FIGURE 20–6 Mechanisms of response to inhaled irritants. The airway is represented microscopically by a cross-section of the wall with branching vagal sensory endings lying adjacent to the lumen. Afferent pathways in the vagus nerves travel to the central nervous system; efferent pathways from the central nervous system travel to efferent ganglia. Postganglionic fibers release acetylcholine (ACh), which binds to muscarinic receptors on airway smooth muscle. Inhaled materials may provoke bronchoconstriction by several possible mechanisms. First, they may trigger the release of chemical mediators from mast cells. Second, they may stimulate afferent receptors to initiate reflex bronchoconstriction or to release tachykinins (eg, substance P) that directly stimulate smooth muscle contraction.
entry into the central nervous system. Studies with this agent have shown that the degree of involvement of parasympathetic pathways in bronchomotor responses varies among subjects. This variation indicates that other mechanisms in addition to parasympathetic reflex pathways must be involved.
Even though the bronchodilation and inhibition of provoked bronchoconstriction afforded by antimuscarinic agents are incomplete, their use is of clinical value, especially for patients intolerant of inhaled β agonists.
Ipratropium appears to be as effective as albuterol in patients with COPD who have at least partially reversible obstruction. Longer-acting antimuscarinic agents, including tiotropium, aclidinium, and umeclidinium, are approved for maintenance therapy of COPD. These drugs bind to M1, M2, and M3 receptors with equal affinity, but dissociate most rapidly from M2 receptors, expressed on the efferent nerve ending. This means that they do not inhibit the M2-receptor-mediated inhibition of acetylcholine release and thus benefit from a degree of receptor selectivity. They are taken by inhalation. A single dose of 18 mcg of tiotropium or 62.5 mcg of umeclidinium has a 24-hour duration of action, whereas inhalation of 400 mcg of aclidinium has a 12-hour duration of action and is thus taken twice daily. Daily inhalation of tiotropium has been shown not only to improve functional capacity of patients with COPD, but also to reduce the frequency of exacerbations of their condition. These drugs have not yet been approved as maintenance treatment for asthma, but the addition of tiotropium is no less effective than addition of an LABA in asthmatic patients insufficiently controlled by ICS therapy alone.
Mechanism of Action
Corticosteroids (specifically, glucocorticoids) have long been used in the treatment of asthma and are presumed to act by their broad anti-inflammatory efficacy, mediated in part by inhibition of production of inflammatory cytokines (see Chapter 39).