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Treatment of diabetes mellitus

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Treatment of diabetes mellitus

  1. 1. Treatment of Diabetes Mellitus Dr. Salman Iftikhar Department of Pharmacology
  2. 2. Diabetes Mellitus • Type 1 (IDDM): – Early onset – Loss of pancreatic B cells  absolute dependence on insulin – Ketoacidosis – prone • Type 2 (NIDDM) – Usually adult onset –  response to insulin – Not Ketoacidosis – prone
  3. 3. Insulin
  4. 4. Oral antidiabetic Agents
  5. 5. Insulin sectretagouges
  6. 6. Sulfonylureas
  7. 7. Sulfonylureas • Mechanism – The acute action of sulfonylureas is to block K+ channels  depolarization  insulin release • Effects of increased insulin –  glucagon release from pancreatic  cells
  8. 8. Sulfonylureas • Acetohexamide (active metabolite,  dose in renal dysfunction) • Tolbutamide (appropriate in renal dysfunction) • Chlorpropamide (long acting, SIADH/disulfiram reaction) • Glipizide ( dose in hepatic dysfunction) • Glyburide (active metabolite,  dose in renal dysfunction)
  9. 9. Sulfonylureas • Adverse effects: – Hypoglycemia – Weight gain – Hypersensitivity (possible cross allergy with sulfonamides) – Drug interactions mainly with first- generation drugs  hypoglycemia with cemetidine, insulin, sulfonamides, salicylates
  10. 10. Meglitinide Drugs • Repaglinide and nateglinide – rapidly absorbed and promptly produce a hypoglycemic effect of short duration – Mechanism is same as sulfonylurea compounds – Taken before meals – Used in combination with metformin but not with other antidiabetics or insulin
  11. 11. Insulin Sensitizing Agents
  12. 12. Metformin • “Euglycemic”,  postprandial glucose levels but does not cause hypoglycemia or weight gain • May involve  tissue sensitivity to insulin and/or  hepatic gluconeogenesis • Adverse effects: possible lactic acidosis; gastrointestinal distress is common
  13. 13. Thiazolidinediones Pioglitazone & Rosiglitazone
  14. 14. • Mechanism: – Bind to nuclear peroxisome proliferator-activating receptors (PPARs) involved in transcription of insulin responsive genes  sensitization of tissues to insulin, plus  in hepatic gluconeogenesis and triglycerides and  insulin receptor numbers – Adverse effects: less hypoglycemia than sulfonylureas, but weight gain and edema reported – pioglitazone may be associated with a slightly increased risk of bladder cancer – Increase the risk of osteoporosis and fractures in older women
  15. 15. Acarbose • No hypoglycemia • Mechanisms: inhibits  glucosidase in brush borders of small intestine   formation of absorbable carbohydrate   postprandial glucose   demand for insulin • Adverse effects: GI discomforts, flatulence and diarrhea; recent concerns over potential hepatotoxicity
  16. 16. New Drugs Amylin Mimetic Incretin Mimetics
  17. 17. PRAMLINTIDE • Synthetic analog of amylin • Injectable: modulates postprandial glucose levels • Suppresses glucagon release via undetermined mechanisms, delays gastric emptying, and has central nervous system- mediated anorectic effects • Administered in addition to insulin in those who are unable to achieve their target postprandial blood sugars
  18. 18. • Renal metabolism and excretion • Always be injected by itself with a separate syringe; it cannot be mixed with insulin • Adverse effects: hypoglycemia and gastrointestinal symptoms including nausea, vomiting, and anorexia. PRAMLINTIDE
  19. 19. EXENATIDE • A synthetic analog of glucagon-like-polypeptide 1 (GLP-1), exenatide is the first incretin therapy to become available for the treatment of diabetes • Approved as an injectable, adjunctive therapy in persons with type 2 diabetes treated with metformin or metformin plus sulfonylureas who still have suboptimal glycemic control • Multiple actions – potentiation of glucose-mediated insulin secretion – Suppression of postprandial glucagon release through as- yet unknown mechanisms – slowed gastric emptying, and a central loss of appetite – The increased insulin secretion is speculated to be due in part to an increase in beta-cell mass
  20. 20. • Adverse effects are nausea (about 44% of users) and vomiting and diarrhea. The nausea decreases with ongoing exenatide usage • Weight loss is reported in some users, presumably because of the nausea and anorectic effects. A serious and, in some cases, fatal adverse effect of exenatide is necrotizing and hemorrhagic pancreatitis. • Safety issues, however, may deter future use. EXENATIDE
  21. 21. SITAGLIPTIN • Inhibitor of dipeptidyl peptidase-4 (DPP-4), the enzyme that degrades incretin and other GLP-1-like molecules • Its major action is to increase circulating levels of GLP- 1 and GIP.
  22. 22. • Decreases postprandial glucose excursions by increasing glucose-mediated insulin secretion and decreasing glucagon levels • Adverse effects include – nasopharyngitis, upper respiratory infections, and headaches. Rarely, severe allergic reactions • Dosage should be reduced in patients with renal impairment. Sitagliptin can be given as monotherapy or combined with metformin or Tzds.
  23. 23. BLOOD
  24. 24. • A patient takes nateglinide before each meal. Which mechanism is responsible for the therapeutic effect of this drug? A. closing of potassium channels B. slowed gastric emptying C. inhibition of α-glucosidase D. inhibition of DPP-4 E. insertion of glucose transporters in cell membranes