T5

Question 1

pharmacogenomics

Answer 1

study of how genetic variances in a genome can influence medication and drug response

Question 2

variance in alleles

Answer 2

single nucleotide polymorphism (SNP) - base pair substitutions that occur in a genome
insertions or deletions of base pairs
star system: used to describes version of a gene

Question 3

star system

Answer 3

*1: “normal” version
alternative versions of the gene that deviate from normal, are numbered
x N can be used to denote multiple copies of an allele

Question 3

diplotype

Answer 3

combination of genotypes from both chromosomes

Question 4

pharmacogene

Answer 4

genes that encode
-drug metabolizing enzymes
-drug transport molecules
-drug targets

Question 5

phase 1 enzymes

Answer 5

cytochrome P450 enzymes
metabolize >75% of all prescription drugs

Question 6

small changes in the genetic base pairs may result

Answer 6

in differences in the expression or function of the pharmacogene

Question 7

phase II enzymes

Answer 7

conjugation of medication or metabolite with another compound

Question 8

ultrarapid metabolizer

Answer 8

active drug: less or no effect
prodrug: more effect (toxicity)

Question 9

rapid metabolizer

Answer 9

active drug: slightly less effect than normal
prodrug: slightly more effect than normal

Question 10

extensive metabolizer

Answer 10

both active drug and prodrug exert expected effects

Question 11

intermediate metabolizer

Answer 11

active drug: slightly more effect than normal
prodrug: slightly less effect than normal

Question 12

poor metabolizer

Answer 12

active drug: more effect (toxicity)
prodrug: less or no effect

Question 13

epigenomics

Answer 13

heritable patterns of gene expression NOT attributable to change in the primary DNA sequence
ex. histone modification, DNA methylation

Question 14

precision medicine

Answer 14

goal is to “fit” the drug to the individual patient
takes into consideration the heterogeneity of the patient population and the target disease process
recent advances in rapid genomic sequencing and reduced cost of sequencing

Question 15

goals of precision medicine

Answer 15

maximize efficacy
minimize toxicity
predict response to therapy
improve patient outcomes

Question 16

types of pharmacogenomic testing

Answer 16

single gene or panel: tests for only one or a series of allele mutations (affordable)
whole genome sequencing: reduced risk of missing rare variant (costly)

Question 17

pre-emptive testing

Answer 17

genetic testing occurs prior to initiation of drug therapies
usually multiple genes or panel testing
enhances treatment precision
most common in chemotherapy treatment

Question 18

reactive testing

Answer 18

genetic testing that occurs after a reaction or adverse effect
usually single gene testing
trial and error based prescribing
more common in general practice

Question 19

23andMe has FDA approval for

Answer 19

CYP2C19 genotyping with regards to citalopram and clopidogrel

Question 20

phase I enzymes

Answer 20

CYP2C19
CYP2D6
CYP2C9
dihydropyrimidine dehydrogenase (DPD)

Question 21

CYP2C19

Answer 21

enzyme known to metabolize numerous acidic drugs
-proton pump inhibitors
-antidepressants
-antiepileptics
-antiplatelets
(clopidogrel, prodrug)

Question 22

CYP2C19 and clopidogrel

Answer 22

poor metabolizer and intermediate metabolizer
-less or no drug converted to its active form
-inadequate antiplatelet activity -> use alternative antiplatelet agent

ultrarapid metabolizer
-drug is converted more quickly to its active form
-increased risk of bleeding -> standard dose and monitor

Question 23

CYP2D6

Answer 23

involved in the metabolism of up to 25% of all drugs
-beta blockers
-antidepressants
-antipsychotics
-opioid analgesics (codeine, prodrug of morphine)

Question 24

CYP2D6 and codeine: poor metabolizer

Answer 24

less or no drug converted to its active form inadequate pain relief -> use alternative analgesic morphine could be an appropriate alternative since it is not metabolized by CYP2D6

Question 25

CYP2D6 and codeine: intermediate metabolizer

Answer 25

less drug is converted to its active form risk of inadequate pain relief -> standard dose and monitor

Question 26

CYP2D6 and codeine: ultrarapid metabolizer

Answer 26

drug is converted more quickly to its active form increased risk of respiratory depression -> use alternative analgesic

Question 27

CYP2C9

Answer 27

acts on acidic drugs reduced function alleles *2 and *3 associated with reduced drug metabolism

Question 28

warfarin

Answer 28

vitamin K antagonism used for prevention and treatment of thromboembolic disorders narrow therapeutic range goal INR 2-3 or 2.5-3.5 dose titration based on INR readings

Question 29

VKORC1

Answer 29

vitamin K epoxide reductase complex subunit 1 drug target of warfarin reduced function allele results in increased sensitivity to warfarin

Question 30

warfarin CYP2C9 poor metabolizer

Answer 30

increased bleed risk and lower doses needed

Question 31

warfarin CYP2C9 rapid metabolizer

Answer 31

impaired efficacy and higher doses needed

Question 32

low expression of VKORC1

Answer 32

lower warfarin doses needed to occupy all available targets

Question 33

high expression of VKORC1

Answer 33

higher warfarin doses needed to occupy all available targets

Question 34

dihydropyrimidine dehydrogenase (DPD)

Answer 34

first and rate limiting step in breakdown of fluoropyrimidine chemotherapy agents 5-fluorouracil (5-FU) toxicity is a significant concern

Question 35

DPD and 5-fluoracil (5-FU)

Answer 35

reduced activity -impaired ability to clear toxic metabolites -reduce dose by 50% complete deficiency -unable to clear toxic metabolites -alternative agent should be used

Question 36

phase II enzymes

Answer 36

UGT1A1 TPMT

Question 37

uridine 5-diphosphoglucuronosyltransferease (UGT1A1)

Answer 37

involved in hepatic excretion of small molecules into the bile

Question 38

UGT1A1 and Irinotecan

Answer 38

chemotherapy for metastatic carcinoma of the colon or rectum enzyme plays a role in inactivation of the active metabolite decreased function of UGT1A1 have an increased risk of toxicity

Question 39

thiopurine S-methyltransferase (TPMT)

Answer 39

responsible for pharmacologic deactivation of thiopurine drugs

Question 40

azathioprine

Answer 40

used as immune altering and chemotherapy agent reduced TPMT activity is associated w increased risk

Question 41

glucose 6-phosphate dehydrogenase (G6PD)

Answer 41

rate limiting step in pentose phosphate pathway X linked inheritance pattern

Question 42

rasburicase

Answer 42

used to treat elevated uric acid levels in patients receiving chemotherapy alternative therapy should be used for patients with G6PD deficiency

Question 43

human leukocyte antigen (HLA)

Answer 43

HLA genes encode a cell surface protein that enables the immune system to distinguish self proteins from foreign proteins polymorphisms in HLA genes are attributed to population based hypersensitivity reactions

Question 44

hypersensitivity reactions

Answer 44

antigens form to a drug or its active metabolites

Question 45

severe hypersensitivity reactions include

Answer 45

drug induced liver injury stevens-johnsen syndrome toxic epidermal necrosis

Question 46

UGT1A1 reduced activity

Answer 46

Gilbert syndrome