4.11 - Pharmacogenomics Flashcards
Define pharmacogenomics
Study of the impact of genetic polymorphisms on drug response
- To personalize/individualize drug therapy
What does pharmacogenomics promise?
The possibility that knowledge of a patient’s DNA sequence could be used to enhance pharmacotherapy
___ are the most common gene variations associated w/ drug response
SNPs
Where can gene modifications occur?
- In the gene
- In the promoters
- Enhancers
- Splice sites
- Sites that control gene transcription or mRNA stability
What types of variations are associated with pharmacokinetics?
- Variation in enzymes of drug metabolism
- Variation in transporters
What genetic variations are associated w/ pharmacodynamics?
Variation in drug targets
Pharmacodynamic and pharmacokinetic interactions have a ___ effect
Polygenic
Genetic variation in ___ affects HLA polymorphism
Immune system function
What are phase 1 and 2 of pharmacokinetics?
- Phase 1 = oxidation/reduction enzymes
- Phase 2 = conjugation enzymes
CYP2D6 converts codeine to
Morphine
In CYP2D6, ___ function is associated with increased toxicity
Increased
IN CYP2D6, decreased function is associated w/ ___
Decreased analgesia
Reduced function in thiopurine S-methyltransferase (TPMT) is associated w/
Increased thiopurine (azathioprine, 6-mercaptopurine, 6-thioguanine) toxicity
In CYP2D6, ultra-rapid metabolizer phenotype has what dosing recommendation?
- Alternative analgesic
- Increased formation of morphine following codeine admin leads to higher risk of toxicity
In CYP2D6, ___ metabolizer phenotype has a standard dosing rate
Extensive metabolizer phenotype
In CYP2D6, which metabolizer phenotype should you monitor closely for lack of analgesic response due to reduced morphine formation?
Intermediate metabolizer phenotype
In CYP2D6, Poor metabolizer phenotype has what dosing recommendation?
- Alternative analgesic
- Reduce morphine formation following codeine administration
- Avoid high doses
CYP2C9 has what affected drug?
Warfarin
Thiopurine S-methyltransferase has what affected drugs?
Azathioprine, mercaptopurine, and thioguanine
CYP2D6 has what affected drugs?
Antidepressents
beta-adrenergic antagonists
Codeine
Debrisoquine
Dextromethorphan
Genetic differences in ___ genes can dramatically alter drug disposition and response
Transporter
Example of an organic anion transporter (OATP)1B1 encoded by the SLCO1B1 gene, that’s responsible for the hepatic uptake of many drugs
Statins
Statins ___ cholesterol levels
decrease
Examples of pharmacodynamics variation in drug targets
- beta2-adrenergic receptor
- some asthma patients don’t respond to 5-lipoxygenase inhibitor Zileuton
Why is it difficult to predict warfarin an ideal dosing?
Genetic variations in both the drug receptor and drug metabolism
Which 2 drugs undergo polymorphism that can affect patient response to warfarin?
CYP4F2 and CYP2C9
Polymorphism in ___ leads to warfarin resistance or warfarin sensitivity phenotype
VKORC1
Severe hypersensitivity reaction associated w/ the HLA-B*5701 allele in HIV patients taking ___
Abacavir
What is abacavir?
A reverse transcriptase inhibitor
Predrug testing for ___ nearly eliminates hypersensitivity reaction w/ abacavir
HLA-B*5701
Genome-Wide Association Study (GWAS)
Analysis of complete genomes of a population of individuals w/ regard to the frequency of association of specific allelic variations w/ a specific phenotype
SNPs analysis through GWAS can be used to predict ___
Predict patients who will have altered metabolism of statins, increasing the frequency of statin-induced myopathy
