Pharmacogenetics

Question 1

Genomics

Answer 1

Relating to the genome

Question 2

Pharmacokinetics

Answer 2

What the body does to the drug

Question 3

Pharmacodynamics

Answer 3

What the drug does to the body

Question 4

Stratified medicine

Answer 4

Selecting therapies for groups of patients with shared biological characteristics

Question 5

Personalised medicine

Answer 5

Therapies tailored to the individual

Question 6

Genetic variations affecting drugs

Answer 6

Single nucleotide polymorphisms (SNPs)
Gene amplification
Promoter polymorphisms
Translocations 
Deletions, insertions

Question 7

E.g. Thiopurine methyltransferase

Answer 7

TPMT inactivates certain drugs
Azathioprine is an immunosuppressant used in organ transplantation and autoimmune disease
TPMT gene polymorphisms reduce TPMT protein activity

Question 8

E.g. N-acetyltransferase activity

Answer 8

They inactivate drugs via acetylation - can be fast and slow acetylators.

Varies via ethnicity
Isoniazid used for TB - slow acetylators have increased side effects inc. neuritis and liver toxicity

Question 9

E.g. succinylcholine

Answer 9

Related to poison curare
Muscle relaxant in anaesthesia (to stop breathing)
Wears off in minutes
Rare BCHE gene variant homozygotes have reduced butyrylcholinesterase activity
Effects could last >1hr and risk of death if not artificially ventilated

Question 10

E.g. aminoglycoside induced hearing loss

Answer 10

MT-RNR1 encodes mitochondrials rRNA.
The change means aminoglycosides are more likely to bind to patients rRNA -> increased risk of hearing loss at young age
Maternal inheritance

Question 11

E.g. warfarin

Answer 11

Widely used oral anticoagulant to reduce embolism/thrombosis
Decrease availability of vit K
Too low = remains at risk
Too high = risk of haemorrhage
Massive variation in optimum dosage… recommended genotyping of CYP2C9 (cyt p450) and VKORC1 (vit K oxidoreductase). Accounts for 50% of genetic variability.

Question 12

Cancer e.g. trastuzumab (herceptin)

Answer 12

20% of breast cancers have over-expression of HER2 (human epidermal growth factor 2). These patients benefit massively from the trastuzumab drug

Question 13

Cancer e.g. BRAF inhibitors

Answer 13

Melanoma is notoriously resistant to chemo
50% of melanomas have a somatic mutation in the BRAF gene
A new targeted therapy shows 48% response rate compared with 5% of standard chemo