クロニジン 化学特性,用途語,生産方法
説明
Closely related structurally to the imidazoline nasal decongestants is clonidine and other developed analogues. Clonidine was originally synthesized as a
vasoconstricting nasal decongestant but, in early clinical trials, was found to have dramatic hypotensive effects—in contrast to all expectations for a vasoconstrictor. Subsequent pharmacological investigations showed that clonidine not only has some α1-agonist (vasoconstrictive) properties in the periphery but also that it is a
powerful α2-adrenergic agonist and exhibits specific binding to nonadrenergic imidazoline binding sites in the CNS (mainly in the medulla oblongata) causing inhibition
of sympathetic output (sympathoinhibition). Because of its peripheral activity on extraneuronal vascular postsynaptic α2B-receptors, initial doses
of clonidine may produce a transient vasoconstriction and an increase in blood pressure that is soon overcome by vasodilation as clonidine penetrates the blood-brain
barrier and interacts with CNS α2A-receptors.
使用
Clonidine is used in various forms of hypertonic diseases and for relieving hypertonic
crises. It is also used in ophthalmological practice for treating wide-angle glaucoma.
生物学の機能
Clonidine (Catapres) is effective orally and is used primarily
for the treatment of moderate hypertension. It is structurally related to the α-adrenoceptor antagonists
phentolamine and tolazoline. Clonidine, however, is not
an α-blocker, but is actually an α-agonist. Its antihypertensive
effectiveness appeared paradoxical until it was
recognized that clonidine activated central 2-receptors,
thus reducing sympathetic outflow to the periphery.
一般的な説明
Clonidine differs from 2-arylimidazoline α 1-agonists mainly by the presence of o-chlorine groups anda NH bridge. The O-chlorine groups afford better activitythan O-methyl groups at α2 sites. Importantly, clonidinecontains a NH bridge (aminoimidazolines) instead of CH2bridge in 2-arylimidazoline. Clonidine is an example of a (phenylimino) imidazolidine derivative that possesses central α2-selectivity. The α1: α2 ratio is 300:1. Under certain conditions, such as intravenous infusion,clonidine can briefly exhibit vasoconstrictive activityas a result of stimulation of peripheral α-receptors.However, this hypertensive effect, if it occurs, is followedby a much longer-lasting hypotensive effect as a result ofthe ability of clonidine to enter into the CNS and stimulate α2-receptors located in regions of the brain such as thenucleus tractus solitarius. Stimulation of these α2-receptorsbrings about a decrease in sympathetic outflow from theCNS, which in turn leads to decreases in peripheral vascularresistance and blood pressure. Bradycardia is also producedby clonidine as a result of a centrally induced facilitationof the vagus nerve and stimulation of cardiacprejunctional α2-receptors. These pharmacological actionshave made clonidine quite useful in the treatment ofhypertension.
作用機序
Clonidine is a selective α2-adrenergic agonist. Clonidine has expressed hypotensive action,
which is associated with a reduction of general peripheral vascular resistance, reduced frequency of cardiac beats, and a reduction of cardiac output. The mechanism of action of
clonidine is caused by stimulation of α2-adrenoreceptors of the inhibitory structures of the
brain as well as a reduction of sympathetic impulses to the blood vessels and brain.
薬理学
An acute intravenous injection of clonidine may produce
a transient pressor response that apparently is due
to stimulation of peripheral vascular α-receptors. The
pressor response does not occur after oral administration,
because the drug’s centrally mediated depressor
action overrides it.
The decrease in blood pressure produced by clonidine
correlates better with a decreased cardiac output
than with a reduction in peripheral vascular resistance.
The reduction in cardiac output is the result of both a
decreased heart rate and reduced stroke work; the latter
effect is probably caused by a diminished venous
return.
Renal blood flow and glomerular filtration are not
decreased, although renal resistance is diminished. Like
α-methyldopa, it is a useful agent for hypertension
complicated by renal disease. Plasma renin activity is reduced
by clonidine, presumably as a result of a centrally
mediated decrease in sympathetic stimulation of the
juxtaglomerular cells of the kidney.
臨床応用
The primary indication for clonidine use is in mild and
moderate hypertension that has not responded adequately
to treatment with a diuretic or a β-blocker. Since
clonidine causes sodium and water retention and plasma
volume expansion, it generally is administered in combination
with a diuretic.A vasodilator can be added to the
clonidine–diuretic regimen in the treatment of resistant
forms of hypertension. Such drug combinations can be
quite effective, since the reflex increases in heart rate
and cardiac output that result from vasodilator administration
are reduced or negated by clonidine-induced decreases
in heart rate and cardiac output.
For severely hypertensive patients, clonidine has
been used in combination with a diuretic, a vasodilator,
and a β-blocker. Some care must be taken, however, because
the coadministration of clonidine and a β-blocker
may cause excessive sedation. Clonidine is especially
useful in patients with renal failure, since its duration of action is not appreciably altered by renal disease and it
does not compromise renal blood flow.
副作用
It is estimated that about 7% of patients receiving clonidine
discontinue the drug because of side effects.
Although the symptoms are generally mild and tend to
subside if therapy is continued for several weeks, as
many as 50% of the patients complain of drowsiness
and dryness of mouth. Other untoward effects include
constipation, nausea or gastric upset, and impotence.
These effects are characteristic of interference with the
functioning of the sympathetic nervous system.
A potentially dangerous effect is rebound hypertension,
which follows abrupt withdrawal of clonidine therapy.
This posttreatment hypertension appears to be the
result of excessive sympathetic activity. The genesis of
the syndrome is not well understood. A contributing
factor may be development of supersensitivity in either
the sympathetic nerves or the effector organs of the cardiovascular
system due to the clonidine-caused chronic
reduction in sympathetic activity.Thus, when the drug is
abruptly withdrawn, an exaggerated response to “normal”
levels of activity may occur. If treatment with
clonidine is terminated gradually, rebound hypertension
is unlikely. Patients should be warned of the danger
of abruptly discontinuing clonidine treatment.
代謝
Clonidine is well absorbed after oral administration.
Peak plasma levels occur between 2 and 4 hours after
drug administration and correlate well with pharmacological
activity.The plasma half-life in patients with normal
renal function is 12 hours. Urinary excretion of
clonidine and its metabolites accounts for almost 90%
of the administered dose, and fecal excretion accounts
for the rest. Approximately 50% of an administered
dose is excreted unchanged; the remainder is oxidatively
metabolized in the liver.
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