Page 2434 - Hematology_ Basic Principles and Practice ( PDFDrive )

2172 Part XII Hemostasis and Thrombosis

Indications Dosing

Dipyridamole plus aspirin was compared with aspirin or dipyri- Aggrenox is given twice daily. Each capsule contains 200 mg of
damole alone, or with placebo, in patients with an ischemic stroke extended-release dipyridamole and 25 mg of aspirin.
or transient ischemic attack. The combination reduced the risk
of stroke by 22.1% compared with aspirin alone and by 24.4%
compared with dipyridamole alone. In a second trial, researchers Side Effects
compared dipyridamole plus aspirin with aspirin alone for secondary
prevention in patients with ischemic stroke. Vascular death, stroke, Because dipyridamole has vasodilatory effects, it must be used with
or myocardial infarction occurred in 13% of patients given combina- caution in patients with coronary artery disease. Gastrointestinal
tion therapy and in 16% of those treated with aspirin alone. When complaints, headache, facial flushing, dizziness, and hypotension also
Aggrenox was compared with clopidogrel, however, there was no can occur. These symptoms often subside with continued use of the
difference in efficacy, and there was more intracranial bleeding with drug.
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Aggrenox. Although Aggrenox is used for stroke prevention, because
of its vasodilatory effects and the paucity of data supporting the
use of dipyridamole in patients with symptomatic coronary artery GPIIb/IIIa Receptor Antagonists
disease, Aggrenox should not be used for stroke prevention in such
patients. As a class, parenteral GPIIb/IIIa receptor antagonists have an estab-
lished niche in patients with acute coronary syndromes. The three
agents in this class are abciximab, eptifibatide, and tirofiban.
Adenosine Reuptake
Mechanism of Action
X Dipyridamole
A member of the integrin family of adhesion receptors, GPIIb/IIIa is
A receptor found on the surface of platelets and megakaryocytes. With about
2
40,000 to 80,000 copies per platelet, GPIIb/IIIa is the most abundant
Platelet Adenylate receptor. Consisting of a noncovalently linked heterodimer, GPIIb/
cyclase IIIa is inactive on resting platelets. When platelets are activated,
ATP inside–outside signal transduction pathways trigger a conformational
activation of the receptor. Once activated, GPIIb/IIIa binds adhesive
molecules, such as fibrinogen and, under high shear conditions, von
cAMP X AMP Willebrand factor. Binding is mediated by Arg-Gly-Asp (RGD)
Phosphodiesterase sequences found on the fibrinogen and von Willebrand factor, as well

Ca 2+ as by the Lys-Gly-Asp (KGD) sequence located within a unique
dodecapeptide domain on the γ-chains of fibrinogen. Once bound,
fibrinogen and/or von Willebrand factor bridge adjacent platelets
together to induce platelet aggregation.
Activation and aggregation
inhibited Although abciximab, eptifibatide, and tirofiban all target the
GPIIb/IIIa receptor, they are structurally and pharmacologically
Fig. 149.3 MECHANISM OF ACTION OF DIPYRIDAMOLE. Dipyri- distinct (Table 149.1). Abciximab is a Fab fragment of a human-
damole increases levels of cyclic adenosine monophosphate (cAMP) in ized murine monoclonal antibody directed against the activated
platelets by (A) blocking the reuptake of adenosine and (B) inhibiting form of GPIIb/IIIa. Abciximab binds to the activated receptor
phosphodiesterase-mediated cAMP degradation. By promoting calcium with high affinity and blocks the binding of adhesive molecules. In
uptake, cAMP reduces intracellular levels of calcium. This, in turn, inhibits contrast to abciximab, eptifibatide and tirofiban are synthetic small
platelet activation and aggregation. AMP, Adenosine monophosphate; molecules. Eptifibatide is a cyclic heptapeptide that binds GPIIb/
ATP, adenosine triphosphate. IIIa because it incorporates the KGD motif, whereas tirofiban is

TABLE Features of GPIIb/IIIa Antagonists
149.1
Feature GPIIb/IIIa Antagonists
Generic name Abciximab Eptifibatide Tirofiban
Trade name ReoPro Integrilin Aggrastat
Description Fab fragment of humanized Cyclical KGD-containing Nonpeptidic RGD mimetic
mouse monoclonal antibody heptapeptide
Specific for GPIIb/IIIa No Yes Yes
Plasma half-life Short (min) Long (2.5 h) Long (2.0 h)
Platelet-bound half-life Long (days) Short Short
Renal clearance No Yes Yes
Dosing 0.25 mg/kg bolus followed by a Two 180 µg/kg boluses 25 µg/kg boluses followed by an
12-h infusion of 10 µg/min given 10 min apart 18-h infusion of 0.15 µg/kg/min
Adjustment for renal impairment No Yes Yes
KGD, Lys-Gly-Asp; RGD, Arg-Gly-Asp.