Page 368 - Basic _ Clinical Pharmacology ( PDFDrive )

354 SECTION IV Drugs with Important Actions on Smooth Muscle

CNS

Airway

Vagal
afferent

Vagal
efferent

Tissue response cells Sensory receptor
(mast cell or eosinophil)
Inhaled irritant
Mediators from
response cell Mucosa
Lumen
Preganglionic fiber
Transmitter (ACh)
Postganglionic neuron Smooth muscle cells

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; effer-
ent pathways from the central nervous system travel to efferent ganglia. Postganglionic fibers release acetylcholine (ACh), which binds to mus-
carinic 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 mcg of tiotropium or 62.5 mcg of umeclidinium has a 24-hour
have shown that the degree of involvement of parasympathetic duration of action, whereas inhalation of 400 mcg of aclidinium
pathways in bronchomotor responses varies among subjects. This has a 12-hour duration of action and is thus taken twice daily.
variation indicates that other mechanisms in addition to parasym- Daily inhalation of tiotropium has been shown not only to
pathetic reflex pathways must be involved. improve functional capacity of patients with COPD, but also to
Even though the bronchodilation and inhibition of provoked reduce the frequency of exacerbations of their condition. These
bronchoconstriction afforded by antimuscarinic agents are incom- drugs have not yet been approved as maintenance treatment for
plete, their use is of clinical value, especially for patients intolerant asthma, but the addition of tiotropium is no less effective than
of inhaled β agonists. addition of an LABA in asthmatic patients insufficiently con-
Ipratropium appears to be as effective as albuterol in patients trolled by ICS therapy alone.
with COPD who have at least partially reversible obstruction.
Longer-acting antimuscarinic agents, including tiotropium, CORTICOSTEROIDS
aclidinium, and umeclidinium, are approved for maintenance
, M , and M recep-
therapy of COPD. These drugs bind to M 1 2 3 Mechanism of Action
tors with equal affinity, but dissociate most rapidly from M
2
receptors, expressed on the efferent nerve ending. This means Corticosteroids (specifically, glucocorticoids) have long been
that they do not inhibit the M -receptor-mediated inhibition of used in the treatment of asthma and are presumed to act by their
2
acetylcholine release and thus benefit from a degree of receptor broad anti-inflammatory efficacy, mediated in part by inhibi-
selectivity. They are taken by inhalation. A single dose of 18 tion of production of inflammatory cytokines (see Chapter 39).