pharmacogenomics Flashcards
(105 cards)
1
Q
T/F: both genetics and genomics influence the genetic factors on an individuals response to a drug
A
TRUE
2
Q
______________ is the study of variations in human genes that are responsible for different responses to drug therapy
A
pharmacogenomics
3
Q
pharmacogenetics
A
- studies variations in genes suspected of effecting drug response
4
Q
__________________ offers a more detailed explanation of drug response variablility beyond: age, gender, drug-drug interactions, nutritional, environmental, and geographical differences
A
pharmacogenomics
5
Q
pharmacogenomics
A
- evolution of genetics research
6
Q
________________ is the study of how chromosomal variations affect drug response
A
pharmacogenomics
7
Q
pharmaco_______________ –> personalized medicine via individualized drug therapy –> better patient outcomes
A
genomics
8
Q
_______________ specifies the trait, and _______________ specifies what form the gene takes
A
genes; alleles
9
Q
allele
A
two or more forms of a gene that occupy a specific position on a specific chromosome
10
Q
_____________ is the percentage of times a specific allele is observed in proportion to the total of all possible alleles that could occur at a specific location on a chromosome
A
allele frequency
11
Q
_______________ is the DNA containing structure of cellular organisms that contains all or most of the genes of the organism
A
chromosome
12
Q
what is a gene
A
sequence of DNA that occupies a specific position on the chromosome and determines a particular characteristic in an organism
13
Q
Genotype
A
representation of an organisms genetic makeup or the particular set of genes that the organism posses
14
Q
_________________ having two different alleles for the same trait; __________ = having an identical allele for a single trait
A
heterozygous; homozygous
15
Q
_________________ = the observable physical or biochemical characteristics of the organisms genetic makeup
A
phenotype
16
Q
polymorphism
A
- a specific genetic alteration that occurs in more than 1% of the population
17
Q
T/F: polymorphism and variant are interchangeable
A
TRUE
18
Q
______________ is the MOST common type of genetic or allelic variation
A
single nucleotide polymorphism (SNP)
19
Q
single nucleotide polymorphism is aka ___________________
A
point mutation
20
Q
_________________ are pair based substitutions that occur in the genome
A
single nucleotide polymorphism
21
Q
what are the four categories of phenotypic metabolic responses to certain drugs based on their genes?
A
- poor metabolizer
22
Q
how many single nucleotide polymorphisms have been identified
A
10 million
23
Q
T/F: A large majority of single nucleotide polymorphisms elicit a drug reponse
A
false; only a SMALL fraction have proven relevant to eliciting a drug response
24
Q
T/F: the human genome is 99.9% identical regardless of race
A
TRUE
25
3 areas of variations with single nucleotide polymorphisms in pharmacology
1. drug-metabolizing enzymes
26
sum of normal allelic activity score ranges between _______________
0 & >/= 3
27
allele activity score of 0 = _______________
poor metabolizer (PM) phenotype
28
allele activity score of 0.5 = __________________
intermediate metabolizer (IM) phenotype
29
allele activity score of 1.0-2.0 = ___________________
extensive metabolizer (EM) phenotype
30
allele activity score of >/= 2 = __________________
ultra metabolizer (UM) phenotype
31
phase I enzymes are involved in biotransformation/metabolism of over ________% of prescription drugs
75
32
having a polymorphism in a phase I enzyme would lead to:
altered blood levels --> altered drug response
33
if you have a duplication polymorphism in a phase I enzyme --> ___________ in overall allele activity score
increase
34
functional activity score categories
1. nonfunctional
35
what is the most common non-functional allele of CYP2D6
CYP2D6*4
36
which alleles of the CYP2D6 gene are fully functional
1 & 2
37
which CYP2D6 allele polymorphisms are nonfunctional?
3,4,5,6
38
95% of phenotypes of the CYP2D6 gene can be accounted for with just _____________ alleles
9
39
which CYP2D6 allele polymorphisms have reduced function
10, 17, & 41
40
the CYP2D6*4 allele is observed at a frequency of 20% in ___________, and is nearly absent (<1%) in _____________
europeans; asians
41
T/F: the CYP2D6*5 deletion is found at similar frequencies across european, african, and asian populations
TRUE
42
the fact that the CYP2D6*5 deletion being found at similar frequencies across european, asian, and african populations suggests what?
that the mutation took place prior to the separation of the three major races more than 100,000 years ago
43
_______________ is responsible for the O-demethylation of codeine to morphine
CYP2D6
44
patients that are extensive metabolizers of CYP2D6 have _____________ metabolism of codeine into morphine to produce desired analgesic effect
normal
45
if someone is a poor metabolizer (PM) of CYP2D6 would have _______________ effect if they take codeine
insufficient analgesia
46
if someone is PM for CYP2D6 what is the recommendation for this patient with codeine
use an alternative agent
47
if someone is an IM of CYP2D6 they would have a _________________ effect with codeine
insufficient analgesia
48
what is the recommendation on administering codeine to a IM of CYP2D6
administer the standard dose
49
which metabolizing phenotype of CYP2D6 with codeine would have the desired effect and can be administered the standard dose
extensive metabolizer (EM)
50
UMs for CYP2D6 if given codeine would have ___________________ effect
increased adverse events
51
recommendation on administering codeine in UM for CYP2D6
use alternative agent
52
which CYP2D6 metabolizer can you use the standard dose of codeine with ?
intermediate (IM) & extensive (EM)
53
__________________ enzymes are responsible for conjugation --> enhanced elimination of endogenous and exogenous substances
phase II
54
polymorphic ___________________ will diminish drug elimination and will increase risk for toxicities
phase II enzymes
55
the UGT1A1 enzyme is a ______________ enzyme that conjugates _____________ into lipophilic molecules
phase II; glucuronic acid
56
UGT1A1 gene has > ____________ alleles
30
57
T/F: reduced fx polymorphisms of the UGT1A1 enzyme are rare
TRUE
58
T/F: antitussive properties of codeine are affected by CYP2D6 polymorphisms
FALSE
59
_________________ s/e of codeine are decreased in those who are PM of CYP2D6
GI (constipation)
60
individuals who are homozygous for the UGT1A1*28 have a 60-70% increase in levels of _______________________ due to 30% reduction in UGT1A1 activity
circulating unconjugated bilirubin
61
T/F: the UGT1A1*28 is common across all 3 major ethnic groups
TRUE
62
homozygous UGT1A1*28 allele is known as ____________________
gilbert syndrome
63
T/F: the UGT1A1*28 is typically benign unless taking a drug that needs this enzyme
TRUE
64
_________________ & ________________ decrease the clearance of irinotecan
UGT1A1*6; UGT1A1*28
65
dosing recommendation of irinotecan for heterozygous UGT1A1(*1/28)
standard starting dose
66
dosing recommendation for irinotecan for homozygous UGT1A1(*28/28)
1. reduce starting dose by at least one dose level - or
67
irinotecan is hydrolyzed by hepatic carboxylesterase enzymes to cytotoxic metabolite, ____________. This inhibits __________________ --> termination of DNA replication and cell death
SN-38; topoisomerase I
68
inactivation of the cytotoxic metabolite of irinotecan, SN-38 is performed via the polymorphic UGT1A1 enzyme. carriers of the ______________ and _________________ polymorphisms are at increased risk for severe life threatening toxicities
UGT1A1*6; UGT1A1*28
69
plasma membrane transporters
1. located on epithelial cells of many tissues (intestinal membranes, renal membranes, hepatic membranes)
70
__________________ play important roles in determining plasma & tissue concentrations of drugs and their metabolites
drug transporters
71
genetic differences in ________________ genes alter drug disposition and response --> increased risk of __________________
transporter genes; toxicities
72
T/F: drug transporters work with drug metabolizing enzymes
TRUE
73
the organic anion transporter (OATP1B1) is encoded by what gene
SLCO1B1
74
what is the fx of the organic anion transporter (OATP1B1)
hepatic uptake of weakly acidic drugs and endogenous compounds (statins, MTX, and bilirubin)
75
over ______________ nonsynonymous single nucleotide polymorphisms have been identified in the OATP1B1 transporter --> _______________ function
40; decreased
76
____________________ is a common reduced function polymorphism of the OATP1B1 that reduces the transport of its substrates in vitro and in vivo
rs4149056
77
the reduced fx polymorphism of rs4149056 to the OATP1B1 transporter results in an amino acid change = _______________. This change is associated with a reduced ____________________
Val174Ala; membrane expression
78
the rs4149056 polymorphism of the OATP1B1 --> reduced function of the transporter at what alleles?
SCLCO1B1*5, 15, and 17
79
rs4149056 polymorphism of the OATP1B1 transporter is rare at allele _______, but is common in most european/asian populations at allele ____________
5; 15, 17 (haplotypes)
80
___________________ variant of the SLCO1B1 gene for the OATP1B1 transporter increases risk of simvastatin induced myopathy
rs4149056
81
if HOMOZYGOUS for the rs4149056 variant there is a _____________% increase in plasma area under the curve for patients
221
82
what diplotypes of the would be homozygous for decreased function of the OAT1P1B1 transporter
5/5; 5/15; 5/17; 15/15; 15/17; 17/15; 17/17
83
which diplotype of the SLCO1B1 gene has intermediate activity for simvastatin
1a or 1b + 5, 15, or 17
84
which diplotype of the SLCO1B1 gene has a low phenotypic activity for the SLCO1B1 gene
[5]/[5, 15, or 17]
85
what diplotypes sof SLC01B1hould you presribe a lower dose for simvastatin 40 mg or consider an alternative statin, and/or routine CK monitoring
[1a or 1b]/[5, 15, 17]
86
many population based hypersensitivity reactions have been attributed to genetic polymorphisms in the ______________ genes
HLA
87
polymorphisms in HLA genes are associated with?
1. stevens-johnson syndrome
88
which HLA gene polymorphisms have been associated with many drug induced hypersensitivity reactions
1. HLA-B
89
HLA polymorphisms are associated with hypersensitivities to what drugs?
1. allopurinol
90
many HLA-________ polymorphisms have been characterized and have varying allelic frequencies depending on racial and ethnic population
B
91
selective recognition of particular drug-bound peptides by some HLA-______ polymorphism products results in population selective drug hypersensitivity reactions
B
92
pharmacogenomic implications for anesthesia include:
1. neuromuscular blocking agents
93
all inherited causes of pseudocholinesterase deficiency are due to point mutations on chromosome __________
3
94
there are ___________ identifiable variants on chromosome 3 --> pseudocholinesterase deficiency
20
95
what are the most common variants on chromosome 3 --> pseudocholinesterase deficiency
1. A variant = Asp70Gly
96
if you are heterozygous for atypical pseudocholinesterase gene your succinylcholine will prolonged by ____________x; if homozygous prolonged up to __________x longer
3-8; 60
97
which pseudochoinesterase deficiency variant is rare
S-variant
98
___________ variant --> atypical pseudocholinesterase, if homozygous, have no pseudocholinesterase activity and can have paralysis for up to 8 hours with single induction dose of succinylcholine
S
99
what opioids are metabolized by the CYP2D6 enzyme
1. codeine
100
if you are ultra-metabolizer of CYP2D6 --> higher risk of life threatening side effects with which opioids
1. codeine
101
OPRM1 GG genotype requires 93% higher ________________ dose as compared to the OPRM1 AA genotype
morphine
102
the ______________ gene codes for the Mu opioid receptor
OPRM1
103
P-glycoprotein transporters are found along the ________________, and are encoded by the __________________ gene
BBB; ABCB1
104
polymorphisms in the ABCB1 gene (encoding for P-glycoprotein transporters) effect opioid variability on ___________________
respiratory depression
105
polymorphisms in the ______________________ gene are what is associated with higher methadone doses for heroin addicts undergoing methadone therapy
ABCB1 (gene that encodes for P-glycoprotein transporter)
