Adverse Drug Reactions Flashcards
What are the types of adverse drug reactions?
Intrinsic/ type A
idiosyncratic/ type B
Describe what an intrinsic adverse drug reaction is
Predictable on the basis of drug concentrations
Describe an idiosyncratic adverse drug reaction
Not predictable based on drug pharmacology
Not usually related to the dose
Rare but often serious
What is key to detecting idiosyncratic adverse drug reactions
Post marketing surveillance as they’re not normally detected before drug is licensed
Old
What idiosyncratic ADRs are associated with Abacavir, carbamazepine, allopurinol
Hypersensitivity/ skin rash
What idiosyncratic ADRs are associated with flucloxacillin
Hepatoxicity
What idiosyncratic ADRs are associated with statins
Myopathy
What idiosyncratic ADR is associated with a variety of compounds
Cardiotoxicity
What results in the maturation of T- cells
Presentation of the MHC
What happens after the T-cell matures
Become either cytotoxic or helper cells
Cytotoxic more harmful as they can kill host cell
The type of T-cell that matures depends on what
The HLA class protein which is presenting the antigen
What are the HLA class I genes expressed on most cells
A, B and C genes
What are the HLA class II genes expressed on most cells
DR, DQ and DP genes
What genotype has proven to show hypersensitivity to Abacavir
One or two HLA B*57:01
Not all patients w this genotype will show a detectable reaction
What happens when T cells from HLA-B*57:01-positive donors are stimulated with abacavir
Proliferate and differentiate giving CD8-positive cytotoxic T cells
How does activated abacavir or its metabolite cause an inappropriate T cell response
Binds directly to B*57:01 gene product and this leads to inappropriate recognition of self peptides
What 2 drugs can induced Stevens-Johnson syndrome (SJS)
Carbamazepine and allopurinol
What allele is associated with SJS induced by CBZ
HLA B*15:02
Usually present in certain East Asian populations e.g chinese
Europeans and Japanese: A*31:01
What allele is associated with SJS induced by allopurinol
Chinese: HLA B*58:01
Minor effects in Eastern Europeans
What is flucloxacillin
Beta-lactamase resistant penicillin with isoxazlyl ring
Which gene is associated with flucloaxacillin DILI
HLA-B*57:01
But doesn’t bind the same way abacavir does
Therefore sensitivity and specify is genotyping lower as predictor
What is the mechanism of DILI due to HLA and related gene associations
Inappropriate T-cell response
Specific HLA protein interacts w drug complex to peptide inappropriately
Presents this to T-cells causing a reaction
= local cellular damage
Describe statin-induce myopathy
Ranges from mild myalgia to life threatening rhabdomyolysis
What gene has shown an important role in myopathy relating to simvastatin
SLCO1B1 variant
= decreased hepatic uptake
What is the role of SLCO1B1
Encodes main inward hepatic statin transporter
What is the effect of the *5 variant of SLCO1B1
Risk allele
Higher plasma level of drug in those with decreased activity
May equal increased uptake into muscle tissue = muscle toxicity
How can some drugs prolong cardiac repolarisation
Usually due to blockage of an outward ion channel with K channels
Which individuals have an increased of sudden death due to drug-induced ventricular fibrillation
Slight genetic abnormality in K+ channels
More serious abnormalities associated with adult sudden death
What do studies on drug induced long-QT show
Polymorphisms are contributing but are not a complete explanation for cardio-toxicity
Only represent about 10% of cases
Which gene affects the length of QT interval
NOS1AP
Nitric oxide signalling may affect cardiac repolarisation
in which patients is NOS1AP most common in
Those showing QT prolongation in response to several drugs
