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41 Cards in this Set
- Front
- Back
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What factors can influence drug response phenotype?
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Age
Gender Disease Genetic Variation |
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What is the promise of pharmacogenomics?
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that the knowledge of a patient's DNA sequence could be used to optimize drug efficacy and reduce adverse effects
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What are the three types of genetic variation that can influence pharmacotherapy?
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Variation in proteins involved in drug metabolism
Variation in drug targets (Variation in proteins associated with idosyncratic effects) |
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What is the most common factor responsible for pharmacogenetic variation in drug response?
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Genetic variation in enzymes that catalyze drug metabolism
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What are the major enzymes with polymorphisms relating to variation in drug metabolism?
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Butrylchilinesterase (BChE)
N-actyltransferase 2 (NAT2) Cytochrome P450 2D6 (CYP2D6) Thiopurine S-methyltransferase (TPMT) |
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What are the drug targets (pharmacodynamics) with relevant genetic polymorphisms?
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5-lipooxygenase
Epidermal Growth Factor Receptor |
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What does BChE do?
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Hydrolyses acetylcholine and its analogues
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What do variations in BChE produce?
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Decreased rate of metabolism in succinylcholine - this results in prolonged paralysis after drug exposure
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What does NAT2 do?
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Catalyzes the acetylation of isoniazid and other drugs
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What are the classifications of patients treated with isoniazid?
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Slow acetylators and Fast acetylators.
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What are slow acetylators?
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metabolize isoniazid slowly
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What is the blood concentration of isoniazid in a "slow acetylator"?
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High
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What are fast acetylators?
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metabolize isoniazid rapidly
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What is the blood concentration of isoniazid in a "fast acetylator"?
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Low
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Which NAT2 genotype is accociated with drug toxicities?
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Slow acetylators?
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What are toxicities that can result in NAT2 polymorphisms?
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Slow acetylators can get:
hydralazine induced lupus procainamide induced lupus isoniazid induced neurotoxicity |
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Why does slow acetylation of isoniazid lead to toxicities?
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In the slow NAT2 genotype, an alternate pathway of metabolism is used - CYP2E1 which produces hepatotoxins
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What are some examples of drugs that CYP2D6 metabolizes?
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antidepressants
antiarrhythmics analgesics |
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What are the phenotypes of the CYP2D6 genotypes?
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ultra-rapid metabolizer
extensive metabolizer (normal) poor metabolizer |
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What is the genotype of a poor metabolizer of CYP2D6?
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homozygous recessive for low activity in CYP2D6
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What is the genotype of an extensive metabolizer of CYP2D6?
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Heterozygous or homozygous for wild type allele
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What is unique about some ultra-rapid CYP2D6 metabiloizers?
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some have multiple copies of the CYP2D6 gene.
some can have up to 13 copies. |
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What ethnicity is more prone to CYP2D6 polymorphisms?
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5-10% of caucasians are poor metabolizers
only 1-2% of east asians are poor metabolizers |
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What are some specific drugs that CYP2D6 metabolizes?
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Metoprolol
Haloperidol Codeine and Dextromethorphan Fluoxetine, imipramine, desipramine |
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Which drug may be toxic in a poor metabolizer?
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Metoprolol
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Which drug may be ineffective in a poor CYP2D6 metabolizer?
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codeine because it requires conversion to morphine.
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What drug may be toxic in ultra-rapid CYP2D6 metabolizers?
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Codeine
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What does Thiopurine S-methyltransferase (TPMT) do?
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catalyzes the S-methylation of the anti-cancer drugs: thiopurine 6-meraptopurine and azathioprine
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What is the most common varient allele in Caucasions in TPMT?
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TPMT*3A - slow activity
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What are homozygotes of TPMT*3A at risk for developing?
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myelosuppresion with standard doses of thiopurine drugs
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What gene codes of 5-lipooxygenase?
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ALOX5 - it has VNTRs, with most common being 5. This is the wild type.
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What is the significance of being homozygous for repeat numbers other than the wild type for the gene coding for 5-lipooxygenase?
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Patients are less responsive to 5-lipooxygenase inhibitors. They do NOT have a higher incidence of asthma.
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What is often over-expressed in non-small cell lung cancer (NSCLC)?
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Epidermal Growth Factor Receptor (EGFR)
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What is Gefitinib?
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Inihbitor of tyrosine kinase of EGFR. Used to treat NSCLC.
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What is the significance of having a mutation in EGFR?
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Patients with mutations in the ATP-binding site of the tyrosine kinase domain of the receptor respond better to gefitinib.
East Asians respond more favorably than Caucasians |
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Why is Warfarin difficult to dose?
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It is a racemic mixture. The S form in more potent than the R form. The stereoisomers are also metabolized by different enzymes.
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What enzyme metabolizes S-warfarin?
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CYP2C9. Variants *2 and *3 have lower affinity than wild type *1.
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What is the consequence of having a variant allele in CYP2C9 with regards to warfarin dosage?
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Patients with varients *2 and *3 need lower doses for anicoagulant effect
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What is the molecular target of warfarin?
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vitamin K epoxide reductase
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What is the gene encoding for vitamin K epoxide reductase?
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VKORC1
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What is the significance of having polymoprhisms in the gene encoding for vitamin K epoxide reductase?
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Polymorphisms in VKORC1 is responsible for 25-30% of the differences in warfarin dose.
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