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Endocrinology Drug Introduction
  • Endocrine medications can be broken down into the following categories
    • Diabetic Agents
    • Hormone Agonists
    • Hormone Antagonists
 
Overview
  • Goals of diabetes treament
    • lower serum glucose to physiologic range
    • keep insulin levels in physiologic range
    • eliminate insulin resistance
  • Modalities of diabetes treatment
    • type I DM
      • insulin
      • low-sugar diet
    • type II DM
      • exercise
      • diet
      • insulin
      • 6 classes of drugs shown below
Class
Example
↑ Insulin secretion
↑ Insulin utilization
↓ Glucose production ↓ Glucose absorption Weight

Hypoglycemia

Insulin Insulin         ++
Sulfonylureas Glyburide ++ + +   ++
Biguanides Metformin   + ++     None
Glitazones(thiazolidinediones) Pioglitazone   ++ +/-   ↑↓ +
α-glucosidase inhibitors Acarbose       ++   None
GLP-1 mimetics (incretin mimetics) Exenatide ++   +   +
Amylin analog Pramlintide +   +     +

 

Insulin
  • Insulin is only given parenterally (subcutaneous or IV)
  • Various preparations have different durations of action
    Preparation
    Onset (hrs)
    Peak (hrs)
    Duration (hrs)
    Lispro (short-acting) 15 min 0.5-1.5 3-4
    Regular (short-acting) 0.5-1 2-4 5-7
    NPH (intermediate) 1-2 6-12 18-24
    Glargine (long-acting) 1 None >24
    Other preparations include aspart (short), detemir (long)
  • Mechanism
    • bind transmembrane insulin receptor
      • activate tyrosine kinase
      • phosphorylate specific substrates in each tissue type
    • liver
      • ↑ glycogenesis
        • store glucose as glycogen
    • muscle
      • ↑ glycogen and protein synthesis
      • ↑ K+ uptake
    • fat
      • increase triglyceride storage
  • Clinical use
    • type I DM
    • type II DM
    • life-threatening hyperkalemia
      • increases intracellular K+
    • stress-induced hyperglycemia
  • Toxicity
    • hypoglycemia
    • hypersensitivity reaction (very rare)

 

Sulfonylureas
  • Drugs
    • first generation
      • tolbutamide
      • chlorpropamide
    • second generation
      • glyburide
      • glimepiride
      • glipizide
  • Mechanism
    • glucose normally triggers insulin release from pancreatic β cells by increasing intracellular ATP
      • → closes K+ channels → depolarization → ↑ Ca2+ influx → insulin release
    • sulfonylureas mimic action of glucose by closing K+ channels in pancreatic β cells
      • → depolarization → ↑ Ca2+ influx → insulin release
    • continued use results in
      • ↓ glucagon release
      • ↑ insulin sensitivity in muscle and liver
  • Clinical use
    • type II DM
      • stimulate release of endogenous insulin
    • cannot be used in type I DM due to complete lack of islet function
  • Toxicity
    • first generation
      • disulfiram-like effects
        • especially chlorpropamide
    • second generation
      • hypoglycemia
    • weight gain

 

Biguanides
  • Drugs
    • metformin
  • Mechanism
    • ↓ gluconeogenesis
      • exact mechanism unknown
      • appears to inhibit complex 1 of respiratory chain
    • may also
      • ↑ insulin sensitivity
      • ↑ glycolysis
      • ↓ serum glucose levels
    • ↓ postprandial glucose levels
  • Clinical use
    • type I and II DM
  • Toxicity
    • no hypoglycemia
    • no weight gain
    • lactic acidosis is most serious side effect 
      • contraindicated in renal failure

 

Glitazones (thiazolidinediones)
  • Thiazolidinediones, also known as the "-glitazones"
  • Drugs
    • pioglitazone
    • rosiglitazone
  • Mechanism
    • bind to nuclear receptors involved in transcription of genes mediating insulin sensitivity
      • peroxisome proliferator-activating receptors (PPARs)
    • ↑ insulin sensitivity in peripheral tissue
    • ↓ gluconeogenesis
    • ↑ insulin receptor numbers
    • ↓ triglycerides
  • Clinical use
    • type II DM
      • as monotherapy or in combination with other agents
  • Toxicity
    • weight gain
    • edema
    • hepatotoxicity
    • CV toxicity
    • less risk of hypoglycemia vs. sulfonylureas

 

α-glucosidase inhibitors
  • Drugs
    • acarbose
    • miglitol
  • Mechanism
    • inhibit α-glucosidases in intestinal brush border
      • delayed sugar hydrolysis
      • delayed glucose absorption
      • ↓ postprandial hyperglycemia
      • ↓ insulin demand
  • Clinical use
    • type II DM
      • as monotherapy or in combination with other agents
  • Toxicity
    • no hypoglycemia
    • GI upset

 

Amylin mimetics
  • Drugs
    • pramlintide
  • Mechanism
    • synthetic analogue of human amylin that acts in conjunction with insulin
      • basis for drug mechanism is the observation that more insulin secreted with oral glucose load compared to IV 
    • ↓ release of glucagon
    • delay gastric emptying
  • Clinical use
    • type I and II DM
  • Toxicity
    • hypoglycemia
      • if given with insulin
    • nausea
    • diarrhea

 

GLP-1 analogs
  • Drugs
    • exenatide
  • Mechanism
    • GLP-1 is an incretin released from the small intestine that aids glucose-dependent insulin secretion
    • exenatide is a GLP-1 agonist
      • ↑ insulin
      • ↓ glucagon release
    • the class of dipeptidyl peptidase inhibitors ↓ degradation of endogenous GLP-1
      • e.g.) -gliptins
  • Clinical use 
    • type II DM
    • patients requiring two drugs and looking to lose weight
      • administer metformin and exenatide 
  • Toxicity
    • nausea, vomiting
    • pancreatitis
    • hypoglycemia
      • if given with sulfonylureas
 

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