Tutorial 9 - Idiosyncratic Reactions Flashcards
What are Type A reactions?
A predictable adverse reaction based on the drug mechanism of action
Most common type of adverse reaction
Can affect any individual if exposure is high enough
What are Type B reactions?
Only occur in susceptible individuals
Can occur at any dose
Known as idiosyncratic hypersensitivity reactions
Develop through mechanism unrelated to drug action
What does HLA stand for?
Human Leukocyte antigen
What is the HLA complex?
A group of genes on chromosome 6 that encode MHC proteins
Includes HLA-A, HLA-B, HLA-C
What is the function of HLA molecules?
Present on all nucleated cells
Present pathogenic antigens to CD8 cytotoxic T cells, initiating an immune response
What are the names of the 3 hypotheses by which the HLA system is implicated in hypersensitivity reactions?
- (Pro)Hapten hypothesis
- Pharmacological interaction with immune receptor (p-i) hypothesis
- Altered self-repertoire hypothesis
What is Abacavir?
Antiretroviral (reverse transcriptase inhibitor) used to treat HIV
Prodrug
What is the mechanism of action of Abacavir?
Metabolised (phosphorylated) into carbovir triphosphate which becomes incorporated into viral DNA instead of dGTP
DNA replication becomes terminated when incorporated
What are the symptoms of an idiosyncratic hypersensitivity reaction to Abacavir?
GI Symptoms Malaise Fever Fatigue Cough Rash
What is the cause of idiosyncratic hypersensitivity reactions to Abacavir?
Abacavir changes the binding specificity of the HLA-B
Causes it to bind abnormal peptides that become recognised by CD8 cytotoxic T cells
Triggers an autoimmune reaction
Which hypothesis do the idiosyncratic hypersensitivity reactions of Abacavir and Carbamazepine fit?
Altered self-repertoire hypothesis
What is Carbamazepine?
Tricyclic drug
Used to treat bipolar disorder, epilepsy and trigeminal neuralgia
What is the mechanism of action of Carbamazepine?
Blocks voltage gated Na+ channels, keeps them in inactivated state to prevent rapid and repetitive action potentials
What are the symptoms of an idiosyncratic hypersensitivity reaction to Carbamazepine?
Cutaneous adverse drug reaction (cADR) i.e. skin lesions, itching, fever
What is the cause of idiosyncratic hypersensitivity reactions to Carbamazepine?
Certain alleles of HLA-A and HLA-B
Example of a Type A reaction
Ultra rapid metabolisers of codeine, with increased CYP2D6 activity, may experience overdose of morphine
Respiratory depression
Loss of consciousness
Nausea and vomiting
What is the (pro)hapten hypothesis?
The drug binds to the peptide that is presented on the HLA molecule. This forms a hapten that is recognised by T cells as an entirely new/foreign antigen, so triggers an immune response
What is the (p-i) hypothesis?
The drug binds to the HLA molecule away from the peptide, but this interferes with the antigen presentation process and triggers a T cell immune response
What is the altered self-repertoire hypothesis?
The drug binds to the ‘binding cleft’ between the HLA molecule. This alters the specificity of the HLA molecule, resulting in presentation of novel peptides. Recognised by T cell, immune response triggered
What does each part of HLA-DRB1*13:01 mean?
HLA = HLA region of chromosome 6 DRB1 = the DRB1 gene 13 = the allele group 01 = the specific allele/variant
What is the process by which peptides are presented by HLA molecules?
- Viral antigen within cell OR self-peptide
- Attached to a HLA-B molecule in the ER
- Exported to cell surface (via Golgi)
- HLA/Peptide complex presented on cell surface, to CD8 cytotoxic T cells
- If peptide is foreign, immune response initiated
Why is there so many HLA variants?
Each variant has a different binding specificity for different amino acids, so will bind different peptides
Why do only some people get a hypersensitivity reaction to Abacavir?
Only certain HLA-B variants produce a molecule that Abacavir can bind to
