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pharm II: opioids, drugs of abuse, genomics > pharmacogenomics > Flashcards

pharmacogenomics Flashcards

1
Q

T/F: both genetics and genomics influence the genetic factors on an individuals response to a drug

A

TRUE

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2
Q

______________ is the study of variations in human genes that are responsible for different responses to drug therapy

A

pharmacogenomics

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3
Q

pharmacogenetics

A
  1. studies variations in genes suspected of effecting drug response
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4
Q

__________________ offers a more detailed explanation of drug response variablility beyond: age, gender, drug-drug interactions, nutritional, environmental, and geographical differences

A

pharmacogenomics

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5
Q

pharmacogenomics

A
  1. evolution of genetics research
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6
Q

________________ is the study of how chromosomal variations affect drug response

A

pharmacogenomics

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7
Q

pharmaco_______________ –> personalized medicine via individualized drug therapy –> better patient outcomes

A

genomics

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8
Q

_______________ specifies the trait, and _______________ specifies what form the gene takes

A

genes; alleles

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9
Q

allele

A

two or more forms of a gene that occupy a specific position on a specific chromosome

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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

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11
Q

_______________ is the DNA containing structure of cellular organisms that contains all or most of the genes of the organism

A

chromosome

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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

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13
Q

Genotype

A

representation of an organisms genetic makeup or the particular set of genes that the organism posses

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14
Q

_________________ having two different alleles for the same trait; __________ = having an identical allele for a single trait

A

heterozygous; homozygous

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15
Q

_________________ = the observable physical or biochemical characteristics of the organisms genetic makeup

A

phenotype

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16
Q

polymorphism

A
  1. a specific genetic alteration that occurs in more than 1% of the population
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17
Q

T/F: polymorphism and variant are interchangeable

A

TRUE

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18
Q

______________ is the MOST common type of genetic or allelic variation

A

single nucleotide polymorphism (SNP)

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19
Q

single nucleotide polymorphism is aka ___________________

A

point mutation

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20
Q

_________________ are pair based substitutions that occur in the genome

A

single nucleotide polymorphism

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21
Q

what are the four categories of phenotypic metabolic responses to certain drugs based on their genes?

A
  1. poor metabolizer
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22
Q

how many single nucleotide polymorphisms have been identified

A

10 million

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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

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24
Q

T/F: the human genome is 99.9% identical regardless of race

A

TRUE

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25
Q

3 areas of variations with single nucleotide polymorphisms in pharmacology

A
  1. drug-metabolizing enzymes
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26
Q

sum of normal allelic activity score ranges between _______________

A

0 & >/= 3

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27
Q

allele activity score of 0 = _______________

A

poor metabolizer (PM) phenotype

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28
Q

allele activity score of 0.5 = __________________

A

intermediate metabolizer (IM) phenotype

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29
Q

allele activity score of 1.0-2.0 = ___________________

A

extensive metabolizer (EM) phenotype

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30
Q

allele activity score of >/= 2 = __________________

A

ultra metabolizer (UM) phenotype

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31
Q

phase I enzymes are involved in biotransformation/metabolism of over ________% of prescription drugs

A

75

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32
Q

having a polymorphism in a phase I enzyme would lead to:

A

altered blood levels –> altered drug response

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33
Q

if you have a duplication polymorphism in a phase I enzyme –> ___________ in overall allele activity score

A

increase

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34
Q

functional activity score categories

A
  1. nonfunctional
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35
Q

what is the most common non-functional allele of CYP2D6

A

CYP2D6*4

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36
Q

which alleles of the CYP2D6 gene are fully functional

A

1 & 2

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37
Q

which CYP2D6 allele polymorphisms are nonfunctional?

A

3,4,5,6

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38
Q

95% of phenotypes of the CYP2D6 gene can be accounted for with just _____________ alleles

A

9

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39
Q

which CYP2D6 allele polymorphisms have reduced function

A

10, 17, & 41

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40
Q

the CYP2D6*4 allele is observed at a frequency of 20% in ___________, and is nearly absent (<1%) in _____________

A

europeans; asians

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41
Q

T/F: the CYP2D6*5 deletion is found at similar frequencies across european, african, and asian populations

A

TRUE

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42
Q

the fact that the CYP2D6*5 deletion being found at similar frequencies across european, asian, and african populations suggests what?

A

that the mutation took place prior to the separation of the three major races more than 100,000 years ago

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43
Q

_______________ is responsible for the O-demethylation of codeine to morphine

A

CYP2D6

44
Q

patients that are extensive metabolizers of CYP2D6 have _____________ metabolism of codeine into morphine to produce desired analgesic effect

A

normal

45
Q

if someone is a poor metabolizer (PM) of CYP2D6 would have _______________ effect if they take codeine

A

insufficient analgesia

46
Q

if someone is PM for CYP2D6 what is the recommendation for this patient with codeine

A

use an alternative agent

47
Q

if someone is an IM of CYP2D6 they would have a _________________ effect with codeine

A

insufficient analgesia

48
Q

what is the recommendation on administering codeine to a IM of CYP2D6

A

administer the standard dose

49
Q

which metabolizing phenotype of CYP2D6 with codeine would have the desired effect and can be administered the standard dose

A

extensive metabolizer (EM)

50
Q

UMs for CYP2D6 if given codeine would have ___________________ effect

A

increased adverse events

51
Q

recommendation on administering codeine in UM for CYP2D6

A

use alternative agent

52
Q

which CYP2D6 metabolizer can you use the standard dose of codeine with ?

A

intermediate (IM) & extensive (EM)

53
Q

__________________ enzymes are responsible for conjugation –> enhanced elimination of endogenous and exogenous substances

A

phase II

54
Q

polymorphic ___________________ will diminish drug elimination and will increase risk for toxicities

A

phase II enzymes

55
Q

the UGT1A1 enzyme is a ______________ enzyme that conjugates _____________ into lipophilic molecules

A

phase II; glucuronic acid

56
Q

UGT1A1 gene has > ____________ alleles

A

30

57
Q

T/F: reduced fx polymorphisms of the UGT1A1 enzyme are rare

A

TRUE

58
Q

T/F: antitussive properties of codeine are affected by CYP2D6 polymorphisms

A

FALSE

59
Q

_________________ s/e of codeine are decreased in those who are PM of CYP2D6

A

GI (constipation)

60
Q

individuals who are homozygous for the UGT1A1*28 have a 60-70% increase in levels of _______________________ due to 30% reduction in UGT1A1 activity

A

circulating unconjugated bilirubin

61
Q

T/F: the UGT1A1*28 is common across all 3 major ethnic groups

A

TRUE

62
Q

homozygous UGT1A1*28 allele is known as ____________________

A

gilbert syndrome

63
Q

T/F: the UGT1A1*28 is typically benign unless taking a drug that needs this enzyme

A

TRUE

64
Q

_________________ & ________________ decrease the clearance of irinotecan

A

UGT1A16; UGT1A128

65
Q

dosing recommendation of irinotecan for heterozygous UGT1A1(*1/28)

A

standard starting dose

66
Q

dosing recommendation for irinotecan for homozygous UGT1A1(*28/28)

A
  1. reduce starting dose by at least one dose level - or
67
Q

irinotecan is hydrolyzed by hepatic carboxylesterase enzymes to cytotoxic metabolite, ____________. This inhibits __________________ –> termination of DNA replication and cell death

A

SN-38; topoisomerase I

68
Q

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

A

UGT1A16; UGT1A128

69
Q

plasma membrane transporters

A
  1. located on epithelial cells of many tissues (intestinal membranes, renal membranes, hepatic membranes)
70
Q

__________________ play important roles in determining plasma & tissue concentrations of drugs and their metabolites

A

drug transporters

71
Q

genetic differences in ________________ genes alter drug disposition and response –> increased risk of __________________

A

transporter genes; toxicities

72
Q

T/F: drug transporters work with drug metabolizing enzymes

A

TRUE

73
Q

the organic anion transporter (OATP1B1) is encoded by what gene

A

SLCO1B1

74
Q

what is the fx of the organic anion transporter (OATP1B1)

A

hepatic uptake of weakly acidic drugs and endogenous compounds (statins, MTX, and bilirubin)

75
Q

over ______________ nonsynonymous single nucleotide polymorphisms have been identified in the OATP1B1 transporter –> _______________ function

A

40; decreased

76
Q

____________________ is a common reduced function polymorphism of the OATP1B1 that reduces the transport of its substrates in vitro and in vivo

A

rs4149056

77
Q

the reduced fx polymorphism of rs4149056 to the OATP1B1 transporter results in an amino acid change = _______________. This change is associated with a reduced ____________________

A

Val174Ala; membrane expression

78
Q

the rs4149056 polymorphism of the OATP1B1 –> reduced function of the transporter at what alleles?

A

SCLCO1B1*5, 15, and 17

79
Q

rs4149056 polymorphism of the OATP1B1 transporter is rare at allele _______, but is common in most european/asian populations at allele ____________

A

5; 15, 17 (haplotypes)

80
Q

___________________ variant of the SLCO1B1 gene for the OATP1B1 transporter increases risk of simvastatin induced myopathy

A

rs4149056

81
Q

if HOMOZYGOUS for the rs4149056 variant there is a _____________% increase in plasma area under the curve for patients

A

221

82
Q

what diplotypes of the would be homozygous for decreased function of the OAT1P1B1 transporter

A

5/5; 5/15; 5/17; 15/15; 15/17; 17/15; 17/17

83
Q

which diplotype of the SLCO1B1 gene has intermediate activity for simvastatin

A

1a or 1b + 5, 15, or 17

84
Q

which diplotype of the SLCO1B1 gene has a low phenotypic activity for the SLCO1B1 gene

A

[5]/[5, 15, or 17]

85
Q

what diplotypes sof SLC01B1hould you presribe a lower dose for simvastatin 40 mg or consider an alternative statin, and/or routine CK monitoring

A

[1a or 1b]/[5, 15, 17]

86
Q

many population based hypersensitivity reactions have been attributed to genetic polymorphisms in the ______________ genes

A

HLA

87
Q

polymorphisms in HLA genes are associated with?

A
  1. stevens-johnson syndrome
88
Q

which HLA gene polymorphisms have been associated with many drug induced hypersensitivity reactions

A
  1. HLA-B
89
Q

HLA polymorphisms are associated with hypersensitivities to what drugs?

A
  1. allopurinol
90
Q

many HLA-________ polymorphisms have been characterized and have varying allelic frequencies depending on racial and ethnic population

A

B

91
Q

selective recognition of particular drug-bound peptides by some HLA-______ polymorphism products results in population selective drug hypersensitivity reactions

A

B

92
Q

pharmacogenomic implications for anesthesia include:

A
  1. neuromuscular blocking agents
93
Q

all inherited causes of pseudocholinesterase deficiency are due to point mutations on chromosome __________

A

3

94
Q

there are ___________ identifiable variants on chromosome 3 –> pseudocholinesterase deficiency

A

20

95
Q

what are the most common variants on chromosome 3 –> pseudocholinesterase deficiency

A
  1. A variant = Asp70Gly
96
Q

if you are heterozygous for atypical pseudocholinesterase gene your succinylcholine will prolonged by ____________x; if homozygous prolonged up to __________x longer

A

3-8; 60

97
Q

which pseudochoinesterase deficiency variant is rare

A

S-variant

98
Q

___________ variant –> atypical pseudocholinesterase, if homozygous, have no pseudocholinesterase activity and can have paralysis for up to 8 hours with single induction dose of succinylcholine

A

S

99
Q

what opioids are metabolized by the CYP2D6 enzyme

A
  1. codeine
100
Q

if you are ultra-metabolizer of CYP2D6 –> higher risk of life threatening side effects with which opioids

A
  1. codeine
101
Q

OPRM1 GG genotype requires 93% higher ________________ dose as compared to the OPRM1 AA genotype

A

morphine

102
Q

the ______________ gene codes for the Mu opioid receptor

A

OPRM1

103
Q

P-glycoprotein transporters are found along the ________________, and are encoded by the __________________ gene

A

BBB; ABCB1

104
Q

polymorphisms in the ABCB1 gene (encoding for P-glycoprotein transporters) effect opioid variability on ___________________

A

respiratory depression

105
Q

polymorphisms in the ______________________ gene are what is associated with higher methadone doses for heroin addicts undergoing methadone therapy

A

ABCB1 (gene that encodes for P-glycoprotein transporter)

pharm II: opioids, drugs of abuse, genomics (4 decks)

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