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

750 consumption. An additional benefit of reducing preload
is that it increases the pressure gradient for perfusion
across the ventricular wall, which favors
subendocardial perfusion. Afterload is the impedance
against which the ventricle must eject. In the absence
of aortic valvular disease, afterload is related to peripheral
resistance. Decreasing peripheral arteriolar resistance
reduces afterload and thus myocardial work and
O 2
consumption.
Organic nitrates decrease both preload and afterload
as a result of respective dilation of venous capacitance
and arteriolar resistance vessels. Organic nitrates
do not appear to significantly alter the inotropic or
chronotropic state of the heart, although NO synthesized
by cardiac myocytes and fibroblasts may play a role in
the modulation of cyclic nucleotide metabolism and
may thereby alter autonomic responses (Gustafsson and
Brunton, 2002). Because nitrates affect several of the
primary determinants of myocardial O 2
demand, their
net effect usually is to decrease myocardial O 2
consumption.
In addition, an improvement in the lusitropic state
of the heart may be seen with more rapid early diastolic
filling. This may be secondary to the relief of ischemia
rather than primary, or it may be due to a reflex increase
in sympathetic activity. Nitrovasodilators also increase
cyclic GMP in platelets, with consequent inhibition of
platelet function (Loscalzo, 2001) and decreased deposition
of platelets in animal models of arterial wall
injury (Lam et al., 1988). While this may contribute to
their anti-anginal efficacy, the effect appears to be modest
and in some settings may be confounded by the
potential of nitrates to alter the pharmacokinetics of
heparin, reducing its anti-thrombotic effect.
When nitroglycerin is injected or infused directly
into the coronary circulation of patients with coronary
artery disease, anginal attacks (induced by electrical
pacing) are not aborted even when coronary blood flow
is increased. However, sublingual administration of
nitroglycerin does relieve anginal pain in the same
patients. Furthermore, venous phlebotomy that is sufficient
to reduce left ventricular end-diastolic pressure
can mimic the beneficial effect of nitroglycerin.
Patients can exercise for considerably longer periods
after the administration of nitroglycerin. Nevertheless,
with or without nitroglycerin, angina occurs at the same
value of the triple product (aortic pressure × heart rate ×
ejection time, which is roughly proportional to myocardial
consumption of O 2
). The observation that angina
occurs at the same level of myocardial O 2
consumption
suggests that the beneficial effects of nitroglycerin result
from reduced cardiac O 2
demand rather than an increase
SECTION III
MODULATION OF CARDIOVASCULAR FUNCTION
in the delivery of O 2
to ischemic regions of myocardium.
However, these results do not preclude the possibility that
a favorable redistribution of blood flow to ischemic subendocardial
myocardium may contribute to relief of pain in
a typical anginal attack, nor do they preclude the possibility
that direct coronary vasodilation may be the major
effect of nitroglycerin in situations where vasospasm compromises
myocardial blood flow.
Mechanism of Relief of Symptoms of Angina Pectoris. The
ability of nitrates to dilate epicardial coronary arteries,
even in areas of atherosclerotic stenosis, is modest, and
the preponderance of evidence continues to favor a
reduction in myocardial work, and thus in myocardial O 2
demand, as their primary effect in chronic stable angina.
Paradoxically, high doses of organic nitrates may
reduce blood pressure to such an extent that coronary
flow is compromised; reflex tachycardia and adrenergic
enhancement of contractility also occur. These effects
may override the beneficial action of the drugs on
myocardial O 2
demand and can aggravate ischemia.
Additionally, sublingual nitroglycerin administration
may produce bradycardia and hypotension, probably
owing to activation of the Bezold-Jarisch reflex.
Other Effects. The nitrovasodilators act on almost all smooth
muscle tissues. Bronchial smooth muscle is relaxed irrespective
of the preexisting tone. The muscles of the biliary tract, including
those of the gallbladder, biliary ducts, and sphincter of Oddi, are
effectively relaxed. Smooth muscle of the GI tract, including that
of the esophagus, can be relaxed and its spontaneous motility
decreased by nitrates both in vivo and in vitro. The effect may be
transient and incomplete in vivo, but abnormal “spasm” frequently
is reduced. Indeed, many incidences of atypical chest pain and
“angina” are due to biliary or esophageal spasm, and these too can
be relieved by nitrates. Similarly, nitrates can relax ureteral and
uterine smooth muscle, but these responses are of uncertain clinical
significance.
Absorption, Fate, and Excretion. More than a century after the first
use of organic nitrates to treat angina pectoris, their biotransformation
remains the subject of active investigation. Studies in the 1970s
suggested that nitroglycerin is reductively hydrolyzed by hepatic
glutathione–organic nitrate reductase. More recent studies have
implicated a mitochondrial aldehyde dehydrogenase enzyme in the
biotransformation of nitroglycerin (Chen et al., 2002). Other enzymatic
and nonenzymatic pathways also may contribute to the biotransformation
of nitrovasodilators. Despite uncertainties about the
quantitative importance of the various pathways involved in nitrovasodilator
metabolism, the pharmacokinetic properties of nitroglycerin
and isosorbide dinitrate have been studied in some detail (Parker
and Parker, 1998).
Preparations
Nitroglycerin. In humans, peak concentrations of nitroglycerin are
found in plasma within 4 minutes of sublingual administration; the