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

868 indications as aminocaproic acid and can be given
intravenously or orally.
Plaque disruption
SECTION III
MODULATION OF CARDIOVASCULAR FUNCTION
Like aminocaproic acid, tranexamic acid is excreted in the
urine and dose reductions are necessary in patients with renal impairment.
The FDA approved oral tranexamic acid tablets for treatment
of heavy menstrual bleeding in 2009. When used for this indication,
tranexamic acid usually is given at a dose of 1 g four times a day for
4 days.
ANTIPLATELET DRUGS
Platelets provide the initial hemostatic plug at sites of
vascular injury. They also participate in pathological
thromboses that lead to myocardial infarction, stroke,
and peripheral vascular thromboses. Potent inhibitors
of platelet function have been developed in recent
years. These drugs act by discrete mechanisms; thus, in
combination, their effects are additive or even synergistic.
Their availability has led to a revolution in cardiovascular
medicine, whereby angioplasty and vascular
stenting of lesions now are feasible with low rates of
restenosis and thrombosis when effective platelet inhibition
is employed. The sites of pharmacological intervention
by the various antiplatelet drugs are highlighted
in Figure 30–8.
Aspirin. Processes including thrombosis, inflammation,
wound healing, and allergy are modulated by oxygenated
metabolites of arachidonate and related polyunsaturated
fatty acids that are collectively termed eicosanoids.
Interference with the synthesis of eicosanoids is the basis
for the effects of many therapeutic agents, including analgesics,
anti-inflammatory drugs, and anti-thrombotic
agents (see Chapters 33 and 34).
In platelets, the major cyclooxygenase product is
TxA 2
(thromboxane A 2
), a labile inducer of platelet
aggregation and a potent vasoconstrictor. Aspirin blocks
production of TxA 2
by acetylating a serine residue near
the active site of platelet cyclooxygenase-1 (COX-1),
the enzyme that produces the cyclic endoperoxide precursor
of TxA 2
. Because platelets do not synthesize new
proteins, the action of aspirin on platelet COX-1 is permanent,
lasting for the life of the platelet (7-10 days).
Thus, repeated doses of aspirin produce a cumulative
effect on platelet function.
Complete inactivation of platelet COX-1 is achieved with a
daily aspirin dose of 75 mg. Therefore, aspirin is maximally effective
as an anti-thrombotic agent at doses much lower than those required
for other actions of the drug. Numerous trials indicate that aspirin,
when used as an anti-thrombotic drug, is maximally effective at doses
of 50-320 mg/day (Antithrombotic Trialists’ Collaboration, 2002;
Patrono et al., 2004). Higher doses do not improve efficacy; moreover,
Tissue factor
Thrombin
SCH530348
E5555
Aspirin
X
Collagen
Platelet adhesion
and secretion
X
TXA 2
COX-1
vWF
ADP
Platelet recruitment
and activation
GPIIb/IIIa activation
Platelet aggregation
Ticlopidine
Clopidrogrel
Prasugrel
Cangrelor
Ticagrelor
they potentially are less efficacious because of inhibition of prostacyclin
production, which can be largely spared by using lower doses
of aspirin. Higher doses also increase toxicity, especially bleeding.
Other NSAIDs that are reversible inhibitors of COX-1 have
not been shown to have anti-thrombotic efficacy and in fact may
even interfere with low-dose aspirin regimens (see Chapters 33 and
34 for details).
Dipyridamole. Dipyridamole (PERSANTINE, others) interferes
with platelet function by increasing the cellular
concentration of cyclic AMP. This effect is mediated by
inhibition of cyclic nucleotide phosphodiesterases
and/or by blockade of uptake of adenosine, which acts
at adenosine A 2
receptors to stimulate platelet adenylyl
cyclase and thence cellular cyclic AMP. Dipyridamole
X
X
Abciximab
Eptifibatide
Tirofiban
Figure 30–8. Sites of action of antiplatelet drugs. Aspirin
inhibits thromboxane A 2
(TxA 2
) synthesis by irreversibly acetylating
cyclooxygenase-1 (COX-1). Reduced TxA 2
release attenuates
platelet activation and recruitment to the site of vascular
injury. Ticlopidine, clopidogrel, and prasugrel irreversibly block
P2Y 12
, a key ADP receptor on the platelet surface; cangrelor and
ticagrelor are reversible inhibitors of P2Y 12
. Abciximab, eptifibatide,
and tirofiban inhibit the final common pathway of platelet
aggregation by blocking fibrinogen and von Willebrand factor
(vWF) from binding to activated glycoprotein (GP) IIb/IIIa.
SCH530348 and E5555 inhibit thrombin-mediated platelet activation
by targeting protease-activated receptor-1 (PAR-1), the
major thrombin receptor on platelets.