Week 4 Pharmogenomics Module

Question 1

what are three benefits of pharmogentics?

Answer 1

avoid adverse drug reactions, improve efficacy of pharmocologic agents, improve cost-effectiveness of pharmocologic therapy

Question 2

what is a locus?

Answer 2

a specific position of a gene on a chromosome (the same locus can have different alleles)

Question 3

what is an allele

Answer 3

a specific gene inherited from one parent. each autosomal locus has two alleles one from mother, one from father)

Question 4

what is allele frequency?

Answer 4

fraction of the total popn that carries a specific allele

Question 5

what is a polymorphism?

Answer 5

2 or more alterantive sequences are present in a more than 1% of popn. (SNPs!)

Question 6

contrast pharmacogenetics and pharmacogenomics

Answer 6

pharmacogenetics: focus on single genes
pharmocogenomics: focus on mulitple genes

Question 7

polymorphisms impact PF, PD, both?

Answer 7

both

Question 8

A pt arrives at the hospital with a rash, the dr give him an oitment. the pt asks if this topical ointment can have systemic effects? what is your reply?

Answer 8

yes, it can be absorbed through the skin and have systemic effects

Question 9

in order for a drug to impact the CNS, what must occur?

Answer 9

drug must cross blood-brain barrier

Question 10

other than the kidney, how else can drugs be excreted?

Answer 10

into the bile where they can be reabsorbed in the SI or voided in feces

Question 11

what occurs in phase 1 drug metabolism? who is the major player

Answer 11

oxidation, reduction, hydrolysis. Cytochrome P450 enzymes

Question 12

what occurs during phase 2 metabolism?

Answer 12

addition of large polar groups

Question 13

what does CYP stand for

Answer 13

Cytochrome P450

Question 14

given: CYP2C198, what does “8” mean? what does *1 refer to?

Answer 14

a different allele of that specific CYP gene. *1 refers to the wt/most abundant allele

Question 15

which CYP gene metabolizes the most of the commonly used genes? does it have much genetic variability?

Answer 15

CYP3A4/5/7, with little genetic variability

Question 16

why do we care about preventing ADRs?

Answer 16

they are a leading cause of death in hospitalized pts. hundreds of thousands of deaths annually in US alone

Question 17

CYP2C9: role, acts on?

Answer 17

hydroxylates (phase I). Acts on warfarin, phenytoin, tolbutamide

Question 18

warfarin role, indications?

Answer 18

anti-cagulant. Use for pulmonary embolism, heart valve replacement, knee or hip replacement

Question 19

phenytoin role

Answer 19

anticonvulsant

Question 20

tolbutamide role

Answer 20

insulin release stimulator

Question 21

what protein does Warfarin target? what protein metabolizes warfarin?

Answer 21

Targets: VKORC1

Metabolized by: CYP2C9

Question 22

Does the FDA require screening for VKORC1 and CYP2C9 alleles prior to prescribing warfarin?

Answer 22

no, although a 28% decrease in hospitalization is seen when this information is used.

Question 23

individuals who have GG in VKORC1 and 1/1 are recommended to take 5 to 7 mg of Warfarin, whereas individuals who are AA in VKORC1 and 3/3 are recommmended to take 0.5 to 2 mg of wararin. what accounts for this?

Answer 23

the GG 1/1 metabolize warfarin better and are less prone to ADRs and can therefore take a higher dose.

Question 24

what are 4 drugs metabolized by CYP2D6? which is a pro-drug?

Answer 24

antispychotic, antidepressants, metoprolol (antihypertensive), tamoxifen (anti-cancer, pro-drug)

Question 25

what drugs inhibit the activity of CYP2D6? 4

Answer 25

cocaine, fluoxetine, paroxetine, protease inhibitors

Question 26

CYP2D6 has 51 different alleles with varying enzyme activity; what are the four metabolizer categories of CYP2D6?

Answer 26

``` Poor metabolizer (PM) intermediate metabolizer (IM) Efficient metabolizer (EM) Ultrarapid metabolizer (UM) ```

Question 27

a mutation that increased the copy number of the CYP2D6 gene (CYP2D6*2xn) would likely be classified as a...what type of mutation is this?

Answer 27

Ultra metabolizer, GOF

Question 28

A drug is metabolized and inactivated in the body. If a person is known to be a UM for the drug, how would you augment their dose? what if they were a PM?

Answer 28

increase dose because they are an Ultra metabolizer (will get rid of drug faster) decrease dose because they are a PM (drug stays longer)

Question 29

a pro-drug is metabolized and activated in the body. if a person is known to be a UM for the drug, how would you augment their dose?

Answer 29

decrease their dose to prevent too much active drug in the system

Question 30

what is the active form of Tamoxifen? what is unique about Tamoxifen?

Answer 30

Endoxifen, it is a pro-drug

Question 31

does the FDA require genetic testing prior to Tamoxifen use?

Answer 31

no

Question 32

three patients: a EM, IM, and PM for Tamoxifen. Each are given the same dose. which has the best change of survival?

Answer 32

EM>IM>PM

Question 33

individuals with G6PD deficiency (a major cause of hemolytic anemia) have an increased risk of hemolytic reaction when taking what drug? does the FDA recommend genetic testing prior to treatment?

Answer 33

Rasburicase. yes

Question 34

patients with HLA-B*1502 allele have an increased risk of developing life-threatening Steven-Johnson syndrome when taking what? does the FDA recommend prior genetic testing?

Answer 34

Carbamazepine (seizure disorder drug), yes

Question 35

patients with HLA-B*5701 have an increased risk of developing severe hypersensitivity rxns when taking what? does the FDA recommend prior genetic testing?

Answer 35

abacavir (HIV treament), yes

Question 36

pts with TPMT-deficiency have an increased risk of myelotoxicicty when taking what? does the FDA recommend prior genetic testing?

Answer 36

Azathioprine, yes

Question 37

what is the role of TPMT?

Answer 37

phase 2 inactivation of thiopurines

Question 38

thiopurines are used to treat what?

Answer 38

suppress immune system

Question 39

low level of TPMT will lead to what if the normal dosage of thiopurine is taken?

Answer 39

leukopenia (decrease plasma WBCs)

Question 40

In general, when a person is deficient/mutant in a gene, when do ADRs occur?

Answer 40

when they are given a drug that is normally metabolized by the deficient/mutant gene

Question 41

what is the efficacy of a drug?

Answer 41

the max response achievable from a drug treatment

Question 42

when does Imatinib have an increased efficacy? is testing done prior to treatment?

Answer 42

when treating C-KIT positive GI tumors. yes

Question 43

when does Maraviroc have an increased efficacy? is testing done prior to starting treatment?

Answer 43

treating pts with CCR5-tropic HIV-1 infection. Yes

Question 44

Trastuzumab has increased efficacy when treating what type (genetic) of breast cancer? is testing done prior to treatment?

Answer 44

HER-2 positive. yes

Question 45

what is the idea behind using genetics to imprice efficacy of drugs?

Answer 45

test for the genetic status prior to determine how likely they are to benefit from the treatment