Page 212 - Basic _ Clinical Pharmacology ( PDFDrive )

198 SECTION III Cardiovascular-Renal Drugs

Pharmacokinetics to nitric oxide (see Chapter 19). Nitric oxide (probably complexed
with cysteine) combines with the heme group of soluble guanylyl
The liver contains a high-capacity organic nitrate reductase that cyclase, activating that enzyme and causing an increase in cGMP.
removes nitrate groups in a stepwise fashion from the parent mol- As shown in Figure 12–2, formation of cGMP represents a first
ecule and ultimately inactivates the drug. Therefore, oral bioavail- step toward smooth muscle relaxation. The production of prosta-
ability of the traditional organic nitrates (eg, nitroglycerin and ) and membrane hyperpolariza-
isosorbide dinitrate) is low (typically < 10–20%). For this reason, glandin E or prostacyclin (PGI 2
tion may also be involved. There is no evidence that autonomic
the sublingual route, which avoids the first-pass effect, is preferred receptors are involved in the primary nitrate response. However,
for achieving a therapeutic blood level rapidly. Nitroglycerin and autonomic reflex responses, evoked when hypotensive doses are
isosorbide dinitrate both are absorbed efficiently by the sublingual given, are common. As described in the following text, tolerance
route and reach therapeutic blood levels within a few minutes. is an important consideration in the use of nitrates. Although
However, the total dose administered by this route must be lim- tolerance may be caused in part by a decrease in tissue sulfhydryl
ited to avoid excessive effect; therefore, the total duration of effect groups, eg, on cysteine, tolerance can be only partially prevented
is brief (15–30 minutes). When much longer duration of action is or reversed with a sulfhydryl-regenerating agent. Increased genera-
needed, oral preparations can be given that contain an amount of tion of oxygen free radicals during nitrate therapy may be another
drug sufficient to result in sustained systemic blood levels of the important mechanism of tolerance. Recent evidence suggests that
parent drug plus active metabolites. Pentaerythritol tetranitrate diminished availability of calcitonin gene-related peptide (CGRP,
(PETN) is another organic nitrate that is promoted for oral use as a potent vasodilator) is also associated with nitrate tolerance.
a “long-acting” nitrate (> 6 hours). Other routes of administration Nicorandil and several other antianginal agents not available
available for nitroglycerin include transdermal and buccal absorp- in the United States appear to combine the activity of nitric oxide
tion from slow-release preparations (described below). release with a direct potassium channel-opening action, thus
Amyl nitrite and related nitrites are highly volatile liquids. providing an additional mechanism for causing vasodilation.
Amyl nitrite is available in fragile glass ampules packaged in a
protective cloth covering. The ampule can be crushed with the B. Organ System Effects
fingers, resulting in rapid release of vapors inhalable through the
cloth covering. The inhalation route provides very rapid absorp- Nitroglycerin relaxes all types of smooth muscle regardless of the
tion and, like the sublingual route, avoids the hepatic first-pass cause of the preexisting muscle tone (Figure 12–3). It has practi-
effect. Because of its unpleasant odor and extremely short duration cally no direct effect on cardiac or skeletal muscle.
of action, amyl nitrite is now obsolete for angina. 1. Vascular smooth muscle—All segments of the vascular
Once absorbed, the unchanged organic nitrate compounds system from large arteries through large veins relax in response
have half-lives of only 2–8 minutes. The partially denitrated to nitroglycerin. Most evidence suggests a gradient of response,
metabolites have much longer half-lives (up to 3 hours). Of the with veins responding at the lowest concentrations and arteries at
nitroglycerin metabolites (two dinitroglycerins and two mononi- slightly higher ones. The epicardial coronary arteries are sensitive,
tro forms), the 1,2-dinitro derivative has significant vasodilator but concentric atheromas can prevent significant dilation. On
efficacy and probably provides most of the therapeutic effect of the other hand, eccentric lesions permit an increase in flow when
orally administered nitroglycerin. The 5-mononitrate metabolite nitrates relax the smooth muscle on the side away from the lesion.
of isosorbide dinitrate is an active metabolite of the latter drug Arterioles and precapillary sphincters are dilated least, partly
and is available for oral use as isosorbide mononitrate. It has a because of reflex responses and partly because different vessels vary
bioavailability of 100%. in their ability to release nitric oxide from the drug.
Excretion, primarily in the form of glucuronide derivatives of A primary direct result of an effective dose of nitroglycerin is
the denitrated metabolites, is largely by way of the kidney.
marked relaxation of veins with increased venous capacitance and
Pharmacodynamics decreased ventricular preload. Pulmonary vascular pressures and
heart size are significantly reduced. In the absence of heart failure,
A. Mechanism of Action in Smooth Muscle cardiac output is reduced. Because venous capacitance is increased,
After more than a century of study, the mechanism of action of orthostatic hypotension may be marked and syncope can result.
nitroglycerin is still not fully understood. There is general agree- Dilation of large epicardial coronary arteries may improve oxygen
ment that the drug must be bioactivated with the release of nitric delivery in the presence of eccentric atheromas or collateral vessels.
oxide. Unlike nitroprusside and some other direct nitric oxide Temporal artery pulsations and a throbbing headache associated
donors, nitroglycerin activation requires enzymatic action. Nitro- with meningeal artery pulsations are common effects of nitroglyc-
glycerin can be denitrated by glutathione S-transferase in smooth erin and amyl nitrite. In heart failure, preload is often abnormally
muscle and other cells. A mitochondrial enzyme, aldehyde dehy- high; the nitrates and other vasodilators, by reducing preload,
drogenase isoform 2 (ALDH2) and possibly isoform 3 (ALDH3), may have a beneficial effect on cardiac output in this condition
appears to be key in the activation and release of nitric oxide from (see Chapter 13).
nitroglycerin and pentaerythritol tetranitrate. Different enzymes The indirect effects of nitroglycerin consist of those compen-
may be involved in the denitration of isosorbide dinitrate and satory responses evoked by baroreceptors and hormonal mecha-
mononitrate. Free nitrite ion is released, which is then converted nisms responding to decreased arterial pressure (see Figure 6–7);