Pharmacogenetics Flashcards
Define genomics
Relating to the genome i.e. total DNA/RNA
Define pharmacokinetics
What the body does the drug
Define pharmacodynamics
What the drug does to the body
Define stratified medicine
Selecting therapies for groups of patients with shared biological characteristics
Define personalised medicine
Therapies tailored to the individual
Are somatic mutations inherited?
No
Define pharmacogenetics
The study of inherited genetic differences in drug metabolic pathways which can affect an individuals response to drugs.
e.g. may result in a positive response to a drug therapy or an adverse drug reaction.
What type of genetic variations can lead to an altered outcome to treatment?
- SNPs (most common)
- Deletions, insertions
- Translocations
- Promoter polymorphisms
- Gene amplification
These all lead to change in protein (e.g. enzyme, transporter, target) structure/activity
What is a SNP?
Single nucleotide polymorphism
A single nucleotide adenine (A), thymine (T), cytosine (C), or guanine (G) is replaced
May change protein structure/activity e.g. missense changes
What is a missense change?
A point mutation in which a single nucleotide change results in a codon that codes for a DIFFERENT amino acid.
What is mitochondrial inheritance?
Always inherited maternally
How can genetic variants affect the metabolism of drugs?
- Absorption
- Activation
- Altered target
- Catabolism (breakdown)
- Excretion
N.B. Drugs may have complex metabolic pathways and single genes are unlikely to explain all variability
What % of UK hospital admissions are related to adverse drug reactions (ADRs)? How much does this cost the NHS?
- 5%
- 3% of those admitted with ADRs died as a result
Costs the NHS approximately £1 Billion/year
What altered outcomes can pharmacogenetics lead to?
- Inactive drug
- Overactive drug (toxic)
How is pharmacogenetics implicated in cancer drugs?
Most cancer drugs have response-rates of ~20% due to genetic variation in the tumour or patient.
How can genetics help this problem?
- 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
- Reintroduce effective drugs which have ADR in few patients
- Stratified/personalised medicine
- Reduce financial costs of inappropriate treatment
Cancers contain genetic variations that are not present in germline DNA (i.e. somatic). How can these variations be used in treatment?
These variations are potential targets (i.e. as drug would have an effect on cancer cells but not normal cells)
What is Trastuzumab? What is its brand name? What is it used to treat? Mechanism of action?
Brand name: Herceptin
Used to treat: Breast cancer
Mechanism: a monoclonal antibody to the HER2 receptor
How is HER2 (human epidermal growth factor receptor 2) and cancer related?
20% of breast cancers have over-expression of HER2 (human epidermal growth factor receptor 2)
What are BRAF inhibitors? What is an example of one? What are they used to treat?
What: BRAF inhibitors are drugs that can shrink or slow the growth of metastatic melanoma in people whose tumours have a BRAF mutation
Example: Vemurafenib
Used to treat: Melanoma
How is the BRAF mutation and cancer related?
~50% of melanomas have a somatic mutation in the BRAF gene
Why is chemo not used for melanoma?
Melanoma is notoriously resistant to chemotherapy treatment
A new targeted therapy Vemurafenib recently showed a 48% response rate compared with 5% for standard chemotherapy
What is Thiopurine methyltransferase (TPMT)?
An enzyme that inactivates certain drugs
E.g. Azathioprine (immunosuppressant used in organ transplantation and autoimmune disease)
What is Ivacaftor? What is it used to treat?
CF drug
Used to treat: cystic fibrosis in people with certain mutations in the CFTR gene
What is Succinylcholine?
Muscle relaxant used in anaesthesia (to stop breathing and facilitate tracheal intubation)
What are Aminoglycosides?
Aminoglycosides are a class of antibiotics used mainly in the treatment of aerobic gram-negative bacilli infections.
What condition can Aminoglycosides lead to?
Aminoglycoside induced hearing loss (mutation in MT-RNR1 gene)
How can Aminoglycoside induced hearing loss occur?
Strongly linked to genetic variations within one particular mitochondrial gene, MT-RNR1
Aminoglycosides appear to generate free radicals within the inner ear, with subsequent permanent damage to sensory cells and neurons, resulting in permanent hearing loss.
What gene variants is warfarin affected by?
Associated with an increased sensitivity to warfarin and lower dose requirements
In 2020, the NHS Genomic Medicine Service becomes fully operational. What will this mean?
Genomic screening and personalised treatments will be the “new normal” in the NHS.
This will enable a better understanding of the links between genes and drug response.
What issues will arise with the NHS Genomic Medicine Service?
a) Genetic data will need to be linked to patient records.
b) Further guidance for patients whose ideal dose, as predicted by their genetics, falls outside the NICE guidelines.
What is the most common type of genetic variant that can affect drug metabolism?
SNPs
What can TPMT gene polymorphisms affect TPMT activity? What can this lead to?
Reduce TPMT protein activity –> can lead to severe toxicity if BOTH copies of the gene have the variant
What proportion of the Caucasian population carry inactivating polymorphisms in TPMT?
10%
What does the TPMT enzyme play a critical role in breaking down?
Thiopurine drugs
How is the mutation in MT-RNR1 gene inherited?
Maternal inheritance (as mitochondrial MT-RNR1 gene)
