Ralph Scott

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 cardiovascular effects of mivacurium chloride (BW B1090U) in patients receiving nitrous oxide-opiate-barbiturate anesthesia

The dose-effect relationship of mivacurium chloride on arterial blood pressure, heart rate, and plasma histamine was determined in 97 consenting ASA physical status I-II patients receiving nitrous oxide-oxygen-opiate-barbiturate anesthesia. In the absence of surgical stimulation during steady state anesthetic conditions with controlled ventilation, average maximum change in tachograph-counted heart rate was 7% or less after 10-15-s injection of mivacurium at all doses from 0.03 to 0.30 mg/kg. Average peak change in mean arterial pressure measured via radial arterial catheter was 7% or less after all doses from 0.03 to 0.15 mg/kg. Transient (0.2-4.5 min) decreases in arterial blood pressure were noted after 10-15-s injection in some patients at 0.20, 0.25, and 0.30 mg/kg. When they occurred, these changes were usually accompanied by facial erythema lasting 2-5 min and were correlated with increases in plasma histamine level (P less than 0.001). Facial erythema, decrease in blood pressure, and elevation of histamine level were all accentuated by increasing the dose of mivacurium and by more rapid injection of the drug. For example, mean blood pressure decreased an average of 13% after injection of mivacurium 0.25 mg/kg over 10-15 s. In contrast, during administration over 30 and 60 s of this dose, arterial pressure decreased 7.6 and 1.5%, respectively (P less than 0.001, 10-15 s vs. 60-s injection). Average peak histamine level, which increased to 132% of control after administration of 0.25 mg/kg over 10-15 s, did not change after injection over 60 s.(ABSTRACT TRUNCATED AT 250 WORDS)

Structure-activity relationships: from tubocurarine to the present day

Summary Many of the structural features of neuromuscular blocking agents that determine activity at the cholinergic nicotinic receptor at the motor endplate were established by the 1960s. The important features were: 1. The presence of two ammonium groups, one of which should be quaternary. 2. The incorporation of the nitrogen atom of these amine groups into an aromatic ring structure. 3. An optimum interonium distance, within certain limits, of 1.4 nm. 4. The presence of either ester groups in the interonium linkage to encourage enzymatic breakdown, or structural features that ensure rapid plasma clearance, to limit duration of action. More recent work has focused upon two particular series of bisquaternary compounds, the bisbenzylisoquinolinium diesters and the 2,16-androstane derivatives, which are relatively free of unwanted cardiovascular sideeffects. Modification of these compounds has given us clinically useful intermediate and long-acting agents. Mivacurium looks promising as a short-acting agent. However, we still do not have an ultrashort-acting non-depolarizing agent with as rapid an onset as suxamethonium, and theoretical considerations suggest that this may be a difficult goal. New approaches with alternative compounds provide reason for optimism that this ideal may yet be achieved.