Biological Functions
The formation of platelet aggregates and thrombi in arterial
blood may precipitate coronary vasospasm and
occlusion, myocardial infarction, and stroke and contribute
to atherosclerotic plaque development. Drugs
that inhibit platelet function are administered for the relatively
specific prophylaxis of arterial thrombosis and
for the prophylaxis and therapeutic management of
myocardial infarction and stroke. After an infarction or
stroke, antiplatelet therapy must be initiated within 2
hours to obtain significant benefit. The antiplatelet
drugs are administered as adjuncts to thrombolytic
therapy, along with heparin, to maintain perfusion and
to limit the size of the myocardial infarction. Recently,
antiplatelet drugs have found new importance in
preventing thrombosis in percutaneous coronary intervention
procedures (angioplasty and stent). Administration
of an antiplatelet drug increases the risk of
bleeding.
Aspirin inhibits platelet aggregation and prolongs
bleeding time. It is useful for preventing coronary
thrombosis in patients with unstable angina, as an adjunct
to thrombolytic therapy, and in reducing recurrence
of thrombotic stroke. It acetylates and irreversibly
inhibits cyclooxygenase (primarily cyclooxygenase-1)
both in platelets, preventing the formation of TxA2, and
in endothelial cells, inhibiting the synthesis of PGI2 While endothelial cells can synthesize cyclooxygenase,
platelets cannot. The goal of therapy with
aspirin is to selectively inhibit the synthesis of platelet
TxA2 and thereby inhibit platelet aggregation. This is accomplished
with a low dose of aspirin (160 to 325 mg
per day), which spares the endothelial synthesis of
PGI2. If ibuprofen is taken concurrently, it will bind reversibly
to cyclooxygenase and prevent the access of aspirin
to its acetylation site and thus antagonize the ability
of aspirin to inhibit platelets. Dipyridamole
(Persantine), a coronary vasodilator, is a phosphodiesterase
inhibitor that increases platelet cyclic adenosine
monophosphate (cAMP) concentrations. It also
may potentiate the effect of PGI2, which stimulates
platelet adenylate cyclase. However, dipyridamole itself
has little effect on platelets in vivo. Dipyridamole in
combination with warfarin is beneficial in patients with
artificial heart valves; it is also useful in combination
with aspirin (Aggrenox) for the secondary prevention
of stroke.
Mechanism of action
Most of the current available antiplatelet drugs, such as aspirin, dipyridamole, ticlopidine, and
sulfinpyrazone, exert their actions by affecting only the secondary platelet aggregation pathways
(87). For example, aspirin and sulfinpyrazone work by inhibiting the biosynthesis of TXA2 in the
platelets. Aspirin works by irreversibly and permanently inactivating cyclooxygenase
(COX) through covalent acetylation of a serine residue in close proximity to the active site of the
enzyme. A cumulative inactivation effect occurs on platelets with long-term therapy, because
platelets do not synthesize new COX (i.e., platelets are unable to synthesize, via de novo pathway,
COX-1, because they are anucleated cells). Therefore, the effects of aspirin last for the lifetime of
the platelet (7–10 days). Sulfinpyrazone also is a potent but reversible COX inhibitor that does not
affect PGI2 synthesis in endothelial cells. Like nonsteroidal anti-inflammatory agents (NSAIDs), such
as aspirin, this action inhibits the aggregation of platelets into thrombi. Dipyridamole interrupts
platelet function through its effect of increasing cellular concentration of cAMP by inhibiting
phosphodiesterase, an enzyme needed for degradation of cAMP. Dipyridamole also may stimulate
PGI2 release and inhibits TXA2 formation. Ticlopidine and clopidogrel selectively inhibit
ADP-induced platelet aggregation with no direct action on prostaglandin production. New and more
selective antiplatelet drugs, such as integrin αIIbβ3 receptor antagonists (GPIIa/IIIb blockers),
thromboxane synthase inhibitor, and TXA2 receptor antagonists, are currently being developed.
