factores que disminuyen la efectividad del clopidogrel
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66 AJN ▼ June 2009 ▼ Vol.
109, No.
6 ajnonline.
com
Watch
FACTORS THAT DECREASE THE
EFFECTIVENESS OF CLOPIDOGREL
• In patients taking both clopidogrel and a proton pump
inhibitor, the drug interaction
that may occur through the...
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66 AJN ▼ June 2009 ▼ Vol.
109, No.
6 ajnonline.
com
Watch
FACTORS THAT DECREASE THE
EFFECTIVENESS OF CLOPIDOGREL
• In patients taking both clopidogrel and a proton pump
inhibitor, the drug interaction
that may occur through the
cytochrome P-450 isoenzyme
system can diminish the effectiveness of clopidogrel.
• A genetic variation in the same
isoenzyme system may impair
the metabolism of clopidogrel,
thereby also diminishing the
effectiveness of the drug.
Recent research indicates that
either a drug interaction or
a genetic variation affecting
metabolism can alter the effectiveness of the antiplatelet drug
clopidogrel (Plavix), posing the
risk of possibly life-threatening
cardiovascular complications.
Clopidogrel, which inhibits
platelet aggregation and therefore can prevent blood clots and
cardiovascular events, is prescribed after recent myocardial
infarction or stroke, after acute
coronary syndromes, and as prophylaxis in patients with peripheral arterial disease.
But clopidogrel can also cause
dyspepsia (gastric distress, including pain, burning, and nausea)
as well as gastric ulceration and
gastrointestinal bleeding, especially when used with aspirin in
the dual antiplatelet therapy
commonly prescribed after acute
coronary syndromes.
Because
proton pump inhibitors (including omeprazole [Prilosec, Zegerid],
lansoprazole [Prevacid], pantoprazole [Protonix], rabeprazole
[Aciphex], and esomeprazole
[Nexium]) decrease gastric acidity and are useful in the treatment of gastroesophageal reflux
disease and stomach ulcers, they
are commonly prescribed to treat
or prevent gastric adverse effects
in patients taking clopidogrel.
However, studies noted by the
Food and Drug Administration
(FDA; see http://bit.
ly/BIeM0 for
more information) describe the
possibility of an interaction
between clopidogrel and omeprazole via the cytochrome P-450
(CYP) isoenzyme system that
appears to significantly diminish
clopidogrel’s antiplatelet effect.
Clopidogrel is a “prodrug,”
meaning it’s not therapeutically
active in its natural state but must
first be metabolized.
CYP 2C19
is one of the principal enzymes in
the liver through which clopidogrel is extensively metabolized.
Therefore, coadministration of
clopidogrel and a drug that
alters the level of CYP 2C19 will
change the amount of clopidogrel
that can be metabolized into the
therapeutically active form.
If the
other drug decreases the available
CYP 2C19, less clopidogrel will
be converted to its therapeutically active form.
Conversely,
if the other drug increases the
amount of CYP 2C19, more
than the expected amount of
clopidogrel will become active.
Proton pump inhibitors exert an
effect on CYP 2C19 in two ways:
they inhibit it and can also be
metabolized by it (that is, it is a
“substrate” of the enzyme).
Both
actions diminish the amount of
CYP 2C19 available to metabolize clopidogrel.
If significantly
less therapeutically active clopidogrel is formed, its effectiveness is
diminished or may even be lost.
Current studies also suggest
that some patients may have a
genetic variation in their CYP
isoenzyme system that predisposes them to poorly metabolize
clopidogrel.
Such patients receive
less therapeutically active drug
and experience worse clinical
outcomes.
When patients with
this genetic variation concurrently take clopidogrel and a
proton pump inhibitor, the problem is compounded.
The FDA is conducting a safety
review of these recent findings
and has asked the manufacturers
of clopidogrel (Sanofi-Aventis
and Bristol-Myers Squibb) to
conduct additional clinical trials
to learn more about the genetic
variation that can alter its effectiveness, as well as additional
research into possible drug interactions, especially in the use of
proton pump inhibitors.
As more
becomes known, it’s possible that
the FDA will request revisions
to the clopidogrel labeling, but
so far none are proposed.
In the meantime, patients likely
to have such drug interactions,
rather than discontinue clopidogrel, should discontinue use of
the proton pump inhibitor and
change to another class of drug
to diminish gastric acidity, such
as the histamine H2 blockers
ranitidine (Zantac), famotidine
(Pepcid), cimetidine (Tagamet),
and nizatidine (Axid), and take
antacids that don’t interfere
with clopidogrel’s effectiveness.
Because not all patients taking
clopidogrel develop gastric
distress, it may be prudent in
light of the new findings not
to use proton pump inhibitors
prophylactically, but instead
restrict their use to patients who
can’t use other drug therapy.
To assess for possible drug
interactions, nurses should review
all other prescribed medications
in patients taking clopidogrel,
especially the concomitant use of
a proton pump inhibitor.
If an
interaction is likely, the prescriber
should be notified to discuss with
the patient a safe substitution for
the other drug.
If use of that drug
must be continued, the nurse should
monitor laboratory data to
assess clopidogrel’s therapeutic
effectiveness.
The patient should
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