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

parotid gland swelling and pain. Postural hypotension and erectile
dysfunction may be prominent in some patients. Clonidine may produce
a lower incidence of dry mouth and sedation when given transdermally,
perhaps because high peak concentrations are avoided.
Less common CNS side effects include sleep disturbances with
vivid dreams or nightmares, restlessness, and depression. Cardiac
effects related to the sympatholytic action of these drugs include
symptomatic bradycardia and sinus arrest in patients with dysfunction
of the SA node and AV block in patients with AV nodal disease
or in patients taking other drugs that depress AV conduction. Some
15-20% of patients who receive transdermal clonidine may develop
contact dermatitis.
Sudden discontinuation of clonidine and related α 2
adrenergic
agonists may cause a withdrawal syndrome consisting of headache,
apprehension, tremors, abdominal pain, sweating, and tachycardia.
The arterial blood pressure may rise to levels above those that were
present prior to treatment, but the syndrome may occur in the
absence of an overshoot in pressure. Symptoms typically occur 18-
36 hours after the drug is stopped and are associated with increased
sympathetic discharge, as evidenced by elevated plasma and urine
concentrations of catecholamines. The exact incidence of the withdrawal
syndrome is not known, but it is likely dose related and more
dangerous in patients with poorly controlled hypertension. Rebound
hypertension also has been seen after discontinuation of transdermal
administration of clonidine (Metz et al., 1987).
Treatment of the withdrawal syndrome depends on the
urgency of reducing the arterial blood pressure. In the absence of
life-threatening target organ damage, patients can be treated by
restoring the use of clonidine. If a more rapid effect is required,
sodium nitroprusside or a combination of an α and β adrenergic
blocker is appropriate. β Adrenergic blocking agents should not be
used alone in this setting, because they may accentuate the hypertension
by allowing unopposed α adrenergic vasoconstriction caused
by activation of the sympathetic nervous system and elevated circulating
catecholamines.
Because perioperative hypertension has been described in
patients in whom clonidine was withdrawn the night before surgery,
surgical patients who are being treated with an α 2
adrenergic agonist
either should be switched to another drug prior to elective surgery or
should receive their morning dose and/or transdermal clonidine prior
to the procedure. All patients who receive one of these drugs should
be warned of the potential danger of discontinuing the drug abruptly,
and patients suspected of being noncompliant with medications
should not be given α 2
adrenergic agonists for hypertension.
Adverse drug interactions with α 2
adrenergic agonists are
rare. Diuretics predictably potentiate the hypotensive effect of these
drugs. Tricyclic antidepressants may inhibit the antihypertensive
effect of clonidine, but the mechanism of this interaction is not
known.
Therapeutic Uses. The CNS effects are such that this
class of drugs is not a leading option for monotherapy
of hypertension. Indeed, there is no fixed place for these
drugs in the treatment of hypertension. They effectively
lower blood pressure in some patients who have not
responded adequately to combinations of other agents.
Enthusiasm for these drugs is diminished by the relative
absence of evidence demonstrating reduction in risk of
adverse cardiovascular events.
Clonidine has been used in hypertensive patients for the diagnosis
of pheochromocytoma. The lack of suppression of the plasma
concentration of NE to >500 pg/mL 3 hours after an oral dose of 0.3
mg of clonidine suggests the presence of such a tumor. A modification
of this test, wherein overnight urinary excretion of NE and epinephrine
is measured after administration of a 0.3-mg dose of
clonidine at bedtime, may be useful when results based on plasma
NE concentrations are equivocal. Other uses for α 2
adrenergic agonists
are discussed in Chapters 12, 13, and 23.
Guanadrel
Guanadrel specifically inhibits the function of peripheral
postganglionic adrenergic neurons. The structure
of guanadrel, which contains the strongly basic guanidine
group, is:
Locus and Mechanism of Action. Guanadrel is an exogenous false
neurotransmitter that is accumulated, stored, and released like NE
but is inactive at adrenergic receptors. The drug reaches its site of
action by active transport into the neuron by the same transporter
that is responsible for the reuptake of NE (see Chapter 8). In the neuron,
guanadrel is concentrated within the adrenergic storage vesicle,
where it replaces NE. During chronic administration, guanadrel acts
as a “false neurotransmitter”: It is present in storage vesicles,
depletes the normal transmitter, and can be released by stimuli that
normally release NE, but is inactive at adrenergic receptors. This
replacement of NE with an inactive transmitter is probably the principal
mechanism of action of guanadrel. Because guanadrel can promote
NE release from pheochromocytomas, it is contraindicated in
those patients.
Pharmacological Effects. Essentially all of the therapeutic and adverse
effects of guanadrel result from functional sympathetic blockade.
The antihypertensive effect is achieved by a reduction in peripheral
vascular resistance that results from inhibition of α receptor–
mediated vasoconstriction. Consequently, arterial pressure is
reduced modestly in the supine position when sympathetic activity
is usually low, but the pressure can fall to a greater extent during situations
in which reflex sympathetic activation is an important mechanism
for maintaining arterial pressure, particularly when standing.
Absorption, Distribution, Metabolism, and Excretion. Because
guanadrel must be transported into and accumulate in adrenergic
neurons, the maximum effect on blood pressure is not seen until
4-5 hours. The t 1/2
of the pharmacological effect of guanadrel is
determined by the drug’s persistence in this neuronal pool and is
probably at least 10 hours.
Adverse Effects. Guanadrel produces undesirable effects that are
related to sympathetic blockade. Symptomatic hypotension during
standing, exercise, ingestion of alcohol, or in hot weather is the
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CHAPTER 27
TREATMENT OF MYOCARDIAL ISCHEMIA AND HYPERTENSION