Week 8.13: Pharmacogenomics Flashcards
8.1 Pharmacogenomics
Topic; Genetic variation and drug dosage, efficacy and adverse effects, mapping pharmacogenomics variants, prediction of effects
Reading: EPG ch 7
Learning outcomes;
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· <!--[endif]-->Define pharmacogenomics
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· <!--[endif]-->Understand the generic principles of drug action.
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· <!--[endif]-->Understand how genomic variations can affect drug action and drug response.
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· <!--[endif]-->Explain the main clinical application of pharmacogenomics
Defining pharmacogenomics in simple terms it is the study of the effect of genetic variation on drug response;
pharmacology + genomics = pharmacogenomics
1.Principles of drug action
Pharmacology;
Pharmacology; the branch of medicine concerned with the uses, effects, and modes of action of drugs
Designing drugs, for example some kind of drug acting in the brain. The brain is a very well protected part of the body, getting a drug from the gut all the way into the brain – crossing the blood-brain barrier. We need to somehow get that drug into the body. Most of these drugs are small molecules that interact with proteins.
Drug does; ingestion à absorption à distribution (plasma concentration) à metabolism à clearance
Two subsections
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· <!--[endif]-->Pharmacokinetics (PK); what the body does to the drug, when you take in a compound the body does stuff to the drug, breaking it down etc.
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· <!--[endif]-->Pharmacodynamics (PD); what the drug does to the body
Pharmacodynamics (PD) genes
PD genes encode proteins that are drug targets – these proteins are encoded by genes, this is where the genomics comes in.
Two different drug types – drug targets are proteins that the drug binds to either activate (agonist) to inhibit (antagonist fills the void stopping things from binding) function of the protein.
Drugs can be one or other of these things
Certain classes of proteins that are targeted by pharmaceutical companies;
Examples include G protein-coupled receptors, enzymes and nuclear hormone receptors.
Serotonin receptors modulate the release of neurotransmitters and hormones, affecting mood, cognition and sleep.
This makes them targets for many psychoactive agonists and antagonists e.g
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Ø <!--[endif]-->Antidepressants
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Ø <!--[endif]-->Hallucinogens
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Ø <!--[endif]-->Migraine treatments
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Ø <!--[endif]-->Aphrodisiacs
How can genotype affect pharmacodynamics?
Variation in gene sequence causes à protein variation
Inactivation; Variation in binding site domain prevents drug from docking with the protein.
Protein abundance not compatible with that required for correct drug action.
Toxicity; Protein variants binds to drug in such a way that it produces a toxic effect (negative side effects)
These events can be caused by
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· <!--[endif]-->Variations in protein structure i.e coding sequence
Or
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· <!--[endif]-->Variation in protein expression, potentially regulatory regions
It matters a lot where the protein genome variations are but it doesn’t have to be protein coding
Pharmacokinetics (PK) genes (what the body does to the drug)
These genes encode proteins involved in adsorption, distribution, metabolism and elimination of the drug (ADME). We hope to be able to get the protein to help the drug…
Example of how PK proteins might assist drug action
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· <!--[endif]-->Produce the active form of a drug from the ingested compound already inside the body
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· <!--[endif]-->Transport the drug to where it needs to act
The same things are relevant here to in pharmacodynamics
A drug designed with knowledge of the proteins that we expect the drug to come into contact with.
Protein variations may cause unwanted effects;
Inactivity; A protein binds to the drug, rendering it inactive before it reaches its target.
A protein breaks down the drug before it gets to its targets
Toxicity; A protein converts the drugs into a toxic compound
These event can be cause by;
Variations in the genome structure (i.e coding sequence)
Or
Variation in protein expression (potentially regulatory regions)
How does this relate to pharmacogenomics?
An individual’s response to a drug can be considered to be a trait, or phenotype, just like any other genetic trait. You may have an allergy to a particular drug.
Such traits can be found by the same methods, e.g. GWAS. The complications is that we need to give people the drug determine the reaction (e.g their trait). This is difficult to do ethically – more complicated than normal GWAS studies.
How are these traits found?
By the same methods as any other trait, e.g GWAS combined with clinical trials. The complication is that we need to give people the drug determine the reaction (e.g their trait)
Example from a paper about liver toxicity from an antibiotic
SNPs according to their locations and the points show the correlation between differences in the SNPs
Very strong signal (rs2395029) – particular SNP has a high risk for particular drug, from a clinical trial
Just like other traits, these can be;
Qualitative e.g indicative of toxicity
Quantitative e.g indicative of optimal dosage
How is this useful?
“Personalised medicine”
How can we use this concept of pharmacogenomics to help people out?
We can target specific medicine to specific people
We can target specific medicine to specific people
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- <!--[endif]-->Application of pharmacogenomics
If a patient has been genotyped, the genotype can be checked for variants that are known to be related to drug response. Information that may be predicted from the genotype include:
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· <!--[endif]-->Efficacy of the drug in the individual – some drugs can be very expensive no point taking them if they have no/little benefit
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· <!--[endif]-->Susceptibility of the individual to adverse drug reactions – avoiding having an adverse reaction
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· <!--[endif]-->Optimal dose of the drug for the individual (Warfarin)
This is…
“Personalised medicine
stratified medicine
precision medicine”
^ Buzz words over the years, basically using genotype information to decide treatment (prescription)
The drugs used in a different way –
There is another reason why a drug may not work for a particular individual:
Many disease are actually conflated sub-diseases, e.g Alzheimer’s disease ** - symptoms** are the same but molecular cause can vary between individuals.
So, a drug developed to treat one sub-type a disease is unlikely to work on patients with another sub-type
Genotyping can help determine which sub-type of disease an individual has, and wheter a particular treatment will be effective.
Main clinical applications
Predicating efficacy
From example, rs5443, a SNP in the GNB3 gene (which encodes for a signalling protein) on chromosome 1 affects efficacy of Viagra:
Genotype Efficacy
TT 90% of population
CT 50% of population
CC 50% of population
Predicting Adverse drug reactions
ADRs are negative side effects caused by a drug.
ADRs reportedly cause 100,000 deaths per year in the US
Finding ADRs
ADRs and links between these and genotype can be discovered at various stages in drug development process. We can identify ADRs along the way through clinical trials, hopefully picking up things before things get too serious. The number of patients per study;
10 100’s 1,000’s 10,000’s+
If you are only dealing with a small population you are not really getting the wider variability in the community, this pharmacovigilance
Getting the correct dose
Everything is toxic in excess, even water for example if you drink too much water you get swelling in the brain
Getting the correct dose – some drugs are particularly sensitive to the dose, it is very important that the clinician gives you the correct dose
One of the benefits to the patient;
Reduce the risk of having an adverse drug reaction, more likely to be prescribed a drug/dose that works
Benefits to the drug company;
Amount of money spending increasing, but fewer drugs every year being reduced
A company can sell a drug that would not otherwise meet efficacy thresholds
A drug may only be effective in people with a minor allele at a given locus,
10% chance of being effective in the general population VS. 100% effective on 10% of the population (licensable)
