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

effects of pentoxifylline on lower-extremity claudication
appear to be modest. Cilostazol is an inhibitor of
PDE3 and promotes accumulation of intracellular cyclic
AMP in many cells, including blood platelets.
Cilostazol-mediated increases in cyclic AMP inhibit
platelet aggregation and promote vasodilation. The drug
is metabolized by CYP3A4 and has important drug
interactions with other drugs metabolized via this pathway
(see Chapter 6). Cilostazol treatment improves
symptoms of claudication but has no effect on cardiovascular
mortality.
As a PDE3 inhibitor, cilostazol is in the same drug class as
milrinone, which had been used orally as an inotropic agent for
patients with heart failure. Milrinone therapy was associated with an
increase in sudden cardiac death, and the oral form of the drug was
withdrawn from the market. Concerns about several other inhibitors
of PDE3 (inamrinone, flosequinan) followed. Cilostazol, therefore, is
labeled as being contraindicated in patients with heart failure,
although it is not clear that cilostazol itself leads to increased mortality
in such patients. Cilostazol has been reported to increase nonsustained
ventricular tachycardia; headache is the most common side
effect. Other treatments for claudication, including naftidrofuryl,
propionyl levocarnitine, and prostaglandins, have been explored in
clinical trials, and there is some evidence that some of these therapies
may be efficacious.
MECHANO-PHARMACOLOGICAL THERAPY:
DRUG-ELUTING ENDOVASCULAR STENTS
Intracoronary stents can ameliorate angina and reduce
adverse events in patients with acute coronary syndromes.
However, the long-term efficacy of intracoronary
stents is limited by subacute luminal restenosis
within the stent, which occurs in a substantial minority
of patients. The pathways that lead to “in-stent
restenosis” are complex, but smooth muscle proliferation
within the lumen of the stented artery is a common
pathological finding. Local antiproliferative therapies
at the time of stenting have been explored over many
years, and the development of drug-eluting stents has
had an important impact on clinical practice (Moses et
al., 2003; Stone et al., 2004). Two drugs are currently
being used in intravascular stents: paclitaxel and
sirolimus. Paclitaxel is a tricyclic diterpene that inhibits
cellular proliferation by binding to and stabilizing polymerized
microtubules. Sirolimus is a hydrophobic
macrolide that binds to the cytosolic immunophilin
FKBP12; the FKBP12–sirolimus complex inhibits the
mammalian kinase target of rapamycin (mTOR),
thereby inhibiting cell cycle progression (see Chapter 60).
Paclitaxel and sirolimus differ markedly in their
mechanisms of action but share common chemical
properties as hydrophobic small molecules. Differences
in the intracellular targets of these two drugs are associated
with marked differences in their distribution in
the vascular wall (Levin et al., 2004). Stent-induced
damage to the vascular endothelial cell layer can lead to
thrombosis; patients typically are treated with
antiplatelet agents, including clopidogrel (for up to 6
months) and aspirin (indefinitely), sometimes in conjunction
with intravenous heparin and/or GPIIb/IIIa
inhibitors administered at the time of the revascularization
procedure. The inhibition of cellular proliferation
by paclitaxel and sirolimus not only affects vascular
smooth muscle cell proliferation but also attenuates the
formation of an intact endothelial layer within the
stented artery. Therefore, antiplatelet therapy (typically
with clopidogrel) is continued for several months after
intracoronary stenting with drug-eluting stents. The rate
of restenosis with drug-eluting stents is reduced
markedly compared with “bare metal” stents, and the
ongoing development of mechanopharmacological
approaches likely will lead to novel approaches in
intravascular therapeutics.
An important caveat in the use of drug-eluting stents is that
stent thrombosis can occur even many months after placement of the
stent, sometimes temporally associated with discontinuation of
antiplatelet therapy with clopidogrel (Hillis and Lange, 2009). Longterm
therapy with clopidogrel added to lifelong therapy with aspirin
may be considered for many patients with drug-eluting stents; such
long-term therapy carries an increased risk of bleeding. In some
patients, the risk-benefit ratio between bare metal and drug-eluting
stents may lead to the choice of a bare metal stent. The relative
efficacy, morbidity, and morbidity of percutaneous coronary revascularization
versus surgical coronary artery bypass grafting are topics
of active investigation and debate, well beyond the scope of this
chapter. Mechano-pharmaclogical therapies influence this important
ongoing discussion.
THERAPY OF HYPERTENSION
Hypertension is the most common cardiovascular disease.
The prevalence of hypertension increases with advancing
age; for example, about 50% of people between the
ages of 60 and 69 years old have hypertension, and the
prevalence is further increased beyond age 70 (Chobanian
et al., 2003).
Elevated arterial pressure causes pathological
changes in the vasculature and hypertrophy of the left
ventricle. As a consequence, hypertension is the principal
cause of stroke; a major risk factor for coronary artery
disease and its attendant complications, MI and sudden
cardiac death; and a major contributor to cardiac failure,
renal insufficiency, and dissecting aneurysm of the aorta.
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CHAPTER 27
TREATMENT OF MYOCARDIAL ISCHEMIA AND HYPERTENSION