Neuromuscular blocking and cardiovascular effects of Org 9487, a new short-acting aminosteroidal blocking agent, in anaesthetized animals and in isolated muscle preparations

Abstract

This study was undertaken to investigate the neuromuscular blocking profile and cardiovascular effects of Org 9487, a new aminosteroidal, non-depolarizing, neuromuscular blocking agent structurally related to vecuronium, in anaesthetized animals and in isolated muscle preparations. In in vitro functional assays of neuromuscular blocking activity, Org 9487 was between eight and 15 times less potent than vecuronium. In cats and monkeys the potency of Org 9487 was approximately one-seventh and one-twentieth, respectively, that of vecuronium. In both species, Org 9487 induced rapidly developing (onset times between 1.5 min and 1.9 min) neuromuscular paralysis, which was shorter-lasting than that of vecuronium and similar in time course to suxamethonium. The vagal: neuromuscular blocking dose ratio for Org 9487 was 3 and ganglion block was seen only at approximately 20 times the neuromuscular blocking dose. There was no evidence in the rat that Org 9487, administered at doses up to 3 mg kg-1, inhibited noradrenaline re-uptake. In anaesthetized dogs, Org 9487 (3 x 90% blocking dose) induced only relatively small and transient haemodynamic effects. The administration of clinically relevant doses of neostigmine or pyridostigmine shortened the time-course profile of Org 9487, even when administered during profound neuromuscular block. In animals, Org 9487 is a low potency, nondepolarizing neuromuscular blocking agent with a time course profile similar to that of suxamethonium. Although Org 9487 is less selective than vecuronium for the neuromuscular junction, it is unlikely to produce prohibitive cardiovascular side effects in man.

Comparison of intubating conditions after rapacuronium (Org 9487) and succinylcholine following rapid sequence induction in adult patients

“…There is evidence that the incidence of cardiovascular side effects of aminosteroidal neuromuscular blocking drugs increases with decreasing potency as a result of vagolytic effects, calcium channel blocking properties and probably nonimmunological histamine release. [11][12][13] The observed side effects of rapacuronium (tachycardia, hypotension and bronchospasm) may be dose-related and warrant further attention in future studies.…”

Rapacuronium: clinical pharmacology

“…1) and like vecuronium and rocuronium is a monoquaternary compound. The compound was shown to have low potency in several animal species [4]. These also showed the onset of block to be rapid when compared to an equipotent dose of vecuronium, and that the block could be antagonized with neostigmine from relatively deep levels.…”

“…Short‐lasting decreases in arterial, right atrial, pulmonary artery and pulmonary capillary wedge pressures have been observed in beagle dogs and pigs with rapacuronium [4]. The vagal and ganglionic to neuromuscular blocking dose ratios in the cat were determined to be 3 : 1 and 22–24 : 1, respectively, for rapacuronium.…”

In vivo animal studies with sugammadex

“…Development of ultra‐short acting NMBs with only a small variability in time course of action might solve the problem. Many compounds have been synthesised and studied [10–14]. However, none of them has fulfilled the desired profile, and many have caused histamine release or adverse cardiovascular effects, or have even been toxic.…”