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

is a vasodilator that, in combination with warfarin,
inhibits embolization from prosthetic heart valves. The
drug has little or no benefit as an anti-thrombotic agent.
In trials in which a regimen of dipyridamole plus aspirin was
compared with aspirin alone, dipyridamole provided no additional
beneficial effect (Antithrombotic Trialists’ Collaboration, 2002).
Two studies suggest that dipyridamole plus aspirin reduces strokes
in patients with prior strokes or transient ischemic attacks (Diener
et al., 1996). A formulation containing 200 mg of dipyridamole, in
an extended-release form, and 25 mg of aspirin (AGGRENOX) is available.
A recent study comparing this combination with clopidogrel
for secondary prevention in patients with stroke or transient ischemic
attacks showed no advantage of dipyridamole plus aspirin.
Ticlopidine (TICLID, others). Platelets contain two
purinergic receptors, P2Y 1
and P2Y 12
; both are GPCRs
for ADP. The ADP-activated platelet P2Y 1
receptor
couples to the G q
–PLC–IP 3
–Ca 2+ pathway and induces
a shape change and aggregation. The P2Y 12
receptor
couples to G i
and, when activated by ADP, inhibits
adenylyl cyclase, resulting in lower levels of cyclic
AMP and thereby less cyclic AMP–dependent inhibition
of platelet activation. Based on pharmacological
studies, it appears that both receptors must be stimulated
to result in platelet activation (Jin and Kunapuli,
1998), and inhibition of either receptor is sufficient to
block platelet activation. Ticlopidine is a thienopyridine
prodrug (Figure 30–9) that inhibits the P2Y 12
receptor.
Ticlopidine is converted to the active thiol metabolite by a
hepatic CYP (Savi et al., 2000). It is rapidly absorbed and highly
bioavailable. It permanently inhibits the P2Y 12
receptor by forming
a disulfide bridge between the thiol on the drug and a free cysteine
residue in the extracellular region of the receptor, and thus has a prolonged
effect. Like aspirin, it has a short t 1/2
but a long duration of
action, which has been termed “hit-and-run pharmacology”
(Hollopeter et al., 2001). Maximal inhibition of platelet aggregation
is not seen until 8-11 days after starting therapy. The usual dose is
250 mg twice daily. Loading doses of 500 mg sometimes are given
to achieve a more rapid onset of action. Inhibition of platelet aggregation
persists for a few days after the drug is stopped.
Adverse Effects. The most common side effects are nausea, vomiting,
and diarrhea. The most serious is severe neutropenia (absolute
neutrophil count <500/μL), which occurred in 2.4% of stroke
patients given the drug during premarketing clinical trials. Fatal
agranulocytosis with thrombopenia has occurred within the first 3
months of therapy; therefore, frequent blood counts should be
obtained during the first few months of therapy, with immediate
discontinuation of therapy should cell counts decline. Platelet
counts also should be monitored, as thrombocytopenia has been
reported. Rare cases of thrombotic thrombocytopenic purpurahemolytic
uremic syndrome (TTP-HUS) have been associated with
ticlopidine, with a reported incidence of 1 in 1600-4800 patients
when the drug is used after cardiac stenting; the mortality associated
S
S
F
O
Ticlopidine
H
N
Clopidogrel
H 3 CO 2 C
N
Prasugrel
N
Cl
Cl
S
Figure 30–9. Structures of ticlopidine, clopidogrel, and prasugrel.
with these cases is reported to be as high as 18-57% (Bennett et al.,
2000). Remission of TTP has been reported when the drug is
stopped (Quinn and Fitzgerald, 1999).
Therapeutic Uses. Ticlopidine has been shown to prevent cerebrovascular
events in secondary prevention of stroke and is at least as good
as aspirin in this regard (Patrono et al., 1998). Because ticlopidine is
associated with life-threatening blood dyscrasias and a relatively
high rate of TTP, it has largely been replaced by clopidogrel.
Clopidogrel (PLAVIX). Clopidogrel is closely related to
ticlopidine (Figure 30–9). Clopidogrel also is an irreversible
inhibitor of platelet P2Y 12
receptors but is more
potent and has a more favorable toxicity profile than
ticlopidine, with thrombocytopenia and leukopenia
occurring only rarely (Bennett et al., 2000). Clopidogrel
is a prodrug with a slow onset of action.
The usual dose is 75 mg/day with or without an initial loading
dose of 300 or 600 mg. The drug is somewhat better than aspirin in the
secondary prevention of stroke, and the combination of clopidogrel
plus aspirin is superior to aspirin alone for prevention of recurrent
ischemia in patients with unstable angina. The superiority of the combination
suggests that the actions of the two drugs are synergistic, as
might be expected from their distinct mechanisms of action.
Clopidogrel is used with aspirin after angioplasty and coronary stent
implantation, and this combination should be continued for at least
4-6 weeks in patients with a bare metal stent and for at least 1 year
in those with a drug-eluting stent. The FDA-approved indications
H
H
O
O
CCH 3
869
CHAPTER 30
BLOOD COAGULATION AND ANTICOAGULANT, FIBRINOLYTIC, AND ANTIPLATELET DRUGS