M. Gionfriddo

Clinical pharmacology of atracurium besylate (BW 33A): a new non-depolarizing muscle relaxant.

Atracurium, a new non-depolarizing neuromuscular blocking agent, was studied in 70 patients anesthetized with fentanyl, thiopental, and nitrous oxide-oxygen. The dose found to produce 95% twitch inhibition (ED95) was 0.2 mg/ kg. The onset time from injection to maximum depression of twitch was 4.0 minutes at this dose; the duration to 95% recovery was 44.1 minutes. Twice the ED95 dose (0.4 mg/kg) had an onset time of 1.7 minutes and a duration of 63.5 minutes. No cardiovascular effects were observed in this dosage range. At higher doses (0.5 and 0.6 mg/kg) arterial pressure decreased 13% and 20% and heart rate increased 5% and 8%, respectively. Sixteen patients received at least four successive doses of atracurium. No clinically significant cumulative effect could be shown when recovery from 25% to 75% of control twitch height was compared for initial and final doses in the series. Atracurium spontaneously decomposes at physiologic pH via the Hofmann elimination reaction and may also undergo ester hydrolysis independent of plasma cholinesterase. These proposed pathways of inactivation may explain the lack of cumulative effect and the drugs intermediate duration of action. Based on the results of this study, atracurium offers several clinical advantages and should undergo more extensive clinical trials.

Safety and efficacy of vecuronium in adolescents and children.

The neuromuscular and cardiovascular effects of vecuronium (Norcuron, ORG NC45) were studied in 40 adolescents (10–17 yr) and children (2–9 yr) anesthetized with 1.5% inspired halothane. Ten adolescents and ten children were given 20 μg/kg incremental doses of vecuronium to establish a cumulative dose-response curve during train-of-four stimulation. The ED95 dose was 56 μ/kg in children and 40 μg/kg in adolescents, children being significantly (P < 0.01) more resistant to the neuromuscular effects of vecuronium than adolescents. Another group of 10 children and 10 adolescents received a bolus dose of 80 μg/kg. This dose provided satisfactory conditions for endotracheal intubation with complete suppression of train-of-four response in all adolescents and children within 2 min. Thereafter, the twitch tension recovered to 5% of control twitch height in 18.5 ± 1.5 min, to 25% in 24.4 ± 1.6 min, and to 95% in 43.3 ± 2.1 min. Vecuronium (20–80 μg/kg) did not significantly alter the heart rate or blood pressure nor did it affect kidney or liver function as assessed by routine clinical laboratory tests. Vecuronium is a useful nondepolarizing neuromuscular blocking agent with a short to intermediate duration of action, which can be used safely in children and adolescents.

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

The clinical pharmacology of BW A444U, a nondepolarizing ester relaxant, was evaluated in 56 consenting ASA class I subjects under nitrous oxide/oxygen-fentanyl-thiopental anesthesia. Using repetitive train-of-four stimulation, the ED95 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) 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 three 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. These properties may be explained at least in part by the finding that 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 (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 to 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.The human neuromuscular pharmacology of BW A444U suggests that nondepolarizing relaxants of intermediate duration of action may be produced from ester materials slowly hydrolyzed by plasma cholinesterase, and that BW A444U may have certain clinical pharmacologic advantages over current nondepolarizing relaxants.