HLA-C Flashcards
HLA-A and HLA-B genes function
-role in immune system
-encodes for proteins expressed on the cell surface
-bind peptides exported from within the cell
-foreign peptides trigger infected cell to self destruct
HLA-A and HLA-B genetic variations
-inc risk of immune disorders and chronic inflammatory conditions
-associated w adverse drug reactions
-allupurinol (HLA-B5801)
-abacavir (HLA-B5701)
-carbamazepine (HLA-A*3101)
Carbamazepine hypersensitivity
-HLA-B*1502
-SJS
-chinese
-association WEAKER in asian populations, but 10x higher
-NOT established in whites
-cross-reactivity possible for other anti-epileptic drugs (oxcarbazepine, lamotrigine, phenytoin)
HLA-B*1502 frequency
-higher in asian and singaporean
Carbamazepine drug labeling
-asian pt should be screened for HLA-B*1502 before initiaing treatment
-consider cross-reactivity with oxcarbamazepine, phenytoin, lamotrigine
Carbamazepine SJS reaction in whites
-HLA-A3101 presence increases risk
-risk dec if absent
-many HLA-A3101 pt will NOT develop SJS so weigh risk v benefit
-not routinely tested for gnee
Abacavir
-Nucleoside Reverse Transcriptase inhibitor (NRTI)
-hypersensitivity risk inc with HLA*5701 gene (BLACK BOX WARNING)
Allopurinol
-inhibits conversion of hypoxanthine and xanthine to uric acid
-severe cutaneous ADRs (SCAR)
-fever, eisonophilia, renal failure
-HLA*5801 (asians) almost all SCAR pt have this gene
Phenytoin
-CYP2C9 substrate
-lower dose in *2 or *3 HOMOZYGOTES
-inc risk with *2 or 3 heterozygotes
-HLA-B1502 associated w SJS (avoid if carrier)
CYP2D6 substrates
-fluoxetine*
-paroxetine*
-venlafaxine
-nortriptyline
-desipramine
-clomipramine
-doxepine
-chlorpromazine
-haloperidol
-perphenazine
-risperidone
-thioridone
-illoperidone
-also aripiprazole
CYP2D6*2 mutations
-inc CYP2D6 activity
-ultrarapid metabolizer
=reduce doses
Aripiprazole metabolism and dose adjustments
-CYP2D6 and 3A4
-poor 2D6 metabolizer: half dose
-poor 2D6 metabolizer + 3A4 inhibitor: 1/4 dose
-strong 2D6 or 3A4 inhibitor: 1/2 dose
-strong 2D6 and 3A4 inhibitors: 1/4 dose
-strong 3A4 INDUCERS: double dose over 1-2 weeks
CYP2C19 substrates
-Amitriptyline
-citalopram
-clomipramine
-escitalopram
CYP genotypes
-normal/inc: 17/17 or 1/17
-normal: 1/1
-intermediate: *1/2, 1/3
-poor metabolizer: 2/2, 2/3, 3/3
Which of the following patients is the most likely to be a carrier of
a CYP2C19*17 allele?
a) A patient with major depression disorder that had no clinical
benefit from citalopram.
b) A patient with schizophrenia that developed extrapyramidal
symptoms with olanzapine.
c) A patient that experienced enhanced euphoria from codeine.
d) A patient that developed serotonin syndrome from paroxetine.
citalopram
CYP1A2 substrates
-fluvoxamine*
-clozapine
-olanzapine
Clinical challenges
-some SSRIs inhibit CYP 2D6 and also substrates
-EMs may resemble IMs or PMs w tx
-2D6 may be active in brain and metabolize serotonin
-concentration-response not always clear cut (nortriptyline may lose effects at higher concentrations
-2D6 PMs w venlafaxine have low response rates
