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BMS > Genetic Variations in Individuals and Populations > Flashcards

Genetic Variations in Individuals and Populations Flashcards

1
Q

Optimizing drug therapies in the face of genetic variation

A

Pharmacogenetics and pharmacogenomics

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2
Q

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

A

Pharmacogenetics

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3
Q

Genetic variability can affect

A

Pharmacokinetics and pharmacodynamics

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4
Q

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

A

Pharmacokinetics

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5
Q

Drug activity and interaction with downstream targets

A

Pharmacodynamics

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6
Q

Pharmacogenetics encompasses

A
  1. ) Pharmacokinetics

2. ) Pharmacodynamics

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7
Q

A ‘genomic’ approach to pharmacogenetics –using GWAS to assess the impact of an ensemble of SNPs on the impact of drug therapy

A

Pharmacogenomics

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8
Q

Genome wide association study

A

GWAS

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9
Q

Single nucleotide polymorphism

A

SNPs

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10
Q

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

A

INR = PTobs / PTnormal

where,

PT = Prothrombin time

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11
Q

What is the normal Prothrombin Time (PT)?

A

11.0-13.5 seconds

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12
Q

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

A

Cytochrome P450 (CYP)

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13
Q

CYP’s can also activate

A

Drugs

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14
Q

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

A

CYPs

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15
Q

Phase I of drug metabolism by CYP is

A

Hydroxylation of molecule

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16
Q

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

A

Phase II of drug metabolism by CYP

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17
Q

Which CYPs react with Xenobiotics?

A

CYP 1, 2, and 3

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18
Q

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

A

Drugs

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19
Q

Which is the most active CYP in common drug metabolism?

A

CYP3A4

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20
Q

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

-2 million prescriptions per year

A

Warfarin (coumadin)

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21
Q

Impairs the synthesis of vitamin K dependent clotting factors

A

Warfarin (coumadin)

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22
Q

Warfarin inhibits a key enzyme in vitamin K recycling called

A

Vitamin K Epoxide Reductase

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23
Q

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

A

Five (C’s 4, 6, 7, 8, and 10)

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24
Q

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

A

S-Warfarin

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25
Q

There is significant variation in the individual activity levels of

A

Cytochrome P450s

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26
Q

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

A

Pharmacokinetics

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27
Q

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

A

Pharmacokinetics

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28
Q

Classified as poor, normal, or ultrafast metabolizers

A

CYP variants

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29
Q

Which CYP2C9 variant has a 25% dose reduction?

A

CYP2C9*2

30
Q

Which CYP2C9 variant has a 35% dose reduction?

A

CYP2C9*3

31
Q

What is the recommended target therapeutic range for INR?

A

INR = 2.0 - 3.0

32
Q

CYP variants are classified as

A

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

33
Q

In the CYP2C9 family, what is an extensive metabolizer?

A

Wild type: CYP2C911

34
Q

In the CYP2C9 family, what are intermediate metabolizers?

A

12 and 13 variants

35
Q

In the CYP2C9 family, what are poor metabolizers?

A

22, 23, and 33 variants

36
Q

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

A

Warfarin

37
Q

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

A

Coagulation factors

38
Q

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

A

Inhibition of VKORC1 by warfarin

39
Q

Single nucleotide polymorphisms (SNPs) in VKORC1 correlate with

A

Warfarin sensitivity

40
Q

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

A

Pharmacodynamics

41
Q

Deals with drug activity and interaction with downstream targets

A

Pharmacodynamics

42
Q

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

A

Linkage Disequilibrium

43
Q

Account for approximately 30% of variation in Warfarin sensitivity

A

VKORC1 + CYP2C9

44
Q

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

A

CYP4F2

45
Q

SNPs in CYP2C18 and CYP2C19 also correlate with a

A

Warfarin sensitivity

46
Q

Codeine intoxication is associated with ultra-rapid

A

CYP2D6 metabolism

47
Q

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

A

Gene duplication

48
Q

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

A

Optimal codeine dosage

49
Q

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

A

Morphine

  • 10%converted by CYP2D6
  • 80% cleared by CYP3A4
50
Q

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.

A

Candidate-gene studies

51
Q

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

A

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

52
Q

Encodes the main metabolizing enzyme for coumarin anticoagulants such as Warfarin

A

CYP2C9 gene

53
Q

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

A

VKORC1 and CYP2C9 genes

54
Q

Accounts for approximately 1.5% of warfarin dosage variability

A

CYP4F2 SNP

55
Q

When a higher dose is required for therapeutic affect

A

Tolerance

56
Q

When a lower dose is required for therapeutic affect

A

Intolerance/sensitivity

57
Q

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

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

A

Pharmacokinetics (PK)

58
Q

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

A

Pharmacodynamics

59
Q

Tells us how quickly our blood clots

A

Prothrombin time (PT)

60
Q

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

A

Toxic

61
Q

CYPs are mostly expressed in the

A

Liver

62
Q

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

A

CYP2D6

63
Q

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

A

Harmful

64
Q

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

A

S-warfarin

65
Q

Processed by CYP2C9 into 7-hydroxywarfarin or 6-hydroxywarfarin

A

S-Warfarin

66
Q

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

A

ABC transporters

67
Q

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

A

CYP2C9 interaction with Warfarin

68
Q

The safe therapeutiv window represents

A

Pharmacodynamic effects

69
Q

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

-requires 25% lower dosage

A

CYP2C9*2

70
Q

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

-requires 35% lower dosage

A

CYP2C9*3

71
Q

Gamma glutamyl carboxylation is necessary for

A

Coagulation

BMS (62 decks)

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