Pharm Pharmacogenetics (11)

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  1. Pharmacogenomics
    • the study of how genetic variations between individuals affect drug dispositions & responses
    • driven mainly by advances in technology, tools have become available to assess multigenic determinants of drug response across the entire genome
    • in the past it meant the study of the genetic basis for varieties in drug response, but it only dealt with a few genes at a time
  2. “Personalized” Medicine
    • medication optimization at the individual level
    • understanding how genetic polymorphisms affect drug response will allow clinicians to select the right drug at the right dose at the outset of therapy, optimizing therapeutic efficacy while minimizing toxicity
    • a possibility as the science of pharmacogenomics advances
  3. Succinylcholine (depo NMB)
    in most people only about 10% of the drug distributes to the NMJ b/c the remainder of the drug is metabolized to inactive metabolites by butyrylcholinesterase (BChE)

    HOWEVER people who have a genetic deficiency in the expression of BChE are more sensitive to succinylcholine
  4. Isoniazid
    • an antimyocobacterial agent commonly used as a prophylactic agent in people carrying latent tuberculosis
    • N-acetyltransferase metabolizes it to inactive metabolites (via acetylation)
    • SOME people have a genetic deficiency in the expression of this enzyme or their enzyme doesn't acetylate efficiently, making them more sensitive to isoniazid
    • these people have a heightened risk of toxicity (specifically neurotoxity) from isoniazid
  5. Primaquine
    • an antimalarial therapy that increases oxidative stress in RBCs
    • G6PD (glucose-6-phosphate dehydrogenase) protects most people from this effect

    SOME people have a genetic deficiency in G6PD, leading to an increased risk of hemolysis & hemolytic anemia when primaquine is taken
  6. When someone with a glucose-6-phosphate dehydrogenase (G6PD) deficiency takes Primaquine what condition develops?
    severe acute hemolytic anemia
  7. A patient is developing severe acute hemolytic anemia after taking the antimalarial drug Primaquine. What enzyme is likely deficient?
    glucose-6-phosphate dehydrogenase (G6PD)
  8. Polymorphisms
    • variations in DNA sequence present at an allele frequency of 1% or greater in a population
    • 2 main types of sequence variations are associated w/ phenotype alterations:

    • 1. single nucleotide polymorphisms (SNPs)
    • 2. insertions/deletions (indels)
  9. SNPs (single nucleotide polymorphisms)
    • single base pair substitutions
    • 1 is present in the human genome for every few hundred to thousand base pairs (depending on the gene region)
    • SNPs account for the majority of observed sequence variations between individuals
    • cSNPs = SNPs in a gene's coding region
    • a SNPs location in relation to a gene determines the effect it will have on said gene
  10. Indels (insertions/deletions)
    infrequent, especially in coding regions, but are more likely to produce a functional effect b/c bases are added or removed instead of substituted
  11. Type I Error
    when it is determined that a genetic polymorphism exists and is relevant to a paradigm when it actually ISN'T

    the effect of a polymorphism on a drug response must be replicated (through research) before applied clinically to avoid a type I error
  12. How do genetic polymorphisms mainly affect drug response?
    • 1. pharmacokinetically
    • 2. pharmacodynamically
    • 3. Other
  13. Effect of Polymorphisms on Pharmacokinetics
    polymorphisms in metabolizing enzymes or transporters alter the way the body handles a medication

    eg. over or under-expression of cytochrome P450 enzymes lead to increased or decreased metabolism of substrate drugs
  14. Effect of Polymorphisms on Pharmacodynamics
    polymorphisms can affect drug receptors & targets, therefore changing a drugs effectiveness

    • eg.
    • vitamin K epoxide reductase for warfarin

    angiotensin converting enzyme for ACE inhibitors

    HMG-CoA reductase for statins (lipid modifying agents)
  15. In what type of patient might a medication that contains estrogen (eg. birth control) be more difficult than usual to use?
    • patients who have a genetic polymorphism in a gene that makes them MORE likely to form coagulation factors in the blood
    • eg. a mutation in the prothrombin gene
    • if they're already predisposed to blood clots, something like the estrogen in birth control might further increase their risk
  16. A patient with a genetic defect in the way their ion channels work would not be a good candidate for what type of drug?
    • a potassium channel blocking anti-arrhythmic agent, such as quinidine
    • such a drug in a predisposed individual may increase the risk for a side effect like QT prolongation (a biomarker for ventricular tachyarrhythmias & a risk factor for sudden death)
  17. HER2/neu (Human Epidermal Growth Factor Receptor 2)
    • a mutated (of normal proteins) peptide made by breast tumor cells
    • if the tumor expresses HER2/neu, a monoclonal antibody called Herceptin can treat the cancer by binding to the surface peptide & killing cells that produce the mutated protein
  18. What is an example of a drug where polymorphisms can impact both its pharmacokinetics & pharmacodynamics?
    • Warfarin
    • CYP2C9 polymorphisms affects its pharmacokinetics (drug metabolism)
    • vitamin K epoxide reductase (VKOR) polymorphisms affect its pharmacodynamics
    • VKOR is an enzymes that activates clotting factors
    • there also tend to be non-genetic factors that also account for variability in drug response such as age, weight, gender, diet, co-morbidities, & other drug interactions
  19. CYP2C9
    • enzyme that metabolizes warfarin to hydroxywarfarin, its inactive metabolite
    • if a polymorphism causes this enzyme to be missing or less effective warfarin may accumulate & cause excessive bleeding → lower dose needed
    • if a polymorphism causes this enzyme to rapidly metabolize warfarin a larger dose might be needed for the drug to take effect
  20. vitamin K epoxide reductase (VKOR)
    • reduces vitamin K to its active form so it may act in the blood coagulation cascade
    • warfarin inhibits VKOR, preventing blood from clotting → thinning the blood
    • underactive/missing: less warfarin needed to exert a desired effect OR warfarin won't work at all because it has nothing to inhibit
    • overactive: a larger dose of warfarin needed to exert a desired effect
  21. What genes are most commonly associated with altered drug responses?
    those encoding transporter, enzyme, & receptor proteins

    • Enzymes:
    • Cytochrome P450 (eg. 2C9, 2C19, 2D6, 3A)
    • UGP-glucuronosyltransferase
    • Sulfotransferase
    • N-actetyltransferase

    Transporters: P-glycoprotein (MDR1)
  22. CYP450 2C19*3 Polymorphisms
    • 2-5% of Europeans & 18-23% of East Asians are poor metabolizers as a result of 2C19*3 polymorphisms
    • polymorphism → non-functioning 2C19*3 enzyme → drugs don't work

    clopidogrel (Plavix) an antiplatelet prodrug metabolized by 2C19*3 that inhibits the formation of blood clots to prevent stroke & MI

    omeprazole (Prilosec) is a proton pump inhibitor that treats reflux disease by inhibiting the 2C19*3 enzyme
  23. CYP450 2D6 Polymorphisms
    • polymorphisms of CYP2D6 tend to produce enzymes that ultra rapidly metabolize certain drugs such as antidepressants, antipsychotics, codeine, & tamoxifen
    • such polymorphisms can be found in 29% of Ethiopians, 1-5% of Europeans, & less than 2% of African American
  24. CYP2D6 & Codeine
    • a CYP2D6 polymorphism that turns someone into a rapid metabolizer results in conversion of more than the usual ~10% of codeine into morphine
    • giving a normal dose to a rapid metabolizer can result in morphine toxicity because they've converted more than a normal person would using their polymorphed CYP2D6 enzyme
  25. Why has adoption of pharmacogenetics into clinical practice been slow despite advances that have been made?
    • there's resistance to abandon the “trial and error” approach most clinicians are comfortable with
    • concerns about genetic discrimination
    • unfamiliarity with the principles of genetics
    • a lack of outcomes data
    • it's not affordable

    hypocrites: it is acceptable for clinicians to make drug dose adjustments based on changes in organ function (eg. liver or kidney) even in the absence of clinical outcomes data
  26. Pharmacogenetic Testing on Drug Labels
    • FDA approved medication labels are including more information on the use of pharmacogenetic testing
    • however few drugs are required or recommended for testing
    • pharmacogenomic biomarkers in drug labels are most often there for informational purposes, like for codeine, warfarin, or clopidogrel
  27. Abacavir (Ziagen)
    a nuceloside reverse transcriptase inhibitor used to treat HIV/AIDS

    patients who have a HLA-B*5701 gene polymorphism are more likely to suffer a hypersensitivity reaction to abacavir
  28. Cetuximab (Erbitux)
    a chimeric monoclonal antibody designed to treat certain types of cancers such as metastatic colon cancer or head & neck cancers
  29. What predicts the efficacy of Cetuximab (Erbitux)?
    • whether the Epidermal Growth Factor Receptor (EGFR) gene is expressed
    • if it is Cetuximab can target the receptor & kill the cell on which its located
  30. Azathioprine
    an immusupressant used for leukemia, inflammatory bowel disease, & other immunologic conditions

    if the TPMT*2 & *3 gene (a conjugating enzyme responsible for metabolism of azathioprine) polymorphism makes the enzymes less effective, toxicity may result due to production of a metabolite via an alternative metabolism pathway
  31. Ironotecan (Camptosar)
    a chemotherapy agent used to treat metastatic colon cancer

    a UGT1A1*28 gene polymorphism (a conjugating enzyme responsible for metabolism of ironotecan) may result in accumulation of a toxic metabolite (SN38)
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Pharm Pharmacogenetics (11)
2013-12-15 23:25:24
Exam 2
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