Pharmacogenomics Flashcards
What is Pharmacogenetics?
Study of how variation in SINGLE gene affect individuals response to drugs
What is Pharmacogenomics?
Study of how variation in MULTIPLE genes affect individuals’s response to drugs
What are 4 types of Genetic Variation?
Single Nucleotide Polymorphism
Deletion/Insertion
Variable Number Tandem Repeats
Copy Number Variation
What are the 4 Metabolic Phenotypes?
1) Ultra Rapid Metabolisers
2) Extensive Metabolisers
3) Intermediate Metabolisers
4) Poor Metaboliser
What is Ultra Rapid Metaboliser?
Fast Clearance -> Reduced Efficacy
Higher dose required
What is Extensive Metaboliser?
Normal Metaboliser
Standard dose
What is Intermediate Metaboliser?
Slower Metabolism
Dose Adjusment (decrease)
What is Poor Metaboliser?
Slowest Clearance, risk of toxicity
Lower Dose needed
What is Warfarin?
Warfarin is an oral anticoagulant (blood thinner), reduces formation of blood clots (thrombosis)
What is Warfarin Action?
Vitamin K Antagonist, Inhibit the synthesis of Vitamin K dependent clotting factors
Prevent blood clots, reduce risk of stroke and heart attack
What is the Challenges of usage of Warfarin?
Narrow Therapeutic Index - Small changes in Plasma Levels can cause bleeding (toxicity) or clot formation (treatment failure)
Individualised dosing required to balance efficacy and safety
What is Warfarin Mechanism of action?
Warfarin is a mixture of R and S enantiomers
S isomer is more potent than R
Warfarin antagonises Vitamink K dependent clotting Pathways (extrinsic and intrinsic)
- antagonises Clotting Factors II, VII, IX and X
- anticoagulant C and S
TARGETS VITAMIN K EPOXIDE REDUCTASE (VKOR)
What metabolises Warfarin?
CYP29 metabolises S-Warfarin (more potent)
CYP1A1, CYP1A2, CYP2C19 metabolises R Warfarin
What affects Warfarin Clearance?
Genetic Polymorphism in CYP29 gene
CYP291 - Wild Type
CYP292 and 3 - Reduce Function Alleles, Poor Metabolisers, Decreases Warfarin metabolism
What is the effect of Reduce function alleles?
CYP29*2 and 3 cause higher bleeding risk, since Warfarin does not get metabolised, and can further exert anticoagulant effect
What to do for CYP2C9*2 3?
Reduce Warfarin Dose
What is the VKORC1?
VKORC1 gene - Vitamin K epoxide reductase complex subunit 1:
PRIMARY TARGET FOR WARFARIN
Encodes for Vitamin K epoxide reductase which catalyses the rate limiting step in Vitamin K recycling
What is the VKORC1 Variant?
VKORC1 (-1639G>A) Promoter region Polymorphism
What are the VKORC genotypes and Warfarin Sensitivity?
Genotype: Enzyme Expression: Warfarin Sensitivity:
AA Low Increased Sensitivity -> Lower Dose
AG Intermediate Moderate Sensitivity -> Standard Dose
GG High Warfarin Resistant -> Higher Dose
with low VKORC expression, lesser Warfarin needed
What are the factors affecting Warfarin Dose/ response?
1) Ethnicity/Genetics - dose: Asians < Caucasians < African Americans
2) Diet - Consuming Large Amounts of Vitamin K -> higher dose of Warfarin required
3) Medication - FLUCONAZOLE -> Strong CYP2C9 Inhibitor
4) Other Health Conditions
What is Gefitinib?
Inhibit EGFR pathway, showing eficacy in metastatic NSCLC
Gef specfically binds to the tyorsin kinase ATP Cleft, blocking signalling
What are the Pharmacogenetics affecting Gefitinib?
1) Sensitising Mutations (Increase Gef efficacy)
L858R Mutation
2) Resistance Mutation (Decrease Gef efficacy)
T790M
What is Irinotecan?
Cancer Therapy to inhibit Topisomerase I
What is Irinotecan Pharmacokinetics?
Phase I Metabolism-
Irinotecan converted in liver by carboxylesterase into active SN-38
Phase II:
UDP glucuronyltransferase (UGT) inactivates SN38 - SN38G
