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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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