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