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

764 a Ca 2+ channel blocker may provide additional relief
over that obtained with either type of agent alone.
Because nitrates primarily reduce preload, whereas
Ca 2+ channel blockers reduce afterload, the net effect
on reduction of O 2
demand should be additive.
However, excessive vasodilation and hypotension can
occur. The concurrent administration of a nitrate and
nifedipine has been advocated in particular for patients
with exertional angina with heart failure, the sick-sinus
syndrome, or AV nodal conduction disturbances, but
excessive tachycardia may be seen.
SECTION III
MODULATION OF CARDIOVASCULAR FUNCTION
Ca 2+ Channel Blockers, β Receptor Antagonists, and
Nitrates. In patients with exertional angina that is not
controlled by the administration of two types of antianginal
agents, the use of all three may provide improvement,
although the incidence of side effects increases
significantly. The dihydropyridines and nitrates dilate
epicardial coronary arteries, the dihydropyridines
decrease afterload, the nitrates decrease preload, and the
β receptor antagonists decrease heart rate and myocardial
contractility. Therefore, there is theoretical, and
sometimes real, benefit with their combination, although
adverse drug interactions may lead to clinically important
events. For example, combining verapamil or diltiazem
with a β receptor antagonist greatly increases
the risk of conduction system and left ventricular dysfunction–related
side effects and should be undertaken
only with extreme caution and only if no other alternatives
exist.
ANTI-PLATELET, ANTI-INTEGRIN, AND
ANTI-THROMBOTIC AGENTS
Aspirin reduces the incidence of MI and death in
patients with unstable angina. In addition, low doses of
aspirin appear to reduce the incidence of MI in patients
with chronic stable angina. Aspirin, given in doses of
160-325 mg at the onset of treatment of MI, reduces
mortality in patients presenting with unstable angina.
The addition of the thioenopyridine clopidogrel to
aspirin therapy reduces mortality in patients with acute
coronary syndromes (Hillis and Lange, 2009); a related
thioenopyridine, prasugrel, has been approved for treatment
of acute coronary syndromes (Wiviott et al.,
2007). Heparin, in its unfractionated form and as lowmolecular-weight
heparin, also reduces symptoms and
prevents infarction in unstable angina (Yeghiazarians et
al., 2000). Thrombin inhibitors, such as hirudin or
bivalirudin, directly inhibit even clot-bound thrombin,
are not affected by circulating inhibitors, and function
independently of antithrombin III. Thrombolytic
agents, on the other hand, are of no benefit in unstable
angina (Yeghiazarians et al., 2000). Intravenous
inhibitors of the platelet GPIIb/IIIa receptor (abciximab,
tirofiban, and eptifibatide) are effective in preventing
the complications of PCIs and in the treatment
of some patients presenting with acute coronary syndromes
(Hillis and Lange, 2009).
TREATMENT OF CLAUDICATION AND
PERIPHERAL VASCULAR DISEASE
Most patients with peripheral vascular disease also have
coronary artery disease, and the therapeutic approaches
for peripheral and coronary arterial diseases overlap.
Mortality in patients with peripheral vascular disease is
most commonly due to cardiovascular disease
(Regensteiner and Hiatt, 2002), and treatment of coronary
disease remains the central focus of therapy. Many
patients with advanced peripheral arterial disease are
more limited by the consequences of peripheral ischemia
than by myocardial ischemia. In the cerebral circulation,
arterial disease may be manifest as stroke or transient
ischemic attacks. The painful symptoms of peripheral
arterial disease in the lower extremities (claudication)
typically are provoked by exertion, with increases in
skeletal muscle O 2
demand exceeding blood flow
impaired by proximal stenoses. When flow to the
extremities becomes critically limiting, peripheral
ulcers and rest pain from tissue ischemia can become
debilitating.
Most of the therapies shown to be efficacious for
treatment of coronary artery disease also have a salutary
effect on progression of peripheral artery disease
(Hirsch et al., 2005). Reductions in cardiovascular morbidity
and mortality in patients with peripheral arterial
disease have been documented with anti-platelet therapy
using aspirin, clopidogrel, or ticlopidine, administration
of ACE inhibitors, and treatment of hyperlipidemia
(Regensteiner and Hiatt, 2002). Interestingly, neither
intensive treatment of diabetes mellitus nor antihypertensive
therapy appears to alter the progression of symptoms
of claudication. Other risk factor and lifestyle
modifications remain cornerstones of therapy for
patients with claudication: Physical exercise, rehabilitation,
and smoking cessation have proven efficacy. Drugs
used specifically in the treatment of lower-extremity
claudication include pentoxifylline and cilostozol (Hiatt,
2001). Pentoxifylline is a methylxanthine derivative that
is called a rheologic modifier for its effects on increasing
the deformability of red blood cells. However, the