A mechanism for rapacuronium-induced bronchospasm: M2 muscarinic receptor antagonism.
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 Rapacuronium, which sought to fulfill these criteria, was withdrawn from clinical use due to a high incidence of bronchospasm resulting in death.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.
Jooste
Edmund
E
Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, P & S Box 46, New York, New York 10032, USA.
Klafter
Farrah
F
Hirshman
Carol A
CA
Emala
Charles W
CW
D000818:Animals; D001279:Atracurium / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects; D001986:Bronchial Spasm / Q000139:chemically induced* / Q000503:physiopathology; D016466:CHO Cells; D002462:Cell Membrane / Q000187:drug effects; D006224:Cricetinae; D003959:Diamines / Q000494:pharmacology; D007202:Indicators and Reagents; D018727:Muscarinic Antagonists; D003473:Neuromuscular Nondepolarizing Agents / Q000633:toxicity*; D010880:Piperidines / Q000494:pharmacology; D011813:Quinuclidinyl Benzilate / Q000494:pharmacology; D011869:Radioligand Assay; D043585:Receptor, Muscarinic M2; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic / Q000187:drug effects*; D014673:Vecuronium Bromide / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity*
D003959:Diamines; D007202:Indicators and Reagents; D018727:Muscarinic Antagonists; D003473:Neuromuscular Nondepolarizing Agents; D010880:Piperidines; D043585:Receptor, Muscarinic M2; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic; D001279:Atracurium; D011813:Quinuclidinyl Benzilate; D014673:Vecuronium Bromide; C042375:4-diphenylacetoxy-1,1-dimethylpiperidinium; C082938:rapacuronium; C054938:methoctramine