Drugs for treatment of Diabetes Mellitus
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These slides contain the brief description of Insulin and the other oral drugs indicated in the treatment of Diabetes Mellitus. Their mechanism of action, effects, uses, Adverse effects etc.
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Drugs for treatment of Diabetes Mellitus
- 1. Antidiabetic Drugs Dr Naser Ashraf Tadvi Associate Professor, Pharmacology Ayaan Institute of Medical Sciences
- 2. Objectives • Recall the synthesis,secretion and structure of Insulin • Describe the Mechanism of Action, Pharmacological actions, ADRs of Insulin and precautions taken to prevent those ADRs • Enlist Insulin preparations and analogs • Outline the management of Diabetic Ketoacidosis • Enlist non-insulin parenteral drugs used in DM • Classify the oral antidiabetic drugs • Discuss the pharmacology of the Oral Antidiabetic drugs
- 3. What Is diabetes mellitus? • A group of metabolic disorders characterized by chronic hyperglycemia associated with disturbances of carbohydrate, fat and protein metabolism due to absolute or relative deficiency in insulin secretion and/or action
- 4. Classification of Diabetes Mellitus • Type I: • Type II: • Type III: • Type IV:
- 6. Structure of insulin 21 amino acids 30 AA
- 7. Difference between human, pork, beef insulin Species A-chain B-chain 8th AA 10th AA 30th AA Human THR 1LEU- THR Pork THR ILEU ALA Beef ALA VAL ALA
- 8. Secretion of insulin > 70 mg/ml GLUT 2
- 9. • Direct stimulation • Plasma glucose or Amino Acids , ketones • Hormonal regulation •Neural regulation • Parasympathetic stimulates insulin release through IP3/ DAG • Sympathetic inhibits insulin release through 2 receptor activation Regulation of insulin secretion
- 11. Pharmacological Actions of insulin • Metabolic: – carbohydrate, lipid , protein, electrolyte • Vascular • Anti-inflammatory • Fibrinolytic • Growth
- 12. Pharmacological Actions of insulin Rapid actions Intermediary actions Long term Sec / min Few hours > 24 hrs E.g Metabolic actions •↑ multiplication •↑ differentiation of cells • Imp role in intrauterine & extrauterine growth Through DNA e.g • ↑ GLUT synthesis • Synthesis of enzymes for AA metabolism
- 13. Carbohydrate metabolism • Over all action of insulin is to ↓ glucose level in blood – ↑ Transport of glucose inside the cell – ↑ Peripheral utilization of glucose – ↑ Glycogen synthesis – ↓ Glycogenolysis – ↓ Neoglucogenesis
- 14. Lipid metabolism • ↓ Lipolysis • ↑ Lipogenesis • ↑ Glycerogenesis • ↓ Ketogenesis • ↑ Clearance of VLDL & chylomicrons from blood through enzyme Vascular Endothelial Lipoprotein Lipase
- 15. Protein metabolism • Protein synthesis • ↑ entry of amino acids in cells Electrolyte metabolism • ↑ transport of K+, Ca++, inorganic phosphates
- 16. Other actions • Vascular actions: – Vasodilation ? Activation of endothelial NO production • Anti-inflammatory action – Especially in vasculature • Decreased fibrinolysis • Growth
- 17. Mechanism of action of insulin
- 18. Insulin Mediated Glucose Transport G INS bb Insulin Receptor Complex INS bb subunit b subunit Insulin molecule Storage vesicle containing GLUT 4 Glucose Tyrosine Kinase Activation Metabolised Stored as Glycogen
- 19. Fate of insulin • Distributed only extracellularly • Must be given parenterally • Addition of zinc or protein decreases its absorption & prolongs the DOA • Insulin released from pancreas is in monomeric form • Half life of insulin = 5 -9 minutes
- 20. Different types of insulin preparations • Conventional preparations of insulin – Produced from beef or pork pancreas – 1 % of other proteins, Potentially antigenic • Highly purified insulin preparations – Gel filtration reduces proinsulin (50-200PPM) • Human insulins (Recombinant) • Newer insulin analogs
- 21. Conventional insulin preparations Type Onset (Hr) Peak (Hr) DOA (Hr) Short acting Regular insulin Semilente 0.5 -1 1 2-4 3-6 6-8 12-16 Intermediate acting Lente Isophane(NPH) 1-2 8-10 20-24 Long acting Ultra lente Protamine Zinc Insulin (PZI) 4-6 14-18 24-36
- 22. Highly purified insulin preparations • Single peak insulins – Purified by gel filtration contain 50 -200 PPM proinsulin – Actrapid: purified pork regular insulin – Monotard: purified pork lente – Mixtard: purified pork regular(30%) + isophane(70%) • Mono component insulins – After gel filtration purified by ion exchange chromatography contain 20 PPM proinsulin – Actrapid MC, Monotard MC
- 23. Human insulins • Human (Actrapid, monotard, insulatard, mixtard) • Obtained by recombinant DNA technology • Advantages – More rapid SC absorption , earlier & more defined peak – Less allergy • Disadvantages – Costly – Slightly shorter DOA
- 24. Indications of human insulin • Insulin resistance • Allergy to conventional preparations • Injection site lipodystrophy • During pregnancy • Short term use of insulin
- 25. Newer Insulin analogs Type Onset Peak (Hr) DOA (Hr) Rapid acting Lispro Aspart Glulisine 5-15 min 10-15 min 5-15 min 1 1 1 3-5 3-5 5-6 Long acting Glargine Detemir 1-2 hrs 2-3 hrs No peak 6-8 hr 24 hr 24 hr
- 28. Advantages of Insulin analogs over conventional insulins • Less nocturnal hypoglycemia • Less weight gain • More physiological action profiles • Less premeal lag time (0-15 mts) • Lispro & Glulisine even after meals • Better PP glucose control • Less intra-patient/inter-patient variability
- 29. Adverse effects of insulin • Hypoglycemia • Local reactions – Lipodystrophy – Lipoatrophy • Allergy • Obesity • Insulin induced edema
- 30. Uses of insulin • Diabetes mellitus – Must for type I diabetics – Can be used in type II diabetics • Diabetic ketoacidosis • Hyperosmolar non ketotic hyperglycemic coma
- 31. Indications of insulin in type II DM • Primary or secondary oral antidiabetic failure • Pregnancy • Perioperative period • CKD • Fasting > 300 mgms HbA1c > 10 • Diabetic Ketoacidosis in Type 2 DM
- 32. Diabetic Ketoacidosis Insulin deficiency Absolute / relative Counter hormone excess ↓ Anabolism ↑ catabolism ↓Peripheral utilization of Glucose Hyperglycemia Heavy Glucosuria (osmotic diuresis) Loss of water & electrolytes ↑ Glycogenolysis ↑ Glycolysis ↑Gluconeogenesis Dehydration + Hyperosmolarity ↓ Fluid intake
- 33. Pathogenesis of DKA (How ketoacidosis occurs) ↑ FFA to liver ↑ Acetyl coA ↓ Alkali reserve ↑ Lipolysis ↑ Acetoacetyl coA Acetoacetate b-Hydroxy butrate Acetone Hyperketonemia Acidosis
- 34. Treatment of DKA • Fluid therapy • Rapid acting regular insulin • Potassium • Bicarbonate • Phosphate • Antibiotics
- 35. Fluid therapy • Adequate tissue perfusion is necessary insulin action • Normal saline is fluid of choice for initial rehydration – 1 litre in first hour then reduced progressively to 0.5 L/ 4 hours (4 to 6 litres in 24 hours) • When BSL reaches 300 mg% fluid should be changed to 5 % dextrose with concurrent insulin
- 36. Insulin in DKA • Regular/ short acting insulin IV treatment of choice • Loading dose = 0.1-0.2 U/kg IV bolus • Then 0.1 U /kg/hr IV by continuous infusion • Rate doubled if no significant fall in BSL in 2 hr • 2-3 U/hr after BSL reaches 300mg% • If patient becomes fully conscious encouraged to take oral food & SC insulin started
- 37. Potassium replacement • 10 mEq/L potassium can be added with 3rd bottle of normal saline • Sr K+ < 3.3 mEq/L : 20 -30 mEq/hr
- 38. Bicarbonates & phosphates • Bicarbonates – If blood pH > 7.1 no need of sodium bicarbonate – In presence of severe acidosis 50 mEq of sodium bicarbonate added to IV fluid • Phosphates – Non availability of ideal preparation – Replacement not very essential unless < 1 mEq/L – potassium phosphate 5-10 m mol/hr
- 39. Newer insulin delivery devices • Prefilled insulin syringes • Pen devices • Jet injectors • Inhaled insulin (Affreza) • Insulin pumps • Insulin complexed with liposomes: intraperitoneal, rectal, oral
- 40. Non Insulin Parenteral drugs used in DM • Glucagon like Peptide 1 Analogs – Exenatide – Liraglutide • Amylin Mimetic Drugs – Pramlintide
- 41. Classification of Oral Antidiabetic drugs
- 42. Sulfonylureas • Mechanism of action – Release of insulin by acting on SUR1 receptors
- 43. Daily dose & Duration of action Sulfonylureas Doses No of doses/day DOA (hrs ) 1 Tolbutamide 0.5 – 2 g 2-3 6-8 2 Chlorpropramide 0.1 to 0.5 g 1 36 -48 3 Glibenclamide 5 to 15 mg 1-2 18-24 4 Gliclazide 40- 240 mg 1-2 12-24 5 Glipizide 5 to 40 mg 1-2 12-18 6 Glimepiride 1 to 6 mg 1 Upto 24
- 44. Individual Sulfonylurea Sulfonylureas Special points 1 Tolbutamide Short acting, low potency , hypoglycemia least likely 2 Chlorpropramide ↑Hypoglycemia, ↑ADH , Disulfiram Like Reaction, Cholestatic jaundice , longest acting 3 Glibenclamide Potent but slow acting 4 Gliclazide Antiplatelet, antioxidant action, may delay Retinopathy, less weight gain 5 Glipizide Fast acting, hypoglycemia & weight gain less likely 6 Glimepiride Long acting
- 45. Adverse effects • Hypoglycemia: • GI disturbances: Nausea, vomiting, metallic taste, diarrhoea & flatulence • Weight gain • Hypersensitivity • Chlorpropamide: – cholestatic jaundice, dilutional hyponatremia, disulfiram like reaction
- 46. Meglitinide analogs(repaglinide, nateglinide ) • Quick & short acting insulin releasers • MOA: same as Sulfonylureas but act through different receptor SUR2 • Mainly used to control Post prandial hyperglycemia • Cause less hypoglycemia
- 47. Biguanides • Metformin & phenformin • Little or no hypoglycemia • Also improves the lipid profile in type II diabetic patients • Metformin dose = 0.5 to 2.5 g/day in 2-3 divided doses
- 48. Mechanism of action of metformin • Suppress hepatic & renal gluconeogenesis – Inhibits AMP activated protein kinase enzyme • ↑ uptake & utilization of glucose by skeletal muscles which reduces insulin resistance • Inhibit alimentary absorption of glucose • Promotion of insulin binding to its receptors
- 49. METFORMIN - INDICATIONS • First line drug in Type 2 Diabetes • Obesity • Insulin resistance • Along with other antidiabetic drugs Sulfonylureas, Thiazolidinediones, Insulin.
- 50. Adverse effects • Anorexia, nausea, vomiting, diarrhoea • Metallic taste • Loss of weight • Skin rashes • Lactic acidosis: rare • Vitamin B12 deficiency: due to malabsorption Usually does not cause hypoglycemia even in large doses (Euglycemic drug)
- 51. Thiazolidinediones (Glitazones) Rosiglitazone & pioglitazone Selective agonists of PPAR Bind to nuclear PPAR Activate insulin responsive genes - regulate carbohydrate & lipid metabolism Sensitize the peripheral tissues to insulin ↓blood glucose by ↑ Glucose transport into muscle & adipose tissue Inhibit hepatic gluconeogenesis Promote lipogenesis
- 52. • Pioglitazone: – 15 to 45 mg once daily orally • Rosiglitazone: – 4 to 8 mg once daily orally • Monotherapy – Hypoglycemia rare
- 53. Adverse effects • Weight gain: due to fluid retention & edema • Worsening of CHF • Mild anemia • Hepatotoxicity : rare • Pioglitazone: bladder cancer
- 54. Alpha glucosidase inhibitors • Acarbose • Miglitol • Voglibose
- 55. Dietary Carbohydrates (Starch) glucosidase enzymes (in the lining of cells of intestinal villi) Pancreatic amylase Absorbed in lower part of intestine Monosaccharides (Glucose, fructose) Oligosaccharides/ Disaccharides Maltose, Isomaltose, Sucrose X Glucosidase inhibitors Mechanism of action
- 56. Adverse effects • Flatulence, diarrhoea, abdominal pain • Do not cause hypoglycemia by themselves but may cause if used with Sulfonylureas • If hypoglycemia occurs should not be treated with routine sugar (sucrose) but glucose • Contraindicated in inflammatory bowel disease & intestinal obstruction
- 57. DPP-IV Inhibitors • Dipeptidyl peptidase- 4 inhibitors – Sitagliptin : 100 mg OD before meals – Vidagliptin : 50 mg OD before meals • Adverse effects – Nasopharyngitis – Acute pancreatitis – Joint pain
- 58. Sodium Glucose cotransporter-2 (SGLT2 Inhibitors) •Canagliflozin: •Dapagliflozin: • Empaglifozin 90% 10% (180 g/day) (180 g/da y) (0 g/day)
- 59. SGLT-2 inhibitors • Advantages – Cause weight loss – No hypoglycemia – Improve insulin resistance – Diuretic effect beneficial in hypertension • Disadvantages: (Adverse effects) – Polyuria – Increased urinary infections – Risk of sodium loss
- 60. Effects of Diabetes Drugs Drug BW Dys- lipidemia Hypoglycemia Risk -glucosidase inhibitors Neutral Improved Low DPP-4 inhibitors Loss Improved Low GLP-1 agonists Loss Improved Low Insulin Gain Improved High Meglitinides Gain Not improved Moderate Metformin Loss Improved Low SGLT2 inhibitors Loss ? Low Sulfonylureas Gain Variable Moderate TZD Gain Improved Low Basile JN. J Diabetes Complications. 2013;27(3):280-286.
- 63. References • Essentials of Medical Pharmacology KD Tripathi • Basic and Clinical Pharmacology Katzung • ADA , STANDARDS OF MEDICAL CARE IN DIABETES—2020