S. J. Basta

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)

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.

Clinical Pharmacology of Doxacurium Chloride A New Long-acting Nondepolarlzlng Muscle Relaxant

Doxacurium chloride (BW A938U) is a bis-quaternary benzyl-isoquinolinium diester nondepolarizing neuromuscular blocking compound that is minimally hydrolyzed by human plasma cholinesterase. The effect of bolus doses of doxacurium ranging from 10 to 80 Mg/kg were studied in 81 consenting ASA physical status I and II patients anesthetized with nitrous oxide-oxygenfentanyl-thiopental. The neuromuscular and cardiovascular effects of doxacurium were compared with those of eight patients receiving 100 μg/kg of pancuronium receiving identical anesthesia. The calculated ED95 for evoked twitch inhibition of the adductor pollicis at 0.15 Hz was 30 μg/kg. At 1.3 times the EDg5 dose of doxacurium, recovery times to 5% and 25% of control twitch height were 59.2 ± 4.1 (n = 23 of 26) and 75.7 ± 5.6 (n = 23 of 26) min respectively. For pancuronium comparable recovery times were 81.7 ± 10.3 (n = 8 of 8) and 83.0 ± 8.4 (n = 5 of 8) min. Residual doxacurium blockade was readily antagonized by neostigmine. No dose-related effect on heart rate or mean arterial pressure was seen with doxacurium at doses up to and including 2.7 times the ED95 (80 μg/kg). Doxacurium administration did not result in any elevation of plasma histamine at doses up to and including 2.7 times the ED05. In this study doxacurium appears to be a long-acting nondepolarizing relaxant with readily reversible neuromuscular blocking effects and devoid of cardiovascular effects. This profile offers clinical advantages over current long-acting agents and further clinical trials seem appropriate.

Pharmacokinetics and Pharmacodynamics of Doxacurium in Young and Elderly Patients During Isoflurane Anesthesia

Preliminary disposition studies of the investigational, long-acting muscle relaxant doxacurium chloride (Nuromax) have demonstrated dual elimination by renal and hepatobiliary pathways, as well as slow hydrolysis by plasma cholinesterase. The present study compares the kinetics and dynamics of doxacurium in eight ASA physical status I or II elderly patients (67–72 yr of age) and eight ASA I or II young patients (22–49 yr of age). After institutionally approved written informed consent, kinetic and dynamic measurements were made after a 25-μg/kg bolus injection of doxacurium during 1.25 MAC nitrous oxide/oxygen/ isoflurane anesthesia. Maximum twitch depression was similar in older patients (96.4% ± 1.3%) to that in the young patients (96.6% ± 1.8%). The time to achieve this level of block was significantly longer in the elderly than in the young (11.2 ±1.1 min versus 7.7 ±1.0 min, respectively). Recovery times to twitch heights of 5% and 25% of control tended to be prolonged and were more variable in the elderly (82.6 ± 17.2 and 97.1 ± 20.1 min, respectively) than in the young (54.8 ± 9 and 67.5 ± 8.2 min, respectively). Elimination half-life (96 ± 20 min) and clearance (2.47 ± 0.69 mL-kg−1-min−1) in the elderly patients were not statistically different from values found in the younger group. Volume of distribution at steady state in the elderly (220 ± 80.2 mL/kg) was significantly larger than in the young (150 ± 40.0 ml/kg). Renal excretion of unchanged drug was an important route of elimination, accounting for 24% of the dose in the elderly and 31% in the young. The observed pharmacokinetic and dynamic profile suggests that doxacurium may be given in a similar dosage regimen to both young and elderly patients.

Clinical pharmacology of mivacurium chloride: A review salvatore

Mivacurium chloride (Mivacron) is a new benzylisoquinolinium choline-like diester neuromuscular blocking drug with an onset of action at equipotent doses that is comparable to atracurium and vecuronium but slower than succinylcholine. Its clinical duration (injection-25% recovery and injection-95% recovery) is twice that of succinylcholine but one-half to one-third that of atracurium and vecuronium. Mivacurium is easy to use as a continuous infusion and when used this way its recovery characteristics are unchanged. It is readily antagonized by anticholinesterase drugs. The ED95 in adults under narcotic-based anesthesia is 0.07-0.08 mg/kg. At twice the ED95 (0.15 mg/kg) onset time is about 2 to 3 minutes, duration to 25% recovery is 15 to 20 minutes, and 5-95% recovery time about 14 minutes. The mean infusion rate in adults is 6 micrograms/kg/min (range 2-15) with a 5-95% recovery time of 14 minutes. Enflurane and isoflurane require a 20-30% decrease in dosage; halothane, enflurane, and isoflurane prolong the duration of mivacurium 25-30%. The ED95 in children 2 to 12 years of age is slightly higher (0.09-0.11 mg/kg) with a faster onset and shorter duration. In these young patients, a dose of 0.2 mg/kg has an onset comparable to succinylcholine. Being chemically related to atracurium, mivacurium may cause histamine release. When administered rapidly at doses of 0.2 mg/kg or greater in adults, histamine release and transient hypotension have been observed. Doses of 0.2 mg/kg or higher are not recommended by the manufacturer. Mivacurium is metabolized by plasma cholinesterase. In vitro, the rate is about 70% that of succinylcholine. In patients with normal or slightly less than normal plasma cholinesterase activity, no prolonged durations of action have been observed. In patients heterozygous for the atypical gene and at a dose of 0.2 mg/kg, 50% prolongation has been shown. Those individuals homozygous for the atypical gene are exquisitely sensitive to mivacurium and have a markedly prolonged blockade that is readily reversible. In these patients and those with acquired deficiencies, mivacurium should not be used. The duration of action in elderly patients is comparable to that in the young, while in prerenal transplant patients, its duration is prolonged by about 50%, and in prehepatic transplant patients, duration of block is increased threefold. Mivacurium possesses the advantages of short duration, unchanged recovery characteristics following infusions (without phase II block or tachyphylaxis), and precise control.(ABSTRACT TRUNCATED AT 250 WORDS)

Histamine release by neuromuscular blocking agents in man

SummarySeveral experimental and clinical studies have suggested that histamine is released following the administration of neuromuscular blocking agents, and that the histamine release is an important aspect in the hemodynamic response to the drug. We have measured plasma histamine following the administration of a series of neuromuscular blocking agents in man. Our data suggests that members of this class of drugs can cause a dose dependent release histamine release in man and that this release is hemodynamically significant. We have also evaluated the roles of rate of administration, of pretreatment with H1 and H2 antagonists and alterations in drug design as clinical strategies in attenuating the adverse reactions.The data obtained in humans can be shown to validate the cat model as a means of screening novel neuromuscular blocking agents.ZusammenfassungMehrere experimentelle und klinische Studien haben angedeutet, daß Histamin bei Gabe von neuromuskulär blockierenden Agentien freigesetzt wird und diese Histaminfreisetzung ein wichtiger Aspekt in der hämodynamischen Reaktion auf dieses Arzneimittel ist. Wir haben Plasmahistaminbestimmungen nach Gabe von einer Reihe neuromuskulär blockierender Agentien beim Menschen durchgeführt. Unsere Daten weisen darauf hin, daß einige Mittel dieser Arzneimittelklasse eine dosisabhängige Histaminfreisetzung bei Menschen bewirken und diese Freisetzung von hämodynamischer Bedeutung ist. Wir haben ebenfalls die Rolle der Art der Verabreichung, der Vorbehandlung mit H1- und H2-Rezeptorantagonisten und die Veränderungen im Arzneimitteldesign als klinische Strategien zur Verminderung der Nebenwirkungen geprüft.Die erhaltenen Daten beim Menschen können zur Validierung des Modells bei Katzen als eine Art Screeningmodell von neuromuskulär blockierenden Agentien angesehen werden.

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.

Effects of Paralysis with Pancuronium on Chest Wall Statics in Awake Humans

The influence of tonic inspiratory muscle activity on the relaxation characteristics of the chest wall, rib cage (RC), and abdominal wall (ABW) has been investigated in four highly trained subjects. Chest wall shape and volume were estimated with magnetometers. Pleural pressure (Pes) and abdominal pressure were measured with esophageal and gastric balloons, respectively. Subjects were seated reclining 30 degrees from upright, and respiratory muscle weakness was produced by pancuronium bromide until RC inspiratory capacity was decreased to 60% of control. Only minor changes were observed for Konno-Mead relaxation characteristics (RC vs. ABW) between control and paralysis. Similarly, although RC relaxation curves (RC vs. Pes) during paralysis were significantly different from control (P less than 0.05), the changes were small and not consistent. The differences between paralysis-induced changes in resting end-expiratory position of the chest wall and helium-dilution functional residual capacity (FRC) suggested changes in volume of blood within the chest wall. We conclude that 1) although tonic inspiratory activity of chest wall muscles exists, it does not significantly affect the chest wall relaxation characteristics in trained subjects; 2) submaximal paralysis produced by pancuronium bromide is likely to modify either spinal attitude or the distribution of blood between extremities and the thorax; these effects may account for the changes in FRC in other studies.