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A mechanism for rapacuronium-induced bronchospasm: M2 muscarinic receptor antagonism.

Publication ,  Journal Article
Jooste, E; Klafter, F; Hirshman, CA; Emala, CW
Published in: Anesthesiology
April 2003

BACKGROUND: A safe and effective ultra-short-acting nondepolarizing neuromuscular blocking agent is required to block nicotinic receptors to facilitate intubation. Rapacuronium, which sought to fulfill these criteria, was withdrawn from clinical use due to a high incidence of bronchospasm resulting in death. Understanding the mechanism by which rapacuronium induces fatal bronchospasm is imperative so that newly synthesized neuromuscular blocking agents that share this mechanism will not be introduced clinically. Selective inhibition of M2 muscarinic receptors by muscle relaxants during periods of parasympathetic nerve stimulation (e.g., intubation) can result in the massive release of acetylcholine to act on unopposed M3 muscarinic receptors in airway smooth muscle, thereby facilitating bronchoconstriction. METHODS: Competitive radioligand binding determined the binding affinities of rapacuronium, vecuronium, cisatracurium, methoctramine (selective M2 antagonist), and 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP; selective M3 antagonist) for M2 and M3 muscarinic receptors. RESULTS: Rapacuronium competitively displaced 3H-QNB from the M2 muscarinic receptors but not from the M3 muscarinic receptors within clinically relevant concentrations. Fifty percent inhibitory concentrations (mean +/- SE) for rapacuronium were as follows: M2 muscarinic receptor, 5.10 +/- 1.5 microm (n = 6); M3 muscarinic receptor, 77.9 +/- 11 microm (n = 8). Cisatracurium and vecuronium competitively displaced 3H-QNB from both M2 and M3 muscarinic receptors but had affinities at greater than clinically achieved concentrations for these relaxants. CONCLUSIONS: Rapacuronium in clinically significant doses has a higher affinity for M2 muscarinic receptors as compared with M3 muscarinic receptors. A potential mechanism by which rapacuronium may potentiate bronchoconstriction is by blockade of M2 muscarinic receptors on prejunctional parasympathetic nerves, leading to increased release of acetylcholine and thereby resulting in M3 muscarinic receptor-mediated airway smooth muscle constriction.

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Published In

Anesthesiology

DOI

ISSN

0003-3022

Publication Date

April 2003

Volume

98

Issue

4

Start / End Page

906 / 911

Location

United States

Related Subject Headings

  • Vecuronium Bromide
  • Receptors, Muscarinic
  • Receptor, Muscarinic M3
  • Receptor, Muscarinic M2
  • Radioligand Assay
  • Quinuclidinyl Benzilate
  • Piperidines
  • Neuromuscular Nondepolarizing Agents
  • Muscarinic Antagonists
  • Indicators and Reagents
 

Citation

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Jooste, E., Klafter, F., Hirshman, C. A., & Emala, C. W. (2003). A mechanism for rapacuronium-induced bronchospasm: M2 muscarinic receptor antagonism. Anesthesiology, 98(4), 906–911. https://doi.org/10.1097/00000542-200304000-00017
Jooste, Edmund, Farrah Klafter, Carol A. Hirshman, and Charles W. Emala. “A mechanism for rapacuronium-induced bronchospasm: M2 muscarinic receptor antagonism.Anesthesiology 98, no. 4 (April 2003): 906–11. https://doi.org/10.1097/00000542-200304000-00017.
Jooste E, Klafter F, Hirshman CA, Emala CW. A mechanism for rapacuronium-induced bronchospasm: M2 muscarinic receptor antagonism. Anesthesiology. 2003 Apr;98(4):906–11.
Jooste, Edmund, et al. “A mechanism for rapacuronium-induced bronchospasm: M2 muscarinic receptor antagonism.Anesthesiology, vol. 98, no. 4, Apr. 2003, pp. 906–11. Pubmed, doi:10.1097/00000542-200304000-00017.
Jooste E, Klafter F, Hirshman CA, Emala CW. A mechanism for rapacuronium-induced bronchospasm: M2 muscarinic receptor antagonism. Anesthesiology. 2003 Apr;98(4):906–911.

Published In

Anesthesiology

DOI

ISSN

0003-3022

Publication Date

April 2003

Volume

98

Issue

4

Start / End Page

906 / 911

Location

United States

Related Subject Headings

  • Vecuronium Bromide
  • Receptors, Muscarinic
  • Receptor, Muscarinic M3
  • Receptor, Muscarinic M2
  • Radioligand Assay
  • Quinuclidinyl Benzilate
  • Piperidines
  • Neuromuscular Nondepolarizing Agents
  • Muscarinic Antagonists
  • Indicators and Reagents