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

sympathetic nerve endings. Activation of α 2
receptors
in the pontomedullary region of the CNS inhibits sympathetic
nervous system activity and leads to a fall in
blood pressure; these receptors are a site of action for
drugs such as clonidine. Blockade of α 2
receptors with
selective antagonists such as yohimbine thus can
increase sympathetic outflow and potentiate the release
of NE from nerve endings, leading to activation of α 1
and β 1
receptors in the heart and peripheral vasculature
with a consequent rise in blood pressure. Antagonists
that also block α 1
receptors give rise to similar effects
on sympathetic outflow and release of NE, but the net
increase in blood pressure is prevented by inhibition of
vasoconstriction.
Although certain vascular beds contain α 2
receptors that promote
contraction of smooth muscle, it is thought that these receptors
are preferentially stimulated by circulating catecholamines,
whereas α 1
receptors are activated by NE released from sympathetic
nerve fibers. In other vascular beds, α 2
receptors reportedly promote
vasodilation by stimulating the release of NO from endothelial cells.
The physiological role of vascular α 2
receptors in the regulation of
blood flow within various vascular beds is uncertain. The α 2
receptors
contribute to smooth muscle contraction in the human saphenous
vein, whereas α 1
receptors are more prominent in dorsal hand
veins. The effects of α 2
receptor antagonists on the cardiovascular
system are dominated by actions in the CNS and on sympathetic
nerve endings.
Yohimbine. Yohimbine (YOCON, APHRODYNE) is a competitive antagonist
that is selective for α 2
receptors. The compound is an
indolealkylamine alkaloid and is found in the bark of the tree
Pausinystalia yohimbe and in Rauwolfia root; its structure resembles
that of reserpine. Yohimbine readily enters the CNS, where it
acts to increase blood pressure and heart rate; it also enhances motor
activity and produces tremors. These actions are opposite to those of
clonidine, an α 2
agonist. Yohimbine also antagonizes effects of 5-HT.
In the past, it was used extensively to treat male sexual dysfunction
(Tam et al., 2001). Although efficacy never was clearly demonstrated,
there is renewed interest in the use of yohimbine in the treatment
of male sexual dysfunction. The drug enhances sexual activity
in male rats and may benefit some patients with psychogenic erectile
dysfunction. However, the efficacies of PDE5 inhibitors (e.g.,
sildenafil, vardenafil, and tadalafil) and apomorphine (off-label) have
been much more conclusively demonstrated in oral treatment of
erectile dysfunction. Several small studies suggest that yohimbine
also may be useful for diabetic neuropathy and in the treatment of
postural hypotension. In the U.S., yohimbine can be legally sold as
a dietary supplement; however, labeling claims that it will arouse or
increase sexual desire or improve sexual performance are prohibited.
Yohimbine (ANTAGONIL, YOBINE) is approved in veterinary medicine
for the reversal of xylazine anesthesia.
Non-selective α Adrenergic Antagonists: Phenoxybenzamine and
Phentolamine. Phenoxybenzamine and phentolamine are nonselective
α receptors antagonists. Phenoxybenzamine, a haloalkylamine
compound, produces an irreversible antagonism; while
phentolamine, an imidazaline, produces a competitive antagonism.
Phenoxybenzamine and phentolamine have played an important role
in the establishment of the importance of α receptors in the regulation
of the cardiovascular and other systems. They are sometimes
referred to as “classical” α blockers to distinguish them from more
recently developed compounds such as prazosin.
The actions of phenoxybenzamine and phentolamine on the
cardiovascular system are similar. These “classical” α blockers cause
a progressive decrease in peripheral resistance, due to antagonism
of α receptors in the vasculature, and an increase in cardiac output
that is due in part to reflex sympathetic nerve stimulation. The cardiac
stimulation is accentuated by enhanced release of NE from cardiac
sympathetic nerve due to antagonism of presynaptic α 2
receptors by these non-selective α blockers. Postural hypotension is
a prominent feature with these drugs and this, accompanied by reflex
tachycardia that can precipitate cardiac arrhythmias, severely limits
the use of these drugs to treat essential hypertension. The more
recently developed α 1
-selective antagonists, such as prazosin, have
replaced the “classical” α blockers in the management of essential
hypertension. Phenoxybenzamine and phentolamine are still marketed
for several specialized uses.
Therapeutic Uses. A use of phenoxybenzamine (DIBENZYLINE) is in
the treatment of pheochromocytoma. Pheochromocytomas are
tumors of the adrenal medulla and sympathetic neurons that secrete
enormous quantities of catecholamines into the circulation. The usual
result is hypertension, which may be episodic and severe. The vast
majority of pheochromocytomas are treated surgically; however,
phenoxybenzamine is often used in preparing the patient for surgery.
The drug controls episodes of severe hypertension and minimizes
other adverse effects of catecholamines, such as contraction of
plasma volume and injury of the myocardium. A conservative
approach is to initiate treatment with phenoxybenzamine (at a dosage
of 10 mg twice daily) 1-3 weeks before the operation. The dose is
increased every other day until the desired effect on blood pressure
is achieved. Therapy may be limited by postural hypotension; nasal
stuffiness is another frequent adverse effect. The usual daily dose of
phenoxybenzamine in patients with pheochromocytoma is 40-120 mg
given in two or three divided portions. Prolonged treatment with phenoxybenzamine
may be necessary in patients with inoperable or
malignant pheochromocytoma. In some patients, particularly those
with malignant disease, administration of metyrosine may be a useful
adjuvant. Metyrosine (DEMSER) is a competitive inhibitor of tyrosine
hydroxylase, the rate-limiting enzyme in the synthesis of
catecholamines (Chapter 8). β Receptor antagonists also are used
to treat pheochromocytoma, but only after the administration of an
α receptor antagonist (described later).
Phentolamine can also be used in short-term control of hypertension
in patients with pheochromocytoma. Rapid infusions of
phentolamine may cause severe hypotension, so the drug should be
administered cautiously. Phentolamine also may be useful to relieve
pseudo-obstruction of the bowel in patients with pheochromocytoma;
this condition may result from the inhibitory effects of catecholamines
on intestinal smooth muscle.
Phentolamine has been used locally to prevent dermal necrosis
after the inadvertent extravasation of an α receptor agonist. The
drug also may be useful for the treatment of hypertensive crises that
follow the abrupt withdrawal of clonidine or that may result from the
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CHAPTER 12
ADRENERGIC AGONISTS AND ANTAGONISTS