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14 Cards in this Set
- Front
- Back
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Definitions:
-Pharmacogenetics -Pharmacogenomics |
Pharmacogenetics = study of single genetic variations (SNPs) and their role in determining individual pharmacokinetic (metabolism) and pharmacodynamic response to a drug
-------------------------------------- Pharmacogenomics = study of ALL gene variants/polymorphisms that influence patient response to given drug |
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Human Genome
-difference amongst individuals -difference is due to? -what is a SNP? -sequence polymorphism consequences |
Any two individuals - 99.5-99.9% similar
-SNPs -Non-SNP variation (insertions, deletions, inversions, copy number variations, segmental duplications) -------------------------------------- Sequence polymorphisms (SNPs) in regulatory/promoter region, exon-intron boundaries, or coding region can affect phenotype --> predispose to disease or alter individual drug response -------------------------------------- SNP must occur in at least 1% of population (if less --> mutation) |
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Traits
-two types -their distribution |
Monogenic
-phenotypic variation due to single gene -bimodal (one allele dominant over the other - heterozygous and homozygous phenotype) -trimodal (codominance - heterozygote = intermediate phenotype) -------------------------------------- Polygenic -phenotype determined by 2 or more genes (w/ 2 or more alleles each) -wide unimodal (bell-shape) distribution |
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Potential genes targeted by SNPs to modify patient drug response
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-metabolizing enzymes
-transporters -target proteins |
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Pharmacogenetic Studies
-phenotype-driven -genotype-driven (advantages & disadvantages) |
Phenotype-driven (forward)
-identify unusual response phenotypes in population (usually ADRs) then identify genes implicated -monogenic traits for ADRs often metabolism-related --> readily phenotyped (measure metabolites in urine to determine phenotype) -HOWEVER, most drug responses are polygenic -------------------------------------- Genotype-driven (pharmacogenomics - exact opposite of pharmacogenetics) -Look at genotype variations first then give drug & phenotype them -Genome SNPs are stable (data doesn't change) -personalized medicine - look at pt SNP profile to determine drug response -need large database -w/ polygenic traits - genotype doesn't always predict phenotype |
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CYP2D6 and CYP2C9
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Responsible for metabolism of most drugs
Different alleles --> different level of activity --> different drug response Genotyping patient useful |
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Isoniazid
-metabolism -genetic variation |
Metabolized by N-acetyltransferase-2 (NAT2)
-slow and fast acetylators -------------------------------------- Fast acetylators -NAT2 w/ normal(full) activity --> therapeutic response Slow acetylators -weak or inactive enzyme --> high drug levels --> neurotoxicity |
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Imipramine
-metabolism -genetic variation |
CYP2D6 metabolism
Variation in CYP2D6 -poor metabolizers = 25% normal dose (can get ADRs) -extensive metabolizers = good efficacy -ultra-rapid metabolizers = 180% normal dose |
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Codeine
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CYPD2D6 metabolism from prodrug to active morphine
Poor metabolizers - low efficacy, prodrug accumulates Extensive metabolizers - good efficacy, rapid therapeutic onset |
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Haloperidol
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CYPD2D6 metabolism to inactive metabolite
Poor metabolizers - tardive dyskinesia Extensive metabolizers - better therapeutic effect, less extrapyramidal symptoms |
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6-mercaptopurine (thiopurine)
-what is it? -MOA -metabolism |
Cancer drug used to treat lymphoblastic leukemia
Converted into nucleotide by HPRT - incorporated into DNA --> blocks replication --> cell death -------------------------------------- TPMT converts drug into inactive metabolite Some have variant allele --> poor metabolism --> elevated levels --> toxicity (lethal myelosuppression) FDA recommends genotyping to guide dosing |
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Warfarin (coumadin)
-testing for initial dosing |
Anti-clotting drug; 30% pts at increased risk for bleeding
Nanosphere genetic test - looks at CYP2C9 and VKORC1 alleles -VKORC1 is enzyme regenerated reduced vit. K cofactor - warfarin blocks it -CYP2C9 metabolizes drug Nomogram - dose depends on which VKORC1 and CYP2C9 alleles are present |
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5-Fluorouracil (5-FU)
-use -MOA -metabolism -gene polymorphisms |
Solid tumors (breast, colorectal)
Uracil analogue; prodrug converted to 5-FdUMP --> inhibits thymidylate synthase (required for denovo pyrimidine synthesis) -------------------------------------- Dihydropyrimidine dehydrogenase (DPD) -pts w/ low DPD activity --> low 5-FU metabolism --> toxic accumulation Thymyidylate synthase (TS) -triple tandem repeat polymorphism --> higher TS activity --> lower response to 5-FU |
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Adrenergic receptor polymorphisms
-A2c -B1 -Bucindolol |
A2c (presynpatic)
-deletion --> decreased activity --> increased NE release B1 -gly-->arg increases function Homozygotes for A2c and B1 polymorphisms --> 10x increase risk for CHF -------------------------------------- Bucindolol used for treating B1 homozygotes - decreased hospitalization & mortality |
