Pharmacogenetiocs Flashcards
What are the three types of interindividual genetic variation that can influence pharmacotherapy?
- variation in drug metabolism or transport (pharmacokinetic)
- variation in drug targets (pharmacodynamics)
- variation associated with idiosyncratic adverse drug effects
NAT-2 catalyzes ____________ which activates/deactivates __________
Acetylation of isoniazid an antimycobacterial agent;
Deactivates isoniazid
Slow/fast acetylators will have high levels of blood drug levels
Mode of inheritance?
Slow; slow acetylators are homozygous recessive
Examples of drugs that slow acetylators are at risk for toxicity:
Isoniazid
Hydralazine and procainamide
Sulfonamides
Adverse effects of isoniazid toxicity
Neuropathy and hepatotoxicity
Adverse effects of hydralazine and procainamide toxicity
SLE
Adverse effects of sulfonamide toxicity
HS reactions, hemolytic anemia and SLE
Patients with genetic variations in butyrlcholinesterase have decreased rate of _______________
Metabolism of succinylcholine resulting in prolonged paralysis
Hereditary mode of transmission of BCHE gene
Autosomal recessive
What kind of drugs and specific ones are metabolized by CYP2D6
Antidepressants: fluoxetine, imipramine, desipramine
antiarrhythmics: metoprolol (β adrenergic blocker)
analgesics: codeine and dextromethorphan
Antipsychotics: haloperidol
What are the 3 different types of metabolizers of CYP2D6 and the hereditary form of each
Poor metabolizers: homozygous recessive
Extensive metabolizers: homozygous wild or heterozygous
Ultra rapid metabolizers: have multiple copies of the gene
Poor metabolizers of CYP2D6 are at risk for adverse effects when taking _________
Metroprolol (β adrenergic blocker) because it stays in the system for longer so need to give a smaller dose
Ultra rapid metabolizers of CYP2D6 are at more risk for adverse effects when taking ________
Codeine because when it is metabolized it is converted to morphine → at risk for respiratory arrest
Function of thiopurine S- Methyltransferase
Catalyzes the S- methylation and thus inactivation of anticancer thiopurines:
6- mercaptopurine
Azathiprine
What are patients with low TPMT activity at risk for when taking thiopurines
Myelosuppression; these patients are homozygous recessive
_________ is often overexpressed in NSLC (non small cell lung cancer)
EGFR (a tyrosine kinase receptor) aka epidermal growth factor receptor
_______ inhibits the ______________ kinase of EGFR
Gefitinib; tyrosine
Used to treat NSLC
Patients with what mutation respond better to gefitinib
Those with a mutation in the ATP binding site of the tyrosine kinase domain of the EGFR
What is the molecular target of warfarin and use?
Targets vitamin K epoxide reductase which supplies reduced vitamin K for the enzyme gamma glutamyl carboxylase which produces clotting factor
Warfarin is an anti-coagulant
Pharmacokinetic variation in warfarin
There are 2 enantiomers of warfarin: S-warfarin is more potent and is mainly metabolized by CYP2C9 while R-warfarin is metabolized by others like CYP3A4 and other isoforms
Explain the importance of genetic variation in the CYP2C9 gene
CYP2C9 is what metabolizes S-enantiomer of warfarin;
Those with variant Allen require ↓ doses of warfarin
Explain the pharmacodynamic component of warfarin
The gene that encodes for the target enzyme Vit K epoxide reductase is called VKORC1 and has a number of polymorphisms that affect therapeutic warfarin dose
What metabolizes the S enantiomer of warfarin?
CYP2C9
Drugs that cause oxidative stress:
Sulfonamides, antimalarials (primaquine and chloroquine) and chloramphenicol
