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Flashcards in Pharmacogenetics Deck (85)
1

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

isoniazid

2

What detoxifies isoniazid?

N-acetyltransferase-2

3

Type of inheritance for NAT-2

autosomal recessive

4

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

homozygous
1 or 2 copies

5

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

CYP2D6 Polymorphism

6

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

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

7

How do we get ultrafast 2D6 metabolizer

up to 13 copies of the gene

8

What is our metabolite of debrisoquine

measure 4-OH DB

9

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

7

10

heterozygotes for poor/normal metabolizer of 2D6 are:

functionally reduced

11

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

2 copies of poor metabolizer allele

12

Most antiD's are handled by which CYP?

2D6

13

2D6 will both:

activate and inactivate the drug

14

2D6 handles what % of all drugs?

25%

15

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?

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

16

This CYP polymorphism for poor metabolism of mephenytoin

2C19

17

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

3-20%

18

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

Clopidogrel
Activates it

19

CYP 2C19 responsible for metabolism of this proton pump inhibitor

omeprazole

20

CYP 2C19 responsible for metabolism of this anti-convulsant

phenytoin

21

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

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

22

When would be a good time to use Clopidogrel?

to inhibit platelet aggregation
-cardiac cath
-CV stent
-Post MI

23

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

M.I. and stroke

24

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

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

25

What is key for the poor metabolizer phenotype of CYP2C9

2 low activity alleles
2C9*2 and 2C9*3

26

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

31%

27

CYP polymorphism that will impact metabolism of Warfarin

2C9

28

Warfarin functions as

anti-coagulant

29

consequence of excessive warfarin?
not enough?

excessive bleeding
excessive clotting and could lead to stroke

30

benefits of genetic testing for 2C9

good for warfarin dosing
-prevents 85,000 serious bleeding events
-prevents 17,000 strokes

31

S-warfarin enatriomer is cleared by:

2C9

32

2C9*2 and 2C9*3 polymorphisms result in:
-clearance?
-half-life?
-maintenance dose?
-increased risk of ?
-takes _____ long to achieve stable anti-coag

reduced clearance
increase 1/2 life
lower maintenance dose
increased risk of bleeding
takes 2xs as long

33

What else effects Warfarin dose besides 2C9?

VKORC1

34

What is VKORC1

subunit of Vit K epoxide reductase complex

35

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

VKORC1

36

How does warfarin affect VKORC1?

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

37

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

28
10

38

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

H1 and H2
Claude A

39

Which VKORC1 haplos need a HIGH dose of warfarin?
What claude is that?

H7/8/9
Claude B

40

polymorphism here results in variant response to succinycholine

Pseudocholinesterase

41

succinycholine used for

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

42

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

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

43

What variants of pseudocholinesterase will polymorphism reduce activity in?

- 30-90% decreased cholinesterase activity
- liver and plasma have decreased butyrylcholinesterase activity

44

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

TPMT polymorphism

45

What causes TPMT polymorphism

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

46

low activity allele has____SNPs in the TPMT gene

2

47

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

homozygous
heterozygous (1 normal and 1 low activity allele)

48

What are the toxic effects of 6-MP

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

49

What happens to normal patients that receive 6-MP?

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

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

bone marrow suppresion

51

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

normal risk for bone marrow suppression from 6-MP

52

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

elevated risk of marrow suppresion from 6-MP

53

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

High risk of marrow suppression from 6-MP

54

S-warfarin enatriomer is cleared by:

2C9

55

2C9*2 and 2C9*3 polymorphisms result in:
-clearance?
-half-life?
-maintenance dose?
-increased risk of ?
-takes _____ long to achieve stable anti-coag

reduced clearance
increase 1/2 life
lower maintenance dose
increased risk of bleeding
takes 2xs as long

56

What else effects Warfarin dose besides 2C9?

VKORC1

57

What is VKORC1

subunit of Vit K epoxide reductase complex

58

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

VKORC1

59

How does warfarin affect VKORC1?

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

60

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

28
10

61

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

H1 and H2
Claude A

62

Which VKORC1 haplos need a HIGH dose of warfarin?
What claude is that?

H7/8/9
Claude B

63

polymorphism here results in variant response to succinycholine

Pseudocholinesterase

64

succinycholine used for

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

65

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

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

66

What variants of pseudocholinesterase will polymorphism reduce activity in?

- 30-90% decreased cholinesterase activity
- liver and plasma have decreased butyrylcholinesterase activity

67

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

TPMT polymorphism

68

What causes TPMT polymorphism

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

69

low activity allele has____SNPs in the TPMT gene

2

70

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

homozygous
heterozygous (1 normal and 1 low activity allele)

71

What are the toxic effects of 6-MP

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

72

What happens to normal patients that receive 6-MP?

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

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

bone marrow suppresion

74

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

normal risk for bone marrow suppression from 6-MP

75

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

elevated risk of marrow suppresion from 6-MP

76

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

High risk of marrow suppression from 6-MP

77

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

get increased net uptake to digoxin

78

Digoxin is a

cardiac glycoside

79

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

Pgp or MDR-1

80

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

efflux
absorbing more==== toxicity

81

Pgp polymporphism effects drug _____
and result in _______ levels of PgP protein

absorption
decreased levels of Pgp protein

82

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

increased
increaed

83

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

increased
increaesd

84

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

increased
increased side effects

85

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

increased
better response to therapy