Pharmacogenetics

Question 1

Give examples of variations causing adverse reactions

Answer 1

Micro satellites, cnvs, snps

Question 2

What can these variations cause in pharmacogenerics

Answer 2

Reduced efficacy or cause toxicity

Question 3

Give an example not in notes of efficacy reduction

Answer 3

Cyp2c19 and clopidegrol

Question 4

Which enzyme methylates and inactivates 6a mecraptopurine chemotherapy

Answer 4

Tpmt

Question 5

If tpmt doesn’t methylate 6-mp, what happens

Answer 5

Too much 6-thioguanine nucleotides incorporated into dna and cause apoptosis

This causes adverse effects (see fr)

Question 6

Which other drug isn’t given if you have tpmt variants

Answer 6

Azathioprine immunosuppressant

Question 7

Which alleles of tpmt cause reduced or no tpmt activity

Answer 7

*2 and *3

Question 8

What symptoms do these cause especially if homozygous

Answer 8

Myelotoxicity and neutropenia (FR)

Question 9

Is tpmt currently recommended as genotyped or look at its enzyme activity so dosing can be changed

Answer 9

Yes for those on 6-mp

Question 10

What are Cyps

Answer 10

Enzymes in phase 1 metabolism expressed in liver. Metabolism through oxidation

Question 11

Which drug was first linked to which cyp for efficacy variation

Answer 11

Cyp2d6 with debrisoquine (hypertensive drug)

Question 12

How common is deficiency of cyp2d6 in uk

Answer 12

6% have it

Autosomal recessive

Question 13

How many variations in cyp2d6

Answer 13

70 but 4 common ones

Question 14

What are ultrametabolisers of cyp2d6 reducing efficacy too

Answer 14

Those with extra copies up to 13

Question 15

Which drug isn’t now given to children due to cyp2d6 variation

Answer 15

Codeine (activated to morphine by the CYP)

Question 16

Why is this

Answer 16

Because mothers who are UM one in a case study killed her baby by having too much active morphine in the breast milk.

Question 17

How are PM cyp2d6 also not given codeine

Answer 17

Not effective as doesn’t metabolise it into morphine

Question 18

Which cyp metabolises s-warfarin anticoagulant

Answer 18

Cyp2c9

Question 19

There are mainly 2 alleles involved in slower action of the enzyme. Which is slowest and works on more than warfarin

Answer 19

*3

*2 also slows cyp2c9 down but not as much

Question 20

What would giving too much of warfarin do eg if PM. This is leading cause of drug deaths

Answer 20

Haemorrhage / bleeding

Since it is an anticoagulant

Question 21

Which enzyme recycles reduced vitamin K so that clotting factors can be activated

Answer 21

VKOR

Question 22

How does warfarin stop this

Answer 22

Blocks action of vkor so no reduced vitamin K is present for clotting

Question 23

Why is it important vkor is also genotyped for warfarin

Answer 23

Cyp2c9 only accounts for 20% of variability

Question 24

There is an snp significant for vkor. How does this affect dosage

Answer 24

It alters a tf binding site so there is lower expression of vkor overall so less warfarin is necessary

Question 25

Which combination of Cyp2c9 and vkor variant would need lowest warfarin dose

Answer 25

3/3 and AA (homo for the vkor variant G-A)

Question 26

Are both these genotypings recommended by fda

Answer 26

Yes

Question 27

What is mdr1

Answer 27

A p-gp which is an atp dependant efflux pump

Question 28

Why is it important

Answer 28

Removes harmful substances eg xenobiotics

Question 29

What disease is associated with reduced mdr1 function variation

Answer 29

Ibd (see notes)

Question 30

Which treatment for CML has been shown to be affected for dosage with mdr1 variants

Answer 30

Imatinib

Question 31

Why would loss of function mdr1 polymorphisms reduce dosage

Answer 31

Because not being effectively cleared and causing toxicity

Question 32

Which drug has been linked to myopathies due to gene variation

Answer 32

Statins (look into the gene variation in notes)

Question 33

How are tumour variations in pharmacy genetics different

Answer 33

Not inherited but somatic

Question 34

Why is Pharmacogenerics in cancer important

Answer 34

Need specific tumour markers/genotypes to see if target specific treatment will work eg her2

Question 35

Which cancer in 25% of subtypes have amplified her2

Answer 35

Breast cancer

Question 36

What is her2

Answer 36

An egfr (tk receptor)

Question 37

What does it do to activate signalling proteins

Answer 37

Dimerises, auto phosphorylates and then phos tyrosine on docking proteins to activate pathways

Question 38

Give example of pathway

Answer 38

Pi3k- akt

And ras, rafmekerk

Question 39

How does herceptin work

Answer 39

Mab binds her2 in cells where it’s over expressed
This stops signalling for cellular proliferation etc

Also now a foreign cell targeted by adcc by NK cells

Question 40

How do you test if tumour cells through number of her2 protein compared to gene copies

Answer 40

IHC

Fish/cish for gene copies

See Fr

Question 41

What is imatinib used to treat

Answer 41

CML (and others see in book but mainly cml)

Question 42

What characteristics does cml have

Answer 42

Increased wbc and undifferentiated

Question 43

95% have a chr association of cml disease. What is this

Answer 43

Translocation between chr 9 and 22 between bcr genes and c - abl

Question 44

What is abl

Answer 44

Tyrosine kinase

Question 45

What does it phosphorylate and what does this cause

Answer 45

Tyrosine on other proteins causing signalling cascaded for cell survival, inactivating differentiation, proliferation

Question 46

Where is the regulatory region normally if not Philadelphia in c-abl

Answer 46

On n terminus. Tightly regulates the signalling cascades but this is lost through the translocation

Question 47

What other forms of bcr-abl are there

Answer 47

For ALL and AML (different breakpoints in bcrabl)

Question 48

Due to constant proliferation, what happens to cells which further expands cml

Answer 48

Mutations in genes like p53

Question 49

What does imatinib block

Answer 49

The atp binding site which abl uses to phosphorylate proteins = no signal transduction