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

signalling pathways other than G s
-adenylyl cyclase–cyclic AMP, and
form altered receptor properties when β 2
and β 3
receptors for
hetero-oligomers (Breit et al., 2004; Rozec et al., 2003). Such
findings suggest opportunities for the development of more focused
β-antagonist therapy in the future.
A number of mechanisms have been proposed to play a role
in the beneficial effects of β receptor antagonists in heart failure.
Since excess effects of catecholamines may be toxic to the heart,
especially through activation of β 1
receptors, inhibition of the pathway
may help preserve myocardial function. Also, antagonism of β
receptors in the heart may attenuate cardiac remodeling, which ordinarily
might have deleterious effects on cardiac function.
Interestingly, activation of β receptors and elevation of cellular cyclic
AMP may promote myocardial cell death by apoptosis (Singh et al.,
2000; Brunton, 2005; Ding et al., 2005). In addition, properties of
certain β receptor antagonists that are due to other, unrelated properties
of these drugs may be potentially important. For example,
afterload reduction by drugs such as carvedilol may be relevant. The
potential importance of the α 1
-antagonistic and antioxidant properties
of carvedilol in its beneficial effects in patients with heart failure
is not clear (Ma et al., 1996).
Use of β Antagonists in Other Cardiovascular Diseases. β Receptor
antagonists, particularly propranolol, are used in the treatment of
hypertrophic obstructive cardiomyopathy. Propranolol is useful for
relieving angina, palpitations, and syncope in patients with this disorder.
Efficacy probably is related to partial relief of the pressure
gradient along the outflow tract. β Blockers also may attenuate catecholamine-induced
cardiomyopathy in pheochromocytoma.
β Blockers are used frequently in the medical management of
acute dissecting aortic aneurysm; their usefulness comes from reduction
in the force of myocardial contraction and the rate of development
of such force. Nitroprusside is an alternative, but when given
in the absence of β receptor blockade, it causes an undesirable tachycardia.
Patients with Marfan’s syndrome may develop progressive
dilation of the aorta, which may lead to aortic dissection and regurgitation,
a major cause of death in these patients. Chronic treatment
with propranolol may be efficacious in slowing the progression of
aortic dilation and its complications in patients with Marfan’s syndrome
(Shores et al., 1994).
Glaucoma. β Receptor antagonists are very useful in the
treatment of chronic open-angle glaucoma. Six drugs are
currently available: carteolol (OCUPRESS, others), betaxolol
(BETAOPTIC, others), levobunolol (BETAGAN, others),
metipranolol (OPTIPRANOLOL, others), timolol (TIMOPTIC,
others), and levobetaxolol (BETAXON). Timolol, levobunolol,
carteolol, and metipranolol are non-selective,
while betaxolol and levobetaxolol are β 1
selective. None
of the agents has significant membrane-stabilizing or
intrinsic sympathomimetic activities. Topically administered
β blockers have little or no effect on pupil size or
accommodation and are devoid of blurred vision and
night blindness often seen with miotics. These agents
decrease the production of aqueous humor, which appears
to be the mechanism for their clinical effectiveness.
Glaucoma and therapies for it are presented in Chapter 64.
β Receptor antagonists generally are administered as eye drops
and have an onset in ~30 minutes with a duration of 12-24 hours. While
topically administered β blockers usually are well tolerated, systemic
absorption can lead to adverse cardiovascular and pulmonary effects
in susceptible patients. They therefore should be used with great caution
in glaucoma patients at risk for adverse systemic effects of
β receptor antagonists (e.g., patients with bronchial asthma, severe
COPD, or those with bradyarrhythmias). The use of topically administered
β blockers for treatment of glaucoma is discussed further in
Chapter 64. Three β blockers (betaxolol, metipranolol, and timolol)
also have been observed to confer protection to retinal neurons, apparently
related to their ability to attenuate neuronal Ca 2+ and Na + influx
(Wood et al., 2003). Betaxolol is the most effective antiglaucoma drug
at reducing Na + /Ca 2+ influx. β Blockers may be able to blunt ganglion
cell death in glaucoma and that levobetaxolol may be a more
important neuroprotectant than timolol because of its greater capacity
to block Na + and Ca 2+ influx (Osborne et al., 2004).
Other Uses. Many of the signs and symptoms of hyperthyroidism
are reminiscent of the manifestations of increased sympathetic nervous
system activity. Indeed, excess thyroid hormone increases the
expression of β receptors in some types of cells. β Receptor antagonists
control many of the cardiovascular signs and symptoms of
hyperthyroidism and are useful adjuvants to more definitive therapy.
In addition, propranolol inhibits the peripheral conversion of thyroxine
to triiodothyronine, an effect that may be independent of β
receptor blockade. However, caution is advised in treating patients
with cardiac enlargement, since the use of β receptor antagonists
may precipitate congestive heart failure (see Chapter 39 for further
discussion of the treatment of hyperthyroidism).
Propranolol, timolol, and metoprolol are effective for the prophylaxis
of migraine (Tfelt-Hansen, 1986); the mechanism of this
effect is not known, and these drugs are not useful for treatment of
acute attacks of migraine.
Propranolol and other β blockers are effective in controlling
acute panic symptoms in individuals who are required to perform in
public or in other anxiety-provoking situations. Public speakers may
be calmed by the prophylactic administration of the drug, and the performance
of musicians may be improved. Tachycardia, muscle tremors,
and other evidence of increased sympathetic activity are reduced.
Propranolol also may be useful in the treatment of essential tremor.
β Blockers may be of some value in the treatment of patients
undergoing withdrawal from alcohol or those with akathisia.
Propranolol and nadolol are efficacious in the primary prevention of
variceal bleeding in patients with portal hypertension caused by cirrhosis
of the liver (Bosch, 1998; Villanueva et al., 1996). Isosorbide
mononitrate may augment the fall in portal pressure seen in some
patients treated with β receptor antagonists. These drugs also may be
beneficial in reducing the risk of recurrent variceal bleeding.
CLINICAL USE OF β ADRENERGIC
RECEPTOR ANTAGONISTS
Selection of a β Receptor Antagonist. The various β receptor
antagonists that are used for the treatment of hypertension
and angina appear to have similar
efficacies. Selection of the most appropriate drug
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CHAPTER 12
ADRENERGIC AGONISTS AND ANTAGONISTS