Clinical Pharmacogenetics – subjects, aim, tasks and clinical Flashcards
define Clinical Pharmacogenetics
study of genetically determined variations in drug response commonly reffered to pharmacogenetics
Objectives: of pharmacogenetics
identification of genetically controlled variations in responses to drugs
The study of the molecular mechanisms causing variations in drug response
evaluation of the variaton’s clinical significance
development of simple methods to identify individuals who may be susceptible to variable responses before drug are administered
define Polymorphism:
monogenic trait caused by the presence in
a set population of more than one allele at the same locus causing more than one phenotype in regard to drug interaction with the organism.
how does Polymorphism affect drug interaction
differences in enzyme activity or receptor structures
differences are expressed in different ethnic groups e.g
Protein structure, configuration and concentration may alter action of the drug in multiple ways.
how genetic differences affect phk/
changes in drug intensity
changes in drug duration of action
how genetic differences affect phD
abnormal effectsw/ genetic transmitted disorders
Acetylation: is done by what ez
N-acetyltransferase
fast and slow acetylators depend on the amount of N-acetyltransferase
genes of fast acylators
autosomal dominant character
genes of slow acylators
recessive
enhanced response to treatment, but also at increased toxicity
require lower doses
Acetylator status: assessment
give orally sulfonamide
measure the relative proportion of acetylated and total sulfonamide in a sample of urine 5-6 hours later.
categorisatino according to oxydation
extensive metabolizer
-normal
poor metabolizer
impaired
autosomal recessive defect
location of defect in cytochrome CYP2D6 for hydroxylation of debrisoquine
poor metabolizers
chromosome 22
Drugs affected in defect of CYP2D6
captopril,
codeine,
metoprolol,
drug inhibiting oxydation
Quinidine
factors affecting the Clinical relevance of pharmacokinetic defects
importance of the affected metabolic pathway to the overall elimination of the drug
therapeutic index of the drug
how easily the variable drug response can be monitored in clinical trials
clinical imprtance of CYP2D6 polymorphism
Considerable as several drugs rewuire this ez in their metabolic PW
antidepressants
antipsychotics
antiarrythmics
Pharmacodynamic defects consequences
increase or decreases pt sensitivity to a drugn
Red cell enzyme defects
erythrocytes are deficient in
1) glucose-6-phospathe dehydrogenase
2) glutathione reductase and
3) methemoglobin reductase
G6PD
diminished production of NADPH
causes accum of
METHAEMOGLOBIN
leads to hemolysis
black variety
G6PD production is probably normal, but its degradation is accelerated
haemolysis occurs on first administration of the drug and lasts a few days after drug is discontinued
in continued use mild hemolysis occurs
Mediterranean variety
enzyme is abnormal
severe haemolysis occurs on first administration and is maintained with continued administration.
Glutathione reductase deficiency
autosomal DOMINANT inheritance
deficiency of reduced glutathion
hemoylisis d/2 increased oxidising agents
drugs causing hemolysis in Glutathione reductase deficiency
Warfarin
Methemoglobin reductase
autosomal recessive inheritance.
Normally methaemoglobin is continuously reduced to heamoglobin
dficiency causes accum of met heam
impaired oxygen delivery to the tissues thus, hypoxemia
rx of methamogoglobin induced hypoxia
methylene blue.
