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4.14 Pharmcogenomics
By Dr. Gregory
26
Pharmacology
Professional
04/14/2012

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Term
People who ahve a high degree of response to a drug are termed ______, while people who have a poor response are termed ______.
Definition
mean good responders; mean poor responders
Term
What types of hereditary variations cause the different responses to drugs?
Definition
variations in drug metabolism, drug inactivation/elimination, and target receptors
Term
Psuedocholinesterase deficiency causes what drug reaction?
Definition
causes abnormally slow degredation of succinylcholine (general anesthetic); deficiency results in prolonged action of succinylcholine, procaine and cocaine
Term
A patient presenting with paralysis of respiratory muscles after a standard dose of anesthesia, might have...
Definition
pseudocholinesterase deficiency
Term
What is teh physiologic function of psuedocholinesterase?
Definition
there is no known function
Term
What percent of the population is heterozygous for pseudocholinesterase deficiency? homozygous?
Definition
4% are heterozygous; 1:3,200 are homozygous
Term
What is the name of the rare varient of the pseudocholinesterase gene that actually has a higher than normal enzyme activity and is resistant to the paralytic effects of succinylcholine?
Definition
C5 variant
Term
What is the incidence of thiopurine methyltransferase "null variants"?
Definition
1/300
Term
What drug interactions occur with thiopurine methyltransferase "null variants"?
Definition
pts cannot metabolize chemo drugs used to treat leukemia (6-mercaptopurine, 6-thioguanine and azathioprine) into their inactive methylated forms
Term
Can you give patients with thiopurine methyltransferase null variant drugs like azathioprine?
Definition
yes but you have to treat them with 10-15x less chemo than commonly prescribed
Term
Should you test every patient you treat with mercatopurines for TPMT metabolism before giving them the drug?
Definition
genotyping or functional assay is now standard practice in cancer centers
Term
How many patients on warfarin experience a major bleeding episode?
Definition
1.2 to 7 patients out of 100
Term
Warfarin is responsible for what percent of hospital admissions?
Definition
10%
Term
What is the relative risk of fatal extracranial bleeds in patients on warfarin?
Definition
0-4.8%
Term
Why is the dosing of warfarin so complex?
Definition
narrow therapeutic index, nonlinear dose-response, wide range of doses to achieve target INR
Term
What genetic variants affect warfarin sensitivity?
Definition
CYP2C9 and VKORC1
Term
T/F Patients with CYP2C9 or VKORC1 may need higher doses of warfarin.
Definition
false; they may need lower doses of warfarin
Term
How can you look at someone and gauge their liklihood of having the CYP2C9 and VKORC1 variants for warfarin metabolism?
Definition
allelic frequencies of these two genes are usually associated with ethnicity
Term
_______ may explain up to 25% of the patient variability in response to warfarin.
Definition
VKORC1 polymorphisms
Term
What must be taken into account with CYP2C9 variants being dosed for warfarin?
Definition
these variants take more time to achieve stable dosinga nd are associated with increased risk of bleeding events
Term
Patients with VKORC1 on warfarin are at risk for..
Definition
exaggerated anticoagulant reponse; therefore they need a lower dose
Term
Clopidogrel is a prodrug that is activated by _______.
Definition
CYP2C19
Term
What drug interaction occurs with CYP2C19 loss of function alleles?
Definition
diminished response to Clopidogrel and higher rates of recurrent cardiovascular events
Term
Which genetic variation affect a patient's response to clopidogrel?
Definition
CYP2C19 loss of function alleles and mutant alleles that are involved in modulating clopidogrel's absorption
Term
What are SNPs?
Definition
single nucleotide polymorphisms that occur throughout the genome about every 1,000 bases. These may be linked to differences in drug response and are under intense study by pharmaceutical companies
Term
Pharmacogenomics will most likely use _____ to calculate the relative risk-benefit ratio of a particular therapeutic course for an individual patient.
Definition
"panels" of polymorphisms
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