7 Pharmacogenetics Flashcards
Define pharmacogenetics
It explores the genetic variations that lead to changes in pharmacokinetics and pharmacodynamics of the drugs between individuals and across populations
- Pharmacogenetics has introduced the concept of personalised medicines into the practice of medicine
Why may patients fail to respond to treatments/have an adverse drug reaction?
- Metabolism
- Renal function
- Interactions
- Resistance
- Pharmacogenetics
What can pharmacogenetics be divided into:
2 categories:
- Pharmacokinetics:
(how genetic variations affect drug absorption, distribution, metabolism, and elimination (ADME) - Pharmacodynamics:
(how genetic variations at the drug target affect what the drug does to the person?)
Drug targets can include:
- Receptors
- Enzymes
Define polymorphisms
An ability to take many forms
Most common: SNP
- Single nucleotide polymorphism
- Mutations - lead to amino acid substitutions - e.g. sickle cell anaemia
Describe metabolism of drugs in the liver
Liver enzymes
- P450 cytochromes constitute a large family of enzymes. They are involved in metabolism (including drugs)
- Humans have around 60 P450 genes - encoding enzyme
- These genes are responsible for the phase I metabolism of around 60% of all drugs
Explain why there may be differences in metabolism
Due to genetic polymorphisms
Certain drugs, like:
- Warfain, aspirin resistance, clopidogrel, rosuvastatin, codeine/Morphine
Describe the significance of this difference in metabolism (e.g. effects of this)
Effects on the metabolism of:
- Metoprolol - enhanced actions in poor metabolisers
- Fluoxetine - enhanced actions in poor metabolisers
- Codeine - requires metabolic conversion and so reduced response in poor metabolisers
- Tamoxifen (multiple metabolic pathways) - in poor metabolisers impaired conversion to active antagonist and impaired survival in breast cancer
Describe the pharmacogenetic elements that exist with the metabolism of Warfarin (to do with CYP2C9),
and what effects it could have
There exists a CYP2C9 polymorphism, where there is a genetic variation in metabolism of the S-enantiomer of Warfarin
- The polymorphism seen in CYP2CP means that this enzyme has reduced metabolism, meaning there is a decrease in the rate of catabolism of S-warfarin
- This means there is more S-Warfarin in serum, meaning effects + activity of Warfarin (antagonistic effects) is increased (more than intended levels) - this is not good
So, to counteract this - the dosage of Warfarin should be decreased
Describe the dietary effects on Warfarin
Vitamin K foods decrease the effectiveness of Warfarin
e. g. Brussel sprouts, spinach, kale
- Counsel patient not to significantly alter diet once stable in Warfarin treatment
Describe aspirin resistance
Due to incomplete enteric absorption of aspirin
- around 25% of patients are resistant to aspirin (not related to COX enzymes)
- They are also at increased risk of CVD
Describe the clopidogrel
it’s MOA
and how it works
Clopidogrel is a prodrug (needs to be activated)
- it is given to prevent thrombosis
It needs a 2 step activation:
- Oxidation
- Hydrolytic cleavage by PON1 enzyme (Paraoxonase1)
Once the drug reaches the activated stage, it can now act as a platelet inhibitor
Describe how clopidogrel’s pharmacological activity is influenced by genotype
As clopidogrel is a prodrug, the pharmacological activity is influenced by its biotransformation
SO, this can be influenced by genotype
- The gene that codes for PON1, PQN1 Q192R can have a pleomorphism
- This means it can alter the shape, function, and hence activity of PON1 enzymes
- Thus meaning less Clopidogrel is activated
HENCE, there is an increased risk of Thrombosis (on a stent)
Give the problems seen between codeine/morphine and genetic differences (pharmacogenetics)
Codeine only gives mild opiod properties (mild analgesics)
- Most of its analgesia + CNS depressant effects result from its biotransformation to morphine
- This reaction is catalysed by CYP2D6
Poor metabolisers would show no response to the analgesic effects of codeine
- (could be due to changes to CYP2D6 enzyme = poor conversion to morphine)
Describe the pharmacodynamic responses seen to VKOR1 differences
VKOR enzyme activates Vitamine K - which activates clotting factor - coagulation
VKORC1 differences
- Pharmacodynamic
- Vitamin K epoxide reductase complex 1 (VKORC1) is the gene encoding subunit 1 of VKOR
- There are different haplotypes with different Warfarin requirements
So, genetic variations of VKORC1 would mean variations to the effects of Warfarin
- Could lead to bleeding
