Pharm - Lecture 5 - Pharmacogenetics Flashcards
What is a Haplotype?
refers to closely linked genetic markers on a chromosome that tend to be inherited together (often within a gene)
What are 2 genetic factors that alter an individuals drug response?
1) genetic polymorphisms
2) less common genetic variants
What is a Halotype?
Refers to a cluster of SNPs that occur together or in an individual and are of interest to a phenotype
They maybe be either in a single gene (similar to haplotype)
or
they maybe be multifactorial on multiple genes not necessarily inherited as a unit
What are potential polymorphisms which could impact pharmacokinetics? (4)
1) Transporters (uptake, distribution)
2) Plasma protein binding
3) Metabolism
4) Excretion
What are potential genetic polymorphisms that could impact pharmacodynamics? (4)
1) receptors
2) Ion channels
3) Enzymes
4) signaling events
What is NAT-2 polymorphism?
Enzyme involved?
Drug effected?
Type of effect? (2)
Disease?
Enzyme: N-acetyltransferase-2 (NAT-2)
Drug affected: isoniazid
Effect: fast and slow acetylation (deactivation of drug)
Disease: drug used as anti-tuberculosis
N-acetyltransferase-2 (NAT-2) is responsible for the metabolism of the anti-tuberculosis drug isoniazid
What drug does NAT-2 metabolize and does it activate or deactivate it?
deactivates isoniazid
What are some CYP2D6 polymorphisms? (2)
poor metabolizers variants: decreased metabolism of debrisoquine causing hypo-tension
Ultrafast metabolizers: rapid clearance of drugs associated with CYP2D6
What is the major class of drugs that CYP2D6 metabolizes?
anti-depressants
What types of CYP2C19 variants exist?
poor metabolizer phenotype
What classes of drugs does CYP2C19 metabolize? (6)
Anti-convulsants proton-pump inhibitors anti-platelet drugs anti-depressants anti-cancer hormones
What anti-convulsant drug does CYP2C19 metabolize?
Effect?
phenytoin
Effect: deactivation
What proton pump inhibitor does CYP2C19 metabolize?
Effect?
omeprazole
Effect: deactivation
What anti-platelet drug does CYP2C19 metabolize?
Effect?
clopidogrel
Effect: activation
What polymorphic variants exist for CYP2C9?
Two poor metabolizer variants: CYP2C92, CYP2C93
What anti-coagulant does CYP2C9 metabolize?
Effect?
Warfarin
effect: deactivation
Which Cytochrome 450 primarily clears warfarin? Which poloymorphic variant has greatest impact on clearance?
CYP2C9 primarily clears warfarin
CYP2C9*3 has largest effect on clearance (poor metabolizer)
What does warfarin do?
anticoagulant - vitamin K antogonist - inhibits activity of the vitamin K epoxide reductase complex
What is VKORC1?
It’s a subunit of the vitamin K epoxide reductase complex
What types of polymorphisms exist for VKORC1?
A clade: haplotypes H1 and H2 associated with lower expression of VKORC1
B Clade: haplotypes H7, H8, H9 associated with higher expression of VKORC1
Which VKORC1 polymorphism requires a higher dose of warfarin? Which one requires a lower dose?
Higher dose: B clade: H7, H8, H9
Lower dose: A clade: H1, H2
What type of polymorphisms exist for Pseudocholinesterase?
reduced activity variant
What drug is metabolized by Pseudocholinesterase? What is the effect of this drug?
succinylcholine
Effect: depolarizing muscle relaxant
What are the polymorphisms for TPMT?
decreased activity variants
What is the role of TPMT?
TPMT inactivates 6-mercaptopurine,
What happens when there is a reduced activity variant for TPMT?
6-mercaptopurine is metabolized to a toxic product
What is 6-mercaptopurine used for? What are its toxic effects?
Used to treat cancer, toxic effects include bone marrow supression
What is the role of P-glycoprotein? (pgp)
It is an ATP-binding protein that effluxes drugs from the gastrointestinal mucosa.
What drug is effected by a P-glycoprotein (pgp) polymorphism?
Decreased levels of pgp lead to Increased net uptake of digoxin
What does digoxin do?
it is a cardiac glycoside (treatment of congestive heart failure)
What are parameters that increase the clinical significance of genetic polymorphisms? (5)
1) drugs are used relatively frequently in the population
2) the pathway affected must be the predominant one
3) if both parent drug and metabolite are equally active, then polymorphisms will not alter efficacy/toxicity
4) more important for drugs with narrow therapeutic windows
5) more important when side effects, or lack of benefit, are potentially serious
