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

vascular resistance is increased and blood pressure is
maintained or elevated. Although the clinical utility of
these drugs is limited, they may be useful in the treatment
of some patients with hypotension, including orthostatic
hypotension, or shock. Phenylephrine and
methoxamine (discontinued in the U.S.) are direct-acting
vasoconstrictors and are selective activators of α 1
receptors.
Mephentermine and metaraminol act both directly
and indirectly. Midodrine is a prodrug that is converted,
after oral administration, to desglymidodrine, a directacting
α 1
agonist.
Phenylephrine
Phenylephrine (NEO-SYNEPHRINE, others) is a α 1
-
selective agonist; it activates β receptors only at much
higher concentrations. Chemically, phenylephrine differs
from epinephrine only in lacking a hydroxyl group
at position 4 on the benzene ring (Table 12–1). The
pharmacological effects of phenylephrine are similar to
those of methoxamine. The drug causes marked arterial
vasoconstriction during intravenous infusion.
Phenylephrine (NEO-SYNEPHRINE, others) also is used as
a nasal decongestant and as a mydriatic in various nasal
and ophthalmic formulations (see Chapter 64 for ophthalmic
uses).
Mephentermine. Mephentermine is a sympathomimetic drug that
acts both directly and indirectly; it has many similarities to ephedrine
(discussed later). After an intramuscular injection, the onset of action
is prompt (within 5-15 minutes), and effects may last for several
hours. Since the drug releases NE, cardiac contraction is enhanced,
and cardiac output and systolic and diastolic pressures usually are
increased. The change in heart rate is variable, depending on the
degree of vagal tone. Adverse effects are related to CNS stimulation,
excessive rises in blood pressure, and arrhythmias. Mephentermine
is used to prevent hypotension, which frequently accompanies spinal
anesthesia. The drug has been discontinued in the U.S.
Metaraminol. Metaraminol is a sympathomimetic drug with prominent
direct effects on vascular α adrenergic receptors. Metaraminol
also is an indirectly acting agent that stimulates the release of NE.
The drug has been used in the treatment of hypotensive states or offlabel
to relieve attacks of paroxysmal atrial tachycardia, particularly
those associated with hypotension (see Chapter 29 for preferable
treatments of this arrhythmia).
administering the drug during periods when the patient will remain
upright, avoiding dosing within 4 hours of bedtime, and elevating
the head of the bed. Very cautious use of a short-acting antihypertensive
drug at bedtime may be useful in some patients. Typical dosing,
achieved by careful titration of blood pressure responses, varies
between 2.5 and 10 mg three times daily.
α 2
-SELECTIVE ADRENERGIC
RECEPTOR AGONISTS
α 2
-Selective adrenergic agonists are used primarily for
the treatment of systemic hypertension. Their efficacy
as antihypertensive agents is somewhat surprising, since
many blood vessels contain postsynaptic α 2
adrenergic
receptors that promote vasoconstriction (Chapter 8).
Indeed, clonidine, the prototypic α 2
agonist, was initially
developed as a vasoconstricting nasal decongestant.
Its capacity to lower blood pressure results from
activation of α 2
receptors in the cardiovascular control
centers of the CNS; such activation suppresses the
outflow of sympathetic nervous system activity from
the brain.
In addition, α 2
agonists reduce intraocular pressure by
decreasing the production of aqueous humor. This action first was
reported for clonidine and suggested a potential role for α 2
receptor
agonists in the management of ocular hypertension and glaucoma.
Unfortunately, clonidine lowered systemic blood pressure even if
applied topically to the eye (Alward, 1998). Two derivatives of clonidine,
apraclonidine and brimonidine, have been developed that retain
the ability to decrease intraocular pressure with little or no effect on
systemic blood pressure.
Clonidine
Clonidine, an imidazoline, was originally tested as a
vasoconstrictor acting at peripheral α 2
receptors.
During clinical trials as a topical nasal decongestant,
clonidine was found to cause hypotension, sedation,
and bradycardia.
295
CHAPTER 12
ADRENERGIC AGONISTS AND ANTAGONISTS
Midodrine. Midodrine (PROAMATINE, others) is an orally effective α 1
receptor agonist. It is a prodrug; its activity is due to its conversion
to an active metabolite, desglymidodrine, which achieves peak concentrations
~1 hour after a dose of midodrine. The t 1/2
of desglymidodrine
is ~3 hours. Consequently, the duration of action is ~4-6 hours.
Midodrine-induced rises in blood pressure are associated with both
arterial and venous smooth muscle contraction. This is advantageous
in the treatment of patients with autonomic insufficiency and postural
hypotension (McClellan et al., 1998). A frequent complication
in these patients is supine hypertension. This can be minimized by
Pharmacological Effects. The major pharmacological
effects of clonidine involve changes in blood pressure
and heart rate, although the drug has a variety of other
important actions. Intravenous infusion of clonidine
causes an acute rise in blood pressure, apparently
because of activation of postsynaptic α 2
receptors in
vascular smooth muscle. The affinity of clonidine for