Pharmacogenomics

Question 1

What is pharmacogenetics?

Answer 1

the study of genetically determined inter-individual differences in therapeutic response to drugs and susceptibility to adverse effects

Question 2

What is pharmacogenomics?

Answer 2

use of genome based techniques in drug development

Question 3

Why might the clinical response to a drug vary widely between individuals?

Answer 3

1) pharmacodynamics –> different responses of cells, tissues and organs to an equal stimulation
2) pharmacokinetics –> different concentrations of drug/active metabolite actually reaching the cell

Question 4

What does polygenic control give rise to? Give an example of polygenetic control.

Answer 4

continuous and uni-modal (gaussian) distribution of the measured variable
eg. salicylate conjugation with glycine or glucuronic acid

Question 5

What does monogenic control give rise to? Give some examples of monogenic control.

Answer 5

discontinuous / multimodal distribution of measured variable
eg. succinylcholine hydrolysis by plasma cholinesterase (rare trait)
debrisoquine hydroxylation by cyp450 (polymorphism)
sulphadimidine N-acetylation by N-acetyltransferase (polymorphism)

Question 6

What is an enhanced/extensive metaboliser?

Answer 6

intensive metabolism, resulting in low plasma conc of drug –> usually heterozygote/homozygote dominant

Question 7

What is a poor/non-metaboliser?

Answer 7

slow/no metabolism of the drug resulting in high plasma conc for an extended time –> usually homozygote recessive

Question 8

What is isoniazid used to treat?

Answer 8

TB

Question 9

How is isoniazid metabolised?

Answer 9

N-acetylation

Question 10

How does isoniazid metabolism vary in the population?

Answer 10

different rates of N-acetylation due to a polymorphic enzyme:
NAT1 and NAT2

Question 11

What does the NAT2 enzyme has a preference for?

Answer 11

sulphadimidine (> isoniazid)

Question 12

How can the NAT genotype present?

Answer 12

wild-type (fast acetylator)
homozygous M1/M1 polymorphism (slow acetylator)
hererozygous M1/wild-type

Question 13

How is the M1 polymorphism detectable?

Answer 13

as the M1 variant of NAT has a substitution of T to G at nucleotide 1098

Question 14

What is the Hardy-Weinberg equation?

Answer 14

(p+q)^2 = p^2 + 2pq + q^2 = 1

Question 15

Would you expect sulpadimidine to be an equally effective drug in all people?

Answer 15

NO