Anticholinergics
The parasympathetic
cholinergic pathway emanating from the vagus nerve exerts the main neuronal
control in human airways. The cholinergic efferent nerves synapse in ganglia
within the airways, and from there, short postganglionic fibers innervate the
end organs, in-cluding the airway smooth muscle and mucous glands. Stimulation of these nerve fibers, with the
resultant re-lease of acetylcholine and activation of muscarinic
choli-noreceptors, elicits bronchoconstriction, mucous secre-tion, and
bronchial vasodilation. Thus, the cholinergic pathways play a key role in the maintenance of the cal-iber of the
airways and contribute to the airway ob-struction in both asthma and chronic
obstructive pul-monary disease.
The airway effects of
released acetylcholine are medi-ated via activation of three distinct
muscarinic receptor subtypes: M1, in parasympathetic ganglia, mucous
glands and alveolar walls; autoinhibitory M2, in parasympa-thetic
nerve terminals; and M3, in airway smooth muscle, mucus glands, and
airway epithelium.
Although atropine and related
compounds possess bronchodilator activity, their use is associated with the
typical spectrum of anticholinergic side effects , and they are no longer used
in the treat-ment of asthma. To improve the clinical utility of
anti-cholinergics, quaternary amine derivatives of atropine were developed. By
virtue of their positive charge, these drugs are absorbed poorly across mucosal
surfaces and thus produce fewer side effects than atropine, especially when
given by inhalation.
Ipratropium bromide (Atrovent) is a quaternary amine
derivative that is used via inhalation in the treatment of chronic obstructive
pulmonary disease and to a lesser extent, asthma. Ipratropium has a slower
onset of action (1–2 hours for peak activity) than β2-adrenoceptor ago-nists and
thus may be more suitable for prophylactic use. Compared with β2-adrenoceptor agonists,
iprat-ropium is generally at least as effective in chronic ob-structive pulmonary
disease but less effective in asthma.
Ipratropium has greater
effectiveness than β2-adreno-ceptor agonists in two settings: in psychogenic asthma and
in patients taking β2-adrenoceptor antagonists. A fixed combination of ipratropium and
albuterol (Combivent) is approved for
use in chronic obstructive pulmonary disease.
Ipratropium is virtually
devoid of the CNS side effects associated with atropine. The most prevalent
peripheral side effects are dry mouth, headache, nervousness, dizzi-ness,
nausea, and cough. Unlike atropine, ipratropium does not inhibit mucociliary
clearance and thus does not promote the accumulation of secretions in the lower
airways.
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