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

1038 the treatment of asthma due to their functional antagonism
of bronchoconstriction. When inhaled from pMDI
or DPI, they are convenient, easy to use, rapid in onset,
and without significant systemic side effects. In addition
to their acute bronchodilator effect, these agents are effective
in protecting against various challenges, such as exercise,
cold air, and allergens. Short-acting 2
agonists are
the bronchodilators of choice in treating acute severe
asthma. The nebulized route of administration is easier
and safer than intravenous administration and just as
effective. Inhalation is preferable to the oral administration
because systemic side effects are less, and inhalation
may be more effective. Short-acting inhaled 2
agonists,
such as albuterol, should be used “as required” by symptoms
and not on a regular basis in the treatment of mild
asthma; increased use indicates the need for more antiinflammatory
therapy.
SECTION IV
INFLAMMATION, IMMUNOMODULATION, AND HEMATOPOIESIS
Oral 2
agonists are occasionally indicated as an additional
bronchodilator. Slow-release preparations (e.g., slow-release
albuterol and bambuterol [a prodrug that slowly releases terbutaline
but is not commercially available in the U.S.]) may be indicated in
nocturnal asthma; however, these agents are less useful than inhaled
agonists because of an increased risk of side effects. Several shortacting
2
agonists are available. With the exception of rimiterol
(which retains the catechol ring structure and is therefore susceptible
to rapid enzymatic degradation), they are resistant to uptake and
enzymatic degradation by COMT and MAO. There is little to choose
between the various short-acting 2
agonists currently available; all
are usable by inhalation and orally, have a similar duration of action
(~3-4 hours; less in severe asthma), and similar side effects.
Differences in 2
selectivity have been claimed but are not clinically
important. Drugs in clinical use include albuterol (salbutamol), levalbuterol,
metaproterenol, terbutaline, as well as several not available
in the U.S., fenoterol, tulobuterol, rimiterol, and pirbuterol.
Long-Acting Inhaled 2
Agonists. The long-acting
inhaled 2
agonists (LABA) salmeterol, formoterol, and
arformoterol have proved to be a significant advance in
asthma and COPD therapy. These drugs have a bronchodilator
action of >12 hours and also protect against
bronchoconstriction for a similar period (Kips and
Pauwels, 2001). They improve asthma control (when
given twice daily) compared with regular treatment
with short-acting 2
agonists (four to six times daily).
Tolerance to the bronchodilator effect of formoterol and the
bronchoprotective effects of formoterol and salmeterol have been
demonstrated, but this is a small loss of protection that does not appear
to be progressive and is of doubtful clinical significance. Although both
drugs have a similar duration of effect in clinical studies, there are differences.
Formoterol has a more rapid onset of action and is an almost
full agonist, whereas salmeterol is a partial agonist with a slower onset
of action. These differences might confer a theoretical advantage for
formoterol in more severe asthma, whereas it may also make it more
likely to induce tolerance. However, no significant clinical differences
between salmeterol and formoterol have been found in the treatment of
patients with severe asthma (Nightingale et al., 2002).
In COPD, LABA are effective bronchodilators that may be
used alone or in combination with anticholinergics or ICS. LABA
improve symptoms and exercise tolerance by reducing both air trapping
and exacerbations. In asthma patients, LABA should never be
used alone because they do not treat the underlying chronic inflammation;
rather, LABA should always be used in combination with
ICS (preferably in a fixed-dose combination inhaler). LABA are an
effective add-on therapy to ICS and are more effective than increasing
the dose of ICS when asthma is not controlled at low doses.
Combination Inhalers. Combination inhalers that contain
a LABA and a corticosteroid (e.g., fluticasone/salmeterol
[ADVAIR], budesonide/formoterol [SYMBICORT]) are
now widely used in the treatment of asthma and
COPD. In asthma there is a strong scientific rationale
for combining a LABA with a corticosteroid because
these treatments have complementary synergistic
actions (Barnes, 2002). The combination inhaler is
more convenient for patients, simplifies therapy, and
improves compliance with ICS because the patients
perceive clinical benefit, but there may be an additional
advantage because delivering the two drugs in
the same inhaler ensures they are delivered simultaneously
to the same cells in the airways, allowing the
beneficial molecular interactions between LABA and
corticosteroids to occur. It is likely that these inhalers
will become the preferred therapy for all patients with
persistent asthma. These combination inhalers are also
more effective in COPD patients than LABA and ICS
alone, but the mechanisms accounting for this beneficial
interaction are less well understood than in
patients with asthma.
Recently, a combination inhaler that contains formoterol and
budesonide was shown to be more effective for relieving acute symptoms
than either terbutaline or formoterol alone, suggesting that the
inhaled corticosteroids may also be contributing to the benefit (Rabe
et al., 2006). This may make it possible to control asthma with a
single inhaler both for maintenance and relief of symptoms.
Stereoselective 2
Agonists. Albuterol is a racemic mixture of
active R- and inactive S-isomers. Animal studies suggest that the
S-isomer may increase airway responsiveness, providing a rationale
for the development of R-albuterol (levalbuterol). Although the
R-isomer is more potent than racemic R/S-albuterol in some studies,
careful dose responses show no advantage in terms of efficacy and
no evidence that the S-albuterol is detrimental in asthmatic patients
(Lotvall et al., 2001). Because levalbuterol is more expensive
than normally used racemic albuterol, this therapy has no clear
clinical advantage (Barnes, 2006b). Stereoselective formoterol (R,
R-formoterol, arformoterol) has now been developed as a nebulized
solution but also appears to offer no clinical advantage over racemic
formoterol (Madaan, 2009).