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

1046 including glycopyrrolate and aclidinium (Cazzola, 2009; Hansel
et al., 2005). Dual-action drugs that are both muscarinic antagonists
and 2
agonist (MABA) are also in clinical development (Ray and
Alcaraz, 2009).
SECTION IV
INFLAMMATION, IMMUNOMODULATION, AND HEMATOPOIESIS
NOVEL CLASSES OF
BRONCHODILATORS
Several new classes of bronchodilator are under development,
but it is difficult to foresee a more effective
bronchodilator than a LABA for asthma and a longacting
anticholinergic for COPD. Inventing new classes
of bronchodilators has been difficult; several agents
have had problems with vasodilator side effects because
they relaxed vascular smooth muscle to a greater extent
than airway smooth muscle. Nonetheless, there are
several classes of bronchodilators under development,
as described next.
Magnesium Sulfate. Increasing evidence indicates that magnesium
sulfate (MgSO 4
) is useful as an additional bronchodilator in patients
with acute severe asthma. Intravenous or nebulized MgSO 4
benefits
adults and children with severe exacerbations (forced expiratory volume
in 1 second [FEV 1
] <30% of predicted value), giving improvement
in lung function when added to nebulized 2
agonist and a
reduction in hospital admissions (Mohammed and Goodacre, 2007).
The treatment is cheap and well tolerated, although the clinical benefit
appears small. Side effects include flushing and nausea but are
usually minor. Magnesium sulfate appears to act as a bronchodilator
and may reduce cytosolic Ca 2+ concentrations in airway smooth
muscle cells. The concentration of magnesium is lower in serum and
erythrocytes of asthmatic patients than in normal controls and correlates
with airway hyperresponsiveness (Emelyanov et al., 1999),
although the improvement in acute severe asthma after magnesium
does not correlate with plasma concentrations. More studies are
needed before intravenous and inhaled MgSO 4
are routinely recommended
for the management of acute severe asthma. There are too
few studies in acute exacerbations of COPD to make any firm recommendation
(Skorodin et al., 1995).
K + Channel Openers. K + channels are involved in recovery of
excitable cells after depolarization and are important in stabilization
of cells. K + channel openers such as cromakalim or levcromakalim
(the levo-isomer of cromakalim) open ATP-dependent K + channels in
smooth muscle, leading to membrane hyperpolarization and relaxation
of airway smooth muscle (Black et al., 1990). This suggests
that K + channel activators may be useful as bronchodilators (Pelaia
et al., 2002). Clinical studies in asthma, however, have been disappointing,
with no bronchodilation or protection against bronchoconstrictor
challenges. The cardiovascular side effects of these drugs
(postural hypotension, flushing) limit the oral dose; furthermore,
inhaled formulations are problematic. New developments include
K + channel openers that open Ca 2+ -activated large conductance K +
channels (maxi-K channels) that are also opened by 2
agonists;
these drugs may be better tolerated. Maxi-K channel openers also
inhibit mucus secretion and cough, and they may be of particular
value in the treatment of COPD.
Atrial Natriuretic Peptides. Atrial natriuretic peptide (ANP) activates
membrane-bound guanylyl cyclase and increases cellular
cyclic GMP, leading to bronchodilation by mechanisms similar to
those of NO on smooth muscle (Chapter 3). ANP and the related
peptide urodilatin are bronchodilators in asthma and give effects
comparable to those of 2
agonists (Angus et al., 1993; Fluge et al.,
1999). Because ANP and congeners work via a mechanism distinct
from that of 2
agonists, they may give additional bronchodilation
that may be useful in acute severe asthma when 2
receptor function
might be impaired.
Vasoactive Intestinal Polypeptide Analogs. Vasoactive intestinal
polypeptide (VIP) is a 28 amino acid peptide that binds to two
GPCRs, VPAC 1
and VPAC 2
, both of which couple primarily to G s
to stimulate the adenylyl cyclase-cAMP-PKA pathway leading to
relaxation of smooth muscle. VIP is a potent dilator of human airway
smooth muscle in vitro but is not effective in patients because
it is rapidly metabolized (plasma t 1/2
~2 minutes); in addition, VIP
causes vasodilator side effects. More stable analogs of VIP, such as
Ro 25-1533, which selectively stimulates VIP receptors in airway
smooth muscle (via the VPAC 2
receptor), have been synthesized.
Inhaled Ro 25-1533 has a rapid bronchodilator effect in asthmatic
patients but is not as prolonged as formoterol (Linden et al., 2003).
Other Inhibitors of Smooth Muscle Contraction. Agents that
inhibit the contractile machinery of airway smooth muscle, including
rho kinase inhibitors, inhibitors of myosin light chain kinase,
and myosin inhibitors, are also in development. Because these agents
also cause vasodilation, it will be necessary to administer them by
inhalation.
CORTICOSTEROIDS
Corticosteroids are used in the treatment of several
inflammatory lung diseases. Oral corticosteroids were
introduced for the treatment of asthma shortly after
their discovery in the 1950s and remain the most effective
controller therapy available for asthma. However,
their considerable side effects have prompted considerable
research into discovering new or related agents
that retain the beneficial action on airways without the
adverse effects. The introduction of ICS (inhaled corticosteroids),
initially as a way of reducing the requirement
for oral steroids, has revolutionized the treatment
of chronic asthma (Barnes et al., 1998b). Because
asthma is a chronic inflammatory disease, ICS are considered
as first-line therapy in all but the mildest of
patients. In marked contrast, ICS are much less effective
in COPD and should only be used in patients with
severe disease who have frequent exacerbations. Oral
corticosteroids remain the mainstay of treatment of several
other pulmonary diseases, such as sarcoidosis,
interstitial lung diseases, and pulmonary eosinophilic
syndromes. The general pharmacology of corticosteroids
is presented in Chapter 42.