EXAM #5: PHARMACOGENOMICS Flashcards Preview

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Flashcards in EXAM #5: PHARMACOGENOMICS Deck (60):
1

What is the monogenic drug response?

Variation in a SINGLE gene that alters a drug response

2

What is a multigenic drug response?

Variation in MULTIPLE genes alters drug response

3

What is the "gene-by-environment" phenotype?

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

4

What is the definition of a polymorphism?

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.*

5

What is an allele?

One of a number of alternate forms of a gene

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

6

What is a SNP?

Single Nucleotide Polymorphism

*A single nucleotide in a gene is changed*

7

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

Base pair change that does NOT cause amino acid substitution

*YES!--can alter splicing

8

What is a Nonsynonymous SNP?

Base pair change that DOES result in amino acid substitution

9

What is an Indel?

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

10

What can an indel result in?

Frameshift mutation

11

List three outcomes of an indel.

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

12

What is a copy number variation?

The deletion or duplication of AN ENTIRE GENE

*Lead to gain or function or loss of function phenotypes

13

What is the difference between a Cosmopolitan and Population polymorphism?

Cosmopolitan= common across all ethnic groups

Population= polymorphisms that differ between ethnicity and race

14

What is the phenotype-to-genotype approach?

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

15

What is a pharmacogenetic trait?

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*****

16

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

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

*BUT also allows for non-genetic influences

17

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

Determine polymorphisms by geotyping a SPECIFIC gene that is predicted to account for phenotypic differences
- Requires knowledge of underlying mechanism
- May study wrong gene

18

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

Genotype everything and then select genes that account for phenotypic differences
- No knowledge of mechanism required
- Unbiased
- BUT at times, too much information

19

What is a polymorphism that effects pharmacokinetics going to alter?

Metabolic enzymes or drug transporters

20

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

Altered drug binding or response

21

What is an indirect effect of a polymorphism?

asdf

22

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

CYP2D6
CYP2C19
CYP2C9
DPD
TPMT

23

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

SLCO1B1

24

What drugs will have altered metabolism because of CYP2D6 polymorphisms?

Tamoxifen
Codeine
Paroxetine

25

What are the different phenotypes of CYP2D6 polymorphisms?

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

26

What is the role of CYP2D6 in Tamoxifen therapy?

*****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

What is the role of CYP2D6 in Codiene therapy?

*****Codiene is a prodrug*****
- PM= inadequate analgesia
- UM= excessive side effects

28

Should you prescribe codiene to CYP2D6 PM and UM?

NO

29

What is the role of CYP2D6 in Paroxitene therapy?

- Paroxitene is a SSRI metabolism by CYP2D6
- PM= increased plasma levels-->side effects
- UM= lack of efficacy

30

What drugs are closely related to polymorphisms in CYP2C19?

Clopidogrel
Omeprazole

31

What is the role of CYP2C19 in Clopidogrel therapy?

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

****Don't prescribe to PM

32

What is the role of CYP2C19 in omeprazole therapy?

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

*****PM have better ulcer cure rates

33

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

Warfarin

34

What is the role of CYP2C9 in Warfarin therapy?

- Warfarin inhibits VKOR
- CYP2C9 metabolizes warfarin
- Reduced function CYP2C9= increased serum warfarin concentration and potential bleeding events

35

What is the role of VKOR in Warfarin therapy?

VKOR= Vitamin K EpOxide Reductase
- Enzyme that Warfarin acts on VKOR
- Reduced VKOR activity= intrinsically increased Warfarin potency

36

What type of effect is seen with VKOR polymorphisms?

PHARMACODYNAIMC

37

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

Give a low dose

38

Polymorphism in SCLO1B1 effects what drug?

Simvastatin

39

What is the active form of 5-FU?

5dUMP

40

What is the MOA of 5dUMP?

Inhibits thymidylate synthase

41

What enzyme inactivates 5-FU?

DDP

42

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

Severe myelosuppression

43

What gene codes for thymidylate synthetase?

TYMS

44

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

PHARMACODYNAMIC

45

What is the role of a nonfunctional polymorphism in TYMS?

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

46

What enzyme inactivates 6-MP?

TPMT

47

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

- Nonfunctional TPMT polymorphisms= increased risk for myelosuppression
- Overactivated TPMT= decreased drug efficacy

48

What is the role of SCLO1B1 in Simvastatin therapy?

- SCLO1B1 is a DRUG TRANSPORTER for SIMVISTATIN
- Transports simvistatin INTO the liver

49

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

T/T= normal
T/C= decreased
C/C= low

50

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

INCREASED risk for statin-induced MYOPATHY

51

What drugs are associated with polymorophisms in ERa genes?

Estrogen and progesterone

*This is an estrogen receptor polymorphism

52

What is the role of ERa in estrogen therapy?

Polymorphism showed increased HDL levels with HRT

53

What drug is associated with ADRB2 polymorphisms?

Albuterol

54

What is the role of ADRB2 in albuterol therapy?

Nonfunctional alleles showed reduced efficacy of albuterol therapy

55

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

asdf

56

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

Factor V and prothrombin

57

What adverse effect is seen with Abacavir?

Hypersensitivity

*Steven Johnson's Syndrome*

58

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

HLA-B--> indirect effect

59

What is interferon-a a common treatment for?

HVC

60

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

IL-28 polymorphisms

*Note that this is an indirect effect*

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