Pharmacogenomics

Question 1

pharmacogenomics

Answer 1

the study of genetics with regard to drug response

Question 2

pharmacogenomics: pharmacodynamics

Answer 2

is the drug target present? / are there alterations in the target?

Question 3

pharmacogenomics: pharmacokinetics

Answer 3

focuses on specific enzymes that genes express, including CYP enzymes and phase II enzymes. drug transporters are also examined as well.

Question 4

carbamazepine example

Answer 4

allele puts people at increased risk for TEN and Steven Johnson Syndrome.

patient can be tested for this allele. if patient tests positive, avoid carbamazepine.

Question 5

clopidogrel example (pro drug)

Answer 5

PGx testing is done to ID poor metabolizers of CYP2C19

Question 6

warfarin PGx testing

Answer 6

looking for over expressions of CYP2C9 and VKORC1. in these cases, higher doses of warfarin would need to be given in order to achieve desired clinical effect

Question 7

single nucleotide polymorphism

Answer 7

an exchange of one nucleotide pair for another

Question 8

SNPs can happen where

Answer 8

in coding or non coding regions

Question 9

synonymous SNP reaction

Answer 9

change occurs in base pairs, but not in the amino acid it is coded for.

Question 10

non synonymous SNP reaction

Answer 10

changes the amino acid it is coding for

Question 11

A B C D gene reference

gene deletion example

Answer 11

A C D

Question 12

A B C D gene reference

inverted gene sequence example

Answer 12

A upside down B C D

Question 13

A B C D gene reference sequence

copy number variant / amplification example

Answer 13

A A A A A A B C D

Question 14

type of SNPs we are focusing on

Answer 14

SNPs that change clinical outcome

Question 15

nucleotide insertion

Answer 15

stop codon occurs early, alteration in gene’s coding sequence occurs and the frameshift moves to the right by 1 space

Question 16

nucleotide deletion

Answer 16

a nucleotide is deleted and the entire frame shift moves to the left by 1 space.

Question 17

ultra metabolism (UM)

Answer 17

you will metabolize a med much faster than an extensive metabolizer would

Question 18

extensive metabolism (EM)

Answer 18

normal metabolizers of meds. what the meds are made for.

Question 19

Intermediate metabolism (IM)

Answer 19

will metabolize at a lower rate than normal extensive metabolizer.

Question 20

Poor metabolism (PM)

Answer 20

under expression of the CYP or phase II enzymes, unable to process meds as easily. profound decrease in metabolism.

Question 21

intermediate and poor metabolizers both have

Answer 21

a degree of loss of function

Question 22

which metabolizers types are we most concerned about in regards to drug dosing when it comes to a specific enzyme?

Answer 22

ultra metabolizers (UM) and poor metabolizers (PM)

Question 23

in terms of PGx black box labels, what are we looking for?

Answer 23

• if genetic testing is required
• if genetic testing is recommended
• actionable PGx
• informative PGx

Question 24

actionable PGx

Answer 24

will positive results necessitate an action?

Question 25

informative PGx

Answer 25

no action required, just informative

Question 26

resources for PGx testing, etc

Answer 26

PharmGKB | UpToDate

Question 27

CYP2C9 PMs: warfarin (APC)

Answer 27

increased risk of bleeding

Question 28

CYP2C9 PMs: phenytoin (APC)

Answer 28

increased risk of ataxia, unconsciousness, confusion

Question 29

CYP2C9 PMs: anti diabetics (APC)

Answer 29

increased risk of potential hypoglycemia

Question 30

CYP2C19 PMs: clopidogrel (pro drug)

Answer 30

decreased response

Question 31

CYP2D6 UMs: codeine (prodrug)

Answer 31

increased risk of adverse effects

Question 32

codeine is metabolized by CYP2D6. if someone has codeine and is an UM

Answer 32

codeine intoxication bc codeine is a prodrug

Question 33

which two CYP enzymes metabolize codeine?

Answer 33

CYP 3A4 and CYP 2D6

Question 34

which enzyme metabolizes the active metabolite of codeine

Answer 34

CYP 2D6

Question 35

which enzyme metabolizes the inactive metabolites of codeine?

Answer 35

CYP3A4

Question 36

CYP2D6 UM for prodrug

Answer 36

inactive prodrug to active metabolite at quicker rate

Question 37

CYP2D6 PM for prodrug

Answer 37

buildup of inactive prodrug with less of the active metabolite. diminished effect.

Question 38

warfarin's therapeutic index

Answer 38

narrow. | target INR 2.5-3.5

Question 39

if not getting appropriate warfarin response...

Answer 39

may need PGx test

Question 40

onset for clinical effect of warfarin

Answer 40

is delayed. be conservative with early dosing

Question 41

two isomers of warfarin

Answer 41

r-warfarin | s-warfarin

Question 42

which isomer of warfarin is more active?

Answer 42

s-warfarin

Question 43

how are warfarin's isomers metabolized

Answer 43

by phase I CYP enzymes

Question 44

CYP enzymes for R-Warfarin (3)

Answer 44

CYP 1A1 CYP 1A2 CYP3A4

Question 45

CYP enzyme for s-warfarin

Answer 45

CYP 2C9

Question 46

enzyme we are most concerned with in warfarin and why

Answer 46

CYP 2C9 because this is the enzyme metabolizing S-warfarin, the active isomer of warfarin.

Question 47

clotting factors warfarin works on

Answer 47

10 9 7 2 | X IX VII II

Question 48

warfarin works by

Answer 48

targeting VKORC1 and preventing oxidized vit K from being reduced, and thus reducing activated clotting factors in the blood stream.

Question 49

R and S Warfarin's target

Answer 49

VKORC1

Question 50

if a patient is not responding the way you'd expect from a medication

Answer 50

PGx testing may be indicated

Question 51

PM of a CYP3A4 substrate APC will have...

Answer 51

increased clinical effect/buildup of the APC

Question 52

PM of a CYP3A4 substrate pro drug

Answer 52

almost no clinical effect/decreased clinical effect.

Question 53

NAVAGATE - N

Answer 53

Is the drug necessary?

Question 54

NAVAGATE - 3 A's

Answer 54

alternatives (are there alternatives?) appropriate turnaround time acceptance (is there provider/patient acceptance if the test is pos/neg?)

Question 55

NAVAGATE - V

Answer 55

Is there a validated test?

Question 56

NAVAGATE - G

Answer 56

Good evidence - is there evidence regarding regarding what to do with the result?

Question 57

NAVAGATE - T

Answer 57

Test reimbursement - how will patient pay?

Question 58

NAVAGATE - E

Answer 58

Evaluate and document - how will the results be documented?

Question 59

PGx tests for what CYP enzyme re: codeine?

Answer 59

CYP2D6

Question 60

What causes most of the PM phenotype?

Answer 60

null alleles

Question 61

If you have diminished level of VKORC1

Answer 61

Less targets for warfarin to bind to - decrease dose

Question 62

purpose of required genetic testing at pharamacokinetic level

Answer 62

to anticipate polymorphism based kinetic changes that significantly reduce efficacy or cause serious adverse effects

Question 63

Purpose of required genetic testing at a pharmacodynamic level

Answer 63

there is a need to determine whether a therapeutic target exists or there is a need to anticipate polymorphisms unrelated to the target that cause serious adverse effects

Question 64

PGx testing at a pharmacokinetic level looks more at ____ while PGx testing at a pharmacodynamic level looks at

Answer 64

CYP enzymes ; drug targets

Question 65

Imatinib required PGx testing

Answer 65

Pharmacodynamic: | Works only in CML with Philadelphia chromosome-Positive.

Question 66

G6PD deficiency required PGx testing

Answer 66

Pharmacokinetic: life threatening hemolysis while taking rasburicase

Question 67

HLA-B

Answer 67

Human leukocyte antigen-B

Question 68

PGx related to HLAs

Answer 68

If patient has the HLA present for the drug in question, they'll have the adverse skin reaction and you'd need to find an alternative.

Question 69

Why is pgx testing required for carbamazepine?

Answer 69

because if they have the HLA specific to the drug, they'll have a life threatening skin reaction (SJS).

Question 70

G6PD deficiency can predispose patients to what when given certain meds?

Answer 70

hemolytic anemia

Question 71

What is the CYP enzyme which primary metabolizes clopidogrel?

Answer 71

CYP2C19

Question 72

Is clopidogrel an APC or a pro drug?

Answer 72

pro drug

Question 73

PM of 2PC19 when given clopidogrel, a pro drug

Answer 73

diminished effect, risk for clotting

Question 74

PMs of CYP2C19 who are prescribed clopidogrel should...

Answer 74

need a different agent or alternative dosing

Question 75

is warfarin an APC or pro drug

Answer 75

APC

Question 76

is codeine an apc or pro drug

Answer 76

pro drug