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

restless leg syndrome, ulcerative colitis, and allergy-induced inflammatory
reactions in patients with extrinsic asthma.
Apraclonidine. Apraclonidine (IOPIDINE) is a relatively
selective α 2
receptor agonist that is used topically to
reduce intraocular pressure. It can reduce elevated as
well as normal intraocular pressure whether accompanied
by glaucoma or not. The reduction in intraocular
pressure occurs with minimal or no effects on systemic
cardiovascular parameters; thus apraclonidine is more
useful than clonidine for ophthalmic therapy.
Apparently apraclonidine does not cross the bloodbrain
barrier. The mechanism of action of apraclonidine
is related to α 2
receptor–mediated reduction in the formation
of aqueous humor.
The clinical utility of apraclonidine is most apparent as shortterm
adjunctive therapy in glaucoma patients whose intraocular pressure
is not well controlled by other pharmacological agents such as
β receptor antagonists, parasympathomimetics, or carbonic anhydrase
inhibitors. The drug also is used to control or prevent elevations
in intraocular pressure that occur in patients after laser trabeculoplasty
or iridotomy (Chapter 64).
Brimonidine. Brimonidine (ALPHAGAN, others), is another
clonidine derivative that is administered ocularly to
lower intraocular pressure in patients with ocular
hypertension or open-angle glaucoma. Brimonidine is
a α 2
-selective agonist that reduces intraocular pressure
both by decreasing aqueous humor production and by
increasing outflow (Chapter 64). The efficacy of brimonidine
in reducing intraocular pressure is similar to
that of the β receptor antagonist timolol. Unlike apraclonidine,
brimonidine can cross the blood-brain barrier
and can produce hypotension and sedation, although
these CNS effects are slight compared to those of clonidine.
As with all α 2
agonists, this drug should be used
with caution in patients with cardiovascular disease.
Guanfacine. Guanfacine (TENEX, others) is an α 2
receptor
agonist that is more selective for α 2
receptors than
is clonidine. Like clonidine, guanfacine lowers blood
pressure by activation of brainstem receptors with resultant
suppression of sympathetic activity. A sustainedrelease
form (INTUNIV) has recently been FDA-approved
for treatment of ADHD in children aged 6-17 years.
The drug is well absorbed after oral administration and has a
large volume of distribution (4-6 L/kg). About 50% of guanfacine
appears unchanged in the urine; the rest is metabolized. The t 1/2
for
elimination ranges from 12-24 hours. Guanfacine and clonidine
appear to have similar efficacy for the treatment of hypertension.
The pattern of adverse effects also is similar for the two drugs,
although it has been suggested that some of these effects may be
milder and occur less frequently with guanfacine. A withdrawal
syndrome may occur after the abrupt discontinuation of guanfacine,
but it appears to be less frequent and milder than the syndrome that
follows clonidine withdrawal. Part of this difference may relate to the
longer t 1/2
of guanfacine.
Guanabenz. Guanabenz (WYTENSIN, others) is a centrally
acting α 2
agonist that decreases blood pressure by a
mechanism similar to those of clonidine and guanfacine.
Guanabenz has a t 1/2
of 4-6 hours and is extensively
metabolized by the liver. Dosage adjustment may be
necessary in patients with hepatic cirrhosis. The adverse
effects caused by guanabenz (e.g., dry mouth and sedation)
are similar to those seen with clonidine.
Methyldopa. Methyldopa (α-methyl-3,4-dihydroxyphenylalanine)
is a centrally acting antihypertensive
agent. It is metabolized to α-methylnorepinephrine in
the brain, and this compound is thought to activate central
α 2
receptors and lower blood pressure in a manner
similar to that of clonidine (Chapter 27).
Tizanidine. Tizanidine (ZANAFLEX, others) is a muscle
relaxant used for the treatment of spasticity associated
with cerebral and spinal disorders. It is also an α 2
agonist
with some properties similar to those of clonidine
(Wagstaff and Bryson, 1997).
MISCELLANEOUS SYMPATHOMIMETIC
AGONISTS
Amphetamine
Amphetamine, racemic β phenylisopropylamine
(Table 12–1), has powerful CNS stimulant actions in
addition to the peripheral α and β actions common to
indirect-acting sympathomimetic drugs. Unlike epinephrine,
it is effective after oral administration and its
effects last for several hours.
Cardiovascular System. Amphetamine given orally
raises both systolic and diastolic blood pressure. Heart
rate often is reflexly slowed; with large doses, cardiac
arrhythmias may occur. Cardiac output is not enhanced
by therapeutic doses, and cerebral blood flow does not
change much. The l-isomer is slightly more potent than
the d-isomer in its cardiovascular actions.
Other Smooth Muscles. In general, smooth muscles respond to
amphetamine as they do to other sympathomimetic amines. The contractile
effect on the sphincter of the urinary bladder is particularly
marked, and for this reason amphetamine has been used in treating
enuresis and incontinence. Pain and difficulty in micturition occasionally
occur. The GI effects of amphetamine are unpredictable. If
enteric activity is pronounced, amphetamine may cause relaxation
and delay the movement of intestinal contents; if the gut already is
relaxed, the opposite effect may occur. The response of the human
uterus varies, but there usually is an increase in tone.
297
CHAPTER 12
ADRENERGIC AGONISTS AND ANTAGONISTS