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

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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.

Original languageEnglish (US)
Pages (from-to)44-52
Number of pages9
JournalBritish Journal of Pharmacology
Volume163
Issue number1
DOIs
StatePublished - May 2011

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Folklore
Muscarinic Antagonists
Muscarinic Receptors
Chronic Obstructive Pulmonary Disease
Asthma
Pharmacology
Pharmaceutical Preparations
Acetylcholine
Muscarinic M3 Receptors
Lung
Adrenergic Agonists
Airway Management
Cholinergic Antagonists
Coma
Smooth Muscle
Mouth
Therapeutics

Keywords

  • aclidinium
  • airway hyperreactivity
  • CHF 5407
  • glycopyrrolate
  • ipratropium
  • M2 muscarinic receptors
  • tiotropium

ASJC Scopus subject areas

  • Pharmacology

Cite this

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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.",
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