Muscarinic receptor antagonists, from folklore to pharmacology; finding drugs that actually work in asthma and COPD

Abstract

In the lungs, parasympathetic nerves provide the dominant control of airway smooth muscle with release of acetylcholine onto M3 muscarinic receptors. Treatment of airway disease with anticholinergic drugs that block muscarinic receptors began over 2000 years ago. Pharmacologic data all indicated that antimuscarinic drugs should be highly effective in asthma but clinical results were mixed. Thus, with the discovery of effective β-adrenergic receptor agonists the use of muscarinic antagonists declined. Lack of effectiveness of muscarinic antagonists is due to a variety of factors including unwanted side effects (ranging from dry mouth to coma) and the discovery of additional muscarinic receptor subtypes in the lungs with sometimes competing effects. Perhaps the most important problem is ineffective dosing due to poorly understood differences between routes of administration and no effective way of testing whether antagonists block receptors stimulated physiologically by acetylcholine. Newer muscarinic receptor antagonists are being developed that address the problems of side effects and receptor selectivity that appear to be quite promising in the treatment of asthma and chronic obstructive pulmonary disease.

Figure 1

Muscarinic receptors in lungs. Muscarinic receptors (MR) are present throughout the lungs and control smooth muscle contraction, gland secretion, acetylcholine (ACh) release from parasympathetic nerves and probably also inflammatory cells. Only receptors with dominant physiological effects are shown, thus for example M2 receptors in airway smooth muscle are not included. The major physiological source of ACh is from postganglionic parasympathetic nerves that supply both muscle and glands (1); ACh release is normally limited by M2 receptors on these nerves. However, muscarinic receptors are distributed throughout smooth muscle and can be stimulated by exogenous acetylcholine administered i.v. or by inhalation (2). References are found in the text.

Figure 2

Anticholinergic drugs in asthma and chronic obstructive pulmonary disease.