Pharmacogenetics and Clinical Trials Flashcards
Codeine
converted to the much more active morphine by CYP2D6
poor metabolizers get little therapeutic effect, rapid metabolizers can quickly become intoxicated
slow metabolizers
caused by missense mutation in CYP gene
risk accumulation of toxic drug in liver
fast metabolizers
can be caused by multiple copies of CYP genes on a chromosome
risk not having enough drug available, no therapeutic effect
UDP glucosyltransferase
usually helps with metabolism of bile etc
camptothecin is an anticancer drug that is metabolized by it, polymorphisms can caused accumulation of toxic metabolites
N-acetyl-transferase
polymorphisms can reduce or enhance the metabolism of isoniazid (TB drug)
Cholinesterase deficiency
mutation in a post-synaptic cholinesterase can caused prolonged post-surgical paralysis after administration of succinylcholine (nACh-R blocker)
G6PD deficiency
normally produces NADPH, regenerates GSH from GSSH, protects against oxidative damage
defects in the gene can lead to increased FR damage to RBC–>hemolytic anemaia
malignant hyperthermia
inhalation anesthetics and succinylcholine
elevated Ca in SR
muscle rigidity, elevated CBT, rhabdo
warfarin
polymorphisms in the CYP enzyme and VKORC1 target cause large degree of variability in the amount of drug needed to achieve blood thinning
Lead compound
chemical that has pharmacological activity whose structure is used as a starting point for chemical modifications
pre-animal testing
preclinical testing
in vitro and vivo studies to eval safety and tox before human trials
phase I
20-50 health subjects
establish toxicity and kinetics
open to E and Subject
Phase II
100-200 pts
establish efficacy
single blind with inert placebo
*failure often occurs here
Phase III
300-3000 pts
efficacy and toxicity
crossover double blind
Phase IV
post marketing surveillance, no fixed duration
monitor drug safety, find rare s/e
