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

Table 30–4
Features of GPIIb/IIIa Antagonists
FEATURE ABCIXIMAB EPTIFIBATIDE TIROFIBAN
Description Fab fragment of humanized Cyclical KGD-containing Nonpeptidic RGD-mimetic
mouse monoclonal antibody heptapeptide
Specific for No Yes Yes
GPIIb/IIIa
Plasma t 1/2
Short (min) Long (2.5 h) Long (2.0 h)
Platelet-bound t 1/2
Long (days) Short (sec) Short (sec)
Renal clearance No Yes Yes
KGD, Lysine - Glycine - Aspartate; RGD, Arginine - Glycine - Aspartate.
agents listed in Table 30–3. The frequency of major hemorrhage in
clinical trials varies from 1-10%, depending on the intensity of anticoagulation
with heparin. Thrombocytopenia with a platelet count
<50,000 occurs in about 2% of patients and may be due to development
of neo-epitopes induced by bound antibody. Since the duration
of action is long, if major bleeding or emergent surgery occurs,
platelet transfusions can reverse the aggregation defect because free
antibody concentrations fall rapidly after cessation of infusion.
Readministration of antibody has been performed in a small number
of patients without evidence of decreased efficacy or allergic reactions.
The expense of the antibody limits its use.
Eptifibatide. Eptifibatide (INTEGRILIN) is a cyclic peptide
inhibitor of the fibrinogen binding site on α IIb
β 3
.
It is administered intravenously and blocks platelet
aggregation.
Eptifibatide is given as a bolus of 180 μg/kg followed by
2 μg/kg/min for up to 96 hours. It is used to treat acute coronary syndrome
and for angioplastic coronary interventions. In the latter
case, myocardial infarction and death have been reduced by
~20%. Although the drug has not been compared directly to abciximab,
it appears that its benefit is somewhat less than that obtained
with the antibody, perhaps because eptifibatide is specific for
α IIb
β 3
and does not react with the vitronectin receptor. The duration
of action of the drug is relatively short, and platelet aggregation
is restored within 6-12 hours after cessation of infusion.
Eptifibatide generally is administered in conjunction with aspirin
and heparin.
Adverse Effects. The major side effect is bleeding, as is the case with
abciximab. The frequency of major bleeding in trials was about 10%,
compared with ~9% in a placebo group, which included heparin.
Thrombocytopenia has been seen in 0.5-1% of patients.
Tirofiban. Tirofiban (AGGRASTAT) is a nonpeptide, smallmolecule
inhibitor of α IIb
β 3
that appears to have a
mechanism of action similar to eptifibatide. Tirofiban
has a short duration of action and has efficacy in non-
Q-wave myocardial infarction and unstable angina.
Reductions in death and myocardial infarction have
been ~20% compared to placebo, results similar to
those with eptifibatide.
Side effects also are similar to those of eptifibatide. The agent
is specific to α IIb
β 3
and does not react with the vitronectin receptor.
Meta-analysis of trials using α IIb
β 3
inhibitors suggests that their
value in antiplatelet therapy after acute myocardial infarction is limited
(Boersma et al., 2002). Tirofiban is administered intravenously
at an initial rate of 0.4 μg/kg/min for 30 minutes, and then continued
at 0.1 mg/kg/min for 12-24 hours after angioplasty or atherectomy.
It is used in conjunction with heparin.
Newer Antiplatelet Agents
New agents in advanced stages of development include
cangrelor and ticagrelor (BRILINTA), direct-acting reversible
P2Y 12
antagonists, and SCH530348 and E5555, orally
active inhibitors of the protease-activated receptor-1
(PAR-1), the major thrombin receptor on platelets.
Cangrelor. Cangrelor is an adenosine analog that binds reversibly to
P2Y 12
and inhibits its activity. The drug has a t 1/2
of 3-6 minutes and
is given intravenously as a bolus followed by an infusion. When
stopped, platelet function recovers within 60 minutes. Recent trials
comparing cangrelor with placebo during coronary interventions or
comparing cangrelor with clopidogrel after such procedures revealed
little or no advantages of cangrelor.
Ticagrelor. Ticagrelor is an orally active, reversible inhibitor of P2Y 12
.
The drug is given twice daily and not only has a more rapid onset and
offset of action than clopidogrel, but also produces greater and more
predictable inhibition of ADP-induced platelet aggregation. When
compared with clopidogrel in patients with acute coronary syndromes
(Wallentin et al., 2009), ticagrelor produced a greater reduction in
cardiovascular death, myocardial infarction, and stroke at 1 year than
clopidogrel did. This difference reflected a significant reduction in
both cardiovascular death and myocardial infarction with ticagrelor.
Rates of stroke were similar with ticagrelor and clopidogrel, and
there were no differences in rates of major bleeding. When minor
bleeding was added to the major bleeding results, however, ticagrelor
showed an increase relative to clopidogrel. Although not yet