Pharmacogenetics Flashcards
Give examples of variations causing adverse reactions
Micro satellites, cnvs, snps
What can these variations cause in pharmacogenerics
Reduced efficacy or cause toxicity
Give an example not in notes of efficacy reduction
Cyp2c19 and clopidegrol
Which enzyme methylates and inactivates 6a mecraptopurine chemotherapy
Tpmt
If tpmt doesn’t methylate 6-mp, what happens
Too much 6-thioguanine nucleotides incorporated into dna and cause apoptosis
This causes adverse effects (see fr)
Which other drug isn’t given if you have tpmt variants
Azathioprine immunosuppressant
Which alleles of tpmt cause reduced or no tpmt activity
*2 and *3
What symptoms do these cause especially if homozygous
Myelotoxicity and neutropenia (FR)
Is tpmt currently recommended as genotyped or look at its enzyme activity so dosing can be changed
Yes for those on 6-mp
What are Cyps
Enzymes in phase 1 metabolism expressed in liver. Metabolism through oxidation
Which drug was first linked to which cyp for efficacy variation
Cyp2d6 with debrisoquine (hypertensive drug)
How common is deficiency of cyp2d6 in uk
6% have it
Autosomal recessive
How many variations in cyp2d6
70 but 4 common ones
What are ultrametabolisers of cyp2d6 reducing efficacy too
Those with extra copies up to 13
Which drug isn’t now given to children due to cyp2d6 variation
Codeine (activated to morphine by the CYP)
Why is this
Because mothers who are UM one in a case study killed her baby by having too much active morphine in the breast milk.
How are PM cyp2d6 also not given codeine
Not effective as doesn’t metabolise it into morphine
Which cyp metabolises s-warfarin anticoagulant
Cyp2c9
There are mainly 2 alleles involved in slower action of the enzyme. Which is slowest and works on more than warfarin
*3
*2 also slows cyp2c9 down but not as much
What would giving too much of warfarin do eg if PM. This is leading cause of drug deaths
Haemorrhage / bleeding
Since it is an anticoagulant
Which enzyme recycles reduced vitamin K so that clotting factors can be activated
VKOR
How does warfarin stop this
Blocks action of vkor so no reduced vitamin K is present for clotting
Why is it important vkor is also genotyped for warfarin
Cyp2c9 only accounts for 20% of variability
There is an snp significant for vkor. How does this affect dosage
It alters a tf binding site so there is lower expression of vkor overall so less warfarin is necessary
Which combination of Cyp2c9 and vkor variant would need lowest warfarin dose
3/3 and AA (homo for the vkor variant G-A)
Are both these genotypings recommended by fda
Yes
What is mdr1
A p-gp which is an atp dependant efflux pump
Why is it important
Removes harmful substances eg xenobiotics
What disease is associated with reduced mdr1 function variation
Ibd (see notes)
Which treatment for CML has been shown to be affected for dosage with mdr1 variants
Imatinib
Why would loss of function mdr1 polymorphisms reduce dosage
Because not being effectively cleared and causing toxicity
Which drug has been linked to myopathies due to gene variation
Statins (look into the gene variation in notes)
How are tumour variations in pharmacy genetics different
Not inherited but somatic
Why is Pharmacogenerics in cancer important
Need specific tumour markers/genotypes to see if target specific treatment will work eg her2
Which cancer in 25% of subtypes have amplified her2
Breast cancer
What is her2
An egfr (tk receptor)
What does it do to activate signalling proteins
Dimerises, auto phosphorylates and then phos tyrosine on docking proteins to activate pathways
Give example of pathway
Pi3k- akt
And ras, rafmekerk
How does herceptin work
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
How do you test if tumour cells through number of her2 protein compared to gene copies
IHC
Fish/cish for gene copies
See Fr
What is imatinib used to treat
CML (and others see in book but mainly cml)
What characteristics does cml have
Increased wbc and undifferentiated
95% have a chr association of cml disease. What is this
Translocation between chr 9 and 22 between bcr genes and c - abl
What is abl
Tyrosine kinase
What does it phosphorylate and what does this cause
Tyrosine on other proteins causing signalling cascaded for cell survival, inactivating differentiation, proliferation
Where is the regulatory region normally if not Philadelphia in c-abl
On n terminus. Tightly regulates the signalling cascades but this is lost through the translocation
What other forms of bcr-abl are there
For ALL and AML (different breakpoints in bcrabl)
Due to constant proliferation, what happens to cells which further expands cml
Mutations in genes like p53
What does imatinib block
The atp binding site which abl uses to phosphorylate proteins = no signal transduction
