NEUROMUSCULAR AND VAGAL BLOCKING ACTIONS OF PANCURONIUM BROMIDE, ITS METABOLITES, AND VECURONIUM BROMIDE (ORG NC 45)AND ITS POTENTIAL METABOLITES IN THE ANAESTHETIZED CAT

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Abstract
The neuromuscular and cardiac vagus blocking actions of pancuronium, vecuronium (Org NC 45) and their respective potential hydroxy metabolites were studied in the chloralose-anesthetized cat. Pancuronium was 3 times more potent as a neuromuscular blocker than its 3-hydroxy derivative, 20 times more potent than the 17-hydroxy derivative and 45 times more potent than the 3,17-dihydroxy derivative. The vagal:neuromuscular block ratios measured at 50% inhibition for these compounds were pancuronium 3.0, 3-hydroxy derivative 6.4, 17-hydroxy derivative 1.1 and 3,17-dihydroxy derivative 0.36 (a value greater than unity indicated greater potency at the neuromuscular junction). Vecuronium was 1.4 times more potent than its 3-hydroxy derivative, 24 times more potent than the 17-hydroxy derivative and 72 times more potent than the 3,17-dihydroxy derivative as a neuromuscular blocker. The vagal:neuromuscular block ratios were vecuronium 79.8, 3-hydroxy derivative 40.4, 17-hydroxy derivative 0.85 and 3,17-dihydroxy derivative 0.15. The 3-hydroxy derivative of vecuronium, the most likely 1st metabolite of vecuronium, possessed only slightly less neuromuscular blocking potency than vecuronium, coupled with a high safety margin between neuromuscular and vagal blocking doses. The time-course of its action was not different from that of vecuronium. This potential metabolite is unlikely to give rise to tachycardia in man. It is unlikely that the 17-hydroxy and 3,17-dihydroxy derivatives of vecuronium would be produced in sufficiently great quantities by metabolism from vecuronium to result in either tachycardia or residual neuromuscular blockade.