Paradoxical antagonism of neuromuscular block by vecuronium metabolites.
Vecuronium is hydrolyzed in the body to 3-deacetyl (ORG 7268), 17-deacetyl (ORG NC58), and 3, 17-bis-deacetyl (ORG 7402) derivatives. Interactions of vecuronium and these metabolites were studied in phrenic nerve-hemidiaphragm preparations of rats. As already reported, ORG 7268 had a potent neuromuscular blocking action, and ORG NC58 and ORG 7402 had a weak neuromuscular blocking action. As expected, ORG 7268 increased the degree of neuromuscular block by vecuronium. However, a low concentration (10 microM) of ORG NC58 and ORG 7402 reversed the block by vecuronium. At a high concentration (50 microM), ORG NC58 and ORG 7402 increased the degree of block by vecuronium. Although we do not have enough data to explain these paradoxical reversal of neuromuscular block at this moment, we postulate that these results reflect the interaction between "slow" and "fast" competitive antagonists. Regardless of the mechanism, it should be emphasized that the concentrations of ORG NC58 and ORG 7402 which are necessary to reverse the block are much lower than those which facilitate the block. It is conceivable that this paradoxical reversal of the block occurs in experimental and clinical situations. Therefore, in determining the neuromuscular blocking action of a compound, the "antagonistic" effect of its metabolites should also be considered.
Ohta
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D000818:Animals; D001711:Biotransformation; D003964:Diaphragm / Q000502:physiology; D004347:Drug Interactions; D004558:Electric Stimulation; D018738:Hexamethonium; D006584:Hexamethonium Compounds / Q000494:pharmacology; D008297:Male; D009388:Neostigmine / Q000494:pharmacology; D009466:Neuromuscular Blocking Agents / Q000494:pharmacology*; D009469:Neuromuscular Junction / Q000187:drug effects / Q000502:physiology*; D010197:Pancuronium / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D010791:Phrenic Nerve / Q000502:physiology; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship; D014673:Vecuronium Bromide / Q000031:analogs & derivatives
D006584:Hexamethonium Compounds; D009466:Neuromuscular Blocking Agents; D009388:Neostigmine; D018738:Hexamethonium; C047941:17-deacetylvecuronium; C047943:3,17-bis-deacetylvecuronium; C047940:3-deacetylvecuronium; D014673:Vecuronium Bromide; D010197:Pancuronium