Pharmacogenetics (15)

Question 1

Genomics

Answer 1

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

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

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

Question 7

Causes of change in protein

Answer 7

Translocations, deletions/insertions, promotor polymorphisms, gene amplification, single nucleotide polymorphisms (SNPs)

Question 8

Single nucleotide polymorphisms

Answer 8

Common genetic variation, changes a single nucleotide, may/may not change protein structure/activity e.g. missense changes

Question 9

Proline causes..

Answer 9

A kink in the chain

Question 10

Different patterns of inheritance

Answer 10

• Autosomal recessive (most severe effect)
• Autosomal dominant
• X-linked recessive
• Mitochondrial inheritance (from mother only)

Question 11

Most cancer drugs response rate is

Answer 11

20% due to genetic variation of tumour/patient

Question 12

How can genetics help?

Answer 12

• Identify genetic variations that lead to altered outcomes
• Change dose of drug where appropriate
• Use a different drug that works better and/or has reduced toxicity
• Guide new targeted drug development
• Stratified/personalised medicine
• Reduce financial costs of inappropriate treatment

Question 13

Thiopurine Methyltransferase (TPMT) role

Answer 13

Inactivates certain drugs e.g. Azathioprine, 6-mercaptopurine and 6-thioguanine (chemotherapies)

Question 14

Azathioprine

Answer 14

Immunosuppressant used in autoimmune disease, organ transplants, malignancy

Question 15

TMPT polymorphisms

Answer 15

Decrease TPMT protein activity, can cause severe toxicity if both copies of gene have variant > DNA damage

Question 16

N-acetyltransferase

Answer 16

Group of liver inactivating drugs by acetylation

Question 17

Problem with N-acetyltransferases

Answer 17

Fast and slow acetylations due to SNP variations e.g. NAT2, different distributions in different ethnic populations

Question 18

Examples of N-acetyltransferases

Answer 18

• Isoniazid (used for TB, if slow acetylator increase risk of neuritis and liver toxicity)
• Sulfasalazine (Crohn’s)
• Hydralazine (Hypertension)

Question 19

Succinylcholine

Answer 19

Muscle relaxant used in anaesthesia (to stop breathing), wears off after a few minutes, related to poison curare

Question 20

Problems with Succinylcholine

Answer 20

Rare BCHE gene variant homozygotes, decrease butyrylcholinesterase activity (can’t inactivate), effects may last up to an hour/more and risk of death if artificial ventilation not continued

Question 21

Amino glycoside induced hearing loss

Answer 21

Mitochondrial mutation G > A, causes structures of rRNA to resemble E.coli 16s rRNA, maternal inheritance

Question 22

Warfarin

Answer 22

Oral anticoagulant, decreases availability of Vit K, optimum dose varies 20X

Question 23

If too little warfarin

Answer 23

Patient remains at risk of thrombosis/embolism

Question 24

If too much warfarin

Answer 24

Risk of haemorrhage

Question 25

Which genes explain 50% of genetic variability in Warfarin?

Answer 25

CYP2CP and VKORC1

Question 26

Tratuzumab (Herceptin)

Answer 26

20% breast cancers have over-expression of HER2 (human epidermal growth factor receptor 2), Tratuzumab is a monoclonal Ab to HER2 receptor

Question 27

BRAF inhibitors

Answer 27

Melanoma is resistant to chemo, 50% melanomas have a somatic mutation in BRAF gene, Vemurafenib new therapy valine > glutamic acid)