Pharmacogenetics Flashcards
What is meant by the term “genomics”?
relating to the genome
i.e. total DNA/RNA
What is the difference between pharmacokinetics and pharmacodynamics?
pharmacokinetics:
this is what the body does to the drug
pharmacodynamics:
this is what the drug does to the body
What is the difference between stratified medicine and personalised medicine?
stratified medicine:
selecting therapies for groups of patients with shared biological characteristics
personalised medicines:
therapies are tailored to the individual
What is the difference between the terms “germline” and “somatic”?
germline:
another word for hereditary
somatic:
acquired and not hereditary as it is not in germline cells
What is meant by ‘pharmacogenetics’?
the study of inherited genetic differences in drug metabolic pathways which can affect an individuals response to drugs
Why is pharmacogenetics important in medicine and patient care?
differences in drug metabolic pathways may result in a positive response to a drug therapy or an adverse drug reaction
it also plays an important role in offering a stratified approach to improve patient care
What are the genetic variations that may affect drug metabolism?
What is the outcome?
What is meant by a single nucleotide polymorphism?
a common type of genetic variation that may change protein structure/activity
e.g. missense changes
What types of patterns of inheritance are seen in genetic variations that affect drug metabolism?
autosomal recessive:
- most severe side effects are seen in those homozygous for the variant
- heterozygote is less affected or unaffected
autosomal dominant:
- a single copy of the variant is enough to cause the problem
X-linked recessive:
- males are carriers of the variant at risk
mitochondrial inheritance:
- inherited from the mother only
What 5 areas of drug metabolism are affected by genetic variation?
- absorption
- activation
- altered target
- catabolism (break down)
- excretion
drugs have complex metabolic pathways and single genes are unlikely to explain all variability
What are the consequences of giving someone the “wrong” drug?
- the drug may remain inactive and there will be a poor/no response
- the drug may be over-active and excess toxins lead to an adverse reaction
- financial costs to health services
What is a problem relating to pharmacogenetics and cancer treatment?
most cancer drugs have response-rates of 20% due to genetic variation in the tumour of the patient
many patients receive toxic treatments without benefit
How can genetics help in prescribing drugs?
if predictive biomarkers are analysed, treatment response can be predicted
this leads to allocation of the ideal treatment the first time round
What are the benefits of using genetics to determine a patient’s response to a particular drug?
- change dose of drug where appropriate
- use a different drug that works better and/or has reduced toxicity
- guide new targeted drug development
- reduce financial costs of inappropriate treatment
- allow for stratified and personalised medicine
How does thiopurine methyltransferase interact with some drugs?
TPMT inactivates certain drugs:
azathioprine:
- immunosuppressant used in organ transplantation and autoimmune disease
6-mercaptopurine & 6-thioguanine:
- used in chemotherapies
How do thiopurine methyltransferase gene polymorphisms affect protein activity?
TPMT gene polymorphisms reduce TPMT protein activity
severe toxicity if both copies of the gene have the variant
What causes cystic fibrosis?
What is the purpose of Ivacaftor therapy?
biallelic mutation of the CFTR gene
Ivacaftor therapy can significantly improve symptoms
e.g. lung function, reduce sweat chloride concentrations
How does Ivacaftor therapy affect CFTR channel activity?
In what genotype is improvement seen with this therapy?
therapy enhances CFTR channel activity , i.e. increases probability of an open channel
significant improvement seen in patients with G551D genotype (hetero- or homozygous)
no improvements are seen in homozygous F508del
What is the use of succinylcholine?
it is related to the poison curare
it is a muscle relaxant used in anaesthesia (to stop breathing) and usually wears off after a few minutes
In which patients should succinylcholine not be given to?
Rare BCHE gene variant homozygotes have reduced butyrylcholinesterase activity
the effects of succinylcholine may last for an hour or more and there is a risk of death if artificial ventilation is not continued
What is the role of mitochondrial MT-RNR1 gene?
it encodes mitochondrial 12s rRNA
What is aminoglycoside induced hearing loss?
What mutation is present?
G > A mutation at nucleoside position 1555 causes non-syndromic hearing loss at later ages
mutation changes the structure of the rRNA to resemble E-coli 16S rRNA
aminoglycosides are more likely to bind to patients rRNA, leading to an increased risk of hearing loss at a younger age
How is aminoglycoside induced hearing loss inherited?
through maternal inheritance
this accounts for 30% of tendency to aminoglycoside toxicity
