L15- Pharmacogenetics

Question 1

What is Genomics

Answer 1

relating to the genome i.e. total DNA/RNA

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

Germline

Answer 6

Hereditary

Question 7

Somatic

Answer 7

Acquired, in non-germline cells, not hereditary

Question 8

What are some genetic variations affecting drugs?

Answer 8

Change in protein (e.g. enzyme, transporter, target) structure/activity

Question 9

How can a Single nucleotide polymorphisms affect drugs

Answer 9

May change protein structure/activity e.g. missense changes

Question 10

Genetic variation can effect processes such as?

Answer 10

Absorption

Activation

Altered target

Catabolism (breakdown)

Excretion

Question 11

Thiopurine methyltransferase

Answer 11

TPMT inactivates certain drugs

Azathioprine (immunosuppressant used in organ transplantation and autoimmune disease)

6-mercaptopurine & 6-thioguanine (chemotherapies)

TPMT gene polymorphisms reduce TPMT protein activity

Severe toxicity if both copies of the gene have the variant

Question 12

N-Acetyltransferase activity

Answer 12

Group of liver enzymes inactivating drugs by acetylation

“Fast” and “slow” acetylators – due to SNP variations in genes e.g. NAT2

Different distributions in different ethnic populations

e.g. isoniazid used for TB – Slow acetylators at increased risk of side effects including neuritis and liver toxicity

Other drugs – sulfasalazine (Crohn’s dis), hydralazine (hypertension)

Question 13

Succinylcholine

Answer 13

Related to the poison curare

Muscle relaxant used in anaesthesia (to stop breathing)

Usually wears off after a few minutes

Rare BCHE gene variant homozygotes have reduced butyrylcholinesterase activity

Effects may last for an hour or more and risk of death if artificial ventilation is not continued

Question 14

Aminoglycoside induced hearing loss

Answer 14

Mitochondrial MT-RNR1 gene encodes mitochondrial 12s rRNA

G>A mutation at nucleotide position 1555 causes non-syndromic hearing loss (at later ages)

Mutation changes the structure of the rRNA to resemble E-coli 16S rRNA

Aminoglycosides more likely to bind to patients rRNA → increased risk of hearing loss at younger age

Question 15

Warfarin

Answer 15

Widely used oral anticoagulant to reduce embolism/thrombosis

Decreases the availability of vitamin K

Dose too low: Patient remains at risk

Dose too high: Risk of haemorrhage

Question 16

Trastuzumab (Herceptin) - cancer genetic variability examples

Answer 16

20% of breast cancers have over-expression of HER2 (human epidermal growth factor receptor 2)

These patients benefit significantly from trastuzumab – a monoclonal antibody to the HER2 receptor

Question 17

BRAF inhibitors- cancer genetic variability examples

Answer 17

Melanoma is notoriously resistant to chemotherapy treatment

~50% of melanomas have a somatic mutation in the BRAF gene