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The pharmacokinetics of pipecuronium bromide (Arduan) studied in animals (rat, dog, cat) and in humans can be described by a two-compartment open model. The elimination half-life in animals was found to be around 40 min, in humans between 44-137 min. The main route of elimination is the excretion of the unchanged molecule in urine. In kidney patients the elimination becomes longer. The metabolism in the elimination is less important, in rats 3-hydroxy-, 17-hydroxy and 3,17-dihydroxy metabolites have been identified.

The experimental results in animals suggest that pipecuronium bromide offers the possibility of a neuromuscular blocking agent without side effects for surgical procedures of long duration. Its mechanism of action is twofold: 1. antagonism of acetylcholine effect at neuromuscular junction (postsynaptic nicotine receptors), 2. inhibition of acetylcholine release (presynaptic nicotine receptors). Its neuromuscular blocking potency is somewhat greater (2.0-3.0) than that of pancuronium in all species studied, and the duration of action is twice of that. It has no remarkable cumulative effect. Neostigmine rapidly and completely antagonises the neuromuscular blockade caused by pipecuronium. Certain structural properties (e.g. pipecuronium has no acetylcholine-like fragments in contrast with pancuronium and the interonium distance is also considerably larger than in pancuronium) may predict advantages. This has been proved by low vagal blocking--and ganglion--blocking potencies. On the basis of these a wide margin of safety can be expected in humans as well in preventing cardiovascular side effects. Pipecuronium is also characterized by interactions--only slight interactions--with other drugs used mainly in perioperative period.

Pipecurium bromide, a new non-depolarizing myorelaxant, was administered intravenously, at a dose of 0.06 mg/kg, to 10 patients suffering from expansive endocranial lesions, who had been anesthetised to undergo neurosurgery. The following parameters were recorded simultaneously, before and after drug administration: intracranial pressure, mean arterial blood pressure, central venous pressure, heart rate and end tidal CO2. No statistically significant changes in the above parameters were observed following the administration of the myorelaxant; these observations, which were considered together with the long duration of action, confirm that pipecurium bromide is a valuable tool in anesthesia for neurosurgery.

The dose-response relation of pipecuronium, the time course of its neuromuscular blocking effects, and the reversibility of the residual block by neostigmine have been investigated in patients under sevoflurane/N2O Anesthesia using a neuromuscular transmission analyzer (Accelograph, Biometer, Denmark). After an initial dose of pipecuronium (0.04 mg.kg(-1), i.v.), the maximum block rate, onset time, the time from administration until 25% recovery and 50% recovery of control twitch height of the first response to train-of-four nerve stimulation and the interval time of administration of maintenance dose (0.005 mg.kg(-1), i.v.) were 93.7 +/- 7.68%, 5.0 +/- 1.84, 55.4 +/- 23.92, 73.0 +/- 29.44 and 38.7 +/- 15.50 minutes, respectively. The average intubation score (excellent; 0, good; 1 fair; 2, poor; 3) was 0.63 +/- 0.56 at the level of 95.88 +/- 5.06% block. Neostigmine (1.5 mg) promptly reversed the residual neuromuscular blockade induced by pipecuronium (reversal time: 10.1 +/- 2.98 minutes). No side effects attributable to pipecuronium was seen in this study. In conclusion, pipecuronium is a very useful nondepolarizing neuromuscular blocking agent especially for moderately long surgical procedure over 4-5 hours.

The onset time and tendency to cumulation of pipecuronium and high-dose vecuronium were studied during nitrous oxide anaesthesia supplemented with isoflurane. Pipecuronium 0.06 mg.kg-1 had a similar duration of action to vecuronium 0.015 mg.kg-1 (42 vs 49 min). Patients who received vecuronium had a shorter onset time of neuromuscular blockade (p less than 0.01). The use of pipecuronium was associated with marked cumulation.

Neuromuscular blocking agents provide muscle relaxation for a great variety of surgical procedures with light planes of general anaesthesia. Besides having a significant impact in the development of anaesthesia and surgery, these agents continue to play an important role as pharmacological tools in the elucidation of the physiological and pharmacological regulation of neuromuscular transmission and the morphofunctional organisation of the neuromuscular junction. In the daily practice of anaesthesia, muscle relaxants are considered to be safe drugs with predictable, straightforward pharmacological actions. However, the use of relaxants constitutes a deliberate encroachment on respiration, one of the most important physiological mechanisms. The pharmacokinetic behaviour of this class of agents is little influenced by age or anaesthetic agents; however, hepatic or renal disease may profoundly alter their excretion pattern, resulting in prolonged duration of neuromuscular blockade. Biotransformation plays an important role in the total elimination of recently introduced compounds. Consequently, knowledge of the disposition pharmacokinetics, excretion and biotransformation of this class of drugs is indispensable for their rational choice for various surgical procedures. In this review, the known pharmacokinetics of standard compounds (introduced before 1980) are briefly summarised and new information generated by the development of vecuronium, rocuronium, pipecuronium (steroidal agents) and atracurium, mivacurium, doxacurium (benzylisoquinolinium esters) is discussed in more detail.

The use of pipecuronium in two patients with myasthenia gravis undergoing thymectomy is described. Neuromuscular function was monitored throughout using the train-of-four (TOF) mechanical twitch response. The cumulative dose-response to pipecuronium was determined in both patients during nitrous oxide-oxygen-narcotic anaesthesia. Both patients were sensitive to pipecuronium. The ED50 doses of pipecuronium were 11.6 and 11.1 micrograms.kg-1 and the ED95 doses were 35 and 33.3 micrograms.kg-1 in patients #1 and 2 respectively. Edrophonium 1 mg.kg-1 and neostigmine 0.06 mg.kg-1 were administered to patients #1 and 2 respectively for antagonism of residual neuromuscular blockade at 25 per cent spontaneous recovery of first twitch (T1) of the TOF stimulation. As with other non-depolarizing muscle relaxants pipecuronium in reduced dosage and with careful neuromuscular monitoring can be used to provide surgical relaxation safely in patients with controlled myasthenia gravis.

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.

The neuromuscular and cardiovascular effects of three different doses of pipecuronium were studied in 60 adult patients. Neuromuscular blockade was measured using electromyographic activity of the adductor pollicis muscle after supramaximal stimulation of the ulnar nerve at 0.1 Hz and 2 Hz. Three subgroups (A, B, C) of 20 patients received pipecuronium doses of 60, 80 and 100 micrograms kg-1, respectively, as an intubating dose and, when necessary, maintenance doses were administered at 25% single twitch recovery in a dose of one-quarter of the initial one. The onset time was 5.4 +/- 2.0 min for 60 micrograms kg-1 and similar for 80 and 100 micrograms kg-1 (3.9 +/- 1.1 and 3.6 +/- 1.1 min). The duration of action was 45 +/- 10 min for 60 micrograms kg-1, 74 +/- 25 and 94 +/- 21 for 80 and 100 micrograms kg-1, respectively. The recovery indices were measured in all patients after neostigmine administration (Groups B and C) and after neostigmine and edrophonium (Subgroup A, 10 patients each). TOF ratio was significant only 2 min after edrophonium administration in Group A patients. Variations of heart rate and blood pressure were not significant.

The pharmacodynamics and -kinetics of pipecuronium were studied in 12 patients, six of whom received 100 micrograms kg-1 for laryngectomy (Group L), and six who underwent choledochotomy after insertion of the T-drain and were given 50 micrograms kg-1 (Group C). Onset time and clinical duration were 2.3 and 109 min and 2.8 and 39 min in Groups L and C, respectively. All patients could be sufficiently reversed with neostigmine. Terminal half-lives were 101.5 min (Group L) and 179 min (Group C) in a three-exponent decay; the distribution volumes at steady state 0.339 l kg-1 (Group L) and 0.506 l kg-1 (Group C); the plasma clearance 3.4 ml kg-1 min-1 (Group L) and 2.5 ml kg-1 min-1 (Group C). Within 24 h, 38.6% and 37% were excreted unchanged in the urine and 4.4% and 1% as 3-desacetyl pipecuronium in Groups L and C, respectively. Within 24 h only 2% was excreted into the bile in Group C. Distribution volume and terminal half-life in Group C were positively correlated with pre-operative serum aminotransferase levels (P less than 0.005).

We have examined the effects of a rapid bolus dose of pipecuronium 0.1 mg kg-1 or tubocurarine 0.5 mg kg-1 on plasma histamine concentration, heart rate and arterial pressure in 20 patients (n = 10 in each group). Anaesthesia was induced with thiopentone 6 mg kg-1 i.v. and maintained with 70% nitrous oxide and halothane in oxygen. Neuromuscular blocking drugs were administered 4 min after administration of thiopentone. Venous blood samples were obtained before induction, 1 min after thiopentone and 1, 3 and 5 min after the administration of the neuromuscular blocking drugs. Tubocurarine caused 240% and 210% increases in plasma concentration of histamine at 1 and 3 min, respectively. These changes were significant (P less than 0.05) at 1 min and associated with a decrease in mean arterial pressure and an increase in heart rate. None of the 10 patients receiving pipecuronium had a significant change in plasma concentration of histamine or in haemodynamic variables.

Haemodynamic variables were measured following administration of pipecuronium 70 micrograms.kg-1 and pancuronium 90 micrograms.kg-1 (approximately equivalent to 1.5 x ED95) in patients anaesthetised with fentanyl 50 micrograms.kg-1 and scheduled to undergo coronary artery bypass grafting. There were significant increases in heart rate (22%), mean arterial pressure (10%), cardiac index (16%), and the rate pressure product (35%) following administration of pancuronium. The absolute values of these parameters were, however, within acceptable clinical limits. Administration of pipecuronium produced minimal and insignificant changes in these parameters. Other measured or derived indices showed only small changes with both agents and these were generally insignificant. There were no incidences of significant bradycardia following pipecuronium administration. The results from the present study suggest that pipecuronium would have advantages for use in patients with significant cardiovascular disease.

The neuromuscular effects of pipecuronium bromide have been evaluated in 90 adult patients anaesthetized with thiopentone, nitrous oxide in oxygen and intravenous fentanyl with or without halothane. Eighty patients received pipecuronium 45 micrograms kg-1 and the remaining ten 70 micrograms kg-1. A separate group of 10 patients received pancuronium in a dose of 60 micrograms kg-1 (equipotent to pipecuronium 45 micrograms kg-1). Neuromuscular block was measured using a single-twitch or train-of-four mode of stimulation. The time to onset of maximum block with pipecuronium 45 micrograms kg-1 varied between 3.5 and 5.7 min depending on the mode of stimulation and the anaesthetic technique used. The time to 25% recovery of this dose varied between 41 and 54 min. The recovery index (time from 25 to 75% recovery) averaged 29 min. These values were generally similar in the group receiving pancuronium 60 micrograms kg-1. The time to onset of complete block with 70 micrograms kg-1 of pipecuronium averaged 2.5 min and the duration to 25% recovery 95 min. There were no significant changes in heart rate and arterial pressure with the use of pipecuronium. The results show pipecuronium to be a drug resembling pancuronium in its neuromuscular effects when used in equipotent doses.

Norcuron injection has been applied for the prolongation of the duration of muscle relaxing action of Arduan in 104 patients. The patients underwent major surgery and 1/5 of them were of advanced age. Neuromuscular blockade could be prolonged for the required duration of operation with lower doses of Norcuron (2 mg, 1 mg) than the currently used ones. For avoiding eventual cumulation or synergism the repetition of lower doses to meet the requirements seems to be the most advantageous method.

A wide range of compounds shows neuromuscular blocking activity, e.g. tubocurarine, chandonium, atracurium, gallamine, pipecuronium and pancuronium. All these compounds have one or more quaternary nitrogen atoms in common.

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.

We have studied five pigs undergoing bilateral clamping of the renal pedicles, seven pigs undergoing orthotopic liver transplantation and three control animals without surgery in order to examine the roles of the kidney and liver in the plasma clearance of pipecuronium. An i.v. infusion of pipecuronium was controlled to maintain a constant 90-95% twitch depression throughout the investigation. The right sciatic nerve was stimulated continuously with supramaximal stimuli at 0.1 Hz and the force of the corresponding evoked isometric muscle contraction was recorded continuously. Control pigs needed an infusion rate of pipecuronium 8-10.7 micrograms kg-1 min-1. In the renal group, it was necessary to reduce the infusion rate of pipe-curonium by about 25% after clamping both renal vascular pedicles (P less than 0.05 compared with controls); in pigs undergoing liver transplantation, it was necessary to reduce the rate by approximately 80% after clamping hepatic vessels (P less than 0.05 compared with controls and from the period after clamping of renal vessels). After hepatic recirculation, the infusion rate of pipecuronium was increased progressively to a rate which corresponded to 50% of baseline values (P less than 0.05 compared with the anhepatic phase and from controls). Plasma concentrations of pipecuronium were comparable in the three animal groups and did not change significantly during the study. These data suggest that the liver plays a more important role than the kidney in the plasma clearance of pipecuronium in pigs.

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)

Mechanomyoscopy as an objective method for determining the degree of decurarisation is particularly useful in the case of uncooperative patients and those who are incapable of adequate neck flexion mostly for spinal column diseases. The authors use for that purpose a Czechoslovak-made neuromuscular stimulator (LSN 110), with constant 50 Hz frequency of stimulation, 0.3 ms impulse duration, max. 50 mA and, depending on skin impedance, 5-140 V. The stimulator switch is manually controlled. The absence of muscular fatigue (fade) on single as well repeated stimulation lasting only a fraction of a second necessary to elicit muscular response does not rule out residual curarisation despite the fact that less than 70% of the cholinergic receptors are blocked. The only reliable sign of clinically sufficient decurarisation is the ability of the muscles of the hand to maintain contraction on tetanic stimulation of the motor point of the ulnar nerve in the wrist for at least 5 seconds without fatigue, and that even on a repeated exercise. This corresponds to a block of less than 60% of the cholinergic receptors. The patient's ability to raise his or her head and to keep it raised at 4 fingerbreaths for a period of 4 seconds is also a manifestation of clinically sufficient decurarisation. The value of forced expiratory volume is not conclusive evidence of sufficient decurarisation, it only gives a rough idea of its degree. The final decision is up to the an anaesthesiologist, his knowledge and experience based on objective data.

The purpose of the study was to measure the neuromuscular effects of pipecuronium bromide (Arduan) and to determine its dosage in paediatric anaesthesiology by recording dose-effect curves in children, infants and newborn babies during diazepam, ketamine, fentanyl, nitrous oxide anaesthesia. These investigations were performed by electromechanographic method. In connection with the pharmacodynamic evaluation, literature on the pipecuronium bromide and on the administration of the muscle relaxants in paediatric anaesthesiology is summarized. From the investigations it can be ascertained that infants are more sensitive and neonates prove to be even more sensitive to pipecuronium than children; therefore it is advisable to administer 80-90 micrograms.kg-1 of Arduan for children, 50-60 micrograms.kg-1 for infants and 40-50 micrograms.kg-1 for newborn babies to ensure appropriate relaxation for surgery.

The antinociceptive properties of dalargin (D) under nembutal anesthesia and artificial ventilation were studied in hemodynamic response to mechanical algesic stimulation in rats. D was introduced i/v (20 micrograms/kg) against a background of myoplegia with Arduan (0.1 mg/kg) and without it. The naloxon (100 micrograms/kg) prevented the protective effects of D. It is considered that injection of D (20 micrograms/kg) on the background of total myoplegia and artificial ventilation prevented hemodynamic response on algesic stimulus. Subsequent dose increase of opium peptide up to 3500 micrograms/kg does not cause amplification of protective properties.

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.

Effect of Dalargin (40 micrograms/kg) on xanthine-oxidase (X) activity in experimental Arduan-induced myoplegia (0.1 mg/kg) was studied in the brain tissue of 70 rats under inhalation anesthesia and artificial ventilation. Neither Dalargin nor Arduan was found separately to induce statistically significant changes in X activity. Dalargin injections in myoplegia caused significant (24.7%) reduction of the enzyme's activity.

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.

Objective: To investigate the pharmacodynamic interaction of H2-receptor antagonists (i.e., famotidine and roxatidine acetate) with a neuromuscular blocker, pipecuronium using sciatic nerve stimulated gastrocnemius preparation of rats in vivo . Materials and Methods: The dose-response curve of pipecuronium (10-50 mg/kg i.v.) was elicited and the dose (ID50; 26.89 mg/kg i.v.) required to cause 50% of blockade of basal contractile twitch response was calculated. Benzyl alcohol (0.9 % v/v), famotidine (0.5, 2.0, 5.0 mg/kg i.v.) or roxatidine acetate (0.05, 0.2, 0.5 mg/kg i.v.) were administered 30 min prior to pipecuronium administration and their effects were studied on the dose-response curve of pipecuronium. Results: Famotidine did not alter the basal contractile twitch responses but with a dose of 2 mg/kg it significantly decreased, while with 5 mg/kg, it significantly increased the ID50 of pipecuronium. At higher dose (5.0 mg/kg) it significantly increased the time required for the onset of blockade without affecting the other parameters. Roxatidine acetate (0.2, 0.5 mg/kg) by itself produced significant neuromuscular blockade but did not alter the ID50 of pipecuronium, while with higher dose (0.5 mg/kg) it significantly decreased the same. Roxatidine (0.05 and 0.2 mg/kg) significantly increased the time required for onset of pipecuronium-induced neuromuscular blockade. At varying doses roxatidine also significantly increased the time required for peak effect and the recovery from the paralysis. Conclusion: Compared to roxatidine, famotidine produced less pharmacodynamic drug interaction with pipecuronium in rats. Such an interaction should be explored in clinical practice.

Background Muscle relaxants affect nicotinic and muscarinic receptors. Interaction of muscle relaxants with muscarinic receptors of human airways has been studied incompletely. Methods The effects of pipecuronium bromide (long-acting, nondepolarizing) and rocuronium bromide (intermediate-acting, nondepolarizing) on prejunctional and postjunctional muscarinic receptors were studied in 96 isolated human bronchial rings from 12 patients. Contractile isometric responses to electric field stimulation of pilocarpine-stimulated and nonstimulated M2 muscarinic receptors were compared before and after incubation with the two muscle relaxants. The effect on postjunctional muscarinic receptors was studied by comparing acetylcholine concentration-response curves before and after incubation with the two muscle relaxants. Results Pipecuronium bromide, but not rocuronium bromide, inhibited pilocarpine-stimulated prejunctional M2 muscarinic receptors. Neither pipecuronium bromide nor rocuronium bromide had significant inhibitory effects on nonstimulated M2 muscarinic receptors and on postjunctional M3 muscarinic receptors. Conclusions The inhibitory effect of pipecuronium bromide on pilocarpine-stimulated prejunctional M2 muscarinic receptors occurred at clinical concentrations.

Background : It has been shown that L-type calcium channel blockers increase the muscle relaxation effects of non-depolarizing neuromuscular blocking agents whereas the potentiated neuromuscular blocking effects by L-type calcium channel blocker are resistant to reversal by neostigmine. The aims of this study were 1) to see whether the pretreatment of L-type calcium channel blocker, such as verapamil, aggravates the pipecuronium-induced muscle relaxation, 2) if so, to see whether these effects are reversed by anticholinesterase, such as neostigmine and edrophonium or potassium channel blocker, such as 4-aminopyridine. Methods : The rat-phrenic nerve-hemidiaphragms(n=60) were prepared. Twenty microgram of pipecuronium was administered to all organ bath. All samples were divided into two groups according to the administration of 10uM of verapamil i.e. verapamil pretreated, non-pretreated group. The amounts of administered pipecuronium were gradually increased by 4ug until the force of twitch decreased to 10% of control value in both groups. Each group was subdivided into three groups according to the administration of 0.75 M of neostigmine, 12.4 uM of edrophonium or 40uM of 4-aminopyridine. Results : The dose of pipecuronium required for the decrease of contractile force to 10% of control value was less in verapamil pretreated group than in non-pretreated group. And, the decrease of contractile force in both groups was more effectively reversed by 4-aminopyridine than neostigmine and edrophonium. Conclusions : Verapamil potentiates the pipecuronium-induced neuromuscular blockade and 4-aminopyridine is more effective to reverse verapamil pretreated, pipecuronium induced neuromuscular blockade. (Korean J Anesthesiol 1997; 33: 228∼236)

To determine the effect of liver cirrhosis on the pharmacokinetics and pharmacodynamics of pipecuronium, the authors administered 100 micrograms/kg of pipecuronium intravenously to eight patients with liver cirrhosis and eight patients with normal liver and renal function undergoing elective abdominal surgery. All patients were anesthetized with thiopental (5-7 mg/kg), nitrous oxide (50-70% in oxygen), and fentanyl in repeated doses (2 micrograms/kg). Plasma concentrations of pipecuronium were determined by high-pressure liquid chromatography. A two-compartment open model was used for pharmacokinetic analysis. Thumb-elicited mechanical response to single-twitch ulnar nerve stimulation was also measured. Total plasma clearance did not differ between controls (2.96 +/- 1.05 mL.min-1.kg-1, mean +/- SD) and cirrhotics (2.61 +/- 1.16 mL.min-1.kg-1). Terminal elimination half-life was 111 +/- 46 min in controls and 143 +/- 25 min in cirrhotics. The total apparent volume of distribution at steady state did not differ between controls (350 +/- 81 mL/kg) and cirrhotics (452 +/- 222 mL/kg). The volume of the central compartment was not different between the two groups. The onset of neuromuscular blocking effect was longer in cirrhotics (233 +/- 112 s) (P < 0.05) than in controls (170 +/- 33 s). The clinical duration (injection until single twitch returned to 25%) was similar between the two groups: 167 +/- 41 min in controls and 165 +/- 48 min in cirrhotics. The authors conclude that hepatic insufficiency due to cirrhosis does not alter the pharmacokinetics and pharmacodynamics of pipecuronium (100 micrograms/kg).

We evaluated the neuromuscular effects of pipecuronium during anesthesia with equipotent concentrations of either sevoflurane, isoflurane or enflurane. Twenty-seven patients scheduled for minor elective otolaryngeal or plastic surgery were studied and randomly assigned to 3 groups, one group per anesthetic agent. Anesthesia was induced with thiamylal 5 mg.kg(-1) and the trachea was intubated with succinylcholine 1 mg.kg(-1), then anesthesia was maintained with 60% nitrous oxide in oxygen and sevolfurane, isoflurane or enflurane, depending on the group. Neuromuscular blocking effects were monitored by recording the electromyographic activity of the adductor pollicis muscle from supramaximal stimulation of the ulnar nerve at 10-s intervals. Pipecuronium 40 microg.kg(-1) was administered when electromyographic activity had reached a stable state, 30 min after succinylcholine administration. The maximum effect (% block of control) and clinical duration (time to 25% recovery) of pipecuronium were 99.1 +/- 1.4% and 63.7 +/- 14.7 min (mean +/- S.D.) for sevoflurane, 99.0 +/- 2.0% and 60.9 +/- 20.5 min for isoflurane, and 98.0 +/- 2.5% and 62.8 +/- 28.7 min for enflurane, respectively. There were no significant differences in these values between the anesthetics. Cardiovascular stimulant effects were not observed in any of the groups. We conclude that the effect of pipecuronium under seveflurane anesthesia is similar to that under isoflurane and enflurane anesthesia.