Pharm Genomics Flashcards
What is PharmacoGENETICS?
Study of how variation in a single gene can affect response to a single drug.
What are the 4 applications for pharmacogenetics?
- Appropriate Pt Selection
- Optomization of drug dosing
- ID Pt risk for adverse events
- Increase efficiency of drug devt of clinical trials
What are the struggles of testing your drug on a diverse population?
Need to test a lot more people to see statistical significance
May be very effective in a select population but drug will never get to market.
What is a mutation?
A difference in the DNA code that occurs in less thn 1% of the population
What is a polymorphism?
Difference in DNA code that occurs in greater than 1% of the population
What is a SNP?
Single nucleotide polymorphism
What is the difference between a synonymous AA and a non-synonymous AA?
Syn- BP change does not cause AA subs
-Decreased transcript stability or aleter splicing
Non syn- Leads to AA substitution
-Change in protein structure, stability, substrate affinity, intro of a stop codon
What is a Copy Number Variation?
A copy number variation. complete deletion or duplication of a particular gene.
What is a Cosmopolitan Polymorphism?
Poly common across all ethnic groups
What is a population polymorhism?
Poly that differ between groups
What is the phenotype to genotype approach?
Directly measure pharmacogenetic trait (warfarin effects on blood coagulation)
What is a Pharmacogenetic trait?
Measurable trait associated with a drug: Enzyme activity Drug levels in bodily fluids Drug metabolites in bodily fluids Physiological Response
What is the Candidate gene approach?
Genotyping a specific gene that is predicted to cause differences
Requires knowledge of cellular mechanism
What is the Genome wide approach?
Doesn’t require knowledge of cellular mechanisms resp. for trait
Unbiased survey of all differences in entire genome bet 2 groups
What are the techniqes used in Genome wide apporach?
Sanger sequencing (gold standard, expensive and time consuming)
SNP Microarrays
Next generation sequencing
What is the SNP Microarray Technique?
Simgle Stranded small fragments of genomic DNA where there are known to be SNPs, fixed to a slide
Ea spot on slide repesents either A or B allele
What is next Generation Sequencing
Allows us to sequence 25 GBases/day or 8 complete genome
Lots of computaional power needed
What are the gene polymorphisms effecting pharm-Kinetics?
Metabolic Ez- CYP2D6 CYP2C19 CYP2C9 DPD (Dohydropyrimidine dehydrogenase) TPMT(Thiopurine methyltransferase) Drug Transporters- Solute Carrier Organic Anion Transporter 1B1(SLCO1B1)
What drugs does CYP2D6 Metabolize?
Tamoxifen
Codeine
Paroxetine
How does CYP 2D6 effect Tamoxifen?
IT metabolizes and ACTIVATES IT! If they are poor metabolizers, they have a higher chance of relapse(best to use another drug(aromatase inhibitor))
How does CYP 2D6 effect Codeine?
it ACTIVATES Codeine by converting it to Morphine. Pt can have either excessive SA or inadequate analgesia.
How does CYP 2D6 effect Paroxetine?
Is INACTIVATED by metabolism.
Poor metabolizers have more SA.
What drug does CYP 2C19 affect?
Clopidogrel
Omeprazole, Lansoprazole
How does CYP 2C19 effect Clopidogrel?
It ACTIVATES Clopidogrel
Poor metabolizers will need to use a different drug
How does CYP 2C19 effect Omeprazole and Lansoprazole(PPI)?
It INACTIVATES these PPIs. Poor metabolizers will have much higher levels
How does CYP 2C9 affect Warfarin?
Warfarin inhibits activtion of VitK.
Slows blood clotting.
CYP 2C9 INACTIVATES Warfarin
Low metabolizers will have risk of bleeding because of buildup of warfarin
What is the effect of VKORC1 on Warfarin?
It is the receptor that Warfarin acts on. Decreased Activity of it will mean less warfarin needed.
What are the Polymorphisms that can effect cancer Tx?
5 fluorouracil
6 mercaptopurine
What is the effect ot DPD on 5 FU?
5 FU is INACTIVATED by DPD.
Low activity of DPD may lead to life threatening myelosupression
What is the Ez that 5FU acts on?
Thymidylate Synthetase
Pharmacodynamic phenotype
What is the difference between pharm-kinetic/dynamic?
Pharmacokinetic is the body having effects on the Drug
Pharmacodynamic isthe effect that the drug has on the body
What Ez acts on 6MP?
TPMT (Thiopurine methyltransferase)
What effect will TPMT have on 6MP?
It INACTIVATES 6MP
What is the effect of SLC01B1 on Simvastatin?
It is a transporter for the drug. Low activity decreases its import into the cell.
Changes to which gene effect response to Albuterol?
ADRB2 increases the body’s response to Albuterol. low activity means they will have less effectiveness of Albuterol
What are the Polymorphisms that can increase thromboembolisms?
Factor V polymorph.
Prothrombin polymorph.
What is the risk of Thromboembolic polymorphisms?
Want to avoid prescribing oral contraceptives.
What is the Mutation that will effect the chance of Adverse reactions to Abacavir?
ABC-HSR
will greatly increase the chance of developing Steven Johnson syndrome.
What mutation can effect Alzheimers drug therapy?
APOE
Absence of this allele will equate to more effective therapy
What are the polymorphic implications in Interferon alpha?
Int-a is a Tx for Heptatitis C Those without SNP poly in IL-28 gene have better response to Interferon
