Comparative pharmacodynamics of pancuronium, cisatracurium, and CW002 in rabbits.

Pancuronium is a long-duration neuromuscular blocking drug (NMBD) that has been used in anesthetized rabbits at 0.1 mg/kg. However, there are limited data regarding the time course for recovery from this dose either spontaneously or with pharmacologic reversal. Here we defined the potency, onset, and recovery characteristics for the intermediate-duration NMBD cisatracurium and CW002 (a novel cysteine-inactivated molecule) in the rabbit, and test the hypothesis that these drugs may be alternatives to 0.1 mg/kg pancuronium for survival procedures. New Zealand white rabbits anesthetized with isoflurane were studied in a cross-over design. Potencies of cisatracurium and CW002 were defined as the effective dose for 95% depression of evoked muscle twitch (ED95). Responses to 3×ED95 were used to define onset (time to maximal effect), recovery index (RI; time from 25% to 75% recovery of twitch), and duration (time to complete recovery). Responses to all drugs were determined with and without reversal by neostigmine-glycopyrrolate or L-cysteine. CW002 was 4-fold more potent than was cisatracurium, but their onset, RI, and duration were similar. Pancuronium had similar onset and RI but longer duration, compared with cisatracurium and CW002. Reversal shortened the recovery index and duration for all 3 drugs. At 3×ED95, cisatracurium and CW002 had the same onset as did standard-dose pancuronium, but durations were shorter and more predictable. In addition, CW002 can be reversed without the potential side effects of cholinergic manipulation. We conclude that cisatracurium and CW002 are viable alternatives to pancuronium for survival studies in rabbits.

Role of cholinesterase activity on pharmacodynamics of mivacurium preceded by pancuronium in elderly and young adults.

Mivacurium- pancuronium combination proved to be more potent than either drug given alone. The goal of this study was to evaluate the safety and efficacy of this combination in elderly group and its correlation to plasma butyryl cholinesterase (Bche) activity. Forty patients, ASA I or II scheduled for elective open cholecystectomy were allocated into two groups of twenty patients each: young group (18- 55 years) and elderly group (60-75 years). Anesthesia was induced with midazolam, fentanyl, and propofol then maintained with isoflurane and opioid supplementation. Neuromuscular blockade (NMB) was monitored by train-of-four (TOF) stimulation of the ulnar nerve. After calibration, NMB was achieved by 16 microg kg(-1) pancuronium followed by 32 microg kg(-1) mivacurium. The following parameters were recorded: The onset time, clinical duration, recovery index and the total dose of mivacurium and pancuronium together with hemodynamic data. Three blood samples for Bche activity were collected: before pancuronium injection, 3 min. and 30 min. afterwards in both groups. The onset time and the recovery index of NMB were comparable in both groups. The duration of action was significantly prolonged in elderly group (49.8 +/- 10.48 min.) compared to young one (37.13 +/- 7.81 min.). The total dose of mivacurium was significantly less in the elderly group (22.56 +/- 2.39 microg kg(-1) hr(-1)) when compared to the young group (25.78 +/- 3.05 microg kg(-1) hr(-1)). For all patients, the preoperative Bche activity was within the normal range. After pancuronium injecttion, it showed a significant reduction in both groups at three and thirty minutes except a non significant value in young at thirty minutes. This reduction showed a significantly higher percent change in the elderly group (30.37 +/- 22.01) than the young group (8.60 +/- 19.19) at thirty minutes. There were significant intra operative variations in the percent changes of hemodynamic data compared to the preoperative values, yet, still within the clinically acceptable range. So, the use of a small dose of pancuronium followed by a small dose of mivacurium with a ratio of 1:2 can produce synergism without affecting either the recovery profile of mivacurium or the clinical hemodynamic stability even in the elderly group.

Interaction between mivacurium and pancuronium: impact of the order of administration.

INTRODUCTION: Potentiation of mivacurium by low-dose pancuronium is mostly due to an inhibition of plasma butyryl cholinesterase (BchE) resulting in a decreased rate of hydrolysis of mivacurium. Nevertheless, an interaction at the receptor site could not be ruled out. By changing the order of the muscle relaxant injections, we may lessen the pharmacokinetic interaction and assess the impact at the acetylcholine receptor level. METHODS: Twenty patients scheduled for general anesthesia with propofol and fentanyl, and isoflurane were randomized into two groups receiving, mivacurium 100 microg kg-1 followed by pancuronium 15 microg kg-1 (group 1) or pancuronium 15 microg kg-1 followed by mivacurium 100 microg kg-1 (group 2). BchE before and after injection of each relaxant was measured. Neuromuscular block was assessed with a force transducer at the adductor pollicis measuring the elicited twitch to ulnar nerve stimulation. RESULTS: The neuromuscular block was greater when pancuronium was administered before mivacurium (100% versus 96+/-3%; P<0.05). Times to recovery of the elicited twitch response to 25% and 75% of control value were increased by 100% (P<0.05). After pancuronium, decreases in BchE of 11% and 14% in groups 1 and 2 were observed, respectively. CONCLUSION: Interaction between mivacurium and low dose pancuronium is significant only when mivacurium is injected after pancuronium.

Potentiation of mivacurium blockade by low dose of pancuronium: a pharmacokinetic study.

BACKGROUND: Mivacurium is potentiated by pancuronium to a much greater extent than other relaxants. In a previous investigation we suggested that this potentiation could be due to the ability of pancuronium to inhibit plasma cholinesterase activity, but we did not measure plasma concentrations of mivacurium. In the current study we performed a pharmacokinetic analysis by measuring the plasma concentration of mivacurium when preceded by administration of a low dose of pancuronium. METHODS: After induction of general anesthesia with propofol and fentanyl and orotracheal intubation, 10 patients (pancuronium-mivacurium group) received 15 microg/kg pancuronium followed 3 min later by 0.1 mg/kg mivacurium, whereas 10 other patients (mivacurium group) received saline followed by 0.13 mg/kg mivacurium 3 min later. Plasma cholinesterase activity was measured before and 3 and 30 min after pancuronium dosing in the pancuronium-mivacurium group and was measured before and after administration of saline in the mivacurium group. Arterial plasma concentrations of mivacurium and its metabolites were measured at 0.5, 1, 1.5, 2, 4, 10, 20, and 30 min after injection. Neuromuscular blockade was assessed by mechanomyography. RESULTS: Plasma cholinesterase activity decreased by 26% in the pancuronium-mivacurium group 3 min after injection of pancuronium (P < 0.01) and returned to baseline values 30 min later; however, no significant variation was observed in the mivacurium group. The clearances of the two most active isomers (Cis-Trans and Trans-Trans) were lower in the pancuronium-mivacurium group (17.6 +/- 5.1, 14.7 +/- 5.3 ml. min-1. kg-1, respectively) than in the mivacurium group (32.4 +/- 20.2, 24.8 +/- 13.5 ml. min-1. kg-1; P < 0.05). CONCLUSIONS: A subparalyzing dose of pancuronium decreased plasma cholinesterase activity and the clearance of the two most active isomers of mivacurium. Pancuronium potentiates mivacurium more than other neuromuscular blocking agents because, in addition to its occupancy of postsynaptic acetylcholine receptors, it slows down the hydrolysis of mivacurium.

Ventajas del uso de dosis de cebado / Advantages of the use of priming doses

Introducción: En la práctica clínica se han ensayado diversas formas de administrar los relajantes muculares con vistas a lograr menores tiempos y mejores condiciones de intubación. Objetivos: Determinar las condiciones y el tiempo de intubación que se lograron al utilizar el principio de dosis de cebado en los pacientes quirúrgicos, y evaluar los valores de la altura del twicht en ese período. Material y método: Se realizó una investigación tipo ensayo clínico en 120 pacientes sometidos a cirugía laparoscópica, subdivididos en 2 grupos. La técnica de dosis de cebado se realizó en 60 pacientes. Los relajantes musculares utilizados fueron: pancuronio (Grupo I) dosis de 0,1 mg/kg, vecuronio (Grupo II) 0,1 mg/kg y atracurio (Grupo III) 0,5 mg/kg. A los pacientes de este grupo se les administró el 10 por ciento de la dosis total calculada en los 4 minutos previos a la administración de la dosis restante. Resultados: Al monitorizar la FNM durante la intubación se observó que el tiempo óptimo de intubación, cuando se utilizaron dosis de cebado con atracurio y vecuronio, fue de 112,12 ñ 3,2 y 118ñ1,4 seg. respectivamente, menores al del grupo pancuronio. Las condiciones de intubación obtenidas según los criterios de Lund y Stouner presentaron un 95 por ciento de condiciones excelentes en los grupos II y III y un 60 por ciento en el grupo I. La altura del twitch en igual período fue semejante para los grupos II y III. Al usar dosis de cebado fue de 28,5 ñ 3,1 y 33,1 ñ 0,8 por ciento respectivamente y de 48,1 ñ 1,5 y 49,1 ñ 2,6 por ciento cuando ésta no se utilizó. Estas diferencias resultaron ser estadísticamente significativas (p<0,05). Como consecuencia de esta técnica, en el Grupo II se encontraron, en un 10 por ciento del total, dificultades para respirar y otro 10 por ciento refirió experiencia subjetiva de parálisis respiratoria y en el 20 por ciento del Grupo III se observaron dificultades respiratorias. Tres pacientes del Grupo I y dos de cada Grupo II y III presentaron diplopia. Conclusiones: Las condiciones de intubación fueron más rápidas cuando se empleó dosis de cebado para los tres fármacos, que cuando no se la utilizó. La laringoscopía y la intubación tuvieron mejores condiciones con los fármacos de acción intermedia (vecuronio y atracurio). La altura del twitch disminuyó más cuando se emplearon dosis de cebado en los tres fármacos que cuando no se utilizaron...(AU)

Fuzzy logic for model adaptation of a pharmacokinetic-based closed loop delivery system for pancuronium.

In this paper, we investigate the ability of fuzzy to adapt the parameters of a pharmacokinetic and pharmacodynamic model-based controller for the delivery of the muscle relaxant pancuronium. The system uses the model to control the rate of drug delivery and uses feedback from a sensor which measures muscle relaxation level to adapt the model using fuzzy logic. The control strategy administers mini-bolus doses of pancuronium and modulates the magnitude and time interval between the bolus doses to maintain a patient's muscle relaxation within an allowable range specified by the user. Before each new dose is given, the fuzzy logic adaptation scheme uses the error between the predicted patient response and the measured response to adapt the model. The system was tested using computer simulation by varying the parameters of the model by 50% from their nominal values. It was also evaluated in a clinical trial of five patients undergoing surgical procedures lasting 5 h or longer.

[The pharmacokinetics of pancuronium bromide in infants, children and adults].

Twenty-four patients scheduled for elective plastic surgery were selected to study the pharmacokinetics of pancuronium bromide under enflurane anesthesia. The patients were divided into three groups by their ages; Group 1 consisted of 5 infants (0.75-2.95 years); Group 2 contained 13 children (4-14 years); Group 3 included 6 adults (16-27 years). An improved fluorimetric assay was used to measure the plasma concentrations of pancuronium bromide after administration of pancuronium bromide at a dose of 100 micrograms/kg. The results showed that the disposition of pancuronium bromide may be best described mathematically by a two-compartment open model in all patients. The younger the patients, the larger the distribution volumes and the higher the Cl. There were significant differences among the three groups with regard to V1, V2, Vdss, Cl, AUC. The T1/2 beta and MRT were longer in Group 1 than in Group 2 and Group 3.

Prolonged paralysis after long-term, high-dose infusion of pancuronium in anaesthetized cats.

We have studied the neuromuscular effects of a 48-h infusion of high-dose pancuronium (400 micrograms kg-1 h-1) in four cats anaesthetized with pentobarbitone, using contraction of tibialis anterior muscles after direct and indirect stimulation. After cessation of the pancuronium infusion, prolonged paralysis existed. The first twitch in the train-of-four stimuli (TOF) reappeared 8-12 h after termination of the pancuronium infusion. Twenty-four hours after termination of the infusion, TOF ratios were less than 0.08 and twitch contraction averaged 39 (SE 8)% of initial values. Twitch contraction after direct stimulation did not differ from initial values. Antagonism of paralysis was accomplished with neostigmine 60 micrograms kg-1 in two animals and neostigmine 90 micrograms kg-1 and 4-aminopyridine 500 micrograms kg-1 in the others. Steady-state plasma concentration of pancuronium (2000 ng ml-1) decreased rapidly after termination of the infusion, but then stabilized at about 130 ng ml-1. These results indicate that prolonged paralysis after long-term administration of high-dose pancuronium is caused primarily by failure of neuromuscular transmission, most likely caused by the persistent plasma concentrations of the drug in the pharmacologically active range.

Clinical pharmacology of the neuromuscular blocking agents.

Neuromuscular blocking agents are among the most commonly used drugs during general anesthesia. They compete with acetylcholine and interfere with the transmission of nerve impulses resulting in skeletal muscle relaxation. Based on their mechanism of action, neuromuscular blocking agents are classified as either depolarizing or nondepolarizing. Succinylcholine is a short-acting depolarizing agent. Commonly used nondepolarizing agents are curare (long-acting), pancuronium (long-acting), atracurium (intermediate-acting), and vecuronium (intermediate-acting). Neuromuscular blocking agents are used clinically to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery. This article provides an overview of the physiology of the neuromuscular transmission and summarizes our current knowledge on the use of these agents during general anesthesia.

Pharmacokinetics of pancuronium in patients undergoing coronary artery surgery with and without low dose dopamine.

Pancuronium is frequently used in coronary artery surgery, but its pharmacokinetics in these patients are still unknown. It is possible that dopamine, administered to prevent renal impairment induced by the surgery, might promote the elimination of pancuronium. Therefore, the pharmacokinetics of a bolus dose of pancuronium were studied in 2 groups of coronary artery surgery patients, with and without dopamine 2 micrograms/kg/min, administered during and after cardiopulmonary bypass. Dopamine in the administered dose did not influence the systemic haemodynamics. The pharmacokinetic variables in both groups did not differ from those found in an earlier study in healthy normothermic patients. Total renal clearance was not influenced by dopamine, due to post-bypass rebound hyperperfusion in the control group. Pancuronium was shown to be subject to considerable tubular reabsorption, and its elimination was found to be increased during hypothermia. Dopamine increases pancuronium elimination by an increase in glomerular filtration rate. The dopamine-induced decrease in tubular solute reabsorption did not enhance the elimination of pancuronium.

Relationship between train-of-four ratio and first-twitch depression during neuromuscular blockade: a pharmacokinetic/dynamic explanation.

Fade, as measured by train-of-four, lags behind twitch depression during the initial phase of nondepolarizing neuromuscular blockade, i.e., the ratio of the fourth to first twitch height in a train (T4/T1) is greater at the onset of the block than during spontaneous recovery for the same level of first twitch depression. We believe that these data can be explained by picturing the muscle as having localized regions that respond much more slowly than the rest, leading to a delay in drug effect in that area, especially when the drug concentration rises rapidly as during bolus administration. This was modeled by computer as a muscle of 15 compartments distributed in a log-normal fashion according to equilibration rate. Experimental data consisting of the time course of first twitch and train-of-four ratio were fitted by nonlinear regression to the model. A good fit was obtained with a median equilibration time t1/2 of 3.3 min and a standard deviation of 2.1. The difference between train-of-four during onset and regression of block at the same level of first twitch depression was reproduced.

[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)

Pharmacokinetics and cardiovascular dynamics of pipecuronium bromide during coronary artery surgery.

The haemodynamic effects of 200 micrograms.kg-1 pipecuronium and pancuronium were compared under etomidate/piritramide anaesthesia in 20 patients scheduled for elective coronary artery surgery. Following the completion of the haemodynamic measurements (ten minutes), anaesthesia was maintained by etomidate/sufentanil infusion. The mean changes in cardiac output were approximately -19 and -2 per cent and in heart rate -1 and +26 per cent for pipecuronium and pancuronium respectively. Plasma and urine concentrations of pipecuronium were also measured and the pharmacokinetic variables obtained indicated rapid initial decrease in plasma concentration (t1/2 = 7.6 minutes) followed by a longer terminal phase (t1/2 = 161 minutes). The central compartment volume was 102 +/- 24 ml.kg-1 and plasma clearance was 1.8 +/- 0.4 ml.kg-1 min-1. Approximately 56 per cent of the dose was recovered from the urine within 24 hours of administration and about 25 per cent of this was the metabolite, 3-desacetyl pipecuronium. High-dose pipecuronium administration under the anaesthetic regimen employed did not produce deleterious haemodynamic effects. The pharmacokinetic variables after bolus injection of pipecuronium did not deviate from those reported under normothermic conditions.

Comparative potency of pipecuronium bromide and pancuronium bromide.

Cumulative dose-response curves were constructed to determine the comparative potency of pipecuronium and pancuronium. From these, the ED50 and ED95 values were calculated. These were 24.96 micrograms kg-1 and 44.96 micrograms kg-1, respectively, for pipecuronium and 30.42 micrograms kg-1 and 61.12 micrograms kg-1, respectively, for pancuronium.

Uptake and excretion of vecuronium bromide and pancuronium bromide in the isolated perfused rat liver.

Using the isolated perfused rat liver preparation, the disappearance from the perfusate and the excretion in the bile of vecuronium bromide and pancuronium bromide and their metabolites were followed for 2 h after the addition of 1 mg of either drug to the perfusate. In addition, the rate of change of the hepatic content of these two compounds was calculated by serially subtracting the amount of the compound and the metabolites in the bile and in the perfusate from the dose of drug added to the perfusate. It was found that, whereas the concentration of pancuronium in the perfusate declined slowly and monoexponentially, vercuronium concentration in the perfusate declined rapidly in a biexponential manner. No metabolites of either drug were detected in the perfusate. Approximately 40% of the injected dose of vecuronium was excreted in the bile as unchanged vecuronium and another 30% as the 3-hydroxy metabolite. No other metabolites of vecuronium were found in the bile. In total only about 7% of pancuronium (unchanged) was collected in the bile by the end of the experiment. It is concluded that, in comparison to pancuronium, the rat liver takes up large amounts of vecuronium rapidly, half of which is eliminated as unchanged vecuronium and half as the 3-hydroxy derivative. A small amount of vecuronium or its 3-hydroxy metabolite is returned to the perfusate from the liver. Some possible mechanisms underlying these differences are discussed.