questions 3

Diabetes Drugs

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Topic updated on 10/04/17 10:01am

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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Qbank (1 Questions)

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(M2.EC.21) A 52-year-old woman comes to your clinic for her annual physical exam. She is obese, does not exercise, and regularly eats fried foods. A random blood glucose is 249 mg/dL. Her hemoglobin A1C is 9.5. Which of the following treatments would be weight neutral or cause weight loss in this patient? Topic Review Topic

1. Glargine
2. Glyburide
3. Pioglitazone
4. Metformin
5. Glipizide

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