Genetic variability in drug response: on target and off target effects Flashcards
What are some of the consequences of ADR’s?
- Long term toxicity e.g. osteoporosis
- Teteragenicity (cause defects in developing fetus) e.g. cleft lip and palate
-Allergic reactions e.g. rash
How do we classify ADR’S and what do these classifications include?
ADR’S are either Type A or Type B.
Type A = Pharmatoxicological effects, effects ‘related’ to the main pharmacology of the drug.
Type B = Hypersensitivity reactions, ones that are ‘unrelated’ to the main pharmacology of the drug and therefore unpredictable.
What do Type A adverse reactions include?
Toxic effects
side effects
secondary effects
drug interactions
What effects do type B adverse reactions have?
immune mediated (allergic) or non-immune effects (non-allergic)
What are they types of immune mediated reactions, how do we classify them?
There are 4 types.
Type 1 and 2 are immediate allergic reactions e.g. nut allergy leading to anaphylaxis, or the development of hives.
Type 3 are immune complex reactions
Type 4 are T-cell mediated, these intense reactions can occur weeks after exposure.
What are the 4 types of T-cell mediated reactions to drugs?
They are classified into 4 groups again, from A to D.
A monocytic inflammation
B Eosinophilic inflammation
C Cytotoxic t-cells
D Neutrophilic inflammation
What are the 3 immunological mechanisms of drug hypersensitivity? (theories) simple outline pls
drawing diagram could be good.
needs simplfiying
normal process. HLA allele present on all cells, peptide binds and is recognised as foreign. Initiating immune reaction,
- pharmacological interaction concept- non-covalently bound drug binds to t-cell receptor. t-cell recognises it as non self and response begins.
in hapten/pro hapten theory,
- Antigen presenting cell takes up drug hapten process and presents it as haptenated receptor to T-cell producing immune response.
- Altered peptide repertoire = non-covalently bound drug (to cell membrane) isn’t presented instead a novel self peptide alters the repertoire of peptides that can bind to the celft of t-cell. that repertoire becomes recognised as non-self and triggers immune response.
What is HLA?
Allele “barcode” that allows your immune system to recognise your cells as ‘self’. sits on your skin cells.
Outline an example of severe ADR’s. What class of adverse reaction is it?
Steven Johnson’s syndrome (SJS)
idiosyncratic reaction, unrelated to drug dose or pharmacology so a Type B reaction.
- certain drugs cause widespread skin blistering due to an immune response, triggered only when genetically predisposed.
- on a spectrum of severity with up to 10% being SJS, and 30% or more being necrolysis.
1 in 3 will die
What region causes predisposition for most ADR’s? Why is it significant?
MHC region on chromosome 6.
- contains around 150 genes many of which are involved in autoimmune or inflammatory diseases. 40% involved in immune system/t-lymphocytes.
Why would MHC region on chr 6 be hard to reliably genotype?
It is highly polymorphic, the large amounts of variation are necessary as this area will code for the proteins that give the unique “barcode” that the immune system recognises as self.
What is the HLA protein and what does it do?
A protein with a binding pocket in which drugs and other peptides can bind amongst amino acid residues in a specific configuration. This binding allows peptides to bind within and then to the t-cell receptors which illicit immune response.
Give an example of off target pharmacology, causing SJS
The drug Nevirapine was used in sub-saharan Africa to treat a HIV infected population. The study showed a 1 in 100 incidence of SJS/TEN. Usually the incidence is recorded at 1 in 10,000. The variant HLA-C*04:01 lead to nearly 5x more risk of getting SJS with nevirapine than those without that allele.
Give a real-life example of why pre-treatment screening is so beneficial.
- Previous studies had concluded that the allele HLA-B*1502 was responsible for a genetic association with SJS when treated with carbamazepine(epilepsy drug) in asians.
- Patients with the allele across 3 studies were on avergae 55x more likely to experience SJS. upon taking carbamazepine.
- The 7.7% of people that had the allele were advised not to take the drug while the rest did.
- The treatment after being observed for two months prior observed zero instances of SJS/TEN. most seen was a mild rash in 4.3%. almost completely eradicated the risk!
What is a test we can do to improve the safety of the drug.
Pre-treatment screening to remove people genetically predisposed to ADR’s before they are exposed saving lives and money. e.g. in taiwan. no cases of SJS were observed after screening when at least 10 were expected.
