Page 213 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 12 Vasodilators & the Treatment of Angina Pectoris 199

A B

10 mN
10 mN

K + NTG
K + NE NE K +

10 min
10 mN
C
NE NTG
10 min
10 mN

K + Verapamil
FIGURE 12–3 Effects of vasodilators on contractions of human vein segments studied in vitro. A shows contractions induced by two
+
vasoconstrictor agents, norepinephrine (NE) and potassium (K ). B shows the relaxation induced by nitroglycerin (NTG), 4 μmol/L. The relaxation
is prompt. C shows the relaxation induced by verapamil, 2.2 μmol/L. The relaxation is slower but more sustained. mN, millinewtons, a measure
of force. (Reproduced, with permission, from Mikkelsen E, Andersson KE, Bengtsson B: Effects of verapamil and nitroglycerin on contractile responses to potassium and
noradrenaline in isolated human peripheral veins. Acta Pharmacol Toxicol 1978;42:14.)

this often results in tachycardia and increased cardiac contractility. The increase in cGMP that results is responsible for a decrease
Retention of salt and water may also be significant, especially in platelet aggregation. Unfortunately, recent prospective trials
with intermediate- and long-acting nitrates. These compensatory have established no survival benefit when nitroglycerin is used in
responses contribute to the development of tolerance. acute myocardial infarction. In contrast, intravenous nitroglycerin
In normal subjects without coronary disease, nitroglycerin can may be of value in unstable angina, in part through its action on
induce a significant, if transient, increase in total coronary blood platelets.
flow. In contrast, there is no evidence that total coronary flow is
increased in patients with angina due to atherosclerotic obstructive 4. Other effects—Nitrite ion (not nitrate) reacts with hemo-
coronary artery disease. However, some studies suggest that redistri- globin (which contains ferrous iron) to produce methemoglobin
bution of coronary flow from normal to ischemic regions may play (which contains ferric iron). Because methemoglobin has a very
a role in nitroglycerin’s therapeutic effect. Nitroglycerin also exerts a low affinity for oxygen, large doses of nitrites can result in pseu-
weak negative inotropic effect on the heart via nitric oxide. docyanosis, tissue hypoxia, and death. Fortunately, the plasma
level of nitrite resulting from even large doses of organic and
2. Other smooth muscle organs—Relaxation of smooth inorganic nitrates is too low to cause significant methemoglobin-
muscle of the bronchi, gastrointestinal tract (including biliary sys- emia in adults. In nursing infants, the intestinal flora is capable
tem), and genitourinary tract has been demonstrated experimen- of converting significant amounts of inorganic nitrate, eg, from
tally. Because of their brief duration, these actions of the nitrates well water, to nitrite ion. In addition, sodium nitrite is used as a
are rarely of any clinical value. During recent decades, the use of curing agent for meats, eg, corned beef. Thus, inadvertent expo-
amyl nitrite and isobutyl nitrite (not nitrates) by inhalation as sure to large amounts of nitrite ion can occur and may produce
recreational (sex-enhancing) drugs has become popular with some serious toxicity.
segments of the population. Nitrites readily release nitric oxide One therapeutic application of this otherwise toxic effect of
in erectile tissue as well as vascular smooth muscle and activate nitrite has been discovered. Cyanide poisoning results from com-
−
guanylyl cyclase. The resulting increase in cGMP causes dephos- plexing of cytochrome iron by the CN ion. Methemoglobin iron
−
phorylation of myosin light chains and relaxation (Figure 12–2), has a very high affinity for CN ; thus, administration of sodium
which enhances erection. This pharmacologic approach to erectile nitrite (NaNO ) soon after cyanide exposure regenerates active
2
dysfunction is discussed in the Box: Drugs Used in the Treatment cytochrome. The cyanomethemoglobin produced can be further
of Erectile Dysfunction. detoxified by the intravenous administration of sodium thiosulfate
−
S O ); this results in formation of thiocyanate ion (SCN ),
(Na 2 2 3
3. Action on platelets—Nitric oxide released from nitroglyc- a less toxic ion that is readily excreted. Methemoglobinemia, if
erin stimulates guanylyl cyclase in platelets as in smooth muscle. excessive, can be treated by giving methylene blue intravenously.