Pharmacogenetics and adverse drug reactions Flashcards
What are intrinsic or Type A adverse reactions?
Predictable on the basis of drug concentrations. More common than idiosyncratic reactions. Usually associated with polymorphisms affecting drug metabolism or transport.
Examples include bleeding due to warfarin dose and liver toxicity due to paracetamol overdose.
What defines idiosyncratic or Type B adverse reactions?
An unusual or exaggerated response to drugs in a few individuals. Difficult to study due to rarity. Affect 1 in 1000 people, potentially serious or fatal. Not predictable based on known drug pharmacology.
Examples include liver toxicity from various drugs and cardiotoxicity.
How common are idiosyncratic adverse drug reactions (ADRs)?
Typically rare, occurring in 1 in 10,000 to 100,000 patients exposed.
Usually not detected before drug licensing; post-marketing surveillance is key.
What is the role of HLA in T-cell responses?
HLA is important in T-cell responses and antigen presentation. MHC (multiple histocompatibility complex) helps in the maturation of T-cells to either helper or cytotoxic cells.
Cytotoxic T-cells can kill host cells and provoke local cellular damage.
What is abacavir hypersensitivity syndrome (AHS)?
A potentially life-threatening immune-mediated reaction occurring in about 5% of patients. Symptoms resolve upon discontinuation of abacavir.
Rechallenge can lead to more severe reactions.
What is the significance of the HLA-B*57:01 allele in abacavir hypersensitivity?
Up to 100% of proven hypersensitivity cases have one or two HLA-B*57:01 alleles.
It is linked to detectable reactions such as fever, rash, GI symptoms, and respiratory distress.
What is the association between carbamazepine and Steven-Johnson Syndrome (SJS)?
Carbamazepine is linked to severe cutaneous adverse drug reactions, including SJS and Toxic Epidermal Necrolysis (TEN).
SJS can occur in up to 10% of patients and may precede hypersensitivity syndrome.
What genetic association is linked with SJS/TEN in East Asians?
HLA-B*15:02 is strongly linked to SJS/TEN in individuals of East Asian and Southeast Asian descent.
Mandatory screening is required in high-risk populations.
What are the clinical implications of HLA genotyping before prescribing carbamazepine?
HLA-B*15:02 testing is required in high-risk ethnic groups to avoid severe adverse reactions.
Alternative AEDs should be considered for patients testing positive.
What is Drug Induced Liver Injury (DILI)?
Rare but serious idiosyncratic toxicity, occurring in 1 in 10,000 to 100,000 patients. Accounts for 20% of hospital admissions due to severe liver injury.
Often requires liver transplant in acute liver failure cases.
What is the association between flucloxacillin and liver injury?
Flucloxacillin is a well-established cause of liver injury and the probable second most important cause of DILI in the UK.
It is a beta-lactamase resistant penicillin used to treat staphylococcal infections.
What is the significance of GWAS in flucloxacillin DILI?
GWAS provided evidence for HLA-B*57:01 association with flucloxacillin DILI, though sensitivity and specificity of genotyping as a predictor are lower compared to abacavir hypersensitivity.
Only 1 in 100 people with B*57:01 would show flucloxacillin-related DILI.
What is the mechanism of abacavir hypersensitivity?
T cells from HLA-B*57:01 positive donors proliferate when stimulated with abacavir, leading to inappropriate immune response due to altered antigen presentation.
Genotyping is required before abacavir treatment.
What is the role of HLA class 1 and class 2 genes?
HLA class 1 genes present endogenous antigens to CD8+ cytotoxic T cells; class 2 genes present exogenous antigens to CD4+ helper T cells.
Critical for adaptive immune response activation.
What are the common drugs associated with idiosyncratic ADRs with pharmacogenetic findings?
Examples include:
* Hypersensitivity/skin rash: Abacavir, carbamazepine, allopurinol
* Hepatotoxicity: Flucloxacillin
* Myopathy: Statins
* Cardiotoxicity: Variety of compounds
What is the relationship between HLA-B*58:01 and allopurinol?
HLA-B*58:01 is strongly linked to SJS/TEN in individuals of East Asian descent and is associated with multiple carbamazepine-induced hypersensitivity reactions.
More common in European and Japanese populations.
What is the role of Amoxicillin in relation to penicillin resistance?
Knocks out B-lactamase gene and causes a defect causing penicillin resistance
Amoxicillin is a penicillin antibiotic that acts as a B-lactamase inhibitor.
What is the underlying mechanism for HLA and DILI?
Inappropriate T-cell response
HLA proteins interact with drugs in a manner that can trigger an immune response.
What is a key feature of statin myopathy?
Ranges from mild to very rare but life-threatening rhabdomyolysis
Statin myopathy encompasses various levels of muscle toxicity.
Which gene variant is associated with simvastatin myopathy?
SLOC1B1*5 variant
This variant is linked to decreased hepatic uptake of statins, resulting in higher plasma levels.
What is the consequence of decreased activity of the SLOC1B1 transporter?
Higher plasma level of simvastatin drug
This may lead to increased uptake into muscle tissue.
What does the D85N polymorphism in KCNE1 indicate?
Increased risk of drug-induced QT prolongation
This polymorphism has an odds ratio of 9 for this complication.
What gene polymorphisms are associated with the response to interferon-a in Hepatitis C treatment?
Polymorphisms adjacent to IL-28B gene
These polymorphisms help predict treatment efficacy in patients.
What was the strongest effect found in the GWAS for biphosphate-induced osteoporosis of the jaw?
CYP2C8 polymorphism
This gene’s role in inflammation contributed to its association with the disease.
What do drugs that prolong cardiac repolarization typically block?
Outward ion channels, primarily K channels
This blockage can lead to serious cardiac events such as ventricular fibrillation.
What is torsades de pointes?
A form of polymorphic ventricular tachycardia with QT prolongation
It is often associated with drug-induced long QT syndrome.
In the study by Paulussen et al., what percentage of patients had non-synonymous polymorphisms?
Approx. 10%
This refers to patients with drug-related long QT syndrome.
What does the NOS1AP gene affect in relation to QT interval?
Length of QT interval
Variants in this gene have been linked to QT prolongation effects.
What SNP in NOS1AP is associated with QT prolongation effects of Verapamil?
RS10494366
This variant significantly enhances the QT prolongation effect of the drug.
What is the general conclusion regarding common genetic variants and drug-induced cardiotoxicity?
They are not important predictors
This conclusion arises from recent GWAS studies which found no genome-wide significance.
What is a challenge in screening for rare variants related to cardiotoxicity?
Sample sizes being too small
Smaller sample sizes limit the power of studies to detect significant associations.
