Drugs 14

• pharmacogenomics


  effect of genetic differences in multiple genes across the genome on drug response
• how gene influence drugs PK

  altering expression or function of proteins involved in ADME of drug, to much or to little drug at site of action
• how genes influence drugs PD

  altering expression or function of drugs target (receptors) or their downstream pathways, increase or decrease effect from drug
• polymorphic gene


  monogenic variant of population level, greater than 1%
• SNPs


  single base mutation (polymorphism), frequency increase if advantageous
• sites of SNPs


  upstream regulatory regions (promotor or enhancer) - change expression of proteins

  coding region (exons) - change activity of protein
• favism 


  after eating fava beans some people jaundice and had red urine was a result of haemolytic anaemia
• cause of favism


  due to G6PD deficiency, the gene is highly polymorphic and changes activity of enzyme
• what dose G6PD do

  catalyses first reaction of pentose phosphate pathway, produces NAPDH which provides reducing power in cells via glutathione (used to reduce oxidised drugs)
• RBCs and G6PD deficiency

  RBCs carry oxygen, risk of free radical damage so rely on G6PD, NAPDH, glutathione for protection. G6PD deficiency causes acute haemolytic due to oxidative stress
• N-acetyltransferase (NAT2) polymorphism


  slow acetylators risk of hepatotoxicity and peripheral neuropathy fast have lower drug bioavailability and poor response
• isoniazid 


  anti TB drug, eliminated by acetylation
• abacavir 


  HIV-1 reverse transcriptase inhibitor, 5% patients serious hypersensitivity reaction immune mediated antigen presentation so must phenotype