ANTIMUSCARINIC AGENTS
Observation
of the use of leaves from Datura
stramonium for asthma treatment in India led to the discovery of atropine,
a potent competitive inhibitor of acetylcholine at postganglionic muscarinic
receptors, as a bronchodilator. Interest in the potential value of
antimuscarinic agents increased with demonstration of the importance of the
vagus nerves in bronchospastic responses of laboratory animals and with the
development of a potent atropine analog that is poorly absorbed after aerosol
administration and is therefore relatively free of systemic atropine-like
effects.
Muscarinic
antagonists competitively inhibit the effect of acetyl-choline at muscarinic
receptors . In the airways, acetylcholine is released from efferent endings of
the vagus nerves, and muscarinic antagonists block the contraction of airway
smooth muscle and the increase in secretion of mucus that occurs in response to
vagal activity (Figure 20–2). Very high concentrations—well above those achieved
even with maximal therapy—are required to inhibit the response of airway smooth
muscle to nonmuscarinic stimulation. This selectivity of muscar-inic
antagonists accounts for their usefulness as investigative tools in examining
the role of parasympathetic pathways in broncho-motor responses but limits
their usefulness in preventing broncho-spasm. In the doses given,
antimuscarinic agents inhibit only that portion of the response mediated by
muscarinic receptors, which varies by stimulus, and which further appears to
vary among indi-vidual responses to the same stimulus.
Antimuscarinic
agents are effective bronchodilators. When given intravenously, atropine, the
prototypical muscarinic antagonist, causes bronchodilation at a lower dose than
that needed to cause an increase in heart rate. The selectivity of atropine’s
effect can be increased further by administering the drug by inhalation or by
use of a more selective quaternary ammonium derivative of atropine, ipratropium bromide. Ipratropium can be
delivered in high doses by this route because it is poorly absorbed into the
circulation and does not readily enter the central nervous system. Studies with
this agent have shown that the degree of involvement of parasympathetic
path-ways in bronchomotor responses varies among subjects. In some,
bronchoconstriction is inhibited effectively; in others, only modestly. The
failure of higher doses of the muscarinic antagonist to further inhibit the
response in these individuals indicates that mechanisms other than
parasympathetic reflex pathways must be involved.
Even
in the subjects least protected by this antimuscarinic agent, however, the
bronchodilation and partial inhibition of pro-voked bronchoconstriction are of
potential clinical value, and antimuscarinic agents are valuable for patients
intolerant of inhaled β-agonist agents. Although antimuscarinic drugs
appear to be slightly less effective than β-agonist agents in reversing asth-matic
bronchospasm, the addition of ipratropium enhances the bronchodilation produced
by nebulized albuterol in acute severe asthma.
Ipratropium
appears to be at least as effective in patients with COPD that includes a
partially reversible component. A longer-acting, selective antimuscarinic
agent, tiotropium, is approved as a
treatment for COPD. It binds to M1, M2, and M3
receptors with equal affinity, but dissociates most rapidly from M2
receptors, expressed on the efferent nerve ending. This means that tiotropium
does not inhibit the M2-receptor–mediated auto–down-regulation of
acetylcholine release, and thus confers a degree of receptor selectivity.
Tiotropium is also taken by inhalation, and a single dose of 18 mcg has 24-hour
duration of action. 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, and tiotropium is approved bythe FDA as a
treatment for COPD. It has not been approved as a treatment for asthma, but the
addition of tiotropium has recently been shown to be as effective as the
addition of a long-acting β-agonist in asthmatic patients insufficiently
controlled by inhaledcorticosteroid therapy alone.
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