Pharmacogenetics

Question 1

What is pharmacogenetics?

Answer 1

Pharmacogenetics is the branch of pharmacology that is concerned with the effect of genetic factors on reactions to drugs.

Question 2

What are the different genetic variants?

Answer 2

No mutation codes for wild-type protein

Missense mutation is when there is a new codon that changes the amino acid to a different one in the amino acid sequence.

Nonsense mutation is when the new codon is a stop codon leading to a premature termination of translation.

Silent mutation is when the new codon codes for the same amino acid and there is no change in amino acid sequence.

Question 3

What are HLA-molecules

Answer 3

Human leukocyte antigen gene produces proteins that play a vital role in the immune system. HLA-A, HLA-B and HLA-C are the main genes in MHC class I and they project proteins that are present on the surface of all cells allowing them to be told apart from foreign invaders.

Question 4

P-I concept

Answer 4

Drug binds primarily to TCR and this binding needs a supplementing interaction with a specific HLA-molecule.

Question 5

Codeine and pharmacogenetics

Answer 5

Codeine is metabolised by CYP2C9 into its active metabolite to morphine.
Poor metabolisers have 2-non functional alleles of CYP2C9 meaning they are unable to convert codeine to morphine so they experience little or no effect.
Ultra rapid metabolisers have at lease 2 functional alleles of CYP2C9 meaning they show no analgesic effect at normal therapeutic doses.

Question 6

Mercatopurine

Answer 6

The enzyme thiopurine S-methyltransferase has different allele variants which reduce the activity of mercaptopurine and lead to toxicity and bone marrow suppression.

Question 7

Abacavir

Answer 7

The pharmacogenetic biomarker is HLA-B*5701 which can lead to hypersensitivity reactions.

Question 8

Phenytoin

Answer 8

Metabolised by CY92C9 and CYP3A4 and should be screened for HLA-B*1502 in South East Asians.

Question 9

Warfarin mechanism

Answer 9

Inhibits vitamin K epoxidase reductase which in turn prevents the formation of vitamin K and prevents activation of clotting factors
It is a racemic mixture where the S-enantiomer is more bioactive

Question 10

Warfarin pharmacogenetics

Answer 10

People with CYP2C92,3,5,8 alleles have reduced metabolism of warfarin and will require lower doses of warfarin

People with VKORC1-1639 have reduced activity of vitamin K epoxide reductase meaning less formation of vitamin K and will require lower doses of warfarin

People with CYP2F4*3 have reduced metabolism of vitamin K via liver vitamin K oxidase meaning they will require higher doses of warfarin.