Diabetic Disorders
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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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Hypoglycemicagents2006

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


Hypoglycemicagents2006

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


Hypoglycemicagents2006

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


Hypoglycemicagents2006

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


Hypoglycemicagents2006

Structures of Sulfonyl Ureas

RR’

Tolbutamide

Chlorpropamide

Tolazamide

Glyburide

Glipizide

Glimepiride

MEDC 603 Fall 2006


Hypoglycemicagents2006

Major Pharmacokinetic Properties of Sulfonyl Ureas

MEDC 603 Fall 2006


Hypoglycemicagents2006

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


Hypoglycemicagents2006

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


Hypoglycemicagents2006

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


Hypoglycemicagents2006

Thiazolidinediones

(glitazones)

Some Metabolites

Rosiglitazone

Troglitazone

Pioglitazone

MEDC 603 Fall 2006


Hypoglycemicagents2006

a-Glucosidase Inhibitors - Acarbose

Inhibitor of Sugar Absorption from the GI tract

a-glucosidase

MEDC 603 Fall 2006


Hypoglycemicagents2006

a-Glucosidase Inhibitors - Acarbose

Transition State of hydrolysis

Acarbose – transition state mimic

MEDC 603 Fall 2006


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