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

(ACE) inhibitors (see Chapter 26) also reduce mortality
in patients with coronary disease (Yusuf et al., 2000) and
are particularly recommended for patients when there is
concomitant impairment of cardiac systolic function
(Gibbons et al., 2003).
Coronary artery bypass surgery and percutaneous coronary
interventions such as angioplasty and coronary artery stent deployment
can complement pharmacological treatment. In some subsets
of patients, percutaneous or surgical revascularization may have a
survival advantage over medical treatment alone. Intracoronary drug
delivery using drug-eluting coronary stents represents an intersection
of mechanical and pharmacological approaches in the treatment
of coronary artery disease. Novel therapies that modify the
expression of vascular or myocardial cell genes eventually may
become an important part of the therapy of ischemic heart disease.
ORGANIC NITRATES
These agents are prodrugs that are sources of nitric oxide
(NO). NO activates the soluble isoform of guanylyl
cyclase, thereby increasing intracellular levels of cyclic
GMP. In turn, cyclic GMP promotes the dephosphorylation
of the myosin light chain and the reduction of cystolic
Ca 2+ and leads to the relaxation of smooth muscle
cells in a broad range of tissues. The NO-dependent
relaxation of vascular smooth muscle leads to vasodilation;
NO-mediated guanylyl cyclase activation inhibits
platelet aggregation and relaxes smooth muscle in the
bronchi and GI tract (Murad, 1996).
The broad biological response to nitrovasodilators
reflects the existence of endogenous NO-modulated
regulatory pathways. The endogenous synthesis of NO
in humans is catalyzed by a family of NO synthases that
oxidize the amino acid L-arginine to form NO, plus
L-citrulline as a co-product. There are three distinct
mammalian NO synthase isoforms termed nNOS,
eNOS, and iNOS (see Chapter 3), and they are involved
in processes as diverse as neurotransmission, vasomotion,
and immunomodulation. In several vascular disease
states, pathways of endogenous NO-dependent
regulation appear to be deranged (reviewed in Dudzinski
et al., 2006).
History. Nitroglycerin was first synthesized in 1846 by Sobrero, who
observed that a small quantity placed on the tongue elicited a severe
headache. The explosive properties of nitroglycerin also were soon
noted, and control of this unstable compound for military and industrial
use was not realized until Alfred Nobel devised a process to stabilize
the nitroglycerin and patented a specialized detonator in 1863.
The vast fortune that Nobel accrued from the nitroglycerin detonator
patent provided the funds later used to establish the Nobel prizes.
In 1857, T. Lauder Brunton of Edinburgh administered amyl nitrite,
a known vasodepressor, by inhalation and noted that anginal pain was
relieved within 30- 60 seconds. The action of amyl nitrite was transitory,
however, and the dosage was difficult to adjust. Subsequently,
William Murrell surmised that the action of nitroglycerin mimicked
that of amyl nitrite and established the use of sublingual nitroglycerin
for relief of the acute anginal attack and as a prophylactic agent to be
taken prior to exertion. The empirical observation that organic nitrates
could dramatically and safely alleviate the symptoms of angina pectoris
led to their widespread acceptance by the medical profession.
Indeed, Alfred Nobel himself was prescribed nitroglycerin by his
physicians when he developed angina in 1890. Basic investigations
defined the role of NO in both the vasodilation produced by nitrates
and endogenous vasodilation. The importance of NO as a signaling
molecule in the cardiovascular system and elsewhere was recognized
by the awarding of the 1998 Nobel Prize in medicine/physiology to
the pharmacologists Robert Furchgott, Louis Ignarro, and Ferid
Murad.
Chemistry. Organic nitrates are polyol esters of nitric acid, whereas
organic nitrites are esters of nitrous acid (Table 27–1). Nitrate esters
(—C—O—NO 2
) and nitrite esters (—C—O—NO) are characterized
by a sequence of carbon–oxygen–nitrogen, whereas nitro compounds
possess carbon–nitrogen bonds (C—NO 2
). Thus glyceryl
trinitrate is not a nitro compound, and it is erroneously called nitroglycerin;
however, this nomenclature is both widespread and official.
Amyl nitrite is a highly volatile liquid that must be administered
by inhalation and is of limited therapeutic utility. Organic nitrates of
low molecular mass (such as nitroglycerin) are moderately volatile,
oily liquids, whereas the high-molecular-mass nitrate esters (e.g.,
erythrityl tetranitrate, isosorbide dinitrate, and isosorbide mononitrate)
are solids. In the pure form (without an inert carrier such as lactose),
nitroglycerin is explosive. The organic nitrates and nitrites,
collectively termed nitrovasodilators, must be metabolized (reduced)
to produce gaseous NO, which appears to be the active principle of
this class of compounds. Nitric oxide gas also can be directly administered
by inhalation (Bloch et al., 2007).
Pharmacological Properties
Mechanism of Action. Nitrites, organic nitrates, nitroso
compounds, and a variety of other nitrogen
oxide–containing substances (including nitroprusside;
see later in the chapter) lead to the formation of the reactive
gaseous free radical NO and related NO-containing
compounds. Nitric oxide gas also may be administered
by inhalation. The exact mechanism(s) of denitration of
the organic nitrates to liberate NO remains an active area
of investigation (Chen et al., 2002).
Phosphorylation of the myosin light chain regulates
the maintenance of the contractile state in smooth
muscle. NO can activate guanylyl cyclase, increase the
cellular level of cyclic GMP, activate PKG, and modulate
the activities of cyclic nucleotide phosphodiesterases
(PDEs 2, 3, and 5) in a variety of cell types.
In smooth muscle, the net result is reduced phosphorylation
of myosin light chain, reduced Ca 2+ concentration
in the cytosol, and relaxation. One important
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CHAPTER 27
TREATMENT OF MYOCARDIAL ISCHEMIA AND HYPERTENSION