Anticholinergics

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.

Basic Pharmacology

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.

Clinical Uses

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.

Adverse Effects

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.