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

1044 is the first drug to demonstrate clear anti-inflammatory
effects; thus, theophylline may have a role in preventing
progression of this disease (Culpitt et al., 2002).
SECTION IV
INFLAMMATION, IMMUNOMODULATION, AND HEMATOPOIESIS
MUSCARINIC CHOLINERGIC
ANTAGONISTS
Chemical antagonism of the effects of acetylcholine at
muscarinic receptors in the lung for the relief of asthma
is not a new idea. Datura stramonium (jimson weed) and
related species of the nightshade family contain a mixture
of muscarinic antagonists (atropine, hyoscyamine,
scopolamine) and were smoked for relief of asthma two
centuries ago. Subsequently, the purified plant alkaloid
atropine was introduced for treating asthma. Due to the
significant side effects of atropine, particularly drying of
secretions, less soluble quaternary compounds, such as
atropine methylnitrate and ipratropium bromide, have
been developed. These compounds are topically active
and are not significantly absorbed from the respiratory
or GI tracts. The basic pharmacology of the antimuscarinic
agents is presented in Chapter 9.
Mode of Action
These agents are competitive antagonists of ACh binding
to muscarinic cholinergic receptors; thus these
drugs block the effects of endogenous ACh at muscarinic
receptors, including the direct constrictor effect
on bronchial smooth muscle mediated via the M 3
-G q
-
PLC-IP 3
-Ca 2+ pathway (Chapter 3). Their predicted
efficacy stems from the role played by the parasympathetic
nervous system in regulating bronchomotor tone.
Multiple and diverse stimuli cause reflex increases in
parasympathetic activity that contribute to bronchoconstriction.
The effects of ACh on the respiratory system
include not only bronchoconstriction but also increased
tracheobronchial secretion and stimulation of the
chemoreceptors of the carotid and aortic bodies. Thus
antimuscarinic drugs might be expected to antagonize
these effects of acetylcholine. One complicating factor
studied in animal models is that myriad inflammatory
mediators involved in the pathogenesis of asthma and
COPD may also induce components of muscarinic
responsiveness, such as G q
and rho, and contribute to
hyperresponsiveness of the airway (Chiba et al., 2008).
Thus, the contractility of bronchial smooth muscle and
antagonism of muscarinic responsiveness could be
moving targets in asthma and COPD.
Basic research is demonstrating that the muscarinic
agonists are not functionally equivalent, however. Recent
research has focused on the differential capacity of muscarinic
antagonists to act as antagonists, as inverse agonists
inhibiting the constitutive activity of the M 3
receptor, and as modulators of upregulation of M 3
receptor
expression (Casarosa et al., 2009). Such differences
may have clinical relevance for long-term use of these
compounds, where tolerance and withdrawal/rebound
could be major issues. In this regard, a long-term study
of tiotropium demonstrates no loss of its capacity for
bronchodilation over 4 years (Tashkin et al., 2008).
In animals and man there is a small degree of resting bronchomotor
tone that is probably due to tonic vagal nerve impulses
that release acetylcholine in the vicinity of airway smooth muscle
because it can be blocked by anticholinergic drugs. Acetylcholine may
also be released from other airway cells, including epithelial cells
(Wessler and Kirkpatrick, 2008). The synthesis of acetylcholine in
epithelial cells is increased by inflammatory stimuli (such as TNF-),
which increase the expression of choline acetyltransferase, which
could contribute to cholinergic effects in airway diseases. Muscarinic
receptors are expressed in airway smooth muscle of small airways
that do not appear to be innervated by cholinergic nerves; these
receptors may be a mechanism of cholinergic narrowing in peripheral
airways that could be relevant in COPD, responding to locally
synthesized, non-neuronal ACh.
Myriad mechanical, chemical, and immunological stimuli
elicit reflex bronchoconstriction via vagal pathways, and cholinergic
pathways may play an important role in regulating acute bronchomotor
responses in animals. These observations suggested that cholinergic
mechanisms might underlie airway hyperresponsiveness and
acute bronchoconstrictor responses in asthma, with the implication
that anticholinergic drugs would be effective bronchodilators. These
drugs may afford protection against acute challenge by sulfur dioxide,
inert dusts, cold air, and emotional factors, but they are less
effective against antigen challenge, exercise, and fog. This is not surprising
because anticholinergic drugs will only inhibit reflex AChmediated
bronchoconstriction and have no blocking effect on the
direct effects of inflammatory mediators, such as histamine and
leukotrienes, on bronchial smooth muscle. Furthermore, cholinergic
antagonists probably have little or no effect on mast cells, microvascular
leak, or the chronic inflammatory response.
Theoretically, anticholinergics may reduce airway mucus
secretion and reduce mucus clearance, but this is generally not
observed in clinical studies. Oxitropium bromide (not available in
the U.S.) in high doses reduces mucus hypersecretion in patients
with COPD with chronic bronchitis.
Clinical Use. In asthmatic patients, anticholinergic drugs are less
effective as bronchodilators than 2
agonists and offer less efficient
protection against bronchial challenges. These drugs may be more
effective in older patients with asthma in whom there is an element
of fixed airway obstruction. Anticholinergics are currently used as an
additional bronchodilator in asthmatic patients not controlled on a
LABA. Nebulized anticholinergic drugs are effective in acute severe
asthma but less effective than 2
agonists. Nevertheless, in the acute
and chronic treatment of asthma, anticholinergic drugs may have an
additive effect with 2
agonists and should therefore be considered