DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

870 for clopidogrel are to reduce the rate of stroke, myocardial infarction,
and death in patients with recent myocardial infarction or stroke,
established peripheral arterial disease, or acute coronary syndrome.
There is wide inter-individual variability in the capacity of
clopidogrel to inhibit ADP-induced platelet aggregation, and some
patients are designated resistant to the antiplatelet effects of the drug.
This variability reflects, at least in part, genetic polymorphisms in the
CYPs involved in the metabolic activation of clopidogrel, most
importantly CYP2C19. Clopidogrel-treated patients with the lossof-function
CYP2C19*2 allele exhibit reduced platelet inhibition
compared with those with the wild-type CYP2C19*1 allele and
experience a higher rate of cardiovascular events (see Table 30–2).
Even patients with the reduced-function CYP2C19*3, *4, or *5 alleles
may derive less benefit from clopidogrel than those with the fullfunction
CYP2C19*1 allele. Concomitant administration of proton
pump inhibitors, which are inhibitors of CYP2C19, with clopidogrel,
produces a small reduction in the inhibitory effects of clopidogrel
on ADP-induced platelet aggregation. The extent to which this
interaction increases the risk of cardiovascular events remains controversial.
Although CYP3A4 also contributes to the metabolic activation
of clopidogrel, polymorphisms in this enzyme do not appear
to influence clopidogrel responsiveness. However, a small study in
patients undergoing percutaneous coronary interventions revealed
that atorvastatin, a competitive inhibitor of CYP3A4, reduced the
inhibitory effect of clopidogrel on ADP-induced platelet aggregation.
The impact of this interaction on clinical outcomes is unknown.
The observation that genetic polymorphisms that affect clopidogrel
metabolism influence clinical outcomes raises the possibilities
that pharmacogenetic profiling may be useful to identify
clopidogrel-resistant patients and that point-of-care assessment of
the extent of clopidogrel-induced platelet inhibition may help detect
patients at higher risk for subsequent cardiovascular events. It is
unknown whether administration of higher doses of clopidogrel to
such patients will overcome this resistance.
Prasugrel (EFFIENT or EFIENT). The newest member of the
thienopyridine class, prasugrel (Figure 30–9) also is a
prodrug that requires metabolic activation. However,
its onset of action is more rapid than that of ticlopidine
or clopidogrel, and prasugrel produces greater and
more predictable inhibition of ADP-induced platelet
aggregation.
SECTION III
MODULATION OF CARDIOVASCULAR FUNCTION
These characteristics reflect the rapid and complete absorption
of prasugrel from the gut and its more efficient activation pathways.
Virtually all of the absorbed prasugrel undergoes activation; by
comparison, only 15% of absorbed clopidogrel undergoes metabolic
activation, with the remainder inactivated by esterases.
Because the active metabolites of prasugrel and the other
thienopyridines bind irreversibly to the P2Y 12
receptor, these drugs
have a prolonged effect after discontinuation. This can be problematic
if patients require urgent surgery. Such patients are at increased
risk for bleeding unless the thienopyridine is stopped at least 5 days
prior to the procedure.
Prasugrel was compared with clopidogrel in patients with
acute coronary syndromes scheduled to undergo a coronary intervention.
The incidence of cardiovascular death, myocardial infarction,
and stroke was significantly lower with prasugrel than with
clopidogrel mainly reflecting a reduction in the incidence of nonfatal
myocardial infarction. The incidence of stent thrombosis also was
lower with prasugrel than with clopidogrel. However, these advantages
were at the expense of significantly higher rates of fatal and
life-threatening bleeding. Because patients with a history of a prior
stroke or transient ischemic attack are at particularly high risk of
bleeding, the drug is contraindicated in those with a history of cerebrovascular
disease. Caution is required if prasugrel is used in
patients weighing <60 kg or in those with renal impairment. After a
loading dose of 60 mg, prasugrel is given once daily at a dose of 10 mg.
Patients >75 years of age or weighing <60 kg may do better with a
daily prasugrel dose of 5 mg.
In contrast to their effect on the bioactivation of clopidogrel,
CYP2C19 polymorphisms appear to be less important determinants
of the activation of prasugrel. There is no association between the
loss-of-function allele and decreased platelet inhibition or increased
rates of cardiovascular events with prasugrel. Therefore, prasugrel
may be a reasonable alternative to clopidogrel in patients with the
loss-of-function CYP2C19 allele.
Glycoprotein IIb/IIIa Inhibitors. Glycoprotein IIb/IIIa is
a platelet-surface integrin, which is designated α IIb
β 3
by
the integrin nomenclature. There are about 80,000 copies
of this dimeric glycoprotein on the platelet surface.
Glycoprotein IIb/IIIa is inactive on resting platelets
but undergoes a conformational transformation when
platelets are activated by platelet agonists such as thrombin,
collagen, or TxA 2.
This transformation endows glycoprotein
IIb/IIIa with the capacity to serve as a receptor for
fibrinogen and von Willebrand factor, which anchor
platelets to foreign surfaces and to each other, thereby
mediating aggregation. Inhibition of binding to this receptor
blocks platelet aggregation induced by any agonist.
Thus, inhibitors of this receptor are potent antiplatelet
agents that act by a mechanism distinct from that of
aspirin or the thienopyridine platelet inhibitors. Three
agents are approved for use at present, and their features
are highlighted in Table 30–4.
Abciximab. Abciximab (REOPRO) is the Fab fragment of
a humanized monoclonal antibody directed against the
α IIb
β 3
receptor. It also binds to the vitronectin receptor
on platelets, vascular endothelial cells, and smooth
muscle cells.
The antibody is administered to patients undergoing percutaneous
angioplasty for coronary thromboses, and when used in conjunction
with aspirin and heparin, has been shown to prevent
restenosis, recurrent myocardial infarction, and death. The unbound
antibody is cleared from the circulation with a t 1/2
of about 30 minutes,
but antibody remains bound to the α IIb
β 3
receptor and inhibits
platelet aggregation as measured in vitro for 18-24 hours after
infusion is stopped. It is given as a 0.25-mg/kg bolus followed by
0.125 μg/kg/min for 12 hours or longer.
Adverse Effects. The major side effect of abciximab is bleeding, and
the contraindications to its use are similar to those for the fibrinolytic