Pharmacogenomics Flashcards
pharmacogenomics
the study of genetics with regard to drug response
pharmacogenomics: pharmacodynamics
is the drug target present? / are there alterations in the target?
pharmacogenomics: pharmacokinetics
focuses on specific enzymes that genes express, including CYP enzymes and phase II enzymes. drug transporters are also examined as well.
carbamazepine example
allele puts people at increased risk for TEN and Steven Johnson Syndrome.
patient can be tested for this allele. if patient tests positive, avoid carbamazepine.
clopidogrel example (pro drug)
PGx testing is done to ID poor metabolizers of CYP2C19
warfarin PGx testing
looking for over expressions of CYP2C9 and VKORC1. in these cases, higher doses of warfarin would need to be given in order to achieve desired clinical effect
single nucleotide polymorphism
an exchange of one nucleotide pair for another
SNPs can happen where
in coding or non coding regions
synonymous SNP reaction
change occurs in base pairs, but not in the amino acid it is coded for.
non synonymous SNP reaction
changes the amino acid it is coding for
A B C D gene reference
gene deletion example
A C D
A B C D gene reference
inverted gene sequence example
A upside down B C D
A B C D gene reference sequence
copy number variant / amplification example
A A A A A A B C D
type of SNPs we are focusing on
SNPs that change clinical outcome
nucleotide insertion
stop codon occurs early, alteration in gene’s coding sequence occurs and the frameshift moves to the right by 1 space
nucleotide deletion
a nucleotide is deleted and the entire frame shift moves to the left by 1 space.
ultra metabolism (UM)
you will metabolize a med much faster than an extensive metabolizer would
extensive metabolism (EM)
normal metabolizers of meds. what the meds are made for.
Intermediate metabolism (IM)
will metabolize at a lower rate than normal extensive metabolizer.
Poor metabolism (PM)
under expression of the CYP or phase II enzymes, unable to process meds as easily. profound decrease in metabolism.
intermediate and poor metabolizers both have
a degree of loss of function
which metabolizers types are we most concerned about in regards to drug dosing when it comes to a specific enzyme?
ultra metabolizers (UM) and poor metabolizers (PM)
in terms of PGx black box labels, what are we looking for?
- if genetic testing is required
- if genetic testing is recommended
- actionable PGx
- informative PGx
actionable PGx
will positive results necessitate an action?
informative PGx
no action required, just informative
resources for PGx testing, etc
PharmGKB
UpToDate
CYP2C9 PMs: warfarin (APC)
increased risk of bleeding
CYP2C9 PMs: phenytoin (APC)
increased risk of ataxia, unconsciousness, confusion
CYP2C9 PMs: anti diabetics (APC)
increased risk of potential hypoglycemia
CYP2C19 PMs: clopidogrel (pro drug)
decreased response
CYP2D6 UMs: codeine (prodrug)
increased risk of adverse effects
codeine is metabolized by CYP2D6. if someone has codeine and is an UM
codeine intoxication bc codeine is a prodrug
which two CYP enzymes metabolize codeine?
CYP 3A4 and CYP 2D6
which enzyme metabolizes the active metabolite of codeine
CYP 2D6
which enzyme metabolizes the inactive metabolites of codeine?
CYP3A4
CYP2D6 UM for prodrug
inactive prodrug to active metabolite at quicker rate
CYP2D6 PM for prodrug
buildup of inactive prodrug with less of the active metabolite. diminished effect.
warfarin’s therapeutic index
narrow.
target INR 2.5-3.5
if not getting appropriate warfarin response…
may need PGx test
onset for clinical effect of warfarin
is delayed. be conservative with early dosing
two isomers of warfarin
r-warfarin
s-warfarin
which isomer of warfarin is more active?
s-warfarin
how are warfarin’s isomers metabolized
by phase I CYP enzymes
CYP enzymes for R-Warfarin (3)
CYP 1A1
CYP 1A2
CYP3A4
CYP enzyme for s-warfarin
CYP 2C9
enzyme we are most concerned with in warfarin and why
CYP 2C9 because this is the enzyme metabolizing S-warfarin, the active isomer of warfarin.
clotting factors warfarin works on
10 9 7 2
X IX VII II
warfarin works by
targeting VKORC1 and preventing oxidized vit K from being reduced, and thus reducing activated clotting factors in the blood stream.
R and S Warfarin’s target
VKORC1
if a patient is not responding the way you’d expect from a medication
PGx testing may be indicated
PM of a CYP3A4 substrate APC will have…
increased clinical effect/buildup of the APC
PM of a CYP3A4 substrate pro drug
almost no clinical effect/decreased clinical effect.
NAVAGATE - N
Is the drug necessary?
NAVAGATE - 3 A’s
alternatives (are there alternatives?)
appropriate turnaround time
acceptance (is there provider/patient acceptance if the test is pos/neg?)
NAVAGATE - V
Is there a validated test?
NAVAGATE - G
Good evidence - is there evidence regarding regarding what to do with the result?
NAVAGATE - T
Test reimbursement - how will patient pay?
NAVAGATE - E
Evaluate and document - how will the results be documented?
PGx tests for what CYP enzyme re: codeine?
CYP2D6
What causes most of the PM phenotype?
null alleles
If you have diminished level of VKORC1
Less targets for warfarin to bind to - decrease dose
purpose of required genetic testing at pharamacokinetic level
to anticipate polymorphism based kinetic changes that significantly reduce efficacy or cause serious adverse effects
Purpose of required genetic testing at a pharmacodynamic level
there is a need to determine whether a therapeutic target exists
or
there is a need to anticipate polymorphisms unrelated to the target that cause serious adverse effects
PGx testing at a pharmacokinetic level looks more at ____ while PGx testing at a pharmacodynamic level looks at
CYP enzymes ; drug targets
Imatinib required PGx testing
Pharmacodynamic:
Works only in CML with Philadelphia chromosome-Positive.
G6PD deficiency required PGx testing
Pharmacokinetic: life threatening hemolysis while taking rasburicase
HLA-B
Human leukocyte antigen-B
PGx related to HLAs
If patient has the HLA present for the drug in question, they’ll have the adverse skin reaction and you’d need to find an alternative.
Why is pgx testing required for carbamazepine?
because if they have the HLA specific to the drug, they’ll have a life threatening skin reaction (SJS).
G6PD deficiency can predispose patients to what when given certain meds?
hemolytic anemia
What is the CYP enzyme which primary metabolizes clopidogrel?
CYP2C19
Is clopidogrel an APC or a pro drug?
pro drug
PM of 2PC19 when given clopidogrel, a pro drug
diminished effect, risk for clotting
PMs of CYP2C19 who are prescribed clopidogrel should…
need a different agent or alternative dosing
is warfarin an APC or pro drug
APC
is codeine an apc or pro drug
pro drug
