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

754 Transmucosal or Buccal Nitroglycerin. This formulation is inserted
under the upper lip above the incisors, where it adheres to the gingiva
and dissolves gradually in a uniform manner. Hemodynamic
effects are seen within 2-5 minutes, and it is therefore useful for
short-term prophylaxis of angina. Nitroglycerin continues to be
released into the circulation for a prolonged period, and exercise tolerance
may be enhanced for up to 5 hours.
SECTION III
MODULATION OF CARDIOVASCULAR FUNCTION
Congestive Heart Failure. The utility of nitrovasodilators
to relieve pulmonary congestion and to increase
cardiac output in congestive heart failure is addressed in
Chapter 28.
Unstable Angina Pectoris and Non-ST-Segment–
Elevation Myocardial Infarction. The term unstable
angina pectoris has been used to describe a broad
spectrum of clinical entities characterized by an acute
or subacute worsening in a patient’s anginal symptoms.
The variable prognosis of unstable angina no doubt
reflects the broad range of clinical entities subsumed
by the term. More recently, efforts have been directed
toward identifying patients with unstable angina on the
basis of their risks for subsequent adverse outcomes
such as MI or death. The term acute coronary syndrome
has been useful in this context: Common to
most clinical presentations of acute coronary syndrome
is disruption of a coronary plaque, leading to local
platelet aggregation and thrombosis at the arterial wall,
with subsequent partial or total occlusion of the vessel.
There is some variability in the pathogenesis of
unstable angina, with gradually progressive atherosclerosis
accounting for some cases of new-onset exertional
angina. Less commonly, vasospasm in minimally atherosclerotic
coronary vessels may account for some
cases where rest angina has not been preceded by
symptoms of exertional angina. For the most part, the
pathophysiological principles that underlie therapy for
exertional angina—which are directed at decreasing
myocardial oxygen demand—have limited efficacy in
the treatment of acute coronary syndromes characterized
by an insufficiency of myocardial oxygen (blood)
supply.
Notably, the degree of coronary stenosis correlates poorly
with the likelihood of plaque rupture. Drugs that reduce myocardial
O 2
consumption by reducing ventricular preload (nitrates) or
by reducing heart rate and ventricular contractility (using β adrenergic
receptor antagonists) are efficacious, but additional therapies
are directed at the atherosclerotic plaque itself and the consequences
(or prevention) of its rupture. As discussed later, these therapies
include combinations of:
• anti-platelet agents, including aspirin and thioenopyridines such as
clopidogrel or prasugrel
• anti-thrombin agents such as heparin and the thrombolytics
• anti-integrin therapies that directly inhibit platelet aggregation
mediated by glycoprotein (GP)IIb/IIIa
• mechano-pharmacological approaches with percutaneously
deployed intracoronary stents
• coronary bypass surgery for selected patients
Along with nitrates and β adrenergic receptor antagonists,
antiplatelet agents represent the cornerstone of therapy for acute
coronary syndrome (Hillis and Lange, 2009). Aspirin (see later in
the chapter) inhibits platelet aggregation and improves survival
(Yeghiazarians et al., 2000). Heparin (either unfractionated or lowmolecular-weight)
also appears to reduce angina and prevent infarction.
These and related agents are discussed in detail in Chapters 34
and 30. Anti-integrin agents directed against the platelet integrin
GPIIb/IIIa (including abciximab, tirofiban, and eptifibatide) are
effective in combination with heparin, as discussed later. Nitrates
are useful both in reducing vasospasm and in reducing myocardial
O 2
consumption by decreasing ventricular wall stress. Intravenous
administration of nitroglycerin allows high concentrations of drug
to be attained rapidly. Because nitroglycerin is degraded rapidly, the
dose can be titrated quickly and safely using intravenous administration.
If coronary vasospasm is present, intravenous nitroglycerin is
likely to be effective, although the addition of a Ca 2+ channel blocker
may be required to achieve complete control in some patients.
Because of the potential risk of profound hypotension, nitrates
should be withheld and alternate anti-anginal therapy administered
if patients have consumed a PDE5 inhibitor within 24 hours (discussed
earlier).
Acute Myocardial Infarction. Therapeutic maneuvers in
MI are directed at reducing the size of the infarct, preserving
or retrieving viable tissue by reducing the O 2
demand of the myocardium, and preventing ventricular
remodeling that could lead to heart failure.
Nitroglycerin is commonly administered to
relieve ischemic pain in patients presenting with MI,
but evidence that nitrates improve mortality in MI is
sparse. Because they reduce ventricular preload through
vasodilation, nitrates are effective in relief of pulmonary
congestion. A decreased ventricular preload
should be avoided in patients with right ventricular infarction
because higher right-sided heart filling pressures are
needed in this clinical context. Nitrates are relatively contraindicated
in patients with systemic hypotension.
According to the American Heart Association/American
College of Cardiology (AHA/ACC) guidelines, “nitrates
should not be used if hypotension limits the administration
of β blockers, which have more powerful salutary
effects” (Antman et al., 2004).
Because the proximate cause of MI is intracoronary
thrombosis, reperfusion therapies are critically
important, employing, when possible, direct percutaneous
coronary interventions (PCIs) for acute MI,
usually using drug-eluting intracoronary stents (Antman
et al., 2004). Thrombolytic agents are administered at