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Pharmacology COPY > EXAM #5: PHARMACOGENOMICS > Flashcards

EXAM #5: PHARMACOGENOMICS Flashcards

1
Q

What is the monogenic drug response?

A

Variation in a SINGLE gene that alters a drug response

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2
Q

What is a multigenic drug response?

A

Variation in MULTIPLE genes alters drug response

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3
Q

What is the “gene-by-environment” phenotype?

A

General principle that drug response is an interplay between environment and genetic factors

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4
Q

What is the definition of a polymorphism?

A

A change in DNA code that occurs in MORE THAN 1% of the population

In contrast to a mutation, which occurs in less than 1% of the population.

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5
Q

What is an allele?

A

One of a number of alternate forms of a gene

*You have two alleles of genes, one from Dad and one from Mom

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6
Q

What is a SNP?

A

Single Nucleotide Polymorphism

A single nucleotide in a gene is changed

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7
Q

What is a Synonymous SNP? Does this result in changes in protein expression?

A

Base pair change that does NOT cause amino acid substitution

*YES!–can alter splicing

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8
Q

What is a Nonsynonymous SNP?

A

Base pair change that DOES result in amino acid substitution

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9
Q

What is an Indel?

A

Insertion or deletion i.e. addition or loss of genetic material

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10
Q

What can an indel result in?

A

Frameshift mutation

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11
Q

List three outcomes of an indel.

A

1) Change in amino acid sequence and protein structure
2) Introduction of a stop codon
3) Altered promoter/ enhancer activity

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12
Q

What is a copy number variation?

A

The deletion or duplication of AN ENTIRE GENE

*Lead to gain or function or loss of function phenotypes

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13
Q

What is the difference between a Cosmopolitan and Population polymorphism?

A

Cosmopolitan= common across all ethnic groups

Population= polymorphisms that differ between ethnicity and race

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14
Q

What is the phenotype-to-genotype approach?

A

1) Start by measuring a pharmacogenetic trait
2) Group individuals with the same pharmacogenetic responses
3) Genotype the patients

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15
Q

What is a pharmacogenetic trait?

A

Any measurable trait associated with a drug

  • Enzyme activity
  • Drug levels
  • Drug metabolite
  • Physiologic response

Note that the pharmacogentic trait is the RESPONSE to the drug

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16
Q

What are the advantages of measuring pharmacogenetic traits? What is the disadvantage?

A

Allows for measurement of ALL genes that give rise to a effect

*BUT also allows for non-genetic influences

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17
Q

What is the candidate gene approach to pharmacogenomics? List the advantages and disadvantages.

A

Determine polymorphisms by geotyping a SPECIFIC gene that is predicted to account for phenotypic differences

  • Requires knowledge of underlying mechanism
  • May study wrong gene
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18
Q

What is the genome-wide approach to pharmacogenomics? List the advantages and disadvantages.

A

Genotype everything and then select genes that account for phenotypic differences

  • No knowledge of mechanism required
  • Unbiased
  • BUT at times, too much information
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19
Q

What is a polymorphism that effects pharmacokinetics going to alter?

A

Metabolic enzymes or drug transporters

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20
Q

What kind of an effect will a polymorphism that effects pharmacodynamics have?

A

Altered drug binding or response

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21
Q

What is an indirect effect of a polymorphism?

A

asdf

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22
Q

What genes encode proteins that will alter metabolic enzymes i.e. pharmacokinetics?

A 
CYP2D6 
CYP2C19 
CYP2C9 
DPD 
TPMT
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23
Q

What gene encodes for a drug transporter that will alter pharmacokinetics?

A

SLCO1B1

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24
Q

What drugs will have altered metabolism because of CYP2D6 polymorphisms?

A

Tamoxifen
Codeine
Paroxetine

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25
Q

What are the different phenotypes of CYP2D6 polymorphisms?

A

1) Ultrametabolizers
2) Extensive metabolizers
3) Intermediate metabolizers
4) Poor metabolizers

26
Q

What is the role of CYP2D6 in Tamoxifen therapy?

A
  • Remember Tamoxifen tx. for ER+ breast cancer*
  • Tamoxifen requires CYP2D6 to be activated into various active metabolites
  • Thus, PM will have less survival of ER+ breast cancer
  • UM and EM have better outcomes
27
Q

What is the role of CYP2D6 in Codiene therapy?

A
  • Codiene is a prodrug*
  • PM= inadequate analgesia
  • UM= excessive side effects
28
Q

Should you prescribe codiene to CYP2D6 PM and UM?

A

NO

29
Q

What is the role of CYP2D6 in Paroxitene therapy?

A
  • Paroxitene is a SSRI metabolism by CYP2D6
  • PM= increased plasma levels–>side effects
  • UM= lack of efficacy
30
Q

What drugs are closely related to polymorphisms in CYP2C19?

A

Clopidogrel

Omeprazole

31
Q

What is the role of CYP2C19 in Clopidogrel therapy?

A
  • Clopiogrel is a prodrug
  • PM= do not activate drug and do not achieve anticoagulation
  • UM= overactivate drug

**Don’t prescribe to PM

32
Q

What is the role of CYP2C19 in omeprazole therapy?

A
  • Omeprazole is metabolized by CYP2C19
  • UM= clear drug too fast–>decreased serum concentrations
  • PM= increased plasma concentrations

*****PM have better ulcer cure rates

33
Q

The activity of what drug is closely related to CYP2C9 polymorphisms?

A

Warfarin

34
Q

What is the role of CYP2C9 in Warfarin therapy?

A
  • Warfarin inhibits VKOR
  • CYP2C9 metabolizes warfarin
  • Reduced function CYP2C9= increased serum warfarin concentration and potential bleeding events
35
Q

What is the role of VKOR in Warfarin therapy?

A

VKOR= Vitamin K EpOxide Reductase

  • Enzyme that Warfarin acts on VKOR
  • Reduced VKOR activity= intrinsically increased Warfarin potency
36
Q

What type of effect is seen with VKOR polymorphisms?

A

PHARMACODYNAIMC

37
Q

In a patient with reduced VKOR and CYP2C9 activity, how would you dose warfarin?

A

Give a low dose

38
Q

Polymorphism in SCLO1B1 effects what drug?

A

Simvastatin

39
Q

What is the active form of 5-FU?

A

5dUMP

40
Q

What is the MOA of 5dUMP?

A

Inhibits thymidylate synthase

41
Q

What enzyme inactivates 5-FU?

A

DDP

42
Q

For patients with DDP polymorphism (nonfunctional) what is the adverse effect associated with 5-FU adminstration?

A

Severe myelosuppression

43
Q

What gene codes for thymidylate synthetase?

A

TYMS

44
Q

What type of effect is a polymorphism in TYMS going to have, pharmacokinetic or pharmacodynamic?

A

PHARMACODYNAMIC

45
Q

What is the role of a nonfunctional polymorphism in TYMS?

A

These patients will respond WELL to 5-FU b/c of intrinsically decreased target levels

46
Q

What enzyme inactivates 6-MP?

A

TPMT

47
Q

What is the role of TPMT polymorphisms in 6-MP therapy?

A
  • Nonfunctional TPMT polymorphisms= increased risk for myelosuppression
  • Overactivated TPMT= decreased drug efficacy
48
Q

What is the role of SCLO1B1 in Simvastatin therapy?

A
  • SCLO1B1 is a DRUG TRANSPORTER for SIMVISTATIN

- Transports simvistatin INTO the liver

49
Q

What is the phenotype of the T/T genotype of SCLO1B1? T/C? C/C?

A 
T/T= normal 
T/C= decreased 
C/C= low
50
Q

What is the functional outcome of a C/C genotype in simvistatin therapy?

A

INCREASED risk for statin-induced MYOPATHY

51
Q

What drugs are associated with polymorophisms in ERa genes?

A

Estrogen and progesterone

*This is an estrogen receptor polymorphism

52
Q

What is the role of ERa in estrogen therapy?

A

Polymorphism showed increased HDL levels with HRT

53
Q

What drug is associated with ADRB2 polymorphisms?

A

Albuterol

54
Q

What is the role of ADRB2 in albuterol therapy?

A

Nonfunctional alleles showed reduced efficacy of albuterol therapy

55
Q

What is the role of 2nd-hand smoke in ADRB2 polymorphisms and albuterol therapy?

A

asdf

56
Q

What indirect pharmacogenetic phenotype is associated with increased risk of venous thromboembolism with oral contraceptive use?

A

Factor V and prothrombin

57
Q

What adverse effect is seen with Abacavir?

A

Hypersensitivity

Steven Johnson’s Syndrome

58
Q

What gene polymorphism is associated with hypersensitivity reactions to Abacavir? What type of effect is associated with this polymorphism?

A

HLA-B–> indirect effect

59
Q

What is interferon-a a common treatment for?

A

HVC

60
Q

What polymorphism is associated with poor response to Interferon-a?

A

IL-28 polymorphisms

Note that this is an indirect effect

Pharmacology COPY (64 decks)

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