Pharmacogenetics

Question 1

How do genetic polymorphisms influence drug responses?

Answer 1

• genetic mutations in drug-metabolizing enzyme genes cause altered pharmacologic response
• SNPs are most common form of polymorphic genetic variation in drug response

Question 2

Define haplotype.

Answer 2

set of SNPs (single nucleotide polymorphisms) that are inherited as a block

Question 3

What are some major genetic influences that affect drug metabolism (Phase I enzymes)?

Answer 3

• CYP2D6 mutations
  
  • mutations that reduce metabolic activity; ex. increased analgesia from codeine
  • mutations that increase metabolic activity; ex. decreased analgesia from codeine
• CPY2C19 mutations
  
  • inactivate enzyme
  • low incidence, higher incidence in Asians and AAs
  • clinical relevance of mutation
    
    • omeprazole: increases its effectiveness
    • clopidogrel: anti-platelet pro-drug, not converted to active form when CYP2C19 is mutated
• CYP2C9 mutations
  
  • ​polymorphisms lead to reduced enzyme activity
  • clinically relevant substrates:
    
    • warfarin, losartan
• Pseudocholinesterase polymorphism
  
  • ​plasma enzyme that metabolizes ACh and succinylcholine
  • extends the duration of action of succinylcholine (anasthesia drug)

Question 4

What are some major genetic influences that affect drug metabolism (Phase II enzymes)?

Answer 4

• Acetylation (NAT2)
  
  • ​acetylates polycyclic amines and other substrates: isoniazid, procainamide, caffeine, dapsone, hydralazine, histamine
  • mutation can render enzyme ineffective (slow acetylators)
  • clinical relevance:
    
    • Isoniazid (TB drug): can alternatively metabolize down minor pathway into toxic compound if NAT2-mediated pathway cannot occur
    • Procainamide (anasthetic, HR): can alternatively metabolize down minor pathway into immune-toxic compound if NAT2-mediated pathway cannot occur –> Lupus, high ANA levels
    • smokers w/ this mutation have increased risk for cancers b/c carcinogens are less likely to be metabolized
• Methylation (Thiopurine methyl transferase- TPMT)
  
  • methylates 6MP (cancer) and azathioprine (immunosuppresive)
  • homozygous mutants lack detectable TMPT activity
  • clinical relevance:
    
    • loss of TPMT leads to increased toxic metabolute of TPMT (6-TGN)

Question 5

What are some major genetic influences that affect drug metabolism (drug receptors)?

Answer 5

• MDR-1/P-glycoprotein gene​
  
  • membrane pump that
  • clinical relevance of mutation facilitates efflux of drugs and metabolites out of cells:
    
    • lower plasma levels of anti-retroviral drugs and increased recovery of CD4 cell counts
    • altered plasma levels of fexofidine
• **ß₂ adrenergic receptor gene **
• Arachidonate 5-lipogenase (5-LOX)
  
  • ​mutation causes reduced incidence in asthma
• **Vitamin K epoxide reductase (VKORC1) **
  
  • critical for regulation of blood clotting
  • clinical relevance: mutation could decrease sensitivity to warfarin