Pharmacogenomics

Question 1

What is pharmacogenomics?

Answer 1

The study of how genetic differences between patients account for differences in their responses to a drug

Question 2

How do genetic differences affect drug response?

Answer 2

Pharmacokinetics
Pharmacodynamics
Co-morbidities

Question 3

Examples of single nucleotide polymorphisms that cause disease(s)

Answer 3

Sickle cell aneamia
(some) cystic fibrosis
Familial hypercholesterolemia

Question 4

What is pharmacogenetics?

Answer 4

The use of genomic information to study individual responses to drugs

Question 5

What is abacavir?

Answer 5

Anti-retroviral

Question 6

Explain abacavir’s hypersensitivity reaction (HSR).

Answer 6

Hypersensitivity reaction; fever, rash, GI and respiratory symptoms typically appear within 6 weeks of initiation of therapy.

HLA-B*5701 allele is more common in patients who have a suspected HSR to abacavir.

Therefore HLA-B*5701 screening can be used to identify patients at high risk for abacavir HSR

Question 7

Azathioprine pharmacogenomic properties

And therapeutic use

Answer 7

pro-drug for 6MP

6MP blocks purine metabolism, kills WBCs and has a narroww therapeutic index

It treats leukaemia and IBD
However killing WBCs increases the risk of sepsis.

Azathioprine is metabolised into 6MP by glutathione

Thiopurine s-methyltransferase enzyme (TPMT)
converts the drug into inactive metabolite

This enzyme can have polymorphisms

Therefore dose requirement is necessary for aziothioprine

(polymorphisms; no activity, normal activity, some activity)

Question 8

Clopidogrel

Answer 8

Antiplatelet drug 
Prevents platelet activation = reduces arterial thrombosis

Question 9

Clopidogrel pharmacogenomic considerations and cyp enzymes

Answer 9

Clopidogrel is metabolised by CYP2C19
Genetic variations can be dependent on ethnicities

Heterozygous - 1 CYP2C19 reduced function allele = higher risk of in-stent thrombosis

Homozygous - 2 CYP2C19 reduced function allele = more higher risk of in-stent thrombosis
(homozygous = very little metabolism of clopidogrel into active metabolite)

Question 10

Codeine pharmacogenomic considerations

Answer 10

Gene CYP2D6 makes proteins responsible for breaking down analgesics e.g. codeine

CYP2D6 breaks down codeine to morphine

CYP2D6 variant = less active = lack of conversion = less effective

CYP2D6 (rapid metabolisers)

Question 11

Warfarin pharmacogenomic considerations

Answer 11

Warfarin reduces thrombosis
It has a narrow therapeutic index
However increases the risk of haemorrhage

Warfarin metabolism is dependent on CYP2C9

Warfarin has 2 isoforms: R, S warfarin

S warfarin is more potent and metabolised by CYP2C9

Patients with CYP2C9 mutations require smaller doses
of warfarin

Question 12

Vitamin K reductase (VKORC1) variations

Answer 12

VKORC1 can have a single nucleotide polymorphism
It reduces the expression of vitamin K reductase
*Individuals with this SNP have a lower requirement of warfarin