sugars (mono-saccharides), which can be absorbed through the intestine. Hence, alpha-glucosidase inhibitors reduce the impact of carbohydrates on blood sugar.

52 MECHANISM OF ACTION : These drugs are taken at the beginning of meals. They act by delaying the digestion of carbohydrates, there by resulting in lower post -prandial glucose levels. Both drugs exert their effects by reversibly inhibiting membrane bound alpha-glucosidase in the intestinal brush border. This enzyme is responsible for the hydrolysis of oligosaccharides to glucose and other sugars. consequently, the post-prandial 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 mono-therapy, they do not cause hypoglycemia. However, when used in combination with the sulfonylureas or with insulin, hypoglycemia may develop.

53 PHARMACOKINETICS: Acarbose is poorly 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.

54 ADVERSE EFFECTS: The major side effects are flatulence, diarrhea and abdominal cramping. Patients with inflammatory bowel disease, clonic ulceration or intestinal obstruction should not use these drugs.

55 GLUCAGON LIKE PEPTIDE : GLP-1 ANALOG:XENATIDE:(BYETTA): GLP is an incretin released from the small intestine which increase the glucose dependent insulin secretion. Xenatide suppress glucogen release and reduce appetite. It is administrated by SC injection.

56 PHARMACOKINETICS: Sitagliptin is well 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.

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