Pharmacogenetics workbook

Question 1

2 reasons for differences in clinical response to drug

Answer 1

1. Pharmacodynamics
   Different responses of cells, tissues and organs to an equal stimulation
2. Pharmacokinetic
   Different concentrations of drug or active metabolite actually reaching the cell

Question 2

Outline pharmacodynamics and pharmacokinetic differences in responses to drugs

Answer 2

PD: (e.g. variation in receptor sensitivity, density and nature)
PK: e.g. factors affecting absorption, distribution, metabolism and excretion

Question 3

Why do differeces in PK and PD arise

Answer 3

either environmental (nurture) or genetic (nature). The only factors which in isolation may generally give rise to more than a 2- to 3- fold difference between individuals are those which are genetically controlled.

Question 4

Differentiate pharmacogenetics nad pharmacogenomics

Answer 4

Pgenetics: Study of genetically determined inter-individuals differences in therapeutic respnse to drugs and susceptibility to adverse effects

Pgenomics:
usee of genomics based techniques in drug therapy

Question 5

Genotype vs phenotype

Answer 5

Gtype= combination of alleles part of the genetic makeup of particular individual

Ptype= manifestation of the genotype, which can be observed and influecned by other characteristcs (environment, acquired characteristc)

Question 6

What derermines a trait (phenotype)

Answer 6

Polygenic control

Several genes act together to give rise to a CONTINUOUS or UNIMODAL (GAUSSIAN) distribution of the measured variable. It is not possible to recognise or discern the influences of single genes.

Owing to the action of a single gene that has a large overriding effect. This gives rise to a DISCONTINUOUS or MULTIMODAL distribution of the measured variable.

Question 7

When would multimodal and when would unimodal distribution occur in a trait

Answer 7

Unimodal: a range with ONE peak. Large differences in responses. Polygenic control.

Multimodal: Discountinuous distrbution. Monogenic control

Question 8

Give an example of unimodal distrubtion

Answer 8

Salicylate conjugation with glycine or glucuronic acid

Question 9

What is it called in multimodal distribution when the population of invidifuals who are ‘different’ from the majority is small, and when that group is large

Answer 9

If the incidence is low the phenomenon is termed a ‘rare trait’ or ‘inborn error’, if it is high (above 1%) it is termed a ‘polymorphism’.

Question 10

Give an example of a rare trait and a polymoprhism in drug metabolism

Answer 10

RARE:  succinylcholine hydrolysis by plasma cholinesterase (incidence of low enzyme activity is about 0.05-0.025%)

2. POLYMORPHISM
   -debrisoquine (+ other drugs) hydroxylation by cytochrome P450 2D6
   (incidence of low enzyme activity is about 7-10% in Europeans, 1-2% in Orientals)

-sulphadimidine (+other drugs) N-acetylation by N-acetyltransferase (incidence of low enzyme activity is about 50% in Europeans)

Question 11

Why do phenotype differences arise

Answer 11

Phenotype differences arise owing to genotype differences, that is, when there are two or more allelic forms of the genetic information at a gene locus

Question 12

If there are 2 alleles F and S (fast and slow metaboliser), when would you get bimodal distribution and when trimodal

Answer 12

TRIMODAL:
If there is no dominant.

FF=fast
FS=medium
SF=medium
SS=slow

BIMODAL:
If there is a dominant. E.g if F is dominant then heterozygous individuals will appear phenotypically fast

FF= fast
FS=fast
SF=fast
SS=slow

Question 13

When might polymorphisms with enzymes result

Answer 13

If the individual alleles (one from each parent) are expressed differently (through different amounts of protein being synthesised or, more commonly, through a different protein being synthesised), then a polymorphism will result.

Question 14

What is the antimode

Answer 14

Occuring between two modes