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

1052 lung function than if treatment is delayed (O’Byrne et al.,
2006), likely reflecting the fact that corticosteroids are
able to modify the underlying inflammatory process
and prevent structural changes (fibrosis, smooth muscle
hyperplasia, etc.) in the airway that occur as a result of
chronic inflammation. ICS are currently recommended
for patients with persistent asthmatic symptoms. There
is evidence for airway inflammation in patients with
episodic asthma, but at present ICS are recommended
only when there are chronic symptoms (e.g., need for
an inhaled 2
agonist more than twice a week).
New corticosteroids with fewer systemic effects
would be desirable. Corticosteroids that are rapidly
metabolized in the airways (“soft steroids”), such as
butixocort and tipredane, proved disappointing in clinical
trials; they are probably metabolized too rapidly to
achieve sufficient concentration and duration to cause
an anti-inflammatory effect. There is a search for corticosteroids
that are metabolized rapidly in the circulation
after absorption from the lungs. The anti-inflammatory
actions of corticosteroids may be mediated via different
molecular mechanisms from side effects (which are
endocrine and metabolic actions of corticosteroids). It
has been possible to develop corticosteroids that dissociate
the DNA-binding effect of corticosteroids (which
mediates most of the adverse effects) from the inhibitory
effect on transcription factors such as NF-B (which
mediates much of the anti-inflammatory effect). Such
“dissociated steroids” or selective glucocorticoid receptor
agonists (SEGRAs) should, theoretically, retain antiinflammatory
activity but have a reduced risk of adverse
effects; achieving this separation of desired and adverse
effects is difficult in vivo (Schacke et al., 2007).
Nonsteroidal SEGRAs are now in development.
Corticosteroid resistance is a major barrier to
effective therapy in patients with severe asthma, in asthmatic
patients who smoke, and in patients with COPD
and cystic fibrosis (Barnes and Adcock, 2009). “Steroidresistant”
asthma is thought to be due to reduced antiinflammatory
actions of corticosteroids. Major strides
have been made in understanding the molecular mechanisms
for this corticosteroid resistance and in the development
of therapies that have the potential to reverse
this resistance and restore steroid responsiveness.
SECTION IV
INFLAMMATION, IMMUNOMODULATION, AND HEMATOPOIESIS
Cromones
Cromolyn sodium (sodium cromoglycate) is a derivative of khellin,
an Egyptian herbal remedy and was found to protect against allergen
challenge without any bronchodilator effect. A structurally related
drug, nedocromil sodium, which has a similar pharmacological profile
to cromolyn, was subsequently developed. Although cromolyn
was popular in the past because of its good safety profile, its use has
sharply declined with the more widespread use of the more effective
ICS, particularly in children. Neither cromolyn nor nedocromil
is available in the U.S. for respiratory indications. For further information,
consult earlier editions of this text.
MEDIATOR ANTAGONISTS
Many inflammatory mediators have been implicated in
asthma and COPD, suggesting that inhibition of synthesis
or receptors of these mediators may be beneficial
(Barnes, 2004; Barnes et al., 1998a). However,
specific inhibitors have been largely disappointing in
both asthma and COPD treatment. Both H 1
antihistamines
and anti-leukotrienes have been applied to airway
disease, but their added benefit over 2
agonists
and corticosteroids is slight. The variability in patient
response to anti-leukotriene agents may focus our attention
on the roles of leukotriene synthesis, action, and
metabolism to some, but not all, asthmatic disease.
Antihistamines. Histamine mimics many of the features of asthma
and is released from mast cells in acute asthmatic responses, suggesting
that antihistamines may be useful in asthma therapy. There
is little evidence that histamine H 1
receptor antagonists provide any
useful clinical benefit, as demonstrated by a meta-analysis (van
Ganse et al., 1997). Newer antihistamines, including cetirizine and
azelastine, have some beneficial effects, but this may be unrelated to
H 1
receptor antagonism. Antihistamines are not recommended in the
routine management of asthma.
Anti-leukotrienes. There is considerable evidence that cysteinylleukotrienes
(LTs) are produced in asthma and that they have potent
effects on airway function, inducing bronchoconstriction, airway
hyperresponsiveness, plasma exudation, mucus secretion, and
eosinophilic inflammation (Figure 36–11; also see Chapter 33 and
Peters-Golden and Henderson, 2007). These data suggested that
blocking the leukotriene pathways with leukotriene modifiers could
be useful in the treatment of asthma, leading to the development of
5-lipoxygenase (5-LO) enzyme inhibitors (of which zileuton
[ZYFLO] is the only drug marketed) and several antagonists of the
cys-LT 1
receptor, including montelukast (SINGULAIR), zafirlukast
(ACCOLATE), and pranlukast (not available in the U.S.).
Clinical Studies. Anti-leukotrienes have been intensively investigated
in clinical studies (Calhoun, 2001). Leukotriene antagonists inhibit
the bronchoconstrictor effect of inhaled LTD 4
in normal and asthmatic
volunteers, and they also inhibit bronchoconstriction induced
by a variety of challenges, including allergen, exercise, and cold air,
by approximately 50%. With aspirin challenge, in aspirin-sensitive
asthmatic patients, there is almost complete inhibition of the
response (Szczeklik and Stevenson, 2003). Similar results have been
obtained with the 5-LO inhibitor zileuton. This suggests there may
be no advantage in blocking LTB 4
in addition to cysteinyl-LTs, in
treating asthma. These drugs are active by oral administration, possibly
an important advantage in chronic treatment.
In patients with mild to moderate asthma, anti-leukotrienes
cause a significant improvement in lung function and asthma