Genetic susceptibility to adverse drug reactions

Question 1

what are the two types of adverse drug reaction

Answer 1

Intrinsic (type A) or Idiosyncratic (type B)

Question 2

what are Intrinsic ADR (and give two examples)

Answer 2

-predictable on the basis of drug conc
Bleeding due to warfarin dose
Liver toxicity due to paracetamol overdose

Question 3

what are idiosyncratic ADR and give 2 examples

Answer 3

• Not predictable based on known drug pharmacology. Not related to dose but is very serious.
  Liver toxicity due to a range of different drugs (at the recommended dose)
  Cardiotoxicity

Question 4

why are Idiosyncratic ADR dangerous

Answer 4

Not normally detected before drug is licensed

Question 5

Give 4 example of Idiosyncratic ADRs with pharmacogenetics finding on susceptibility

Answer 5

Hypersensitivity/Skin rash = (Abacavir, carbamazepine, allopurinol)
Hepatoxicity = (Flucloxacillin)
Myopathy = (Statins)
Cardiotoxicity

Question 6

what is Rhabdomyalysis

Answer 6

muscle tissue is broken down and then releases its proteins and electrolytes into the blood.

Question 7

what gene is liked to serious drug reaction

Answer 7

HLA gene
Class I genes (A,B,C) = expressed on most
Class II genes (DR,DQ,DP) = expressed on most cells

Question 8

what do HLA proteins normally do

Answer 8

present peptide antigens to T cells

Question 9

what is Abacavir widely used for

Answer 9

antiretroviral reverse-transcriptase inhibitor

Question 10

what happen when patients who have previously developed hypersensitivity reaction in relation to HLA and Abacavir are re-challenged

Answer 10

more severe reactions occur

Question 11

Up to 100% of proven hypersensitivity cases have __ though not all patients with this genotype will show detectable reaction

Answer 11

one or two HLA B*57:01 alleles

Question 12

what % of patients develops hypersensitivity reaction from abacavir

Answer 12

5

Question 13

where are hypersensitivity reactions seen

Answer 13

Skin and lungs

Question 14

T cells from HLA-B*57:01-positive donors only proliferate and differentiate in vitro when stimulated with __ giving __ cytotoxic T cells

Answer 14

abacavir
CD8-positive

Question 15

Activated abacavir/metabolite binds directly to B*57:01 gene product and this leads to …

Answer 15

Inappropriate recognition of “self peptides” and inappropriate T cell response

Question 16

What is required prior to abacavir treatment

Answer 16

B*57:01

Question 17

True or False, the binding of abacavir and HLA-B*57:01 is covalent

Answer 17

false

Question 18

Why do the Chinese population show signs of Stevens-Johnson Syndrome

Answer 18

usually positive for HLA-B*15:02

Question 19

What ADR are seen in carbamazepine

Answer 19

Stevens Johnson Syndrome
skin rashes

Question 20

Which populations are screened for B*15:02 before carbamazepine treatment

Answer 20

East Asian

Question 21

what HLA gene is responsible for ADR in Europeans and Japanese when given carbamazepine

Answer 21

A*31:01

Question 22

When given allopurinol, what gene is responsible for Stevens-Johnson syndrome in the chinese population

Answer 22

HLA B*58:01

Question 23

What are the two top causes of drug induced liver injury

Answer 23

Augmentin (Amoxicilin-clavulante)
Flucloxacillin

Question 24

Which gene+allele is associatied with Flucloxacillin and drug induced liver injury

Answer 24

HLA B*57;01

Question 25

How does Flucloxacillin hypersensity differ to abacavir

Answer 25

- less sensitivity and specificity - Covalent binding between Flucloxacillin and B*57:01 gene product

Question 26

what are some HLA and related gene associations that have DILI-underlying mechanism

Answer 26

Inappropriate T-cell response Specific HLA protein interacts with drug complex to peptide inappropriately and presents this to T cells causing reaction Local cellular damage

Question 27

What are some idiosyncratic ADR of statins

Answer 27

mild myalgia to Rhabdomyolysis

Question 28

What gene is linked to statin induced myopathy and what is its effect

Answer 28

SLCO1B1 variant (*5) - associated with decreased hepatic uptake SLCO1B1 encodes main inward hepatic statin transporter

Question 29

what is seen in People with SLCO1B1*5

Answer 29

higher plasma level of drug, due to decreased activity may result in increased uptake into muscle tissue

Question 30

There are some ADR involved with cardiac repolarisation, what do most of these drugs do

Answer 30

- Prolong cardiac repolarisation - blockage of an outward ion channel with K channels

Question 31

why do some individuals have a higher risk of suffering from cardiac ADR when given certain drugs

Answer 31

Slight genetic abnormality can caused increased risk of sudden death due to drug-induced ventricular fibrillation

Question 32

what are the two types of cardiac effects seen with blocking K+ channels

Answer 32

- QT intervals can be prolonged and delay depolarisation - Torsades de pointes where depolarisation is completly disrupted

Question 33

How do polymorphism affect cardiac ADR

Answer 33

contribute but not completely explained and only represent about 10% cases Evidence of polymorphism in hERG (coded for potassium channel) and other other genes. hERG is screened for

Question 34

what gene SNP's have been linked to affecting the length of GT intervals

Answer 34

NOS1AP (nitric oxide synthase 1 activating protein) affects QT length in population study Nitric oxide signalling may affect cardiac repolarization

Question 35

Is there any genome wide significant between Polymorphisms and drug induced cardiotoxicity

Answer 35

No