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Diabetic Disorders

Diabetic Disorders. 4 th Leading cause of deaths in the US 75% of those afflicted with diabetes die from CHD Major complications of diabetes Fearsome 15

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Diabetic Disorders

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  1. Diabetic Disorders • 4th Leading cause of deaths in the US • 75% of those afflicted with diabetes die from CHD • Major complications of diabetes • Fearsome 15 • Elevated triglycerides and LDL; reduced HDL; High blood pressure; obesity; kidney failure; blindness; peripheral neuropathy; decline in cognitive abilities; atherosclerosis; heart attack; stroke; peripheral vascular disease; poor wound healing; frequent infections MEDC 603 Fall 2006

  2. Diabetes Mellitus • Type I Diabetes • aka IDDM (Insulin-dependent diabetes mellitus) • Inability of b-islet cells of pancreas to produce insulin • Type II Diabetes • aka NIDDM (Non-insulin-dependent diabetes mellitus) • Either a reduced ability of pancreas to produce or secrete insulin (some residual capacity) and/or reduced ability of target cells to respond to insulin • Gestational Diabetes MEDC 603 Fall 2006

  3. Overview for Controlling Hyperglycemia Absorption from Diet Biosynthesis in Liver a-Glucosidase Inhibitors Biguanides Cellular Uptake Serum Sugar Biguanides; thiazolidinediones Sulfonylureas; Benzoic Acids Pancreas Insulin MEDC 603 Fall 2006

  4. Sulfonyl Ureas Ionization Mechanism of Action Stimulates release of insulin from b-cells Act through ion-channels that generate a Ca+2 influx Affinity to this receptor correlates with hypoglycemic effect In addition, there are extra-pancreatic effects, e.g., effects on glucose transporter MEDC 603 Fall 2006

  5. Structures of Sulfonyl Ureas R R’ Tolbutamide Chlorpropamide Tolazamide Glyburide Glipizide Glimepiride MEDC 603 Fall 2006

  6. Major Pharmacokinetic Properties of Sulfonyl Ureas MEDC 603 Fall 2006

  7. Substituted Benzoic Acids Meglitinide • Structural similarity to SUs • Functional similarity to SUs • More rapidly active • Shorter duration of action • Less problematic hypoglycemia • Reduced weight gain Replaglinide Nateglinide MEDC 603 Fall 2006

  8. Phenformin Metformin Biguanides Mechanism of Action (Metformin) Unclear Does not depend on insulin (synthesis or secretion) Anti-hyperglycemic (not hypoglycemic) Possibly two components: increased sugar usage and inhibition of gluconeogenesis MEDC 603 Fall 2006

  9. Thiazolidinediones (glitazones) R group Pioglitazone (racemic) Ciglitazone (racemic) Mechanism of Action Enhance glucose and lipid metabolism through action on PPARg Enhance sensitivity to insulin in target cells Troglitazone (racemic) Rosiglitazone (racemic) MEDC 603 Fall 2006

  10. Thiazolidinediones (glitazones) Some Metabolites Rosiglitazone Troglitazone Pioglitazone MEDC 603 Fall 2006

  11. a-Glucosidase Inhibitors - Acarbose Inhibitor of Sugar Absorption from the GI tract a-glucosidase MEDC 603 Fall 2006

  12. a-Glucosidase Inhibitors - Acarbose Transition State of hydrolysis Acarbose – transition state mimic MEDC 603 Fall 2006

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