Genetic Variations in Individuals and Populations Flashcards Preview

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Flashcards in Genetic Variations in Individuals and Populations Deck (71):
1

Optimizing drug therapies in the face of genetic variation

Pharmacogenetics and pharmacogenomics

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The study of inherited differences (variation) in drug metabolism and response

Pharmacogenetics

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Genetic variability can affect

Pharmacokinetics and pharmacodynamics

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Clearance/excretion, metabolism, transportation, and absorption of drug

Pharmacokinetics

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Drug activity and interaction with downstream targets

Pharmacodynamics

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Pharmacogenetics encompasses

1.) Pharmacokinetics
2.) Pharmacodynamics

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A 'genomic' approach to pharmacogenetics --using GWAS to assess the impact of an ensemble of SNPs on the impact of drug therapy

Pharmacogenomics

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Genome wide association study

GWAS

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Single nucleotide polymorphism

SNPs

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How do we find the international normalized ratio (INR)?

INR = PTobs / PTnormal

where,

PT = Prothrombin time

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What is the normal Prothrombin Time (PT)?

11.0-13.5 seconds

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56 enzymes, each encoded by a separate gene. All are heme-containing proteins expressed primarily in the liver. Responsible for detoxifying and exporting both endogenous and xenobiotic compounds

Cytochrome P450 (CYP)

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CYP's can also activate

Drugs

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Accept electrons from donors such as NADPH to catalyze a number of different reactions, most importantly the addition of oxygen to C, N, or S atoms

CYPs

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Phase I of drug metabolism by CYP is

Hydroxylation of molecule

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Functionalization of the hydroxyl group by a sugar or acetyl group, increasing drug solubility and allowing it to be excreted

Phase II of drug metabolism by CYP

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Which CYPs react with Xenobiotics?

CYP 1, 2, and 3

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Six genes in particular: CYP1, CYP1A1, CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 are responsible for the metabolism of 90% of commonly used

Drugs

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Which is the most active CYP in common drug metabolism?

CYP3A4

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Used in the prevention of thrombosis, embolism in cases of heart valve prosthesis, recurrent stroke, DVT, and pulmonary embolism

-2 million prescriptions per year

Warfarin (coumadin)

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Impairs the synthesis of vitamin K dependent clotting factors

Warfarin (coumadin)

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Warfarin inhibits a key enzyme in vitamin K recycling called

Vitamin K Epoxide Reductase

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How many major sites of modification by CYPs are there on warfarin?

Five (C's 4, 6, 7, 8, and 10)

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Warfarin metabolized in the liver cell by C7 hydroxylation or C6 hydroxylation by CYP2C9

S-Warfarin

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There is significant variation in the individual activity levels of

Cytochrome P450s

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Is the CYP2C9 interaction with warfarin considered a component of Pharmacokinetics or Pharmacodynamics?

Pharmacokinetics

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The action of drugs in the body over a period of time, including the processes of absorption, distribution, and localization in tissues

Pharmacokinetics

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Classified as poor, normal, or ultrafast metabolizers

CYP variants

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Which CYP2C9 variant has a 25% dose reduction?

CYP2C9*2

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Which CYP2C9 variant has a 35% dose reduction?

CYP2C9*3

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What is the recommended target therapeutic range for INR?

INR = 2.0 - 3.0

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CYP variants are classified as

Poor (PM), Normal (intermediate, IM), or Ultrafast (extensive, EM) metabolizers

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In the CYP2C9 family, what is an extensive metabolizer?

Wild type: CYP2C9*1*1

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In the CYP2C9 family, what are intermediate metabolizers?

*1*2 and *1*3 variants

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In the CYP2C9 family, what are poor metabolizers?

*2*2, *2*3, and *3*3 variants

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Vitamin K epoxide reductase (gene: VKORC1) is a target of

Warfarin

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Inhibition of VKORC1 by warfarin prevents regeneration of reduced vitamin K, which is necessary for gamma glutamyl carboxylation of

Coagulation factors

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Prevents regeneration of reduced vitamin K, which is necessary for gamma glutamyl carboxylation of coagulation factors

Inhibition of VKORC1 by warfarin

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Single nucleotide polymorphisms (SNPs) in VKORC1 correlate with

Warfarin sensitivity

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Is the VKORC1 interaction with warfarin considered a component of pharmacokinetics or pharmacodynamics?

Pharmacodynamics

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Deals with drug activity and interaction with downstream targets

Pharmacodynamics

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Combinations of alleles or genetic markers which occur more or less frequently than expected at random

Linkage Disequilibrium

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Account for approximately 30% of variation in Warfarin sensitivity

VKORC1 + CYP2C9

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Accounts for another 1-2% of warfarin sensitivity (according to a GWAS study of 2000 patients)

CYP4F2

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SNPs in CYP2C18 and CYP2C19 also correlate with a

Warfarin sensitivity

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Codeine intoxication is associated with ultra-rapid

CYP2D6 metabolism

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A study found that there are 3+ copies of the CYP2D6 allele, which indicates

Gene duplication

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It was then found that naturally occurring variation in CYP3A4 has no observable effect on

Optimal codeine dosage

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The combination of the gene duplication in CYP2D6 and the natural variation in CYP3A4 resulted in ultra-rapid conversion of codeine to

Morphine

-10%converted by CYP2D6
-80% cleared by CYP3A4

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Have provided valuable data in the areas of pharmacogenetics and pharmacogenomics. This is especially the case for adverse drug reactions attributable to alleles of a single gene, often one that encodes an enzyme contributing to metabolism of the
drug.

Candidate-gene studies

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What are some of the factors that have limited GWA studies to date?

Sample size, phenotypic characterization, replication of findings, and effect size

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Encodes the main metabolizing enzyme for coumarin anticoagulants such as Warfarin

CYP2C9 gene

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Markers in which two genes are the main predictors for coumarin dosage?

VKORC1 and CYP2C9 genes

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Accounts for approximately 1.5% of warfarin dosage variability

CYP4F2 SNP

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When a higher dose is required for therapeutic affect

Tolerance

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When a lower dose is required for therapeutic affect

Intolerance/sensitivity

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Has nothing to do with the mechanism of action of the drug.

-Just tells us how well the drug gets to its target

Pharmacokinetics (PK)

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Tells us about the drugs activity and how well it interacts with its downstream targets

Pharmacodynamics

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Tells us how quickly our blood clots

Prothrombin time (PT)

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The therapeutic window is an INR of 2-3, below the therapeutic window, the drug is not helpful. Above the therapeutic window, the drug is

Toxic

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CYPs are mostly expressed in the

Liver

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CYPs can activate drugs, an example of this is the activation of codeine to morphine by

CYP2D6

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The conversion of acetometophin to N-Acetyl-P-Benzoquinone imine by CYP3A4 is an example of how CYPs can be

Harmful

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We are given a racemic mixture of Warfarin, but which isomer is more active?

S-warfarin

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Processed by CYP2C9 into 7-hydroxywarfarin or 6-hydroxywarfarin

S-Warfarin

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Multi-drug transporters that will push all xenobiotics out of the cell

ABC transporters

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An example of pharmacokinetics because it deals with how the drug is distributed and how it is processed

CYP2C9 interaction with Warfarin

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The safe therapeutiv window represents

Pharmacodynamic effects

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An Arg-->Cys mutation that results in reduced affinity for P450 reductase, which makes you more sensitive to Warfarin

-requires 25% lower dosage

CYP2C9*2

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An Ile-->Leu mutation that alters substrate specificity of CYP2C9 and will make you more sensitive to Warfarin

-requires 35% lower dosage

CYP2C9*3

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Gamma glutamyl carboxylation is necessary for

Coagulation

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