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

the only preparation available in a breath-activated meter-dose
inhaler, a device meant to optimize medication delivery by releasing
a spray of medication only on the patient’s initiation of inspiration.
Terbutaline. Terbutaline is a β 2
-selective bronchodilator. It contains
a resorcinol ring and thus is not a substrate for COMT methylation.
It is effective when taken orally, subcutaneously, or by inhalation
(not marketed for inhalation in the U.S.).
Effects are observed rapidly after inhalation or parenteral
administration; after inhalation its action may persist 3-6 hours. With
oral administration, the onset of effect may be delayed 1-2 hours.
Terbutaline (BRETHINE, others) is used for the long-term treatment of
obstructive airway diseases and for treatment of acute bronchospasm,
and also is available for parenteral use for the emergency
treatment of status asthmaticus (Chapter 36).
Isoetharine. Isoetharine was the first β 2
-selective drug widely used
for the treatment of airway obstruction. However, its degree of selectivity
for β 2
receptors may not approach that of some of the other
agents. Although resistant to metabolism by MAO, it is a catecholamine
and thus is a good substrate for COMT (Table 12–1).
Consequently, it is used only by inhalation for the treatment of acute
episodes of bronchoconstriction. Isoetharine is no longer marketed
in the U.S.
Bitolterol. Bitolterol (TORNALATE) is a novel β 2
agonist in which the
hydroxyl groups in the catechol moiety are protected by esterification
with 4-methylbenzoate. Esterases in the lung and other tissues
hydrolyze this prodrug to the active form, colterol, or terbutylnorepinephrine
(Table 12–1). Animal studies suggest that these esterases
are present in higher concentrations in lung than in tissues such as
the heart. The duration of effect of bitolterol after inhalation ranges
from 3-6 hours. Bitolterol has been discontinued in the U.S.
Fenoterol. Fenoterol (BEROTEC) is a β 2
-selective receptor agonist.
After inhalation, it has a prompt onset of action, and its effect typically
is sustained for 4-6 hours. The possible association of fenoterol
use with increased deaths from asthma, although controversial
(Pearce et al., 1995; Suissa and Ernst, 1997), has led to its withdrawal
from the market. It is thought that the dysrhythmias and cardiac
effects are due to effects on β 1
adrenergic receptors.
Procaterol. Procaterol (MASCACIN, others) is a β 2
-selective receptor
agonist. After inhalation, it has a prompt onset of action that is sustained
for ~5 hours. Procaterol is not available in the U.S.
Long-Acting β 2
Adrenergic Agonists
Salmeterol. Salmeterol (SEREVENT) is a β 2
-selective
agonist with a prolonged duration of action (>12
hours); it has at least 50-fold greater selectivity for β 2
receptors than albuterol. It provides symptomatic relief
and improves lung function and quality of life in
patients with COPD; in this setting, it is as effective as
the cholinergic antagonist ipratropium and more effective
than oral theophylline. It has additive effects when
used in combination with inhaled ipratropium or oral
theophylline.
Like formoterol, it is highly lipophilic and has a sustained
duration of action; for salmeterol, this long action reflects binding to
a specific site within the β 2
receptor that allows for its prolonged
activation. It also may have anti-inflammatory activity. Salmeterol is
metabolized by CYP3A4 to α-hydroxy-salmeterol, which is eliminated
primarily in the feces. Since the onset of action of inhaled salmeterol
is relatively slow, it is not suitable monotherapy for acute
breakthrough attacks of bronchospasm. Salmeterol or formoterol are
the agents of choice for nocturnal asthma in patients who remain
symptomatic despite anti-inflammatory agents and other standard
management.
Salmeterol generally is well tolerated but has the potential to
increase heart rate and plasma glucose concentration, to produce
tremors, and to decrease plasma potassium concentration through
effects on extrapulmonary β 2
receptors. Salmeterol should not be
used more than twice daily (morning and evening) and should not be
used to treat acute asthma symptoms, which should be treated with
a short-acting β 2
agonist (e.g., albuterol) when breakthrough symptoms
occur despite twice-daily use of salmeterol (Redington, 2001).
Many patients with moderate or severe persistent asthma have
benefited immensely with the use of long-acting β agonists like salmeterol
together with an inhaled corticosteroid. These benefits have
to be counterbalanced against the results of the Salmeterol
Multicenter Asthma Research Trial (SMART), in which the addition
of a long acting β agonist to “usual therapy” was associated with an
increased risk of fatal or near-fatal asthmatic attacks, as compared
with “usual therapy” alone. This study is controversial and often criticized
because only a minority of subjects in SMART were taking
inhaled corticosteroids and there is a lack of reports of increased
asthma mortality among patients taking both a long-acting β agonist
and an inhaled corticosteroid (Fanta, 2009). Nevertheless, the
FDA has placed a black-box warning in the labeling information for
salmeterol, formoterol, and arformoterol. Moreover, national and
international expert panels (Fanta, 2009) have recommended the use
of long-acting agonists only for patients in whom inhaled corticosteroids
alone either have failed to achieve good asthma control or
for initial therapy.
Formoterol. Formoterol (FORADIL, others) is a long-acting
β 2
-selective receptor agonist. Significant bronchodilation
occurs within minutes of inhalation of a therapeutic
dose, which may persist for up to 12 hours (Faulds
et al., 1991). It is highly lipophilic and has high affinity
for β 2
receptors. Its major advantage over many
other β 2
-selective agonists is this prolonged duration of
action, which may be particularly advantageous in
settings such as nocturnal asthma. Formoterol’s sustained
action is due to its insertion into the lipid bilayer
of the plasma membrane, from which it gradually diffuses
to provide prolonged stimulation of β 2
receptors.
It is FDA-approved for treatment of asthma, bronchospasm,
prophylaxis of exercise-induced bronchospasm,
and chronic obstructive pulmonary disease
(COPD). It can be used concomitantly with short-acting
β 2
agonists, glucocorticoids (inhaled or systemic), and
theophylline (Goldsmith and Keating, 2004).
Arformoterol. Arformoterol (BROVENA), the (R,R) enantiomer
of formoterol, is a selective long-acting β 2
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CHAPTER 12
ADRENERGIC AGONISTS AND ANTAGONISTS