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

296 these receptors is high, although the drug is a partial
agonist with relatively low efficacy at these sites. The
hypertensive response that follows parenteral administration
of clonidine generally is not seen when the drug
is given orally. However, even after intravenous administration,
the transient vasoconstriction is followed by a
more prolonged hypotensive response that results from
decreased sympathetic outflow from the CNS. The
exact mechanism by which clonidine lowers blood
pressure is not completely understood. The effect
appears to result, at least in part, from activation of α 2
receptors in the lower brainstem region. This central
action has been demonstrated by infusing small
amounts of the drug into the vertebral arteries or by
injecting it directly into the cisterna magna.
SECTION II
NEUROPHARMACOLOGY
Questions remain about whether the sympatho-inhibitory
action of clonidine results solely from its α 2
receptor agonism or
whether part or all of its actions are mediated by imidazoline receptors.
Imidazoline receptors include three subtypes (I 1
, I 2
, and I 3
) and
are widely distributed in the body, including the CNS. Clonidine, as
an imidazoline, binds to these imidazoline receptors, in addition to its
well-described binding to α 2
receptors. Two newer antihypertensive
imidazolines, rilmenidine and moxonidine, have profiles of action
similar to clonidine’s, suggesting a role for I 1
receptors. However, the
lack of an antihypertensive effect of clonidine in knockout mice lacking
α 2A
receptors supports a key role for these receptors in blood pressure
regulation (Zhu et al., 1999). Others argue that, while the action
of clonidine may be mediated by α 2
receptors, the I 1
receptor mediates
the effects of moxonidine and rilmenidine. Finally, α 2
and imidazoline
receptors may cooperatively regulate vasomotor tone and
may jointly mediate the hypotensive actions of centrally acting drugs
with affinity for both receptor types.
Clonidine decreases discharges in sympathetic preganglionic
fibers in the splanchnic nerve and in postganglionic fibers of cardiac
nerves. These effects are blocked by α 2
-selective antagonists such
as yohimbine. Clonidine also stimulates parasympathetic outflow,
which may contribute to the slowing of heart rate as a consequence
of increased vagal tone and diminished sympathetic drive. In addition,
some of the antihypertensive effects of clonidine may be mediated
by activation of presynaptic α 2
receptors that suppress the
release of NE, ATP, and NPY from postganglionic sympathetic
nerves. Clonidine decreases the plasma concentration of NE and
reduces its excretion in the urine.
Absorption, Fate, and Excretion. Clonidine is well absorbed after
oral administration, and its bioavailability is nearly 100%. The peak
concentration in plasma and the maximal hypotensive effect are
observed 1-3 hours after an oral dose. The elimination t 1/2
of the drug
ranges from 6-24 hours, with a mean of ~12 hours. About half of an
administered dose can be recovered unchanged in the urine, and the
t 1/2
of the drug may increase with renal failure. There is good correlation
between plasma concentrations of clonidine and its pharmacological
effects. A transdermal delivery patch permits continuous
administration of clonidine as an alternative to oral therapy. The drug
is released at an approximately constant rate for a week; 3-4 days
are required to reach steady-state concentrations in plasma. When
the patch is removed, plasma concentrations remain stable for ~8 hours
and then decline gradually over a period of several days; this
decrease is associated with a rise in blood pressure.
Adverse Effects. The major adverse effects of clonidine are dry
mouth and sedation. These responses occur in at least 50% of
patients and may require drug discontinuation. However, they may
diminish in intensity after several weeks of therapy. Sexual dysfunction
also may occur. Marked bradycardia is observed in some
patients. These and some of the other adverse effects of clonidine
frequently are related to dose, and their incidence may be lower with
transdermal administration of clonidine, since antihypertensive efficacy
may be achieved while avoiding the relatively high peak concentrations
that occur after oral administration of the drug. About
15-20% of patients develop contact dermatitis when using clonidine
in the transdermal system. Withdrawal reactions follow abrupt discontinuation
of long-term therapy with clonidine in some hypertensive
patients (Chapter 27).
Therapeutic Uses. The major therapeutic use of clonidine (CATAPRES,
others) is in the treatment of hypertension (Chapter 27). Clonidine
also has apparent efficacy in the off-label treatment of a range of other
disorders. Stimulation of α 2
receptors in the GI tract may increase
absorption of sodium chloride and fluid and inhibit secretion of bicarbonate.
This may explain why clonidine has been found to be useful
in reducing diarrhea in some diabetic patients with autonomic neuropathy.
Clonidine also is useful in treating and preparing addicted
subjects for withdrawal from narcotics, alcohol, and tobacco (Chapter
24). Clonidine may help ameliorate some of the adverse sympathetic
nervous activity associated with withdrawal from these agents, as
well as decrease craving for the drug. The long-term benefits of clonidine
in these settings and in neuropsychiatric disorders remain to be
determined. Clonidine may be useful in selected patients receiving
anesthesia because it may decrease the requirement for anesthetic and
increase hemodynamic stability (Hayashi and Maze, 1993; Chapter
19). Other potential benefits of clonidine and related drugs such as
dexmedetomidine (PRECEDEX; a relatively selective α 2
receptor agonist
with sedative properties) in anesthesia include preoperative sedation
and anxiolysis, drying of secretions, and analgesia. Transdermal
administration of clonidine (CATAPRESTTS) may be useful in reducing
the incidence of menopausal hot flashes.
Acute administration of clonidine has been used in the differential
diagnosis of patients with hypertension and suspected
pheochromocytoma. In patients with primary hypertension, plasma
concentrations of NE are markedly suppressed after a single dose of
clonidine; this response is not observed in many patients with
pheochromocytoma. The capacity of clonidine to activate postsynaptic
α 2
receptors in vascular smooth muscle has been exploited in
a limited number of patients whose autonomic failure is so severe
that reflex sympathetic responses on standing are absent; postural
hypotension is thus marked. Since the central effect of clonidine on
blood pressure is unimportant in these patients, the drug can elevate
blood pressure and improve the symptoms of postural hypotension.
Among the other off-label uses of clonidine are atrial fibrillation,
attention-deficit/hyperactivity disorder, constitutional growth delay
in children, cyclosporine-associated nephrotoxicity, Tourette’s
syndrome, hyperhidrosis, mania, posthepatic neuralgia, psychosis,