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Pharm Block 1 > Pharmacogenetics > Flashcards

Pharmacogenetics Flashcards

1
Q

this drug was given to patients to tx TB and we saw initial neurological side effects

A

isoniazid

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2
Q

What detoxifies isoniazid?

A

N-acetyltransferase-2

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3
Q

Type of inheritance for NAT-2

A

autosomal recessive

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4
Q

inheritance pattern for slow acetylators are ______ for slow allele
Fast acetylators have ________copies of fast allele
-on NAT-2

A

homozygous

1 or 2 copies

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5
Q

People suffered severe hypotension following administration of the anti-hypertensive debrisoquine d/t

A

CYP2D6 Polymorphism

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6
Q

Poor metabolizer of CYP2D6 inheritance was:
w/ mutant allele frequency of:
and a poor metabolizer frequency in the population of:

A

autosomal gene, (75 variants!!!)
30%
2-10%

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7
Q

How do we get ultrafast 2D6 metabolizer

A

up to 13 copies of the gene

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8
Q

What is our metabolite of debrisoquine

A

measure 4-OH DB

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9
Q

____ variants of 2D6 account for >90% of the poor metabolizers, making them excellent screeing targets

A

7

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10
Q

heterozygotes for poor/normal metabolizer of 2D6 are:

A

functionally reduced

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11
Q

how many copies of poor metabolizer do you need to express that phenotype of 2D6?

A

2 copies of poor metabolizer allele

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12
Q

Most antiD’s are handled by which CYP?

A

2D6

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13
Q

2D6 will both:

A

activate and inactivate the drug

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14
Q

2D6 handles what % of all drugs?

A

25%

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15
Q

Patient is put on anti-D with known 2D6 activation for metabolism of drug…. w/in 1-2 weeks patient complains of severe side effects, why?

A

patient is POOR metabolizer, and is most likely CYP2D6 poor metabolizer homologous thus is building up a lot of drug right away

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16
Q

This CYP polymorphism for poor metabolism of mephenytoin

A

2C19

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17
Q

2C19 homo.poor.met present in what % population

A

3-20%

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18
Q

CYP 2C19 responsible for metabolism of this anti-platelet drug
Does it activate it or break it down

A

Clopidogrel

Activates it

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19
Q

CYP 2C19 responsible for metabolism of this proton pump inhibitor

A

omeprazole

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20
Q

CYP 2C19 responsible for metabolism of this anti-convulsant

A

phenytoin

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21
Q

How can being a poor metabolizer of CYPC219 be of benefit when taking omeprazole

A

bc will alter response of proton pump inhibition and poor metabolizers have higher drug levels which correlates with increased gastric pH and higher cure rates

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22
Q

When would be a good time to use Clopidogrel?

A

to inhibit platelet aggregation

  • cardiac cath
  • CV stent
  • Post MI
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23
Q

Those with even one slow allele (for CYP2C19) have less active drug and >50% increase in
_____ and ______ when taking clopidogrel

A

M.I. and stroke

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24
Q

What is a complication of taking aspirin and clopidogrel post MI?

A

Patients are often prescribed a PPI to help with reflux. The PPI is often omeprazole which uses CYP2C19 as does clopidogrel (anti-coAg) and the two drugs will compete with each other
–higher rate of death and reoccurance of MI if you take the two together

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25
Q

What is key for the poor metabolizer phenotype of CYP2C9

A

2 low activity alleles

2C92 and 2C93

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26
Q

Together *2 and/or *3 are in up to what % of patients

A

31%

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27
Q

CYP polymorphism that will impact metabolism of Warfarin

A

2C9

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28
Q

Warfarin functions as

A

anti-coagulant

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29
Q

consequence of excessive warfarin?

not enough?

A

excessive bleeding

excessive clotting and could lead to stroke

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30
Q

benefits of genetic testing for 2C9

A

good for warfarin dosing

  • prevents 85,000 serious bleeding events
  • prevents 17,000 strokes
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31
Q

S-warfarin enatriomer is cleared by:

A

2C9

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32
Q

2C92 and 2C93 polymorphisms result in:

  • clearance?
  • half-life?
  • maintenance dose?
  • increased risk of ?
  • takes _____ long to achieve stable anti-coag
A 
reduced clearance
increase 1/2 life
lower maintenance dose
increased risk of bleeding
takes 2xs as long
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33
Q

What else effects Warfarin dose besides 2C9?

A

VKORC1

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34
Q

What is VKORC1

A

subunit of Vit K epoxide reductase complex

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35
Q

What is our key protein to modify clot factors II, VII, IX, X

A

VKORC1

36
Q

How does warfarin affect VKORC1?

A

inhibits activity of the complex–it’s a vitamin K antagonist thus decreases maturation of clotting factors

37
Q

HOw many SNPS are identified for VKORC1? and how many are commn?

A

28

10

38
Q

Which haplotypes result in a LOW warfarin dose when it comes to VKORC1 polymorphisms?
What claude are they in?

A

H1 and H2

Claude A

39
Q

Which VKORC1 haplos need a HIGH dose of warfarin?

What claude is that?

A

H7/8/9

Claude B

40
Q

polymorphism here results in variant response to succinycholine

A

Pseudocholinesterase

41
Q

succinycholine used for

A

surgical muscle relaxant that works for 5 minutes after dose is stopped

42
Q

What happens if you are given succinycholine and you have a pseudocholinesterase polymorphism?

A

will experience apnea and paralysis for 2-3 hrs and increase susceptibility to insecticides and cocaine toxicity

43
Q

What variants of pseudocholinesterase will polymorphism reduce activity in?

A
  • 30-90% decreased cholinesterase activity

- liver and plasma have decreased butyrylcholinesterase activity

44
Q

Presents as increased risk for life-threatening bone marrow suppression in cancer patients treated with thiopurine drugs (e.g. 6-mercaptopurine, 6-MP)

A

TPMT polymorphism

45
Q

What causes TPMT polymorphism

A

Due to variants with decreased activity of thiopurine methyltransferase (TPMT)

46
Q

low activity allele has____SNPs in the TPMT gene

A

2

47
Q

TPMT allele frequency:
• 0.3% are________ for low activity allele
• 11% _________

A

homozygous

heterozygous (1 normal and 1 low activity allele)

48
Q

What are the toxic effects of 6-MP

A

goes down HGPRT path and will inhibit purine synthesis and results in 6-thioguinine NTs misincorporated into DNA and RNA

49
Q

What happens to normal patients that receive 6-MP?

A

they use their TMPT to inactivate alot of the 6-MP into 6-methyl-MP which is the inactive form while a little will disrupt DNA

50
Q

The more abnormal or low activity allele TMPT alleles you have (0-1-2) the higher risk you are for?

A

bone marrow suppresion

51
Q

If you have a normal/normal genotype (alleles) of TMPT what is your phenotype?

A

normal risk for bone marrow suppression from 6-MP

52
Q

If you have normal/slow TMPT genotype, what is your phenotype?

A

elevated risk of marrow suppresion from 6-MP

53
Q

If you have slow/slow TMPT genotype, what is your pheno?

A

High risk of marrow suppression from 6-MP

54
Q

S-warfarin enatriomer is cleared by:

A

2C9

55
Q

2C92 and 2C93 polymorphisms result in:

  • clearance?
  • half-life?
  • maintenance dose?
  • increased risk of ?
  • takes _____ long to achieve stable anti-coag
A 
reduced clearance
increase 1/2 life
lower maintenance dose
increased risk of bleeding
takes 2xs as long
56
Q

What else effects Warfarin dose besides 2C9?

A

VKORC1

57
Q

What is VKORC1

A

subunit of Vit K epoxide reductase complex

58
Q

What is our key protein to modify clot factors II, VII, IX, X

A

VKORC1

59
Q

How does warfarin affect VKORC1?

A

inhibits activity of the complex–it’s a vitamin K antagonist thus decreases maturation of clotting factors

60
Q

HOw many SNPS are identified for VKORC1? and how many are commn?

A

28

10

61
Q

Which haplotypes result in a LOW warfarin dose when it comes to VKORC1 polymorphisms?
What claude are they in?

A

H1 and H2

Claude A

62
Q

Which VKORC1 haplos need a HIGH dose of warfarin?

What claude is that?

A

H7/8/9

Claude B

63
Q

polymorphism here results in variant response to succinycholine

A

Pseudocholinesterase

64
Q

succinycholine used for

A

surgical muscle relaxant that works for 5 minutes after dose is stopped

65
Q

What happens if you are given succinycholine and you have a pseudocholinesterase polymorphism?

A

will experience apnea and paralysis for 2-3 hrs and increase susceptibility to insecticides and cocaine toxicity

66
Q

What variants of pseudocholinesterase will polymorphism reduce activity in?

A
  • 30-90% decreased cholinesterase activity

- liver and plasma have decreased butyrylcholinesterase activity

67
Q

Presents as increased risk for life-threatening bone marrow suppression in cancer patients treated with thiopurine drugs (e.g. 6-mercaptopurine, 6-MP)

A

TPMT polymorphism

68
Q

What causes TPMT polymorphism

A

Due to variants with decreased activity of thiopurine methyltransferase (TPMT)

69
Q

low activity allele has____SNPs in the TPMT gene

A

2

70
Q

TPMT allele frequency:
• 0.3% are________ for low activity allele
• 11% _________

A

homozygous

heterozygous (1 normal and 1 low activity allele)

71
Q

What are the toxic effects of 6-MP

A

goes down HGPRT path and will inhibit purine synthesis and results in 6-thioguinine NTs misincorporated into DNA and RNA

72
Q

What happens to normal patients that receive 6-MP?

A

they use their TMPT to inactivate alot of the 6-MP into 6-methyl-MP which is the inactive form while a little will disrupt DNA

73
Q

The more abnormal or low activity allele TMPT alleles you have (0-1-2) the higher risk you are for?

A

bone marrow suppresion

74
Q

If you have a normal/normal genotype (alleles) of TMPT what is your phenotype?

A

normal risk for bone marrow suppression from 6-MP

75
Q

If you have normal/slow TMPT genotype, what is your phenotype?

A

elevated risk of marrow suppresion from 6-MP

76
Q

If you have slow/slow TMPT genotype, what is your pheno?

A

High risk of marrow suppression from 6-MP

77
Q

How do Pgp (MDR-1) polymorphs affect digoxin uptake in gut?

A

get increased net uptake to digoxin

78
Q

Digoxin is a

A

cardiac glycoside

79
Q

D/t digoxin’s narrow therapetutic windonw, polymorphism here can lead to toxicity

A

Pgp or MDR-1

80
Q

Patients with abnormal Pgp don’t _____as much drug and end up_______

A

efflux

absorbing more==== toxicity

81
Q

Pgp polymporphism effects drug _____

and result in _______ levels of PgP protein

A

absorption

decreased levels of Pgp protein

82
Q

Impact of low expression TT Pgp allele:
On cardiac glycoside digoxin results
________ drug concentration
_________toxicity

A

increased

increaed

83
Q

Impact of low expression TT Pgp allele:
On anti-convulsant phenytoin results
________ drug concentration
_________side effects

A

increased

increaesd

84
Q

Impact of low expression TT Pgp allele:
On anti-D nortripyline results
________ drug concentration
_________side effects

A

increased

increased side effects

85
Q

Impact of low expression TT Pgp allele:
On anti-HIV results
________ drug concentration
_________response to therapy

A

increased

better response to therapy

Pharm Block 1 (23 decks)

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