Hydralazine
The vasodilation produced by
hydralazine (Apresoline) depends in
part on the presence of an intact blood ves-sel endothelium. This implies that
hydralazine causes the release of nitric oxide, which acts on the vascular
smooth muscle to cause relaxation. In addition, hy-dralazine may produce
vasodilation by activating K+ channels.
Hydralazine is well absorbed
(65–90%) after oral ad-ministration. Its peak antihypertensive effect occurs in
about 1 hour, and its duration of action is about 6 hours.
The major pathways for its
metabolism include ring hydroxylation, with subsequent glucuronide conjuga-tion
and N-acetylation. Hydralazine
exhibits a first-pass effect in that a large part of an orally administered
dose is metabolized before the drug reaches the systemic cir-culation. The
first-pass metabolism occurs in the intes-tinal mucosa (mostly N-acetylation) and the liver. The
primary excretory route is through renal elimination, and about 80% of an oral
dose appears in the urine within 48 hours. About 10% is excreted unchanged in
the feces.
Approximately 85% of the
hydralazine in plasma is bound to plasma proteins. Although this does not
ap-pear to be a major therapeutic concern, the potential for interactions with
other drugs that also bind to plasma proteins does exist. The plasma half-life
of hydralazine in patients with normal renal function is 1.5 to 3 hours.
Interestingly, the half-life
of the antihypertensive effect is somewhat longer than the plasma half-life.
This may occur because hydralazine is specifically accumulated in artery walls,
where it may continue to exert a vasodila-tor action even though plasma
concentrations are low.
The plasma half-life of
hydralazine may be in-creased fourfold or fivefold in patients with renal
fail-ure. If renal failure is present, therefore, both the anti-hypertensive
and toxic effects of hydralazine may be enhanced. Since N-acetylation of hydralazine is an im-portant metabolic pathway and
depends on the activity of the enzyme N-acetyltransferase,
genetically deter-mined differences in the activity of this enzyme in cer-tain
individuals (known as slow acetylators) will result in higher plasma levels of
hydralazine; therefore, the drug’s therapeutic or toxic effects may be
increased.
Hydralazine produces
widespread but apparently not uniform vasodilation; that is, vascular
resistance is de-creased more in cerebral, coronary, renal, and splanch-nic
beds than in skeletal muscle and skin. Renal blood flow and ultimately
glomerular filtration rate may be slightly increased after acute treatment with
hy-dralazine. However, after several days of therapy, the renal blood flow is
usually no different from that before drug use.
In therapeutic doses,
hydralazine produces little ef-fect on nonvascular smooth muscle or on the
heart. Its pharmacological actions are largely confined to vascular smooth
muscle and occur predominantly on the arterial side of the circulation; venous
capacitance is much less affected. Because cardiovascular reflexes and venous
ca-pacitance are not affected by hydralazine, postural hy-potension is not a
clinical concern. Hydralazine treat-ment does, however, result in an increase
in cardiac output. This action is brought about by the combined ef-fects of a
reflex increase in sympathetic stimulation of the heart, an increase in plasma
renin, and salt and water re-tention. These effects limit the hypotensive
usefulness of hydralazine to such an extent that it is rarely used alone.
Hydralazine is generally
reserved for moderately hy-pertensive ambulatory patients whose blood pressure
is not well controlled either by diuretics or by drugs that interfere with the
sympathetic nervous system. It is al-most always administered in combination
with a di-uretic (to prevent NA+ retention) and a β-blocker, such as
propranolol (to attenuate the effects of reflex cardiac stimulation and
hyperreninemia). The triple combina-tion
of a diuretic, β-blocker, and hydralazine constitutes a unique hemodynamic
approach to the treatment of hy-pertension, since three of the chief
determinants of blood pressure are
affected: cardiac output ( β-blocker), plasma volume (diuretic), and peripheral
vascular re-sistance (hydralazine).
Although hydralazine is
available for intravenous administration and has been used in the past for
hyper-tensive emergencies, it is not generally employed for this purpose. The
onset of action after intravenous in-jection is relatively slow, and its
actions are somewhat unpredictable in comparison with those of several other
vasodilators.
Most side effects associated
with hydralazine adminis-tration are due to vasodilation and the reflex
hemody-namic changes that occur in response to vasodilation. These side effects
include headache, flushing, nasal con-gestion, tachycardia, and palpitations.
More serious manifestations include myocardial ischemia and heart failure.
These untoward effects of hydralazine are greatly attenuated when the drug is
administered in conjunction with a β-blocker.
When administered chronically
in high doses, hy-dralazine may produce a rheumatoidlike state that when fully
developed, resembles disseminated lupus erythematosus.
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