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Genetic Determinants of Drug Response

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Genetic Determinants of Drug Response, Pharmacogenomics, Pharmacogenetics

  • See Also
  • Definition
  1. Genetic Polymorphism as it relates to medication response
  1. CYP2D6 Gene Variants
    1. Poor metabolizers (5-10%)
      1. No response (or reduced response) to Codeine, Tramadol
      2. Fluoxetine and Nortriptyline risk of toxicity
      3. Amitriptyline, Nortriptyline, Paroxetine risk of toxicity (reduce starting dose by 50%)
      4. Aripiprazole (Abilify) risk of toxicity (reduce starting dose)
      5. Atomoxetine (Strattera) risk of toxicity (reduce starting dose)
    2. Ultra-metabolizers (1-2%)
      1. Codeine risk of toxicity (deaths have occurred)
      2. Amitriptyline, Nortriptyline, Paroxetine with reduced response (consider other agents)
  2. CYP2C19 Gene Variants
    1. Poor metabolizers (2-15%)
      1. Clopidogrel with reduced conversion to active form (higher risk for stent closure)
      2. Amitriptyline and Nortriptyline risk of toxicity (reduce starting dose by 50%)
      3. Citalopram, Escitalopram, Sertraline risk of toxicity (reduce starting dose by 50%)
    2. Ultra-Metabolizers
      1. Citalopram, Escitalopram, Sertraline with reduced effect (consider alternative agents)
  3. CYP2C9 Gene Variants
    1. Poor metabolizers
      1. Reaching a steady-state INR on Coumadin requires >3 months
        1. Higher risk of toxicity and bleeding complications
  • Examples
  • HLA Variants
  1. HLA-B*1502
    1. Carbamazepine induced Stevens–Johnson syndrome risk in asian patients (test before use)
  2. HLA-B*5701
    1. Abacavir (HIV agent) induced Hypersensitivity risk in HLA-B*5701 positive patients
  • Examples
  • Miscellaneous genetic variants
  1. TPMT Deficiency
    1. Severe hematologic response to Azathioprine and mercaptopurine
  2. ADRB2 Variant
    1. Asthma status worsens on Inhaled Beta Agonist (e.g. Albuterol)
  • Efficacy
  1. Pharmacogenetic testing is indicated in specific cases
  2. Broader screening for pharmacogenetic variation is not yet supported by the Medical Literature in 2015
    1. Wang (2014) JAMA Intern Med 174(12):1938-44 +PMID:25317785 [PubMed]