Genetic susceptibility to adverse drug reactions Flashcards
what are the two types of adverse drug reaction
Intrinsic (type A) or Idiosyncratic (type B)
what are Intrinsic ADR (and give two examples)
-predictable on the basis of drug conc
Bleeding due to warfarin dose
Liver toxicity due to paracetamol overdose
what are idiosyncratic ADR and give 2 examples
- Not predictable based on known drug pharmacology. Not related to dose but is very serious.
Liver toxicity due to a range of different drugs (at the recommended dose)
Cardiotoxicity
why are Idiosyncratic ADR dangerous
Not normally detected before drug is licensed
Give 4 example of Idiosyncratic ADRs with pharmacogenetics finding on susceptibility
Hypersensitivity/Skin rash = (Abacavir, carbamazepine, allopurinol)
Hepatoxicity = (Flucloxacillin)
Myopathy = (Statins)
Cardiotoxicity
what is Rhabdomyalysis
muscle tissue is broken down and then releases its proteins and electrolytes into the blood.
what gene is liked to serious drug reaction
HLA gene
Class I genes (A,B,C) = expressed on most
Class II genes (DR,DQ,DP) = expressed on most cells
what do HLA proteins normally do
present peptide antigens to T cells
what is Abacavir widely used for
antiretroviral reverse-transcriptase inhibitor
what happen when patients who have previously developed hypersensitivity reaction in relation to HLA and Abacavir are re-challenged
more severe reactions occur
Up to 100% of proven hypersensitivity cases have __ though not all patients with this genotype will show detectable reaction
one or two HLA B*57:01 alleles
what % of patients develops hypersensitivity reaction from abacavir
5
where are hypersensitivity reactions seen
Skin and lungs
T cells from HLA-B*57:01-positive donors only proliferate and differentiate in vitro when stimulated with __ giving __ cytotoxic T cells
abacavir
CD8-positive
Activated abacavir/metabolite binds directly to B*57:01 gene product and this leads to …
Inappropriate recognition of “self peptides” and inappropriate T cell response
What is required prior to abacavir treatment
B*57:01
True or False, the binding of abacavir and HLA-B*57:01 is covalent
false
Why do the Chinese population show signs of Stevens-Johnson Syndrome
usually positive for HLA-B*15:02
What ADR are seen in carbamazepine
Stevens Johnson Syndrome
skin rashes
Which populations are screened for B*15:02 before carbamazepine treatment
East Asian
what HLA gene is responsible for ADR in Europeans and Japanese when given carbamazepine
A*31:01
When given allopurinol, what gene is responsible for Stevens-Johnson syndrome in the chinese population
HLA B*58:01
What are the two top causes of drug induced liver injury
Augmentin (Amoxicilin-clavulante)
Flucloxacillin
Which gene+allele is associatied with Flucloxacillin and drug induced liver injury
HLA B*57;01
How does Flucloxacillin hypersensity differ to abacavir
- less sensitivity and specificity
- Covalent binding between Flucloxacillin and B*57:01 gene product
what are some HLA and related gene associations that have DILI-underlying mechanism
Inappropriate T-cell response
Specific HLA protein interacts with drug complex to peptide inappropriately and presents this to T cells causing reaction
Local cellular damage
What are some idiosyncratic ADR of statins
mild myalgia to Rhabdomyolysis
What gene is linked to statin induced myopathy and what is its effect
SLCO1B1 variant (*5) - associated with decreased hepatic uptake
SLCO1B1 encodes main inward hepatic statin transporter
what is seen in People with SLCO1B1*5
higher plasma level of drug, due to decreased activity
may result in increased uptake into muscle tissue
There are some ADR involved with cardiac repolarisation, what do most of these drugs do
- Prolong cardiac repolarisation
- blockage of an outward ion channel with K channels
why do some individuals have a higher risk of suffering from cardiac ADR when given certain drugs
Slight genetic abnormality can caused increased risk of sudden death due to drug-induced ventricular fibrillation
what are the two types of cardiac effects seen with blocking K+ channels
- QT intervals can be prolonged and delay depolarisation
- Torsades de pointes where depolarisation is completly disrupted
How do polymorphism affect cardiac ADR
contribute but not completely explained
and only represent about 10% cases
Evidence of polymorphism in hERG (coded for potassium channel) and other other genes.
hERG is screened for
what gene SNP’s have been linked to affecting the length of GT intervals
NOS1AP (nitric oxide synthase 1 activating protein) affects QT length in population study
Nitric oxide signalling may affect cardiac repolarization
Is there any genome wide significant between Polymorphisms and drug induced cardiotoxicity
No
