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PharmacoKinetics
52
Pharmacology
Professional
12/05/2013

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Term
sotalol; most patients it is a good beta blocker
Definition
others it can cause arrhithmias
Term
troglitazone
Definition
death via hepatic failure, but not class effect
Term
statins
Definition
rhabdomyalisis
Term
steven johnson's syndrome
Definition
allergic reaction that can cause death
Term
DNA four base-pairs
Definition
ATCG
Term
pharmacogenetics
Definition
coding region variants, DNA variants in non-coding regions and variable drug transport
Term
pharmacogenomics
Definition
genes encoding drug targets (receptors) and controlling the biological context in which drugs act
Term
non-coding region
Definition
can effect regulation of gene
Term
coding region variants
Definition
changes in DNA sequence that occur in regions that encode protein may lead to changes in primary AA sequence and protein function
Term
types of coding region variants of interest
Definition
TPMT and CYP superfamily
Term
CYP coding region variants
Definition
frequency vary by ethnicity
Term
CYP2D6--poor metabolizers
Definition
10% Caucasian and African Americans are homozygous for loss of activity; can be good, can be bad
Term
poor metabolizers may have accumulation and
Definition
increased side effects with some anti-depressants
Term
poor metabolizers do not metabolize codeine to it's active metabolite morphine
Definition
therefore have reduced analgesia
Term
CYP2C19 poor metabolizer
Definition
Asian-Americans mostly have higher cure rates of H.pylori with omeprazole therapy
Term
CYP2C19 poor metabolizer and clopidogrel
Definition
increased risk of CV death, MI or stroke compared to other better able to convert prodrug to active metabolite
Term
non-coding region variants
Definition
small fraction of genome; regulation of amount of mRNA, amount of proteins generated and differences in response to drugs
Term
UGT1A1
Definition
encodes glucuronosyltransferase which is important in the metab of bilirubin and some drugs
Term
two extra base-pairs in the regulatory region (non-coding/promoter region) of UGT1A1
Definition
results in reduced protein expression of gene
Term
Gilbert's syndrome and UGT1A1 mutation with extra base pairs
Definition
jaundice because inability to produce functioning enzyme that normally should break down conjugated bilirubin
Term
UGT1A1 mutation and camptosar (irinotecan)
Definition
more diarrhea and neutropenia--immunocompromised
Term
testing available for
Definition
UGT1A1*28
Term
variable drug transport
Definition
drug entry into and removal from cells are dependent on specific drug transport molecules--can lead to variable drug response
Term
p-glycoprotein and organic ion transporters (OAT's)
Definition
important eflux transporters; protective mechanism to shunt things in and out of cells
Term
p-glycoproteins
Definition
transport drugs into the GI tract (part of 1st pass or gatekeeprs for CYP), out of brain and into renal tubules
Term
drugs mediated by p-glycoproteins
Definition
colchicine, immunosuppressive agents, glycosides, steroids, and antiretroviral agent
Term
OAT's (uptake transporters)
Definition
directional movement of drugs across organs, substrates of this secretory pathway are strikingly diverse
Term
drugs mediated by OAT's
Definition
lactam antibiotics, probenacid, loop and thiazide diuretcs, ACE inhibitors and statins
Term
genetically determined PD
Definition
variability in the genes encoding drug targets, variability in biological context in which drugs act
Term
drugs can produce highly variable effects
Definition
even in the absence of change in drug concentrations at the site of action
Term
PD variability tends to be more
Definition
drug or disease specific, compared with PK
Term
beta2 receptor polymorphism and response to agonist therapy
Definition
differences in genotype can result down regulation of receptors
Term
genetic surveys of patients with drug-induced torsades
Definition
have identified pre-disposing mutations not only to the drug target (KCNH2) but also to other genes that control the QT interval
Term
variability in the physiologic control of the QT interval
Definition
can contribute to the variable effects of KCNH2 blockers
Term
genetically determined PD
Definition
variability in the genes encoding drug targets, variability in biological context in which drugs act
Term
drugs can produce highly variable effects
Definition
even in the absence of change in drug concentrations at the site of action
Term
PD variability tends to be more
Definition
drug or disease specific, compared with PK
Term
beta2 receptor polymorphism and response to agonist therapy
Definition
differences in genotype can result down regulation of receptors
Term
genetic surveys of patients with drug-induced torsades
Definition
have identified pre-disposing mutations not only to the drug target (KCNH2) but also to other genes that control the QT interval
Term
variability in the physiologic control of the QT interval
Definition
can contribute to the variable effects of KCNH2 blockers
Term
s-warfarin
Definition
more active moiety
Term
mutation in one gene had been selected for and had spread through the population of rats over time
Definition
CYP2C9--lead to studies in resistant humans
Term
VKORC1 gene mutation
Definition
warfarin resistance that necessitates daily doses in excess of 15 mg/day
Term
CYP2C9 gene mutation
Definition
especially homozygosity for the *3 allele can result in sensitivity to the drug such that doses less than 1mg/day are sufficient
Term
about 20-30% variability
Definition
VKORC1
Term
about 6-10% of the variability
Definition
CYP2C9
Term
TPMT homozygous wild type
Definition
high activity; 89%
Term
TPMT heterozygous
Definition
low activity; 11%
Term
homozygous mutant TPMT
Definition
negligible activity; 0.3%
Term
TPMT activity
Definition
converts 6MP to active and inactive metabolites
Term
TPMT inactivity results in
Definition
toxicity of 6MP due to a dramatic decrease in degradation of drug into inactive form
Term
ultra-rapid CYP2D6 metabolism
Definition
dramatic increase of conversion of codeine to morphine may result in overdose and serious respiratory depression
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