Tutorial 9 - Idiosyncratic Reactions

Question 1

What are Type A reactions?

Answer 1

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

Question 2

What are Type B reactions?

Answer 2

Only occur in susceptible individuals
Can occur at any dose
Known as idiosyncratic hypersensitivity reactions
Develop through mechanism unrelated to drug action

Question 3

What does HLA stand for?

Answer 3

Human Leukocyte antigen

Question 4

What is the HLA complex?

Answer 4

A group of genes on chromosome 6 that encode MHC proteins

Includes HLA-A, HLA-B, HLA-C

Question 5

What is the function of HLA molecules?

Answer 5

Present on all nucleated cells

Present pathogenic antigens to CD8 cytotoxic T cells, initiating an immune response

Question 6

What are the names of the 3 hypotheses by which the HLA system is implicated in hypersensitivity reactions?

Answer 6

1. (Pro)Hapten hypothesis
2. Pharmacological interaction with immune receptor (p-i) hypothesis
3. Altered self-repertoire hypothesis

Question 7

What is Abacavir?

Answer 7

Antiretroviral (reverse transcriptase inhibitor) used to treat HIV
Prodrug

Question 8

What is the mechanism of action of Abacavir?

Answer 8

Metabolised (phosphorylated) into carbovir triphosphate which becomes incorporated into viral DNA instead of dGTP
DNA replication becomes terminated when incorporated

Question 9

What are the symptoms of an idiosyncratic hypersensitivity reaction to Abacavir?

Answer 9

GI Symptoms
Malaise
Fever
Fatigue
Cough
Rash

Question 10

What is the cause of idiosyncratic hypersensitivity reactions to Abacavir?

Answer 10

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

Question 11

Which hypothesis do the idiosyncratic hypersensitivity reactions of Abacavir and Carbamazepine fit?

Answer 11

Altered self-repertoire hypothesis

Question 12

What is Carbamazepine?

Answer 12

Tricyclic drug

Used to treat bipolar disorder, epilepsy and trigeminal neuralgia

Question 13

What is the mechanism of action of Carbamazepine?

Answer 13

Blocks voltage gated Na+ channels, keeps them in inactivated state to prevent rapid and repetitive action potentials

Question 14

What are the symptoms of an idiosyncratic hypersensitivity reaction to Carbamazepine?

Answer 14

Cutaneous adverse drug reaction (cADR) i.e. skin lesions, itching, fever

Question 15

What is the cause of idiosyncratic hypersensitivity reactions to Carbamazepine?

Answer 15

Certain alleles of HLA-A and HLA-B

Question 16

Example of a Type A reaction

Answer 16

Ultra rapid metabolisers of codeine, with increased CYP2D6 activity, may experience overdose of morphine
Respiratory depression
Loss of consciousness
Nausea and vomiting

Question 17

What is the (pro)hapten hypothesis?

Answer 17

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

Question 18

What is the (p-i) hypothesis?

Answer 18

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

Question 19

What is the altered self-repertoire hypothesis?

Answer 19

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

Question 20

What does each part of HLA-DRB1*13:01 mean?

Answer 20

HLA = HLA region of chromosome 6
DRB1 = the DRB1 gene
13 = the allele group
01 = the specific allele/variant

Question 21

What is the process by which peptides are presented by HLA molecules?

Answer 21

1. Viral antigen within cell OR self-peptide
2. Attached to a HLA-B molecule in the ER
3. Exported to cell surface (via Golgi)
4. HLA/Peptide complex presented on cell surface, to CD8 cytotoxic T cells
5. If peptide is foreign, immune response initiated

Question 22

Why is there so many HLA variants?

Answer 22

Each variant has a different binding specificity for different amino acids, so will bind different peptides

Question 23

Why do only some people get a hypersensitivity reaction to Abacavir?

Answer 23

Only certain HLA-B variants produce a molecule that Abacavir can bind to