Pharmacogenetics Flashcards
What are genes?
Unit of information encoding a specific trait
What is inheritance?
Transmission of traits from parent offspring
What is phenotype?
Physical manifestation of genetic information
What is pharmacogenetics?
The study of the genetic basis for the difference between individuals
What is polymorphism?
Genetic variation that occurs with a frequency >1% in ethnically diverse population
What are the different types of polymorphisms?
SNPs
Repetitive DNA sequences
What does polymorphism alter?
The expression level or conformation of a drug-related protein
What does the outcome of genetic variation depend on?
Where in the genome changes
What do SNPs result in?
Alteration in amino acid sequence of protein
What could happen to protein structures if a SNP occurs?
Phenotypic differences between the subjects, such as variation in response to medication
What does SNP stand for?
Single nucleotide polymorphism
Why is pharmacogenetics important for pharmacy?
Patients can suffer adverse effects due to genetics
Adverse reactions can cause death
Severe adverse effects = withdrawal of blockbuster drugs
At what stages can genetic variation affect a patient’s response to a drug?
Metabolism
Target response
Catabolism + excretion
Why can metabolism be affected by genetic variation?
2 phases of drug metabolism
Phase 1 = cytochrome P450 enzymes
Phase 2 = enzymes controlling drug excretion
Why can target response be affected by genetic variation?
Process or pathway targeted responds differently
eg. Tyrosine kinase inhibitors
Why can catabolism + excretion be affected by genetic variation?
Individuals differ in the rate at which they clear active drug, can lead to adverse drug reactions
What are cytochrome P450s?
Major enzymes involved in drug metabolism + bioactivation
What are differences in metabolism due to?
CY2D6 polymorphisms
What codeine?
Commonly used opioid
Prodrug
Must be metabolised into morphine for activity
Where is cytochrome P450 metabolising enzyme?
Liver
What does a prodrug need to work?
Metabolism
What is an active drug inactivated by?
Metabolism
What happens if a prodrug has a poor metaboliser phenotype?
Poor efficacy
Possible accumulation of prodrug
What happens if an active drug has a poor metaboliser phenotype?
Good efficacy
Accumulation of active drug can produce adverse effects
May need lower dose
What happens if a prodrug has a ultra-rapid metaboliser phenotype?
Good efficacy
Rapid effect
What happens if an active drug has a ultra-rapid metaboliser phenotype?
Poor efficacy
Needs greater dose or slow release formulation
What is the main rate limiting step in TCA metabolism mediated by?
CY2D6 isoenzyme
What happens if you have a functional impairment of CY2D6 isoenzyme?
Lead to toxic levels occurring
What is the most widely prescribed oral anticoagulant drug?
Warfarin
How is Warfarin activated?
By a coagulation test to ensure adequate yet safe dose is taken
What serious adverse effects of Warfarin can occur?
Levels too high = haemorrhage
Levels too low = thrombosis or embolism
What is Warfarin a mix of?
S- and R-warfarin
BOTH isoforms are active
What is S-warfarin catalysed by?
Mainly CYP2C9
What is R-warfarin catalysed by?
CYP1A2 + CYP3A4
What are the 2 common CYP2C9 polymorphisms?
Arg144Cys
IIe358Leu
What is genetic variation of Warfarin associated with?
Decreased CYP2C9 activity
When is it more common to have decreased CYP2C9 activity?
Patients requiring a lower dose of Warfarin (increased risk of haemorrhage), shown to have 1 or more of these alleles
What do the FDA recommend for before giving Warfarin?
Genotyping for CYP2C9 + VKORC1
Describe azathioprine metabolism
Converted to 6-meracaptopurine
Converted to inactive form by xanthine oxidase + TPMT
What is seen as the future of current medicine?
Personalised medicine
What are the ethical implications of pharmacogenetics?
Do people want to know?
Will treatment be appropriate?
How informed does pharmacist need to be?
Who would have access to personal genetic info?
