(15) Pharmacogenetics Flashcards
Define genomics
Relating the genome i.e. total DNA/RNA
What is pharmacokinetics vs. pharmacodynamics?
Pharmacokinetics = what the body does to the drug
Pharmacodynamics = what the drug does to the body
What is stratified medicine?
Selecting therapies for groups of patients with shared biological characteristics
What is personalised medicine?
Therapies tailored to the individual
What is germline vs somatic?
Germline = hereditary
Somatic = acquired, in non-germline, not hereditary
Give some examples of genetic variations
- gene amplification
- promoter polymorphisms
- translocations
- deletions, insertions
- single nucleotide polymorphisms (SNPs)
Genetic variations lead to what?
Change in protein (eg. enzyme, transporter, target) structure/activity
This leads to altered outcome to treatment
What is a single nucleotide polymorphism (SNP)?
A variation in a single nucleotide that occurs at a specific position in the genome, where each variation is present to some appreciable degree within a population - the most common type of genetic variation
What effect may SNPs cause?
May change protein structure/activity eg. missense changes
Give 4 different types of inheritance pattern
- autosomal recessive
- autosomal dominant
- X-linked recessive
- mitochondrial inheritance
In autosomal recessive genetic variations that affect drugs, who are the most severe side effects seen in?
In those homozygous for the variant
Heterozygote = less affected or unaffected
Which gender is at risk in X-linked recessive variants?
Males
Who does mitochondrial genetic information come from?
From mother only
Genetic variations can cause effects in what? (concerning drugs/pharmacology)
- absorption
- activation
- altered target
- catabolism (breakdown)
- excretion
NB. drugs may have complex metabolic pathways and single genes are unlikely to explain all variability
What are the consequences of getting in wrong? (genetic variation and drugs)
- inactive drug (poor response/ no response)
- over-active drug (excess toxicities)
- financial costs to health services
How big a problem is ADRs (adverse drug reactions)?
- 6.5% of UK hospital admissions related to ARDs
- median hospital stay = 8 days
- 4% of hospital bed occupancy
- 2.3% of those with ARDs died as a result
Why do most cancer drugs have response rates of around 20%?
Due to genetic variation in the tumour or in the patient
Many patients receive toxic treatments without benefit
How can genetics help in pharmacology?
- identify genetic variations that lead to altered outcomes
- change dose of drug where appropriate
- use a different drug that works better and/or has reduced toxicity
- guide new targeted drug development
- stratified/personalised medicine
- reduce financial costs of inappropriate treatment
What is TPMT?
Thiopurine methyltransferase
What does TPMT do?
Inactivates certain drugs
What drugs does TPMT inactive?
- 6-mercaptopurine and 6-thioguanine (chemotherapies)
- azathioprine (immunosuppressant)
What do TPMT gene polymorphisms do?
Reduce TPMT protein activity
What is the consequence if a patient has variants in both copies of the TPMT gene?
Severe toxicity
What are N-acetyltransferases?
Group of liver enzymes inactivating drugs by acetylation
Different distributions in different ethnic populations
