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

782 ameliorated by a β receptor antagonist or an ACE inhibitor, with
enhancement of blood pressure control.
The increased cardiac output evoked by minoxidil has particularly
adverse consequences in those hypertensive patients who
have left ventricular hypertrophy and diastolic dysfunction. Such
poorly compliant ventricles respond suboptimally to increased volume
loads, with a resulting increase in left ventricular filling pressure.
This probably is a major contributor to the increased pulmonary
artery pressure seen with minoxidil (and hydralazine) therapy in
hypertensive patients and is compounded by the retention of salt and
water caused by minoxidil. Cardiac failure can result from minoxidil
therapy in such patients; the potential for this complication can
be reduced but not prevented by effective diuretic therapy.
Pericardial effusion is an uncommon but serious complication of
minoxidil. Although more commonly described in patients with cardiac
and renal failure, pericardial effusion can occur in patients with
normal cardiovascular and renal function. Mild and asymptomatic
pericardial effusion is not an indication for discontinuing minoxidil,
but the situation should be monitored closely to avoid progression to
tamponade. Effusions usually clear when the drug is discontinued
but can recur if treatment with minoxidil is resumed.
Flattened and inverted T waves frequently are observed in the
electrocardiogram following the initiation of minoxidil treatment.
These are not ischemic in origin and are seen with other drugs that
activate K + channels. These drugs accelerate myocardial repolarization,
shorten the refractory period, and one of them, pinacidil, lowers
the ventricular fibrillation threshold and increases spontaneous ventricular
fibrillation in the setting of myocardial ischemia (Chi et al., 1990).
The effect of minoxidil on the refractory period and ischemic ventricular
fibrillation has not been investigated; whether or not such
findings enhance the risk of ventricular fibrillation in human myocardial
ischemia is unknown.
SECTION III
MODULATION OF CARDIOVASCULAR FUNCTION
Hypertrichosis occurs in patients who receive
minoxidil for an extended period and is probably a consequence
of K + channel activation. Growth of hair
occurs on the face, back, arms, and legs and is particularly
offensive to women. Frequent shaving or depilatory
agents can be used to manage this problem. Topical
minoxidil (ROGAINE) is marketed over-the-counter for
the treatment of male pattern baldness and hair thinning
and loss on the top of the head in women. The topical
use of minoxidil also can cause measurable cardiovascular
effects in some individuals.
Other side effects of the drug are rare and include
rashes, Stevens-Johnson syndrome, glucose intolerance,
serosanguineous bullae, formation of antinuclear
antibodies, and thrombocytopenia.
Therapeutic Uses. Systemic minoxidil is best reserved
for the treatment of severe hypertension that responds
poorly to other antihypertensive medications, especially
in male patients with renal insufficiency (Campese,
1981). It has been used successfully in the treatment of
hypertension in both adults and children. Minoxidil
should never be used alone; it must be given concurrently
with a diuretic to avoid fluid retention and with a sympatholytic
drug (usually a β receptor antagonist) to control
reflex cardiovascular effects. The drug usually is
administered either once or twice a day, but some
patients may require more frequent dosing for adequate
control of blood pressure. The initial daily dose of
minoxidil may be as little as 1.25 mg, which can be
increased gradually to 40 mg in one or two daily doses.
Sodium Nitroprusside
Although sodium nitroprusside has been known since
1850 and its hypotensive effect in humans was
described in 1929, its safety and usefulness for the
short-term control of severe hypertension were not
demonstrated until the mid-1950s. Several investigators
subsequently demonstrated that sodium nitroprusside
also was effective in improving cardiac function in
patients with left ventricular failure (see Chapter 28).
Locus and Mechanism of Action. Nitroprusside is a nitrovasodilator
that acts by releasing NO. NO activates the
guanylyl cyclase–cyclic GMP–PKG pathway, leading to
vasodilation (Linder et al., 2005), mimicking the production
of NO by vascular endothelial cells, which is
impaired in many hypertensive patients (Ramchandra
et al., 2005). The mechanism of release of NO is not
clear and likely involves both enzymatic and nonenzymatic
pathways (Feelisch, 1998). Tolerance develops to
nitroglycerin but not to nitroprusside (Fung, 2004). The
pharmacology of the organic nitrates, including nitroglycerin,
was presented earlier.
Pharmacological Effects. Nitroprusside dilates both arterioles
and venules, and the hemodynamic response to
its administration results from a combination of venous
pooling and reduced arterial impedance. In subjects
with normal left ventricular function, venous pooling
affects cardiac output more than does the reduction of
afterload; cardiac output tends to fall. In contrast, in
patients with severely impaired left ventricular function
and diastolic ventricular distention, the reduction of
arterial impedance is the predominant effect, leading to
a rise in cardiac output (see Chapter 28).
Sodium nitroprusside is a nonselective vasodilator,
and regional distribution of blood flow is little
affected by the drug. In general, renal blood flow and