lecture 23 -- neurology and psychiatry Flashcards
(28 cards)
what is the role of human leukocyte antigen complex (HLA-A and HLA-B)?
critical role in immune system
encodes for proteins expressed on the cell surface
proteins binds peptides exported from within the cell
foreign peptides trigger the infected cell to self-destruct
what are the major HLA associations with drugs?
allopurinol – HLA-B5801 – severe skin rash
abacavir – HLA-B5701 – fevers, chills, rash
carbamazepine – HLA-A*3101 – SJS-TEN
how does HLA-B*1502 and carbamazepine affect race?
association weaker in asians (still 10x higher) with no establishment in caucasians
what is the frequency of HLA-B*1502 mutation by ethnicity/population?
asian - 5.1 with largest number in singapore and smallest in korea
0 in europe, hispanic, and native american
what is the BBW of carbamazepine?
pt with ancestry in genetically at-risk populations (asian, mostly) should be screen for presence of HLA-B*1502 PRIOR to initiating treatment
if positive, do not start
how does HLA-A*3101 affect caucasian populations?
if allele present, increased risk of SJS-TEN by 5-26%
if absent, decreased risk by 5-3.8%
does SJS/TEN only occur in HLA-A3101/B1502 positive pts?
no, it can occur but infrequently in negative
even so, most positive pts will not develop it
how does SCAR correlate to HLA*5801?
almost 100% of pts with SCAR (severe cutaneous AR) are carriers of HLA*5801
frequency higher in asian populations
how does being a homozygous affect phenytoin consumption?
37% lower dose required
how does being a heterozygote affect phenytoin consumption?
greater risk of toxicity based on case reports
what gene is associated with phenytoin-induced SJS/TEN?
HLA-B*1502
what type of substrate is phenytoin?
p-glycoprotein (MDR1) and P450 substrates
what are the psychiatric drug targets?
monoamine degrading enzymes
transporters
receptors for GF, glucocorticoids, and melanocortin
receptors for NTs
signal transduction proteins
what is the name of the main serotonin transporter target?
SLC6A4
if the parent drug is active, how does CYP2D6 influence effectiveness/toxicity?
UM/EM – decrease effectiveness
PM – increase effectiveness, increase toxicity
if the parent drug is less active, how does CYP2D6 influence effectiveness/toxicity?
UM/EM – increased effectiveness, increased toxicities
PM – decreased effectiveness
what antidepressants are primarily metabolized by CYP2D6?
fluoxetine, paroxetine
venlafaxine
nortriptyline
desipramine
clomipramine
doxepin
all mention in labeling
what antipsychotics are primarily metabolized by CYP2D6?
chlorpromazine
haloperidol
perphenazine
risperidone
thioridazine
iloperidone
all mentioned in labeling except for C/H
what drugs are strong CYP2D6 inhibitors?
fluoxetine, paroxetine
bupropion, duloxetine
what anti-psychotic has substantial metabolism by CYP2D6?
aripiprazole
how does having the allele CYP2D6*2XN affect activity and metabolizer status?
increased (duplication) activity
Ultrarapid (UM) metabolizer
what is the MOA of aripiprazole?
parent drug is active and primarily responsible for therapeutic response
partial agonist of DA and 5HT receptors
what anti-depressants are primarily metabolized by CYP2C19?
amitriptyline
citalopram, clomipramine –> mentioned in labeling
escitalopram
what defines an UM in CYP2C19?
two gain of func alleles (17) or one wild type and one gain of func (1/*17)
