Anticholinergics

Human airways are innervated by a supply of efferent, cholinergic, parasympathetic autonomic nerves. Motor nerves derived from the vagus form ganglia within and around the walls of the airways. This vagally derived innervation extends along the length of the bronchial tree, but predominates in the large and medium-sized airways. Postganglionic fibers derived from the vagal ganglia supply the smooth muscle and submucosal glands of the airways as well as the vascular structures. Release of acetylcholine (ACh) at these sites results in stimulation of muscarinic receptors and subsequent airway smooth muscle contraction and release of secretions from the submucosal airway glands.

There are three pharmacologically distinct subtypes of muscarinic receptors within the airways, known as M1, M2 and M3 receptors. M1 receptors are present on peribronchial ganglion cells where the preganglionic nerves transmit to the postganglionic nerves. M2 receptors are present on the postganglionic nerves; they are activated by the release of acetylcholine and promote its reuptake into the nerve terminal. M3 receptors are present on smooth muscle. Muscarinic receptor activation of these M3 receptors leads to a decrease in intracellular cAMP levels, resulting in contraction of airway smooth muscle and bronchoconstriction.

Atropine is the prototype anticholinergic bronchodilator. Ipratropium is a quaternary amine, which is poorly absorbed across biologic membranes. Atropine and ipratropium antagonize the actions of ACh at parasympathetic, postganglionic, effector cell junctions by competing with ACh for M3 receptor sites. This antagonism of ACh results in airway smooth muscle relaxation and bronchodilation.

Ipratropium is given exclusively by inhalation from a metered-dose inhaler or a nebulizer. Inhaled ipratropium has a relatively slow onset and long duration of action. The duration of bronchodilating action of ipratropium is up to approximately 6 hours.

Clinical trials of anticholinergic therapy have generally failed to show significant benefit in asthma. This relative lack of efficacy in asthma contrasts with COPD, in which anticholinergic agents are among the most effective therapies.

Category: Pharmacology Notes