Anti diabetics

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Anti diabetics

  1. 1. DIABETES MELLITUSOrator: Mr. Ratan J. Lihite NIPER-Guwahati 1
  2. 2. DIABETES MELLITUSMostly asymptomaticTendency increase with obesityOne of the leading cause of death by diseaseOne of the leading cause of blindness One of the leading cause of renal failure 2
  3. 3. Comparison between Normal Beta celland Diabetes Beta cell.
  4. 4. 4
  5. 5. Characteristic Type 1 ( 10% ) Type 2Onset (Age) Usually < 30 Usually > 40Type of onset Abrupt GradualNutritional status Usually thin Usually obeseClinical symptoms Polydipsia, polyphagia, Often asymptomatic polyurea, Wt lossKetosis Frequent Usually absentEndogenous insulin Absent Present, but relatively ineffectiveRelated lipid Hypercholesterolemia Cholesterol & triglyceridesabnormalities frequent, all lipid fractions often elevated; carbohydrate- elevated in ketosis induced hypertriglyceridemia commonInsulin therapy Required Required in only 20 - 30% of patientsHypoglycemic drugs Should not be used Clinically indicatedDiet Mandatory with insulin Mandatory with or without drug 5
  6. 6. EFFECTS OF INSULIN FATCARBOHYDRATES LIPOLYSISGLUCOSE UPTAKEGLYCOGEN SYNTHESIS( STORAGE) PROTEINGLUCONEOGENEIS(LIVER) AMINO ACID UPTAKEGLYCOLYSIS (MUSCLE) (PROTEIN SYTHESIS)CONVERSION OF CARBOHYDRATE TO FAT (LIPOGENESIS) POTASSIUM K+ UPTAKE INTO CELLS 6
  7. 7. Mechanism of Action of insulin
  8. 8. INSULIN DEFICIENCY – DIABETES MELLITUS GLUCOSE UPTAKE AA LIPOLYSIS mobilizationHYPERGLYCEMIA PLASMA FFA PLASMA AAGLYCOSURIA Glucose KETOSIS 8
  9. 9. Insulin Degradation Hydrolysis of the disulfide linkage between A&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) not teratogenic Usual places for injection: upper arm, front& side parts of the thighs& the abdomen. Not to inject in the same place ( rotate) Should be stored in refrigerator& warm up to room temp before use. Must be used within 30 days. 9
  10. 10. TYPES OF INSULIN PREPARATIONS1. Ultra-short-acting2. Short-acting (Regular)3. Intermediate-acting4. Long-acting 10
  11. 11. Short-acting (regular) insulins Ultra-Short acting insulins e.g. Humulin R, Novolin R e.g. Lispro, aspart, glulisineUses Designed to control postprandial Similar to regular insulin but hyperglycemia & to treat designed to overcome the limitations emergency diabetic ketoacidosis of regular insulinPhysical Clear solution at neutral pH Clear solution at neutral pHcharacteristicsChemical structure Hexameric analogue Monomeric analogueRoute & time of S.C. 30 – 45 min before meal S.C. 5 min (no more than 15 min)administration I.V. in emergency before meal (e.g. diabetic ketoacidosis) I.V. in emergency (e.g. diabetic ketoacidosis)Onset of action 30 – 45 min ( S.C ) 0 – 15 min ( S.C )Peak serum levels 2 – 4 hr 30 – 90 minDuration of action 6 – 8 hr 3 – 4 hrUsual 2 – 3 times/day or more 2 – 3 times / day or more 11administration
  12. 12. 3. Intermediate - acting insulinIsophane (NPH)Turbid suspensionInjected S.C.(Only)Onset of action 1 - 2 hrPeak serum level 5 - 7 hrDuration of action 13 - 18 hr 12
  13. 13. 3. Intermediate - acting insulin (contd.) Lente insulin Turbid suspension Mixture of 30% semilente insulin 70% ultralente insulin Injected S.C. (only) Onset of action 1 - 3 hr Peak serum level 4 - 8 hr Duration of action 13 - 20 hr 13
  14. 14. 3. Intermediate - acting insulin (contd.)Lente and NPH insulins Are roughly equivalent in biological effects. They are usually given once or twice a day. They are not used during emergencies (e.g. diabetic ketoacidosis). 14
  15. 15. 4. Long – acting insulin e.g.Insulin glargine• Onset of action 2 hr• Absorbed less rapidly than NPH&Lente insulins.• Duration of action upto 24 hr• Designed to overcome the deficiencies of intermediate acting insulins• Advantages over intermediate-acting insulins:• Constant circulating insulin over 24hr with no pronounced peak.• More safe than NPH&Lente insulins due to reduced risk of hypoglycemia(esp.nocturnal hypoglycemia).• Clear solution that does not require resuspention before administration. 15
  16. 16. Methods of Administration Insulin Syringes Pre-filled insulin pens External insulin pump Under Clinical Trials Oral tablets Inhaled aerosol Intranasal, Transdermal Insulin Jet injectors Ultrasound pulses 16
  17. 17. COMPLICATIONS OF INSULIN THERAPY 1. Severe Hypoglycemia (< 50 mg/dl )– Life threatening Overdose of insulin Excessive (unusual) physical exercise A meal is missed 2. Weight gain 3. Local or systemic allergic reactions (rare) 4. Lipodystrophy at injection sites 5. Insulin resistance 6. Hypokalemia 17
  18. 18. Severe insulin reaction Diabetic coma (Hypoglycemic Shock) (Diabetic Ketoacidosis)Onset Rapid Slow- Over several daysInsulin Excess Too littleAcidosis & No KetoacidosisdehydrationSigns and sympsB.P. Normal or elevated Subnormal or in shockRespiration Normal or shallow Deep & air hungerSkin Pale & Sweating Hot & dryCNS Tremors, mental confusion, General depression sometimes convulsionsBlood sugar Lower than 70 mg/100cc Elevated above 200 mg/100ccKetones Normal Elevated 18
  19. 19. Oral Hypoglycemics All taken orally in the form of tablets.Pts with type11 diabetes have two physiological defects:3. Abnormal insulin secretion4. Resistance to insulin action in target tissues associated with decreased number of insulin receptors 19
  20. 20. Oral Hypoglycemic agents Classes of Oral Hypoglycemic Agents Drug class Agents Sulfonylureas First generation Acetohexamide (Dymelor) Chlorpropamide (Diabinese) Tolazamide (Tolinase) Tolbutamide (Orinase)
  21. 21. Second generation Glyburide (Micronase) Glipizide (Glucotrol) Glimepiride (Amaryl)Meglitinides Repaglinide (Prandin) Nateglinide (Starlix)Biguanides Metformin (Glucophage)Thiazolidinediones Pioglitazone (Actos) Rosiglitazone (Avandia)Alpha-glucosidase inhibitors Acarbose (Precose) Miglitol (Glycet)
  22. 22. Oral Anti-Diabetic AgentsSulfonylureas Drugs other than Sulfonylurea 22
  23. 23. Sulfonylureas (Oral Hypoglycemic drugs) First generation Second generation Short Intermediate Long Short Long acting acting acting acting acting Chlorpropamide GlyburideTolbutamide Acetohexamide Glipizide (Glibenclamide) Tolazamide Glimepiride 23
  24. 24. FIRST GENERATION SULPHONYLUREA COMPOUNDS Tolbutamid Acetohexamide Tolazamide Chlorpropamide short-acting intermediate- intermediate- long- acting acting actingAbsorption Well Well Slow WellMetabolism Yes Yes Yes YesMetabolites Inactive* Active +++ ** Active ++ ** Inactive **Half-life 4 - 5 hrs 6 – 8 hrs 7 hrs 24 – 40 hrsDuration of Short Intermediate Intermediate Longaction (6 – 8 hrs) (12 – 20 hrs) (12 – 18 hrs) ( 20 – 60 hrs)Excretion Urine Urine Urine Urine * Good for pts with renal impairment ** Pts with renal impairment can expect long t1/2 24
  25. 25. SECOND GENERATION SULPHONYLUREA COMPOUNDS Glipizide Glibenclamide Glimepiride Short- acting (Glyburide) Long-acting Long-actingAbsorption Well Well WellMetabolism Yes Yes YesMetabolites Inactive Inactive InactiveHalf-life 3 – 4 hrs Less than 3 hrs 5 - 9 hrsDuration of 10 – 16 hrs 12 – 24 hrs 12 – 24 hrsactionExcretion Urine Urine Urine 25
  26. 26. MECHANISM OF ACTION OF SULPHONYLUREAS1) Release of insulin from β-cells2) Reduction of serum glucagon concentration3) Potentiation of insulin action on target tissues 26
  27. 27. SIDE EFFECTS OF SULPHONYLUREAS1) Nausea, vomiting, abdominal pain, diarrhea2) Hypoglycaemia3) Dilutional hyponatraemia & water intoxication (Chlorpropamide)4) Disulfiram-like reaction with alcohol (Chlorpropamide)5) Weight gain 27
  28. 28. 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 28
  29. 29. CONTRAINDICATIONS OF SULPHONYLUREAS 1) Type 1 DM ( insulin dependent) 2) Parenchymal disease of the liver or kidney 3) Pregnancy, lactation 4) Major stress 29
  30. 30. DRUGS THAT AUGMENT THE HYPOGLYCEMIC ACTION OF SULPHONYLUREAS WARFARIN SULFONAMIDES SALICYLATES PHENYLBUTAZONE PROPRANOLOL ALCOHOL CHLORAMPHENICOL FLUCONAZOLE 30
  31. 31. DRUGS THAT ANTAGONIZE THE HYPOGLYCEMIC ACTION OF SULPHONYLUREASDIURETICS (THIAZIDE, FUROSEMIDE)DIAZOXIDECORTICOSTEROIDSORAL CONTRACEPTIVESPHENYTOIN, PHENOBARB., RIFAMPINALCOHOL ( chronic pts ) 31
  32. 32. Drugs other than SulfonylureaMeglitinides Biguanides α-Glucosidase Thiazolidinediones InhibitorsRepaglinide Metformin Acarbose RosiglitazoneNateglinide Pioglitazone 32
  33. 33. MEGLITINIDESe.g. Repaglinide, NateglinidePHARMACOKINETICSTaken orallyRapidly absorbed ( Peak approx. 1hr )Metabolized by livert1/2 = 1 hrDuration of action 4-5 hr 33
  34. 34. MEGLITINIDES (Contd.)MECHANISM OF ACTIONBind to the same KATP Channelas do Sulfonylureas,to cause insulin release from β-cells. 34
  35. 35. MEGLITINIDES (Contd.)CLINICAL USEApproved as monotherapy and in combination with metformin in type 2 diabetesTaken before each meal, 3 times / dayDoes not offer any advantage over sulfonylureas;Advantage: Pts. allergic to sulfur or sulfonylureaSIDE EFFECTS:HypoglycemiaWt gain ( less than SUs )Caution in pts with renal & hepatic impairement. 35
  36. 36. BIGUANIDESe.g. MetforminPHARMACOKINETICSGiven orallyNot bind to plasma proteinsNot metabolizedExcreted unchanged in urinet 1/2 2 hr 36
  37. 37. BIGUANIDES (Contd.)MECHANISM OF ACTION1. Increase peripheral glucose utilization2. Inhibits gluconeogenesis3. Impaired absorption of glucose from the gut 37
  38. 38. Advantages of Metformin over SUsDoes not cause hypoglycemiaDoes not result in wt gain ( Ideal for obese pts ) 38
  39. 39. BIGUANIDES (Contd.)SIDE EFFECTS1. Metallic taste in the mouth2. 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) 39
  40. 40. BIGUANIDES (Contd.)CONTRAINDICATIONS1. Hepatic impairment2. Renal impairment3. Alcoholism4. Heart failure 40
  41. 41. BIGUANIDES (Contd.)INDICATIONS1. Obese patients with type II diabetes2. Alone or in combination with sulfonylureas 41
  42. 42. α-GLUCOSIDASE INHIBITORSe.g. AcarbosePHARMACOKINETICSGiven orallyNot absorbed from intestine except small amountt1/2 3 - 7 hrExcreted with stool 42
  43. 43. α-GLUCOSIDASE INHIBITORS (Contd.)MECHANISM OF ACTIONInhibits intestinal alpha-glucosidases anddelays carbohydrate absorption, reducing postprandial increase in blood glucose 43
  44. 44. α-GLUCOSIDASE INHIBITORS (Contd.)MECHANISM OF ACTION Acarbose Acarbo se Acarbos e 44
  45. 45. α-GLUCOSIDASE INHIBITORS (Contd.)MECHANISM OF ACTION 45
  46. 46. α-GLUCOSIDASE INHIBITORS (Contd.)SIDE EFFECTSFlatulenceLoose stool or diarrheaAbdominal painAlone does not cause hypoglycemia 46
  47. 47. α-GLUCOSIDASE INHIBITORS (Contd.)INDICATIONSPatients with Type 11 inadequately controlled bydiet with or without other agents( SU, Metformin)Can be combined with insulinmay be helpful in obese Type 11 patients(similar to metformin) 47
  48. 48. THIAZOLIDINEDIONE DERIVATIVES New class of oral antidiabetics e.g.: Rosiglitazone Pioglitazone 48
  49. 49. 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% 49
  50. 50. THIAZOLIDINEDIONE DERIVATIVES (Contd.) MECHANISM OF ACTION Increase target tissue sensitivity to insulin by: reducing hepatic glucose output & increase glucose uptake & oxidation in muscles & adipose tissues. They do not cause hypoglycemia (similar to metformin and acarbose ) . 50
  51. 51. THIAZOLIDINEDIONE DERIVATIVES (Contd.) ADVERSE EFFECTS - Mild to moderate edema - Wt gain - Headache - Myalgia - Hepatotoxicity 51
  52. 52. THIAZOLIDINEDIONE DERIVATIVES (Contd.) INDICATIONS Type II diabetes alone or in combination with metformin or sulfonylurea or insulin in patients resistant to insulin treatment. 52
  53. 53. 53

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