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

decrease in blood pressure. Pulmonary vascular resistance
and cardiac output are slightly reduced. Doses of nitroglycerin
that do not alter systemic arterial pressure may
still produce arteriolar dilation in the face and neck,
resulting in a facial flush, or dilation of meningeal arterial
vessels, causing headache. The molecular basis for the
differential response of arterial versus venous tissues to
nitroglycerin remains incompletely understood.
Higher doses of organic nitrates cause further
venous pooling and may decrease arteriolar resistance as
well, thereby decreasing systolic and diastolic blood pressure
and cardiac output and causing pallor, weakness,
dizziness, and activation of compensatory sympathetic
reflexes. The reflex tachycardia and peripheral arteriolar
vasoconstriction tend to restore systemic vascular resistance;
this is superimposed on sustained venous pooling.
Coronary blood flow may increase transiently as a result
of coronary vasodilation but may decrease subsequently
if cardiac output and blood pressure decrease sufficiently.
In patients with autonomic dysfunction and an inability to
increase sympathetic outflow (multiple-system atrophy and pure
autonomic failure are the most common forms, much less commonly
seen in the autonomic dysfunction associated with diabetes), the fall
in blood pressure consequent to the venodilation produced by
nitrates cannot be compensated. In these clinical contexts, nitrates
may reduce arterial pressure and coronary perfusion pressure significantly,
producing potentially life-threatening hypotension and even
aggravating angina. The appropriate therapy in patients with orthostatic
angina and normal coronary arteries is to correct the orthostatic
hypotension by expanding volume (fludrocortisone and a
high-sodium diet), to prevent venous pooling with fitted support garments,
and to carefully titrate use of oral vasopressors. Because
patients with autonomic dysfunction occasionally may have coexisting
coronary artery disease, the coronary anatomy should be defined
before therapy is undertaken.
Effects on Total and Regional Coronary Blood Flow.
Myocardial ischemia is a powerful stimulus to coronary
vasodilation, and regional blood flow is adjusted
by autoregulatory mechanisms. In the presence of
atherosclerotic coronary artery narrowing, ischemia
distal to the lesion stimulates vasodilation; if the stenosis
is severe, much of the capacity to dilate is used to
maintain resting blood flow. When demand increases,
further dilation may not be possible. After demonstration
of direct coronary artery vasodilation in experimental
animals, it became generally accepted that
nitrates relieved anginal pain by dilating coronary arteries
and thereby increasing coronary blood flow. In the
presence of significant coronary stenoses, there is a disproportionate
reduction in blood flow to the subendocardial
regions of the heart, which are subjected to the
greatest extravascular compression during systole;
organic nitrates tend to restore blood flow in these
regions toward normal.
The hemodynamic mechanisms responsible for these effects
are not entirely clear. Most hypotheses have focused on the ability of
organic nitrates to cause dilation and prevent vasoconstriction of large
epicardial vessels without impairing autoregulation in the small vessels,
which are responsible for ~90% of the overall coronary vascular
resistance. The vessel diameter is an important determinant of the
response to nitroglycerin; vessels >200 μm in diameter are highly
responsive, whereas those >100 μm respond minimally.
Experimental evidence in patients undergoing coronary bypass surgery
indicates that nitrates do have a relaxant effect on large coronary
vessels. Collateral flow to ischemic regions also is increased. Moreover,
analyses of coronary angiograms in humans have shown that sublingual
nitroglycerin can dilate epicardial stenoses and reduce the resistance
to flow through such areas (Brown et al., 1981; Feldman et al.,
1981). The resulting increase in blood flow would be distributed preferentially
to ischemic myocardial regions as a consequence of vasodilation
induced by autoregulation. An important indirect mechanism
for a preferential increase in subendocardial blood flow is the nitroglycerin-induced
reduction in intracavitary systolic and diastolic pressures
that oppose blood flow to the subendocardium (see below). To
the extent that organic nitrates decrease myocardial requirements for
O 2
(see the next section), the increased blood flow in ischemic regions
could be balanced by decreased flow in nonischemic areas, and an
overall increase in coronary artery blood flow need not occur. Dilation
of cardiac veins may improve the perfusion of the coronary microcirculation.
Such redistribution of blood flow to subendocardial tissue
is not typical of all vasodilators. Dipyridamole, e.g., dilates
resistance vessels nonselectively by distorting autoregulation and is
ineffective in patients with typical angina.
In patients with angina owing to coronary artery spasm,
the ability of organic nitrates to dilate epicardial coronary
arteries, and particularly regions affected by
spasm, may be the primary mechanism by which they
are of benefit.
Effects on Myocardial O 2
Requirements. By their effects
on the systemic circulation, the organic nitrates also can
reduce myocardial O 2
demand. The major determinants
of myocardial O 2
consumption include left ventricular
wall tension, heart rate, and myocardial contractility.
Ventricular wall tension is affected by a number of factors
that may be considered under the categories of
preload and afterload. Preload is determined by the
diastolic pressure that distends the ventricle (ventricular
end-diastolic pressure). Increasing end-diastolic volume
augments the ventricular wall tension (by the law
of Laplace, tension is proportional to pressure times
radius). Increasing venous capacitance with nitrates
decreases venous return to the heart, decreases ventricular
end-diastolic volume, and thereby decreases O 2
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CHAPTER 27
TREATMENT OF MYOCARDIAL ISCHEMIA AND HYPERTENSION