Cross-reactions between hydrazine derivatives occur. Hydralazine may sometimes cause flushing and reversible Lupus erythematosis
Apresoline HCl,Ciba,US,1952
Inhibits DNA methyltransferase and modulates epigenetic regulation of gene expression. Non-selective MAO-A/B inhibitor; semicarbazide-sensitive amine oxidase inhibitor. Antihypertensive
Hydralazine is widely used cardiovascular drug dilating arterioies by relaxation of artetiolar smooth muscles.
Hydralazine is a non-nucleoside analog that inhibits DNA methylation and reactivates the expression of tumor suppressor genes. Non-selective MAO-A/B inhibitor; semicarbazide-sensitive amine oxidase inhibitor. Antihypertensive.
ChEBI: The 1-hydrazino derivative of phthalazine; a direct-acting vasodilator that is used as an antihypertensive agent.
30 parts by weight of phthalazone are converted to 1-chlorophthalazine by the
method described in Ber. d. deutsch. chem. Ges., vol 26, page 521 (1893).
The freshly obtained yet moist chloro compound is heated on the water bath
for two hours in a mixture of 100 parts by volume of ethyl alcohol and 90
parts by volume of hydrazine hydrate. Preferably after filtering, 1-hydrazinephthalazine crystallizes out in yellow needles on cooling.
It is filtered with suction and washed with cold ethyl alcohol. The compound is
crystallized from methyl alcohol, and melts, when rapidly heated, at 172° to
173°C. On warming in alcoholic or aqueous hydrochloric acid, the
hydrochloride of MP 273°C (with decomposition) is obtained.
Apresoline (Novartis); Dralzine (Teva).
The vasodilation produced by hydralazine (Apresoline)
depends in part on the presence of an intact blood vessel
endothelium. This implies that hydralazine causes
the release of nitric oxide, which acts on the vascular
smooth muscle to cause relaxation. In addition, hydralazine
may produce vasodilation by activating K+
channels.
Hydralazine is a hydrazine derivative used as a antihypertensive
drug. Skin rashes have been described during
treatment. Exposure occurs mainly in the pharmaceutical
industry. Cross-sensitivity is frequent with hydrazine,
which is considered to be a potent sensitizer.
Hydralazine exhibits an antihypertensive effect by directly relaxing smooth muscles of the
vessels. It has an effect on arterial vessels while having a minimal effect on venous vessels.
As a result, resistance of peripheral vessels decreases, and blood pressure is reduced
(diastolic more than systolic).
It does not have a substantial effect on nonvascular smooth musculature or cardiac tissues.
Homeostatic circulatory reflexes remain natural, and the resulting hypotension activates cardiovascular
reflexes, which are expressed as an increase of heart work, power, and volume
of cardiac output. Therefore, it is most effectively used in combination with β-blockers.
Hydralazine produces widespread but apparently not
uniform vasodilation; that is, vascular resistance is decreased
more in cerebral, coronary, renal, and splanchnic
beds than in skeletal muscle and skin. Renal blood
flow and ultimately glomerular filtration rate may be
slightly increased after acute treatment with hydralazine.
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 effect
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 capacitance
are not affected by hydralazine, postural hypotension
is not a clinical concern. Hydralazine treatment
does, however, result in an increase in cardiac
output.This action is brought about by the combined effects
of a reflex increase in sympathetic stimulation of the
heart, an increase in plasma renin, and salt and water retention.
These effects limit the hypotensive usefulness of
hydralazine to such an extent that it is rarely used alone.
Hydralazine is generally reserved for moderately hypertensive
ambulatory patients whose blood pressure is
not well controlled either by diuretics or by drugs that
interfere with the sympathetic nervous system. It is almost
always administered in combination with a diuretic
(to prevent Na+ retention) and a β-blocker, such
as propranolol (to attenuate the effects of reflex cardiac
stimulation and hyperreninemia). The triple combination
of a diuretic, β-blocker, and hydralazine constitutes
a unique hemodynamic approach to the treatment of hypertension,
since three of the chief determinants of
blood pressure are affected: cardiac output (β-blocker),plasma volume (diuretic), and peripheral vascular resistance
(hydralazine).
Although hydralazine is available for intravenous
administration and has been used in the past for hypertensive
emergencies, it is not generally employed for
this purpose. The onset of action after intravenous injection
is relatively slow, and its actions are somewhat
unpredictable in comparison with those of several other
vasodilators.
Most side effects associated with hydralazine administration
are due to vasodilation and the reflex hemodynamic
changes that occur in response to vasodilation.
These side effects include headache, flushing, nasal congestion,
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, hydralazine
may produce a rheumatoidlike state that
when fully developed, resembles disseminated lupus
erythematosus.
Hydralazine, 1-hydrazinonaphthalazine (22.6.4), is synthesized by the
oxidative chlorination of phthalide with simultaneous hydrolysis of product, which results
in hydroxyphthalide (22.6.1), which upon reaction with hydrazine changes to phthalazone
(22.6.2). This undergoes a reaction with phosphorous oxychloride, forming 1-chlorophthalazine
(22.6.3), in which substitution of the chlorine atom with hydrazine gives the
desired hydralazine (22.6.4).
Hydralazine is well absorbed (65–90%) after oral administration.
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 conjugation
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 circulation.
The first-pass metabolism occurs in the intestinal
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 appear
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 vasodilator
action even though plasma concentrations are low.
The plasma half-life of hydralazine may be increased
fourfold or fivefold in patients with renal failure.
If renal failure is present, therefore, both the antihypertensive
and toxic effects of hydralazine may be
enhanced. Since N-acetylation of hydralazine is an important
metabolic pathway and depends on the activity
of the enzyme N-acetyltransferase, genetically determined
differences in the activity of this enzyme in certain
individuals (known as slow acetylators) will result
in higher plasma levels of hydralazine; therefore, the
drug’s therapeutic or toxic effects may be increased.
It crystallises from MeOH. UV: max 656nm at pH ~11. It complexes with Bi3+ , Zn2+ , Fe2+ and Co2+ .
