Inhibition of histamine N-methyltransferase (HNMT) in vitro by neuromuscular relaxants.

There have been reports of hypotension and flushing following vecuronium administration. The etiology of these symptoms, which are similar to those of histamine release, is not clear. The steroidal neuromuscular relaxants (NMRs), unlike muscle relaxants structurally similar to curare, have been shown not to cause histamine release after the administration of typical clinical doses. Histamine levels in plasma reflect a balance between release and catabolism. In humans, histamine N-methyl-transferase (HNMT) is the enzyme primarily degrading for histamine. Therefore, we performed in vitro kinetic studies of purified HNMT to determine the effects of the steroidal and curare-like NMRs and also of gallamine on histamine catabolism. We demonstrated that all NMRs tested were inhibitors of HNMT in vitro. The inhibition was competitive with respect to the cosubstrate S-adenosyl-L-[3H-methyl] methionine, and noncompetitive with respect to histamine. The rank order of inhibition was vecuronium greater than pancuronium greater than gallamine greater than d-tubocurarine greater than metocurine greater than atracurium greater than pipecuronium, with Ki values ranging from 1.2 to 44.8 microM. Our data suggest that HNMT-based radioenzymatic assays for histamine should be susceptible to inhibition by concurrent use of NMRs, particularly vecuronium.

Comparative evaluation of the neuromuscular and cardiovascular effects of pipecuronium, pancuronium, atracurium, and vecuronium under isoflurane anesthesia.

The neuromuscular and cardiovascular effects of intubating doses of pipecuronium 80 micrograms/kg, pancuronium 100 micrograms/kg, atracurium 500 micrograms/kg, and vecuronium 100 micrograms/kg were compared in 62 patients under isoflurane (end-tidal concentration = 0.5-1%) anesthesia. Pipecuronium, pancuronium, and vecuronium had no significant effect on systolic or diastolic blood pressure. In one patient the administration of atracurium resulted in significant hypotension. Heart rate was significantly increased only after the administration of pancuronium. The neuromuscular-blocking effect of pipecuronium and pancuronium appears to be twice as long as that of vecuronium and atracurium. Administration of neostigmine resulted in significantly faster recovery of muscle function in patients receiving vecuronium or atracurium. Although pipecuronium's neuromuscular-blocking effect is similar to that of pancuronium, its lack of cardiovascular effects more closely resembles that of vecuronium.

Comparison of the onset, spontaneous recovery and train of four fade of the clinical neuromuscular block produced by pancuronium and pipecuronium.

The following study was performed to delineate the possible differences in the onset, recovery and "train of four" (TOF) fade characteristics of pancuronium (Pan) and pipecuronium (Pip). Eighty adult American Society of Anesthesiologists (ASA) class I and II surgical patients were studied with institutional approval. After premedication, general anesthesia was induced with thiopental sodium i.v. followed by N2/O2 halothane and fentanyl. The lungs were ventilated. Normocarbia and normothermia were maintained. Two groups of 40 patients received pancuronium (0.1 mg/kg i.v.) or pipecuronium (0.07 mg/kg i.v.). Neuromuscular block (NMB) was measured simultaneously by mechanomyography (MMG) and electromyographically (EMG) on the thumb adductor muscle. Supramaximal (TOF) stimuli were applied to the ulnar nerve every 20 seconds. The onset of neuromuscular blocking action, duration of action (to 25% recovery of twitch response). TOF fade during onset and up to 25% T1 response recovery, hemodynamic changes following induction of anesthesia and after the muscle relaxant and subsequent oral intubation were determined. Mean values and the differences in the two treatments groups were statistically analyzed. The onset of action of the two agents were similar: 3.62 +/- 0.02 minutes (MMG) and 4.94 +/- 0.05 minutes (EMG, Pan) and 3.74 +/- 0.02 minutes (MMG) and 4.36 +/- 0.012 minutes (EMG, Pip). TOF fade ratios during the onset phase were similar. TOF fade at the 25% twitch responses recovery level was 100% with the MMG responses and (96% (Pan) and 94.8% (Pip) with the EMG responses at the 25% twitch response recovery level. Hemodynamic changes were similar after the single dose administration of the bolus administration of the two NMB agents.(ABSTRACT TRUNCATED AT 250 WORDS)

Antagonism of non-depolarising neuromuscular blockade by aminopyridines in cats.

The antagonism of pipecuronium- and vecuronium-induced neuromuscular blockade by 4-aminopyridine (4AP), 3,4-diaminopyridine (3,4AP) and 3-[(dimethylamino)-carbonyl] amino-4-aminopyridine (LF14) were studied in anaesthetized cats during constant infusion of the relaxants. Aminopyridines were administered cumulatively at steady state 90% block level. The ED50 values of 4AP, 3,4AP and LF14 were 243, 106 and 254 micrograms kg-1 in pipecuronium, and 232, 195 and 235 micrograms kg-1 in vecuronium blockade. It has been assumed that in cats the anticurare effect of aminopyridines is mainly a result of K+ channel blockade on motor nerve terminals which enhances the evoked release of acetylcholine.

The effect of non-depolarizing neuromuscular blocking agents on the release of acetylcholine from the right atrium of the guinea pig.

The effect of various non-depolarizing neuromuscular blocking agents (gallamine, pancuronium, vecuronium, d-tubocurarine, metocurine, atracurium and pipecuronium) on [3H]acetylcholine release in the response to field electrical stimulation was investigated in vitro in preparations of the guinea pig right atrium. In this preparation, atropine enhanced and oxotremorine, a muscarinic agonist, reduced the release of [3H] acetylcholine. Atropine reversed the inhibitory effect of oxotremorine in a concentration dependent manner, indicating that there is negative feedback modulation of acetylcholine release from the vagal nerve. While pancuronium, gallamine and atracurium enhanced the release of [3H]acetylcholine, d-tubocurarine, metocurine, vecuronium and pipecuronium did not affect it. Pancuronium and gallamine also reduced the inhibitory effect of oxotremorine and the Kd value of pancuronium for muscarinic receptors located on cholinergic nerve terminals was 2.31 microM. These findings indicate that pancuronium and gallamine enhanced the release of acetylcholine from the atrial parasympathetic nerve, probably by inhibiting presynaptic muscarinic receptors.

Economic considerations in the use of neuromuscular blocking drugs.

The acceptance of new and increasingly expensive technologies is a major component of the rising costs of health care. While the practice of anesthesia has been relatively immune from the effects of cost containment, it is inevitable that practitioners will have to justify costly practices. Available pharmacoeconomic methods can be applied to the use of all anesthetic drugs, particularly neuromuscular blocking drugs. Cost-effectiveness analysis allows the practicing anesthesiologist to prioritize the use of neuromuscular blocking drugs to maximize their benefit while reducing unnecessary costs.

Effect of pipecuronium and pancuronium on intracranial pressure and cardiovascular parameters in patients with supratentorial tumours.

A prospective, randomised, single blind study was conducted to evaluate and compare the intracranial pressure (ICP) and cardiovascular effects of pipecuronium (PPC) and pancuronium (PNC) in 20 patients undergoing supratentorial surgery. Patients were randomly divided into two groups. Patients in Group I (n = 10) received pancuronium (0.1 mg kg(-1)) and in Group II (n = 10) pipecuronium (0.07 mg kg(-1)) for intubation. Intracranial pressure (ICP), heart rate (HR), systolic, diastolic and mean arterial pressures (SAP, DAP, MAP), central venous pressure (CVP), nasopharyngeal temperature and arterial blood gases (ABG) were monitored at the following time periods: before induction (0 minutes); 3 minutes after thiopentone and muscle relaxant; immediately after intubation; and 4, 6, 8, 10, 20 and 30 minutes following intubation. The rise in intracranial pressure at intubation was significantly greater in group I (21.10+/-3.97 torr, 122.59%) when compared to group II patients (1.80+/-0.70 torr, 10.04%) (p<0.0 1). Cardiovascular parameters also showed a significantly greater degree of rise in group I when compared to group II patients. Heart rate increased by 29+/-6.32 beats min(-1) (33.52%) and systolic arterial pressure by 11.60+/-7.37 torr (9.47%) in group I. These parameters did not change significantly in group II. No significant alterations were observed in the other measured parameters in either of the two groups.

Effects of pipecuronium and pancuronium on cerebrospinal fluid pressure in neurosurgical patients.

Arterial hypertension and/or tachycardia may alter intracranial pressure in neurosurgical patients. We compared the effects of pancuronium 0.1 mg/kg and pipecuronium 0.1 mg/kg given as i.v. bolus on cerebrospinal fluid (CSF) pressure in 2 groups of 10 patients each scheduled for intracranial surgery in the supine position. Before surgery, no patient presented clinical symptoms of elevated intracranial pressure (ICP). Anesthesia was induced and maintained with fentanyl and midazolam. Ventilation with 50% nitrous oxide in oxygen was adjusted to maintain arterial pCO2 at 30-35 mmHg. After induction of anesthesia, CSF pressure was registered via a lumbar subarachnoid catheter before and 3, 5, 10, and 30 min after pipecuronium or pancuronium administration. Hemodynamics were monitored using radial and pulmonary artery catheters. All variables underwent analyses of variance for repeated measures with p < 0.05 considered significant. Mean CSF pressure decreased insignificantly from 15 +/- 5 mmHg (before injection) to 14 +/- 4 mmHg in patients given pipecuronium and from 13 +/- 4 mmHg to 10 +/- 3 mmHg in the pancuronium group without significant differences between the study groups. Heart rate and arterial pressure increased significantly (p < 0.001) in patients given pancuronium but remained stable after pipecuronium. Onset and duration of neuromuscular blockade were comparable between groups. Based on our results, pipecuronium is a safe alternative to pancuronium during neurosurgical procedures in patients without abnormally high intracranial pressure.

[Evaluation of pipecuronium bromide during halothane or enflurane anesthesia--a comparison with pancuronium regarding the optimal dose and the effect of volatile anesthetics on neuromuscular blockade].

Pipecuronium, a new muscle relaxant, was examined in surgical patients in a multi-center cooperative study. Neuromuscular blocking action, circulatory effect and side effects of pipecuronium were investigated in comparison with those of pancuronium bromide. Mechanical twitch responses of adductor pollicis muscle evoked by supramaximal stimulation of the ulnar nerve every ten seconds were recorded. The following results were obtained. 1. Approximately 100% twitch depression was obtained after the administration of pipecuronium 0.04 mg.kg-1. 2. Enflurane and halothane did not influence the onset time and recovery time. But enflurane showed more prolonging effect on the duration of pipecuronium induced block than halothane. 3. No clinically significant changes in heart rate and blood pressure were observed. It was concluded that the minimum of 0.04 mg.kg-1 of pipecuronium is necessary for an initial dose and the maintenance dose of pipecuronium can be reduced under enflurane anesthesia.

[Comparative pharmacokinetics of pipecuronium bromide, pancuronium bromide and vecuronium bromide in anesthetized man].

The pharmacokinetics of pipecuronium bromide was studied in 9 male patients (ASA class 1-2, 20-65 years of age). Following a single intravenous dose of pipecuronium 0.08 mg.kg-1, plasma levels were measured by capillary gas chromatography. Plasma concentration-time curves were evaluated by fitting the data to a bi-exponential equation. The pharmacokinetic parameters of pipecuronium were compared with those of pancuronium (0.08 mg.kg-1) and vecuronium (0.08 mg.kg-1) previously obtained under the same anesthesia (66% N2O, 33% O2 and 1% halothane). With pipecuronium, following pharmacokinetic parameters were obtained; distribution half-life; T1/2 alpha = 3.9 +/- 0.7 min (mean +/- SEM), elimination half-life; T1/2 beta = 102 +/- 12 min, volume of the central compartment; V1 = 95 +/- 13 ml.kg-1, volume of distribution at steady state; Vdss = 264 +/- 41 ml.kg-1, clearance; Cl = 1.8 +/- 0.2 ml.min-1.kg-1. Microconstants of two-compartment open models (k12, k21, k10) were also calculated. Using Mann-Whitney's U-test, these parameters of pipecuronium were compared with those of pancuronium (n = 3) and vecuronium (n = 4). V1 and Vdss of pipecuronium were significantly larger than those of pancuronium (V1; 38 +/- 12 ml.kg-1 and Vdss; 120 +/- 4 ml.kg-1) (both P less than 0.10). Reflecting the larger central volume of pipecuronium, pipecuronium tended to have a larger clearance than that of pancuroniumu (Cl; 1.1 +/- 0.2 ml.min-1.kg-1).(ABSTRACT TRUNCATED AT 250 WORDS)

[Determinations of steroidal muscle relaxants and their metabolites].

Pancuronium, vecuronium and pipecuronium are quaternary ammonium steroidal neuromuscular blocking agents. These drugs are typical nondepolarizing muscle relaxants. The steroidal compounds and/or their metabolites have been determined using mass spectrometry or gas chromatography. In this review, these analytical methods and application of the methods to pharmacokinetics are introduced.

[Evaluation of the action of pipecuronium bromide in patients under halothane anesthesia--a comparison with pancuronium bromide regarding their neuromuscular blocking and cardiovascular effects].

Neuromuscular blocking and circulatory actions of pipecuronium bromide (PPB) were evaluated in patients under halothane-nitrous oxide-oxygen anesthesia in comparison with those of pancuronium bromide (PCB) in a multi-center cooperative study. Twitch tension of the adductor pollicis muscle was elicited by supramaximal stimulation of the ulnar nerve every 10 seconds. The study was performed according to the following 4 steps and the results were obtained. 1) Cumulative administration of 0.01 mg.kg-1 of PPB or PCB resulted in the potency ratio of 1.3:1.0 and the dose response curves of the two agents paralleled with each other. 2) With PPB 0.05 mg.kg-1 or 0.1 mg.kg-1, almost 100% block of the twitch was obtained. Both duration of action and the recovery time were shorter with 0.05 mg.kg-1 group. 3) After the first dose of 0.04 mg.kg-1 when the twitch recovered to 25% of the initial height 0.02 mg.kg-1 was given and this was repeated. Intervals between the doses showed large individual differences and no significant change was observed with repeated doses. 4) Safety of the drug. No significant change in heart rate or blood pressure was observed with PPB but with PCB a significant increase in heart rate was observed. The study revealed that PPB is slightly more potent than PCB and the duration of action is longer, but it has no untoward cardiovascular action in man under halothane anesthesia.

[Clinicopharmacology of Arduan]. / Arduan klinikofarmakológiai vizsgálatok.

The paper presents clinicopharmacological investigations of Arduan carried out in Hungary and in other countries. The aim of the research work is to find an ideal muscle relaxant without side-effects, which are mainly cardiovascular. Pipecuronium bromide (Arduan) is a compound with steroid structure; it has a long duration of action and, most importantly, it does not affect circulation. The properties of pipecuronium bromide will be discussed and compared to those of pancuronium and vecuronium bromide.

Comparative neuromuscular blocking potency of pipecuronium and pancuronium.

The effects of pipecuronium bromide (Pi.) and pancuronium bromide (Pa.) on the contractile response of rat-phrenic nerve diaphragm and frog's musculus rectus abdominis preparation were studied. Pi. and Pa. were found to have a dose-dependent reduction in the contractile response of the tested preparation. Trials were made to estimate the potency of Pi. in a comparison with Pa. In this respect Pi. exhibited a more potent effect than Pa. The duration of action is about twice as long as that of Pa. in equieffective doses. Neostigmine rapidly and completely antagonises the neuromuscular blockade caused by Pi. and Pa.

Comparative haemodynamic alterations induced by pipecuronium and pancuronium.

Haemodynamic effects of pipecuronium bromide (Pi.) and pancuronium bromide (Pa.) were studied on isolated rabbit's heart, guinea pig's tracheal chain as well as the blood pressure in pentobarbital anaesthetized dogs. Pi. induced negative inotropic and chronotropic effects on the isolated rabbit's heart especially in lower concentrations. However, higher concentrations provoked two opposite effects, negative chronotropic and positive inotropic activity. In addition, Pa. in lower concentrations caused positive inotropic and negative chronotropic activity, while higher concentrations induced negative inotropic and chronotropic activity. Cardioinhibitory actions of both tested drugs are not due to either cholinergic or beta 1-adrenergic blocking effect but it may be due to nicotine-like activity. In anaesthetized dogs, i.v. injections of both tested drugs produced a transient decrease in systolic and diastolic pressure in doses above the therapeutic level. This effect may be referred to the partial ganglion blocking effect of both tested drugs.

[The characteristics of the action of nondepolarizing myorelaxants during operations on children with thermal injuries]. / Osobennosti deistviia nedepoliarizuiushchikh miorelaksantov vo vremia operatsii u detei s termicheskoi travmoi.

Effects of nondepolarizing myorelaxants pancuronium, arduan, and tracrium were studied during surgery in 347 children with thermal injuries aged from several months to 15 years. Nondepolarizing myorelaxants are drugs of choice for providing myoplegia in children operated on for thermal injuries. The optimal initial dose of these agents in children with burns is 30-50% higher than the recommended dose and depends on the size of the lesion. For controllable myoplegia, the doses of subsequent injections are to be 1.-5-2 times lowered in comparison with the initial dose. The effects of pancuronium and arduan depend on the hepatorenal function. Tracrium ensures sufficient controllable myorelaxation in children with burns even in cases with hepatorenal dysfunction.

Reversal of pipecuronium bromide with pyridostigmine.

Pipecuronium Bromide (Arduan, Organon, Inc, West Orange) is a long-acting, nondepolarizing neuromuscular blocking agent. The efficacy of pyridostigmine 170 micrograms/kg intravenously (approximately 10 mg/70 kg) for reversing pipecuronium has not been reported. This study was performed to determine the time required to obtain a train-of-four (TOF) ratio of 0.7 after administration of pyridostigmine 140 micrograms/kg at 25% recovery of T1 after pipecuronium-induced neuromuscular blockade. Sixteen, American Society of Anesthesiology (ASA) I or II patients undergoing surgical procedures of at least 90 minutes, requiring intubation and muscle relaxation were included. Neuromuscular blockade was assessed using the Puritan-Bennett/Datex NMT 221 placed for ulnar nerve stimulation. Anesthesia was maintained with a nitrous oxide/narcotic technique and the use of potent inhalational anesthetics was avoided. The mean reversal time was found to be 16.14 minutes, with a minimum of 10.3 minutes and a maximum of 24.3 minutes. The standard error was +/- 1.05 minutes with a variance of 17.68 minutes.

Pipecuronium and pancuronium: comparison of pharmacokinetics and duration of action.

The pharmacokinetics of pipecuronium 0.07 mg kg-1 and pancuronium 0.1 mg kg-1 were compared in 39 ASA class I or II patients. Plasma concentrations of these agents were measured for 6 h following administration, using a sensitive and specific capillary gas chromatographic assay. Concentration v. time data were analysed by non-linear regression and fitted to a two- or three-compartment model as appropriate. Neuromuscular blockade was assessed by measuring the mechanical evoked response of the adductor pollicis muscle to train-of-four stimulation of the ulnar nerve. Pipecuronium had a larger steady-state volume of distribution (Vss) (309 (SD 103) ml kg-1) and greater plasma clearance (Cl) (2.4 (0.6) ml kg-1 min-1) than pancuronium (199 (54) ml kg-1 and 1.5 (0.4) ml kg-1 min-1, respectively). The volumes of the central compartment, distribution and elimination half-lives and mean residence times were similar for both agents and within the range expected for drugs of this type. The durations of action (injection to 25% recovery of twitch tension) of pipecuronium and pancuronium were similar: 98.0 (36.1) min and 117.2 (35.8) min, respectively. We conclude that the time courses of neuromuscular blockade following pipecuronium and pancuronium are similar, despite the differences in Vss and Cl.