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

752 angina when a nitrate-free interval is employed using
nitroglycerin patches; such patients may require another
class of anti-anginal agent during this period. Tolerance
is not universal, and some patients develop only partial
tolerance. The problem of anginal rebound during
nitrate-free intervals is especially problematic in the
treatment of unstable angina with intravenous nitroglycerin.
As tolerance develops, increasing doses are required
to achieve the same therapeutic effects; eventually,
despite dose escalation, the drug loses efficacy.
SECTION III
MODULATION OF CARDIOVASCULAR FUNCTION
A special form of nitroglycerin tolerance is observed in individuals
exposed to nitroglycerin in the manufacture of explosives. If
protection is inadequate, workers may experience severe headaches,
dizziness, and postural weakness during the first several days of
employment. Tolerance then develops, but headache and other symptoms
may reappear after a few days away from the job—the
“Monday disease.” The most serious effect of chronic exposure is a
form of organic nitrate dependence. Workers without demonstrable
organic vascular disease have been reported to have an increase in
the incidence of acute coronary syndromes during the 24-72-hour
periods away from the work environment (Parker et al., 1995).
Coronary and digital arteriospasm during withdrawal and its relaxation
by nitroglycerin also have been demonstrated radiographically.
Because of the potential problem of nitrate dependence, it seems
prudent not to withdraw nitrates abruptly from a patient who has
received such therapy chronically.
Toxicity and Untoward Responses
Untoward responses to the therapeutic use of organic
nitrates are almost all secondary to actions on the cardiovascular
system. Headache is common and can be
severe. It usually decreases over a few days if treatment
is continued and often can be controlled by
decreasing the dose. Transient episodes of dizziness,
weakness, and other manifestations associated with
postural hypotension may develop, particularly if the
patient is standing immobile, and may progress occasionally
to loss of consciousness, a reaction that
appears to be accentuated by alcohol. It also may be
seen with very low doses of nitrates in patients with
autonomic dysfunction. Even in severe nitrate syncope,
positioning and other measures that facilitate
venous return are the only therapeutic measures
required. All the organic nitrates occasionally can produce
drug rash.
Interaction of Nitrates with PDE5 Inhibitors. Erectile dysfunction
is a frequently encountered problem whose risk
factors parallel those of coronary artery disease. Thus
many men desiring therapy for erectile dysfunction
already may be receiving (or may require, especially if
they increase physical activity) anti-anginal therapy. The
combination of sildenafil and other phosphodiesterase 5
(PDE5) inhibitors with organic nitrate vasodilators can
cause extreme hypotension.
Cells in the corpus cavernosum produce NO during sexual
arousal in response to nonadrenergic, noncholinergic neurotransmission
(Burnett et al., 1992). NO stimulates the formation of cyclic
GMP, which leads to relaxation of smooth muscle of the corpus cavernosum
and penile arteries, engorgement of the corpus cavernosum,
and erection. The accumulation of cyclic GMP can be enhanced by
inhibition of the cyclic GMP–specific PDE5 family. Sildenafil (VIA-
GRA, REVATIO) and congeners inhibit PDE5 and have been demonstrated
to improve erectile function in patients with erectile
dysfunction. Not surprisingly, PDE5 inhibitors have assumed the
status of widely used recreational drugs. Since the introduction of
sildenafil, two additional PDE5 inhibitors have been developed for
use in therapy of erectile dysfunction. Tadalafil (CIALIS, ADCIRCA)
and vardenafil (LEVITRA) share similar therapeutic efficacy and sideeffect
profiles with sildenafil; tadalafil has a longer time to onset of
action and a longer therapeutic t 1/2
than the other PDE5 inhibitors.
Sildenafil has been the most thoroughly characterized of these compounds,
but all three PDE5 inhibitors are contraindicated for
patients taking organic nitrate vasodilators, and the PDE5 inhibitors
should be used with caution in patients taking α or β adrenergic
receptor antagonists (see Chapter 12).
The side effects of sildenafil and other PDE5 inhibitors are
largely predictable on the basis of their effects on PDE5. Headache,
flushing, and rhinitis may be observed, as well as dyspepsia owing
to relaxation of the lower esophageal sphincter. Sildenafil and vardenafil
also weakly inhibit PDE6, the enzyme involved in photoreceptor
signal transduction (Chapters 3 and 64), and can produce
visual disturbances, most notably changes in the perception of color
hue or brightness. In addition to visual disturbances, sudden onesided
hearing loss has also been reported. Tadalafil inhibits PDE11,
a widely distributed PDE isoform, but the clinical importance of this
effect is not clear. The most important toxicity of all these PDE5
inhibitors is hemodynamic. When given alone to men with severe
coronary artery disease, these drugs have modest effects on blood
pressure, producing >10% fall in systolic, diastolic, and mean systemic
pressures and in pulmonary artery systolic and mean pressures
(Herrmann et al., 2000). However, sildenafil, tadalafil, and vardenafil
all have a significant and potentially dangerous interaction with
organic nitrates, the therapeutic actions of which are mediated via
their conversion to NO with resulting increases in cyclic GMP. In
the presence of a PDE5 inhibitor, nitrates cause profound increases
in cyclic GMP and can produce dramatic reductions in blood pressure.
Compared with controls, healthy male subjects pretreated with
sildenafil or the other PDE5 inhibitors exhibit a much greater
decrease in systolic blood pressure when treated with sublingual
glyceryl trinitrate, and in many subjects a fall of more than 25 mm
Hg was detected. This drug class toxicity is the basis for the warning
that PDE5 inhibitors should not be prescribed to patients receiving
any form of nitrate (Cheitlin et al., 1999) and dictates that
patients should be questioned about the use of PDE5 inhibitors
within 24 hours before nitrates are administered. A period of longer
than 24 hours may be needed following administration of a PDE5
inhibitor for safe use of nitrates, especially with tadalafil because of
its prolonged t 1/2
. In the event that patients develop significant
hypotension following combined administration of sildenafil and