Pharmacogenetics/pharmacogenomics

Front 1

definition of pharmacogenetics/pharmacogenomics?

Back 1

investigation of variations in DNA sequence and RNA sequences/characteristics as related to drug response and toxicity

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consequences of genetic polymorphisms?

Back 2

increased risk of adverse effects, lack of efficacy, enhanced efficacy, increase or decreased susceptibility to pathological agents

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difficulty of prescribing meds for children?

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genes may not express the same as if they were an adult

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4 drugs that have explicit recommendations for using pharmacogenetic info to improve efficacy and safety?

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6-mercaptopurine, irinotecan, tamoxifen, abacavir

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phenotype or genotype determinations easier and more valuable?

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genotype: amplify gene of interest without need of specific probe, invasiveness, or confounding by diet, disease, etc

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genetic basis of slow acetylators?

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SNP in one or both of alleles for NAT2 (N-acetyltransferase) gene

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acetylation polymorphism is often seen with?

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ethnicity differences

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slow acetylators treated with isoniazid and hydralazine?

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peripheral neuropathy more common

Front 9

slow acetylators treated with procainamide and hydralazine?

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drug-induced lupus and ANA development more common

Front 10

slow acetylators treated with sulfonamides?

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hypersensitivity reactions more common

Front 11

rapid acetylators treated with amonafide?

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myelosuppression more common

Front 12

slow acetylators and smoking?

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urinary bladder cancer more common

Front 13

thiopurine-s-methyltransferase?

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cytosolic enzyme that catalyzes s-methylation (deactivation) of anticancer and antiinflammatory drugs such as mercaptopurine and azathioprine

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thiopurine-s-methyltrasferase genetic polymorphisms?

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deficient as AR, variant alleles with reduced stability/catalytic activity

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thiopurine-s-methyltransferase deficient patients treated with thiopurines?

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AR: severe hematopoietic toxicity;
heterozygous: increased risk of toxicity

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UGTs (uridine diphosphate glucuronyltransferase)?

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glucuronidation of bilirubin as well as vrious drugs and xenobiotics

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lower than normal UGT activity?

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gilbert's syndrome

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genetic polymorphism in UGT?

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TA repeats in proximal promoter vary from 5-8 in length; lower the number of repeats, the more efficient the trxnal activity of the gene

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allele associated with gilbert's syndrome?

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UGT1A1*28

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UGT1A1 polymorphism treated with irinotecan?

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increased toxicity (myelosuppression and diarrhea)

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FDA-required package insert for irinotecan?

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homozygous for UGT1A1*28 alleles are at increased risk for neutropenia

Front 22

which drug does FDA have required package insert and pharmacogenetic test to identify these individuals?

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irinotecan

Front 23

consequences of CYP2D6 poor metabolizer phenotype?

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accumulation of parent drug for a number of beta-blockers, antiarrhythmics, tricyclic and atypical antidepressants, and neuroleptics

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CYP2D6 poor metabolizer treated with tamoxifen?

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decreased metabolism to active drug; independent predictor of breast cancer outcome in post-menopausal women receiving tamoxifen for early breast cancer

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CYP2D6 poor metabolizer treated with codeine?

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less metabolism to morphine leading to therapeutic failure

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CYP2D6 poor metabolizer treated with phenacetin?

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shift of metabolism to alternate and more toxic pathways

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CYP2C9?

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oxidation of S-warfarin, sulfonylureas, phenytoin

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variant CYP2C9 treated with warfarin?

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reduced oxidation of warfarin leading to higher blood concentration and risk of bleeding complications

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2 important drug oxidation polymorphisms?

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CYP2D6, CYP2C9

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variant allele for serum cholinesterase?

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change in critical aa in substrate binding site causing reduced affinity for succinylcholine

Front 31

serum ChE polymorphism treated with succinylcholine?

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reduced hydrolyzation leading to succinylcholine apnea

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variant associated with abacavir hypersensitivity?

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HLA-B variants

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clinical consequence of β2 agonists on β2 receptor polymorphism?

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bronchodilation, susceptibility to agonist induced desensitization, cardiovascular effects

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P-glycoprotein variant effect?

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altered drug disposition and response of anticancer drugs and cardiac glycosides