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Pharm 557 > Pharmacogenomics (Anderson's lectures) > Flashcards

Pharmacogenomics (Anderson's lectures) Flashcards

1
Q

CYP2C19 IM relative frequency?

A

*2 is most common, but also *3 - *8
Reduced metabolism
Asian
Caucasian

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2
Q

CYP2C19 UM relative frequency?

A 
*17
Ultra rapid metabolizer
Black
White
Heterozygous most common
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3
Q

CYP2C9 IM relative frequency?

A

*2
Reduced activity (70%)
Caucasian

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4
Q

CYP2C9 PM relative frequency?

A

*3
Little activity (2-5%)
Caucasian

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5
Q

CYP2D6 UM relative frequency

A

Multiple copies of *1, *2
Hyper-functional
Ethiopan, Saudi Arabian

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6
Q

CYP2D6: IM relative frequency

A

9, 10, *17
(or can be heterozygous for *1)
Asian (10)
Black (17)

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7
Q

CYP2D6: PM relative frequency

A

*3 - *6 (loss of function)

White

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8
Q

How does gene-dose effect relate to clopidogrel metabolism?

A

PM/IM have a higher chance of a fatal CV event (not converted to the active form - remember, it’s a prodrug)
UM: greater risk of bleeding, but better outcome overall

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9
Q

How does gene-dose effect relate to es/citalopram metabolism?

A

PM have a higher risk of QT prolongation, cardiotoxicity

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10
Q

How does the number of NAT2*4 (rapid metabolizer) genes influence isoniazid dosing?

A

The presence of 1 allele drops the dose (normally 7.5 mg/kg/day) by 2.5 mg/kg for each allele.

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11
Q

Per CPIC, which groups have recommended changes in clopidogrel?

A

IM/PM: have reduced platelet inhibition and more platelet aggregation –> increased risk of CV events. Use an alt. and genotype anyone undergoing PCI

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12
Q

Per CPIC, which groups have recommended changes in es/citalopram and why?

A

UM: increased metabolism, lower plasma concentration –> treatment failure. Use an alt.
PM: reduced metabolism and high plasma concentration –> adverse reaction. Consider 50% dose reduction, titrate. Or use an alt.

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13
Q

What are some moderate inhibitors of CYP2D6?

A

Cimetidine
Duloxetine
Fluvoxamine
Sertraline

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14
Q

What are some strong inhibitors of CYP2D6?

A

Buproprion
Fluoxetine
Paroxetine
Quinidine

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15
Q

What are substrates CYP2C19?

A 
PPI's
Clopidogrel
Sertraline
Es/citalopram
Amitryptyline
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16
Q

What are substrates of CYP2C9 that we talked about in class?

A

S-warfarin

Phenytoin

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17
Q

What are substrates of CYP2D6 that we talked about in class?

A

Codeine, tamoxifen

Also other pain meds, beta blockers, haloperidol, risperidone

18
Q

What are the dose changes for tamoxifen recommended by CPIC?

A

PM: use alt
IM: higher dose, avoid ANY inhibitors
EM/UM: normal dose, avoid strong/moderate inhibitors

19
Q

What factors would make us decrease the dose of warfarin?

A

Age
VKORC1 allele (28% per each)
Drugs like amiodarone
*2 or *3 allele (19 - 33%)

20
Q

What factors would make us increase the dose of warfarin?

A

Target INR
BSA
Current thrombosis

21
Q

Abacavir HLA allele

A

HLA-B*5701

Increased likelihood of drug related hypersensitivity

22
Q

Phenytoin HLA allele

A

HLA-B:15:02 (weak evidence that it can cause SJS/TEN).
Not having this allele doesn’t rule out this reaction.
CYP2C9 is the major path. *3 genotype associated w/ SJS/TEN

23
Q

Abacavir recommendation

A

Screen all naive patients before starting therapy.

If a carrier, avoid use and use alt.

24
Q

Allopurinol recommendation

A

Contraindicated if positive for *58:01.

Consider genotyping in Han Chinese/Thai, or if Korean with CKD stage 3 or worse.

25
Q

What is the dose change of warfarin for a CYP2C9 *2 (intermediate activity)?

A

Drop the dose by 19% per allele

26
Q

What is the dose change of warfarin for a CYP2C9 *3 (poor activity)?

A

Drop the dose by 33% per allele

27
Q

What is the frequency of NAT2 rapid acetylators?

A

Highest in Vietnamese, Japanese, Chinese

28
Q

What is the frequency of NAT2 slow acetylators?

A

Most in white and black

29
Q

What is the frequency of the VKORC1 variant?

A

Asian 90%

White 40%

30
Q

What is the gene-dose effect?

A

Some medications do not need genotyping because you can titrate to effect. Not 100% of the time, though.

31
Q

Allopurinol HLA allele

A

HLA-B*58:01

Increased risk of SJS/TEN and DRESS - drug related eosinophillia.

32
Q

Carbamazepine/oxcarbazepine HLA allele(s)

A

HLA-B*15:02 –> greater risk of SJS and TEN

HLA-A*31:01 –> greater risk of MPE, DRESS, SJS/TEN

33
Q

What is the implication of the VKORC1 variant?

A

WT G allele is replaced by A allele.
Leads to less VKORC1 made.
These patients need lower doses of warfarin.

34
Q

What is the implication of medium activity OAT1B1?

A

TC genotype
Have intermediate myopathy risk
Recommendation: use low dose or alt

35
Q

Carbamazepine/oxcarbazepine recommendation

A

Screen for both alleles in naive patients. Avoid use and use alt if positive for either.

36
Q

What is the implication of reduced function OAT1B1?

A

CC genotype
Carriers have high myopathy risk
Recommendation: use low dose or alt & consider routine CK monitoring

37
Q

What is the risk of slow acetylators of NAT2 and isoniazid and sulfonamides?

A

Isoniazid: increased hepatotoxicity (more toxic metabolite)
Sulfonamides: hypersensitivity reactions

38
Q

What are the CPIC guidelines for ami/nortriptyline dosing?

A

UM/PM: avoid, use alt.

IM: Consider reducing dose 25% to start

39
Q

What are the CPIC guidelines for paroxetine dosing?

A

UM: consider alternative
EM/IM: No change
PM: consider alt. or reduce dose 50%

40
Q

What are the CPIC guidelines for codeine dosing?

A

UM/PM: avoid, use alt (but for different reasons)
UM: risk of toxicity
PM: lack of efficacy
IM: use normal dose or use alt.

41
Q

What are the CPIC guidelines for phenytoin dosing?

A 
2D6:
IM *2: drop starting dose 25%
PM *3: drop starting dose 50%
titrate with TDM for both
HLA-B*15:02:
If phenytoin naive do not use

Pharm 557 (7 decks)

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