Flashcards in Lec Pharmacogenetics Deck (17):
What's the most common cause of genetic variation in drug response?
Single Nucleotide Polymorphisms
What is an SNP
Single BP change that alters the coding sequence of a particular gene
Derisoquin-sparteine polymorphism - Changes response to certain drugs (codeine, oxycodone, antidepressants and B blockers)
- Inactivate enzymes
- Higher in Asians and African Americans
- Leads to Loss of Function:
1. Increase efficacy of Proton Pump Inhibitors
2. Leads to loss of inhibition of platelet activity by clopidogrel
Reduced activity which slows down metabolism
- Sensitivity to Warfarin is reduced due to SNP in Viamin K epoxide reductase gene (VKORC1) (recylces Vitamin K and affects sensitivity to Warfarin).
Higher dose of Warfarin may be needed, need to do INR to measure prothrombin time for clotting
Antiarrhythmic Drug - If NAT2 doesn't work right procainamide is metabolized by FMO instead to become a toxic compound that may even trigger Lupus (drug-induced lupus)
What drugs are metabolized by NAT2?
Normally not toxic, with mutation of NAT2 you get production of a neurotoxic compound
Anesthesia lasts longer due to extension of duration of action for succinylcholine
What are "fast acetylators" at risk for?
Colon cancer as a result of increase metabolism of pro-carcinogens
Thiopurine Methyl Transferase
What does TPMT do?
Methylates 6-thioguanine nucleotides to inactivate them. Activity can be measured in RBC assays.
Also metabolizes Azathioprine, an immunosuppressant
Build up in life threatening 6-thioguanine nucleotides = myelosupression
Large gene, also called P-glycoprotein. Produces a membrane pump that facilitates the efflux of metabolites and drugs from cells. Also forms part of the blood brain barrier.
MDR-1 SNP Reactions
1. Silent SNP - Reduces the level of expression of the protein in the duodenum, causing lower plasma levels of anti-retroviral drugs and increased recovery of CD4 cell counts
2. Second SNP - Causes a substitution that enhances MDR-1 function
Beta-2-Adrenergic Receptor (ADRB2) polymorphism
Rapid desensitization by agonist in veins but increased bronchodilator response