Page 215 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 12 Vasodilators & the Treatment of Angina Pectoris 201

reverse the favorable hemodynamic changes initially caused by TABLE 12–2 Beneficial and deleterious effects of
nitroglycerin. nitrates in the treatment of angina.
Tolerance does not occur equally with all nitric oxide donors.
Nitroprusside, for example, retains activity over long periods. Effect Mechanism and Result
Other organic nitrates appear to be less susceptible than nitro- Potential beneficial effects
glycerin to the development of tolerance. In cell-free systems, Decreased ventricular volume Decreased work and myocardial
soluble guanylate cyclase is inhibited, possibly by nitrosylation of oxygen requirement
the enzyme, only after prolonged exposure to exceedingly high Decreased arterial pressure
nitroglycerin concentrations. In contrast, treatment with antioxi- Decreased ejection time
dants that protect ALDH2 and similar enzymes appears to prevent Vasodilation of epicardial Relief of coronary artery spasm
or reduce tolerance. This suggests that tolerance is a function of coronary arteries
diminished bioactivation of organic nitrates and, to a lesser degree, Increased collateral flow Improved perfusion of ischemic
a loss of soluble guanylate cyclase responsiveness to nitric oxide. myocardium
Continuous exposure to high levels of nitrates can occur in the Decreased left ventricular Improved subendocardial
chemical industry, especially where explosives are manufactured. diastolic pressure perfusion
When contamination of the workplace with volatile organic Potential deleterious effects
nitrate compounds is severe, workers find that upon starting their Increased myocardial oxygen
work week (Monday), they suffer headache and transient dizziness Reflex tachycardia requirement; decreased diastolic
(“Monday disease”). After a day or so, these symptoms disap- perfusion time and coronary
pear owing to the development of tolerance. Over the weekend, perfusion
when exposure to the chemicals is reduced, tolerance disappears, Reflex increase in contractility Increased myocardial oxygen
so symptoms recur each Monday. Other hazards of industrial requirement
exposure, including dependence, have been reported. There is no
evidence that physical dependence develops as a result of the thera-
peutic use of short-acting nitrates for angina, even in large doses. Coronary arteriolar resistance tends to decrease, though to a lesser
extent. However, nitrates administered by the usual systemic
C. Carcinogenicity of Nitrate and Nitrite Derivatives routes may decrease overall coronary blood flow (and myocar-
Nitrosamines are small molecules with the structure R –N–NO dial oxygen consumption) if cardiac output is reduced due to
2
formed from the combination of nitrates and nitrites with amines. decreased venous return. The reduction in oxygen demand is the
Some nitrosamines are powerful carcinogens in animals, appar- major mechanism for the relief of effort angina.
ently through conversion to reactive derivatives. Although there
is no direct proof that these agents cause cancer in humans, there B. Nitrate Effects in Variant Angina
is a strong epidemiologic correlation between the incidence of Nitrates benefit patients with variant angina by relaxing the
esophageal and gastric carcinoma and the nitrate content of food smooth muscle of the epicardial coronary arteries and relieving
in certain cultures. Nitrosamines are also found in tobacco and coronary artery spasm.
in cigarette smoke. There is no evidence that the small doses of
nitrates used in the treatment of angina result in significant body C. Nitrate Effects in Unstable Angina
levels of nitrosamines. Nitrates are also useful in the treatment of the acute coronary
syndrome of unstable angina, but the precise mechanism for
Mechanisms of Clinical Effect their beneficial effects is not clear. Because both increased coro-
nary vascular tone and increased myocardial oxygen demand can
The beneficial and deleterious effects of nitrate-induced vasodila- precipitate rest angina in these patients, nitrates may exert their
tion are summarized in Table 12–2.
beneficial effects both by dilating the epicardial coronary arteries
and by simultaneously reducing myocardial oxygen demand. As
A. Nitrate Effects in Angina of Effort previously noted, nitroglycerin also decreases platelet aggregation,
Decreased venous return to the heart and the resulting reduction and this effect may be of importance in unstable angina.
of intracardiac volume are important beneficial hemodynamic
effects of nitrates. Arterial pressure also decreases. Decreased intra-
ventricular pressure and left ventricular volume are associated with Clinical Use of Nitrates
decreased wall tension (Laplace relation) and decreased myocardial Some of the forms of nitroglycerin and its congeners and their
oxygen requirement. In rare instances, a paradoxical increase in doses are listed in Table 12–3. Because of its rapid onset of action
myocardial oxygen demand may occur as a result of excessive (1–3 minutes), sublingual nitroglycerin is the most frequently
reflex tachycardia and increased contractility. used agent for the immediate treatment of angina. Because its
Intracoronary, intravenous, or sublingual nitrate adminis- duration of action is short (not exceeding 20–30 minutes), it is
tration consistently increases the caliber of the large epicardial not suitable for maintenance therapy. The onset of action of intra-
coronary arteries except where blocked by concentric atheromas. venous nitroglycerin is also rapid (minutes), but its hemodynamic