The Clinical Pharmacology of BW A444U A Nondepolarizing Ester Relaxant of Intermediate Duration

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Abstract
The clinical pharmacology of BW A444U, [p-phenylene diacrylic acid bis-benzylisoquinolinium diester], a nondepolarizing ester relaxant, was evaluated in 56 consenting ASA [American Society of Anesthesiologists] class I subjects under N2O/O2 fentanyl-thiopental anesthesia. Using repetitive train-of-four stimulation, the ED95 [95% effective dosage] for inhibition of the first twitch in the train (T1) was 0.11 mg/kg. At 0.12 mg/kg, 97% inhibition of T1 developed within 4.6 .+-. 0.6 (SE [standard error of the mean]) min from injection; recovery of T1 to 95% of the control height occurred within 52.3 .+-. 3.1 min. In a comparative group of subjects given 0.5 mg/kg d-tubocurarine, onset and depth of block were not significantly different, but the duration of recovery of T1 to 75% of control was at least 3 times longer (P < 0.001). The duration of BW A444U-induced block therefore may be classified as intermediate between d-tubocurarine and succinylcholine. There was little cumulative effect, since 5-25 and 25-75% recovery times did not vary significantly on either repetitive or increasing dosage, perhaps because BW A444U is hydrolyzed relatively slowly in vitro by human plasma cholinesterase, at 5.4% the rate of succinylcholine. Consistent with these observations, at the ED100 [100% effective dosage] (0.2 mg/kg) there was a significant inverse linear correlation between the duration of block and plasma cholinesterase activity. Neuromuscular block by BW A444U was antagonized readily by neostigmine. No changes in arterial pressure or heart rate were noted at up to 0.12 mg/kg (97% block). At higher dosages (0.16-0.20 mg/kg), brief (2-5 min), moderate decreases in mean arterial pressure, slight increases in heart rate, and facial erythema were observed occasionally. These changes correlated well with small increases in serum histamine. Apparently, nondepolarizing relaxants of intermediate duration of action may be produced from ester materials slowly hydrolyzed by plasma cholinesterase, and BW A444U may have certain clinical pharmacologic advantages over current nondepolarizing relaxants.