N. Sunder

The Clinical Neuromuscular Pharmacology of Mivacurium Chloride (bw B1090u). A Short-acting Nondepolarizing Ester Neuromuscular Blocking Drug

Mivacurium chloride (BW B1090U), a bis-benzylisoquinolinium diester compound, was found to undergo hydrolysis in vitro by purified human plasma cholinesterase in a pH-stat titralorat 88% of the rate of succinylcholine at pH 7.4,37°C and 5 μM substrate concentration. In 72 consenting ASA Physical Status I-II patients receiving nitrous oxide/oxygen-narcotic-thiopental anesthesia, the neuromuscular blocking effect of mivacurium was assessed following bolus doses from 0.03 to 0.30 mg/kg, as well as during and following continuous infusions from 35 to 324 min in length. The calculated ED95 for inhibition of adductor pollicis twitch evoked at 0.15 Hz was 0.08 mg/kg. At 0.1 mg/kg, 96% block developed, onset to maximum block required 3.8 ± 0.5 min, and recovery to 95% twitch height occurred 24.5 ± 1.6 (SE) min after injection. At 0.25 mg/kg, onset was 2.3 ± 0.3 min; 95% recovery developed within 30.4 ± 2.2 min, an increase in duration of action of only 24% versus 150% higher dosage. Comparative recovery indices from 5 to 95% or from 25 to 75% twitch heights did not differ significantly among all dosage groups from 0.1 to 0.3 mg/kg (range 12.9 to 14.7 and 6.6 to 7.2 min, respectively). In 38 patients who received mivacurium by continuous infusion (duration 88.1 ± 7.1/47.1 min, SE/SD) for maintenance of 95 ± 4% twitch inhibition, the mean 5–95% and 25–75% recovery indices after discontinuation of infusion were 14.4 ± 0.6 and 6.5 ± 0.3 min (P > 0.5 vs. all single bolus doses). The train-of-four (T4) ratio, within 2.6 ± 0.5 min after 95% twitch recovery following bolus doses, averaged 79.5 ± 1.8% (n = 32). Similarly, after discontinuation of infusions, the T4 ratio reached 73.4 ± 1.9% within 3.4 ± 1.9 min after 95% twitch recovery (n = 33). Antagonism of residual block was seldom indicated, but, to test case of reverals, eight patients electively received ncostigmine (0.06 mg/kg) with atropine (0.03 mg/kg) at 67 to 93 (76.6 ± 3.5) % block. Twitch returned to 95% of control within 4.5 to 9.5 (6.3 ± 0.5) min after neostigmine. Mivacurium may offer increased versatility in providing clinical muscle relaxation in a variety of situations. Further studies seem appropriate.

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.

Clinical Pharmacology of Atracurium Given in High Dose

The safety and efficacy of atracurium 0.8 mg kg-1 was determined in healthy patients with particular attention to the speed of onset of blockade, and to changes in haemodynamic variables. Atracurium 0.8 mg kg-1 had a shorter onset time than atracurium 0.5 mg kg-1, and satisfactory intubating conditions were achieved earlier. Priming produced no significant improvement in onset time or intubating conditions. Onset times were significantly shorter with nitrous oxide-opioid anaesthesia than following thiopentone alone. Although a 0.8-mg kg-1 bolus resulted in a significant reduction in mean arterial pressure to 75% of control and was associated with a significant increase in plasma histamine concentrations, this response could be prevented by injecting the drug over 75 s. Priming or a 30-s injection produced no haemodynamic protection. The protection achieved by pretreatment with anti-histamines was incomplete: mean arterial pressure decreased to 83% of control.