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Muscle relaxants are indispensable for surgical anesthesia. Early studies suggested that a classical non-depolarizing muscle relaxant pancuronium competitively binds to the ligand binding site to block nicotinic acetylcholine receptors (nAChR). Our group recently showed that nAChR which has two distinct subunit combinations are expressed in zebrafish muscles, αβδε and αβδ, for which potencies of pancuronium are different. Taking advantage of the distinct potencies, we generated chimeras between two types of nAChRs and found that the extracellular ACh binding site is not associated with the pancuronium sensitivity. Furthermore, application of either 2 μM or 100 μM ACh in native αβδε or αβδ subunits yielded similar IC50 of pancuronium. These data suggest that pancuronium allosterically inhibits the activity of zebrafish nAChRs., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Sakata, Ono. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Neuromuscular blocking drugs produce muscle weakness by interaction with nicotinic-acetylcholine receptors. Cardiovascular side effects have been reported. In this study the neuromuscular blocking drug vecuronium and the controls gallamine and pancuronium slowed the rate of atropine induced [(3)H]N-methylscopolamine dissociation from Chinese hamster ovary cells expressing recombinant human muscarinic M2 receptors K(off) values min(-1); vecuronium (125 nM), atropine 0.45+/-0.07+blocker 0.04+/-0.02; gallamine (21 nM), atropine 0.42+/-0.05+blocker 0.15+/-0.04; pancuronium(21 nM), atropine 0.36+/-0.03+blocker 0.03+/-0.01). These data indicate that vecuronium, gallamine and pancuronium interact with an allosteric site on the muscarinic M2 receptor (located on the heart) and this may explain some of their cardiac side effects.

We recently demonstrated that conserved tyrosines Tyr198 of the alpha subunit and Tyr117 of the gamma subunit of the acetylcholine receptor stabilize binding of the curariform antagonist dimethyl-d-tubocurarine (DMT). To test the hypothesis that DMT interacts directly with these tyrosines, and therefore bridges the alpha-gamma subunit interface, we introduced point mutations into these key positions and expressed one or both mutant subunits in alpha 2 beta gamma 2 acetylcholine receptors in 293 HEK cells. Binding of DMT, measured by competition against the initial rate of 125I-alpha-bungarotoxin binding, shows high affinity for aromatic mutations, reduced affinity for polar mutations, and lowest affinity for arginine mutations. Similar side chain dependences were observed for both Tyr alpha 198 and Tyr gamma 117, indicating interaction of these residues with two symmetrical chemical groups in DMT. Two more bisquaternary antagonists, pancuronium and gallamine, show side chain dependences similar to that of DMT, indicating that the primary stabilizing interactions are aromatic-quaternary in both subunits. For the rigid ligands DMT and pancuronium, co-expressing mutant alpha and gamma subunits revealed independent contributions by each determinant, but strict independence was not observed for the flexible ligand gallamine. The free energy contributed by each aromatic-quaternary interaction was estimated to be 2-4 kcal/mol, as determined from the free energy difference between aromatic and alkyl hydroxyl mutations. Our results suggest that bis-quaternary competitive antagonists bridge the alpha-gamma subunit interface by fitting into a pocket bounded by tyrosines at positions 198 of the alpha subunit and 117 of the gamma subunit.

Alteration of the ligand-binding domain of the nicotinic acetylcholine receptor through site-directed mutagenesis offers a powerful approach to the elucidation of structure-function relations in the receptor. Several conserved tyrosine residues in the large extracellular amino terminus of the alpha subunit of the receptor have been implicated by both chemical labeling and mutagenesis studies as playing an important role in the interaction of acetylcholine with the receptor. We and others have previously shown that substitution of phenylalanine for tyrosine at position 198 of the alpha subunit (alpha Y198F) leads to a rightward shift in the dose-response curve for acetylcholine-elicited currents. We have further investigated this particular mutation by examining the interaction of the competitive antagonist d-tubocurarine (curare) with the receptor. In contrast to the effect on the interaction of agonists with the receptor, this mutation leads to a marked increase in the affinity of the receptor for curare. Furthermore, this enhancement in affinity is selective for curare and is not seen with other competitive antagonists (pancuronium, beta-erythroidine, and gallamine). Examination of the structures of these competitive antagonists leads to the proposal that this enhancement is due to the formation of an aromatic-aromatic interaction between the phenylalanine ring at position alpha 198 in the mutant and one of the aromatic rings of curare and that this can provide information about the spatial arrangement of this residue in the binding site.

Since binding of an agonist to an ionotropic neurotransmitter receptor causes not only channel opening, but also desensitization of the receptor, inhibition of the receptor by the antagonist sometimes becomes very complicated. The transient state kinetics of ligand association and dissociation, and desensitization of the receptor were considered on the basis of the minimal model proposed by Hess' group, and the following possibilities were proposed. 1) When an agonist is simultaneously applied to the receptor with an antagonist whose affinity to the receptor is extremely strong and different from that of the agonist, it is usually impossible to estimate the real inhibition constant exactly from the responses because desensitization of the receptor proceeds before the equilibrium of the ligand binding. Simultaneous addition of the antagonist with strong affinity to the receptor may apparently accelerate inactivation (desensitization) of the receptor. The association rate constant of the antagonist can be estimated by analyses of the rate of the inactivation in the presence and the absence of the antagonist. 2) A preincubated antagonist with a slow dissociation rate constant, i.e., a very effective inhibitor, may cause apparent noncompetitive inhibition of the receptor, since the receptor is desensitized by an agonist as soon as the antagonist dissociates from the receptor and the dissociation of the antagonist from the receptor becomes the rate-determining step. A nicotinic acetylcholine receptor (nAChR) was expressed in Xenopus oocytes by injecting mRNA prepared from Electrophorus electricus electroplax and used for the experiments on inhibition by an antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

There are many new neuromuscular blocking drugs now going through the clinical trials required before new drugs can be used clinically on a routine basis. It is safe to say that within the next five years the muscle relaxants now in common use will be replaced by new and more "ideal" muscle relaxants. This review has attempted to define for the practicing anesthesiologist the goals of muscle relaxant research and the drugs that have been developed from that research. It is hoped that some familiarity with these drugs before they become widely available may hasten their extensive use by practitioner in the interest of better anesthetic patient care.

Plasma concentration curves of patients with normal and impaired renal function are fitted to a tri-exponential function according to an open three compartment pharmacokinetic model. A detailed discussion of the relationship between theoretical distribution volumes, clinical pharmacodynamics and morphological or biochemical structures provides the basis for the concept of a central application and measuring compartment, a pharmacologically specific compartment and a non specific one. The distirbution of pancuronium from the application compartment to the specific compartment results in the onset of muscular paralysis. The recovery is governed by renal elimination of the unchanged drug as well as by its redistribution into the non specific compartment. In anuric patients the spontaneous recovery after 3--4 h is the effect of redistribution only. Neither metabolic degradation nor increased biliary elimination can sufficiently compensate for the lack of the renal pathway. The clinician should always keep in mind that after the recovery from pancuronium-induced muscular paralysis, both in patients with or without renal pathology, considerable residues of the active drug are stored at nonspecific and even specific receptor sites for many hours.

The effects of age on the pharmacokinetics of pancuronium were investigated. The distribution volume of pancuronium did not appear to be age-dependent, but elimination of the drug decreased with increasing age. The clinical implications of these findings are discussed.

The renal and hepatic elimination and biotransformation, as well as the relation between disposition and duration of action of pancuronium and two of its analogues, dacuronium and ORG.6368, have been investigated in the cat. In pharmacokinetic studies, appreciable amounts of the latter two compounds were found in the urine, bile and liver 8 h after their intravenous administration. Various proportions of the injected dose of the respective drugs were metabolized. In another series of experiments it was shown that the early hepatic uptake (during the first 3 min after the injection) of ORG.6368 was significantly greater than that of dacuronium and pancuronium. The intensity and duration of action of the neuromuscular blocking effect of the three compounds were studied after intravenous and "close" intraarterial injection. On the basis of these pharmacokinetic and neuromuscular studies, it was concluded that the short duration of action of ORG.6368 is due primarily to its early hepatic uptake. The possibility cannot be excluded, however, that differences in the kinetics of the drug action of ORG.6368 and the other two compounds also contributed significantly to the differences seen in the duration of action of these compounds.

The metabolic disposition of pancuronium was investigated in man under clinical condition. Pancuronium and its desacetylated derivatives were determined in body fluids using the previously described bromophenol blue method (3). The metabolites were isolated by thin layer chromatography. One minute after the intravenous injection of a mg of pancuronium the drug reaches a serum concentration of 2,2 plus or minus 0,2mug/ml. As an exponential function the concentration curve then falls to half of the initial value during the first 30 to 60 min. The end of the neuromuscular block conincides with a concentration of 0,1 to 0,3 mug/ml serum which is reached about 2 hours after the injection. After 3 to 4 hours no more pancuronium can be detected in the serum. The renal elimination of pancuronium can be folowed up for 12 hours. On average half of the injected dose is recovered in the urine. 80% of this proportion is unchanged pancuronium and 20% desacetylated metabolites. The monodesacetylated derivatives of pancuronium are still pharmacologically active. The biliary excretion 24 hours after the administration of pancuronium accounts for 5 to 10% of the injected dose...

The neuromuscular blocking action of repeated injections of atracurium and vecuronium was studied in 74 surgical patients during balanced anaesthesia (methohexitone or etomidate, intubation after suxamethonium, fentanyl, droperidol, N2O). The initial bolus dose (ID) of atracurium was 0.25 mg/kg and of vecuronium 0.05 mg/kg followed by repeated increments (RD) of atracurium 0.1 mg/kg and vecuronium 0.0125 mg/kg when neuromuscular function (EMG) had recovered to about 30% of pre-relaxant control. Dose-response relationships revealed atracurium to be about 1/5 as potent as vecuronium; the ED50 of atracurium was 0.13 +/- 0.03 mg/kg and of vecuronium 0.023 +/- 0.007 mg/kg. The ID of both relaxants produced a neuromuscular blockade of about 90% within 4 min. The duration from the time of injection to 30% recovery was slightly longer in atracurium 26 +/- 9 min. In all patients the RD produced within 3.5 min satisfactory muscle relaxation with a neuromuscular block of about 85%. The mean duration of atracurium (18 min) was 5-10 min longer than of vecuronium (12 min). To maintain good surgical relaxation (more than 70% blockade) atracurium 0.32 mg/kg X h and vecuronium 0.056 mg/kg X h were required. No cumulation could be measured after repeated injections. The recovery time of atracurium and vecuronium at the end of anaesthesia was 10-12 min. Neither cardiovascular side-effects nor signs of histamine release were observed after both relaxants in our particular dose range. It is concluded, that atracurium is a favourable blocker for anaesthetic practice: The time of onset is approximately the same compared with vecuronium. The duration of action, however, is slightly longer but still truly intermediate long.(ABSTRACT TRUNCATED AT 250 WORDS)

We tested the effect of hypothermia on the pharmacokinetics and pharmacodynamics of pancuronium in the cat. In 14 cats given pancuronium, 120 microgram/kg i.v., we found that neuromuscular block lasted between 2.5 and 3.0 times longer at 29 degrees C (N = 5) than at 34 degrees C (N = 5) or 39 degrees C (N = 4). The apparent plasma elimination half-life was 46 +/- 7 min (S.E.) at 29 degrees C as compared to 21 +/- 2 and 25 +/- 6 min at 34 and 39 degrees C, respectively. The volume of distribution of the central compartment and total volume of distribution at steady state were less at 29 and 34 dgrees C than at 39 degrees C. Total plasma clearance was 4.3 +/- 0.4 ml/kg/min at 29 degrees C and 10.7 +/- 0.9 and 10.9 +/- 1.5 ml/kg/min at 34 and 39 degrees C, respectively. The reduced plasma clearance resulted at least in part from a markedly reduced biliary and urinary excretion of pancuronium at 29 degrees C as compared to 34 and 39 degrees C. In four other cats, the plasma concentration of pancuronium was correlated with depression of twitch tension under steady-state conditions. The ED50 of pancuronium (plasma concentration required for a 50% depression of twitch tension) was 0.035 and 0.073 microgram/ml at 29 and 38 degrees C, respectively. We conclude that a pancuronium neuromuscular block is prolonged at 29 degrees C because of an increased sensitivity of the neuromuscular junction to pancuronium and delayed biliary and urinary excretion.

The neuromuscular blocking effects of equipotent doses of the three putative metabolites of vecuronium (3-hydroxy vecuronium, 17-hydroxy vecuronium and 3,17-dihydroxy vecuronium) were compared with those of an equipotent dose of vecuronium. Results obtained with the liver excluded from the circulation and after intraportal injection were compared with those following i.v. injection, in the cat. Following injection i.v., and with the liver excluded from the systemic circulation, there was a marked prolongation of duration of action (which averaged 100%) with all four compounds. After intraportal injection the only significant results were shortening of the duration of action and a decrease in the maximum blockade achieved with the 3-hydroxy metabolite. It is concluded that, in the cat, the hepatic removal of these compounds from the circulation is a major determinant of their duration of action. This process seems to be of importance for all four compounds, although the 3-hydroxy derivative appeared the most sensitive.

To determine the potency of pancuronium and its metabolites, 3-OH-, 17-OH- and 3,17-OH-pancuronium, cumulative dose-response curves were determined in five anesthetized patients with each drug. Pancuronium (ED50 = 0.041 mg/kg) was 2 times more potent than 3-OH-pancuronium (ED50 = 0.082 mg/kg), 50 times more potent than 17-OH-pancuronium (ED50 = 2.0 mg/kg) and 54 times more potent than 3,17-OH--pancuronium (ED50 = 2.15 mg/kg). In 21 other patients, one equipotent dose of either pancuronium or one of its metabolites was given as an i.v. bolus. Onset time and duration of neuromuscular blockade from 3-OH- and 3,17-OH-pancuronium did not differ significantly from that of pancuronium; 17-OH-pancuronium had a shorter duration of action than did pancuronium. Although pancuronium tended to have a slightly longer elimination half-life, the pharmacokinetics of the four drugs did not differ significantly. The elimination half-lifes were 110, 68, 73 and 71 min for pancuronium and its 3-OH, 17-OH and 3,17-OH derivatives, respectively. We conclude that although pancuronium is more potent than its 3-OH, 17-OH and 3,17-OH metabolites, the pharmacokinetics of these three metabolites do not differ from each other and from that of pancuronium.

A simple microcomputer program written in Microsoft Basic estimates pharmacokinetic parameters using the coordinate search technique to minimize the sum of squared errors. The program developed for portable computers combines a plot of data and curve fitting so as to find rapidly the initial parameters with the subsequent optimization of the parameter estimate.

Vecuronium is hydrolyzed in the body to 3-deacetyl (ORG 7268), 17-deacetyl (ORG NC58), and 3, 17-bis-deacetyl (ORG 7402) derivatives. Interactions of vecuronium and these metabolites were studied in phrenic nerve-hemidiaphragm preparations of rats. As already reported, ORG 7268 had a potent neuromuscular blocking action, and ORG NC58 and ORG 7402 had a weak neuromuscular blocking action. As expected, ORG 7268 increased the degree of neuromuscular block by vecuronium. However, a low concentration (10 microM) of ORG NC58 and ORG 7402 reversed the block by vecuronium. At a high concentration (50 microM), ORG NC58 and ORG 7402 increased the degree of block by vecuronium. Although we do not have enough data to explain these paradoxical reversal of neuromuscular block at this moment, we postulate that these results reflect the interaction between "slow" and "fast" competitive antagonists. Regardless of the mechanism, it should be emphasized that the concentrations of ORG NC58 and ORG 7402 which are necessary to reverse the block are much lower than those which facilitate the block. It is conceivable that this paradoxical reversal of the block occurs in experimental and clinical situations. Therefore, in determining the neuromuscular blocking action of a compound, the "antagonistic" effect of its metabolites should also be considered.

To determine the influence of renal failure on the pharmacokinetics and neuromuscular blockade of Org NC 45 (Norcuron), a new monoquaternary homologue of pancuronium, 13 patients under halothane and nitrous oxide anesthesia were studied. Org NC 45 was administered by 2-min infusion in doses of 0.28 mg kg-1 (normal renal function group, n = 4) and 0.14 mg kg-1 (renal failure group, n = 5). Four additional patients with normal renal function were given Org NC 45 0.14 mg kg-1 to determine the onset, duration and recovery rate of neuromuscular blockade. The serum concentration of Org NC 45 was determined by normal-phase high performance liquid chromatography (sensitivity 50 ng ml-1), and a two-compartment open pharmacokinetic model was fitted to resulting data. Estimates of distribution half-life (T 1/2 alpha), elimination half-life (T 1/2 beta), volume of distribution at steady state (Vss) and clearance of Org NC 45 did not differ significantly between patients with normal renal function and those with renal failure. The onset, duration and recovery rate times of the neuromuscular blockade by Org NC 45 0.14 mg kg-1 in patients with normal renal function and those with renal failure did not differ significantly.

The recovery of the rat diaphragm from neuromuscular blockade was studied in order to separate the contributions of drug binding and tissue washout. The in vitro rat diaphragm preparation was perfused with a cholinesterase-free solution via the phrenic vein and stimulated electrically via the phrenic nerve. Muscle paralysis was induced by infusion of a depolarizing blocker succinylcholine or by the nondepolarizing blocker pancuronium. The time for recovery from 25-75% recovery averaged 1.0 +/- 0.1 min for pancuronium and 0.8 +/- 0.1 min for succinylcholine at the fast (1.9 ml/min) perfusion rate. This was prolonged to 2.0 +/- 0.3 min for pancuronium and 1.4 +/- 0.1 min for succinylcholine at the slower (0.76 ml/min) rate. More sensitive paired tests of recovery utilizing recovery time and rate demonstrated no drug difference in three comparisons and a 44% longer recovery time for pancuronium only at the lower perfusion rate. In general, recovery times were similar for both drugs. The rapid recovery from pancuronium blockade in this mammalian system as perfusion rate was increased suggests that recovery from this drug is not impaired by drug binding but is strongly dependent on organ perfusion.

Two groups consisting of 10 A.S.A. class I-II neurosurgical patients each were studied to determine whether patients require greater quantities of pancuronium to maintain paralysis after having been given furosemide, 1 mg/kg. After a standardized barbiturate, narcotic and nitrous oxide induction of anesthesia, pancuronium was given intravenously until twitch response was suppressed by 95%. The study group received in addition furosemide, 1 mg/kg, 10 minutes prior to induction of anesthesia. Mean recovery time from 95% to 50% twitch suppression was 21.8 minutes in the control group and 14.7 minutes in the study group. Urinary output was significantly greater (13.5 vs 674 ml) and serum potassium levels lower (4.05 vs 3.85 meq/L) in the study group during recovery of twitch response. Furosemide, 1 mg/kg, facilitates recovery of evoked twitch response after pancuronium.

To establish whether the plasma concentration of pancuronium reflects magnitude of neuromuscular blockade, the authors determined times of recovery from neuromuscular blockade and associated plasma concentrations following equipotent doses of pancuronium using three methods of pancuronium administration: the isolated-arm technique in conscious volunteers (n = 4), and the bolus intravenous injection (n = 7) and continuous-infusion methods (n = 3) in anesthetized patients. Although maximum depressions of twitch tension were similar (85 +/- 11,91 +/- 6, and 92 +/- 4 per cent, respectively) with the three techniques, times to recovery from neuromuscular blockade differed significantly, being 10 +/- 2 min with the isolated-arm technique, 23 +/- 7 min with the bolus-injection technique, and 46 +/- 5 min with the continuous-infusion method. The plasma concentration of pancuronium necessary for neuromuscular blockade was least with the isolated-arm technique and greatest with continuous infusion. At 25 and 75 per cent recovery, mean plasma concentrations were 0.07 +/- 0.01 and 0.04 +/- 0.01 microgram/ml in the isolated arm; 0.13 +/- 0.04 and 0.09 +/- 0.02 microgram/ml after bolus injection, and 0.20 +/- 0.04 and 0.11 microgram/ml during continuous infusion, respectively. It is concluded that the relationship between plasma concentration of pancuronium and magnitude of neuromuscular blockade depends on the method of pancuronium administration.

It has been demonstrated that a simple two-compartment kinetic model may account for the changes in plasma concentration of pancuronium after i.v. administration. However, it can be shown that this simple model does not account satisfactory for the observed changes in muscle twitch response. By the addition of a receptor (biophase) compartment, twitch response can be reconciled with model behavior and the characteristics resemble those predicted by animal studies. The complete model is applied to the problem of total renal failure, and shows that patients with this condition are likely to be marginally resistant to small doses of pancuronium, with a normal rate of recovery. However, larger doses are likely to result in delayed recovery, the duration of effect increasing in a dose-dependent manner.

The pharmacokinetics and pharmacodynamics of vecuronium (25-50 micrograms/kg) and pancuronium (25-50 micrograms/kg) were determined in nine ASA class I or II patients anesthetized with nitrous oxide and halothane. Force of thumb adduction in response to supramaximal stimulation of the ulnar nerve was quantified and recorded. Serum concentrations of the muscle relaxants were determined for eight hours after their administration using a mass spectrometry assay. Data were analyzed by nonlinear regression and fit to a three-compartment pharmacokinetic model and a four-compartment pharmacodynamic model. Vecuronium had a more rapid clearance (5.2 +/- 0.7 ml X kg-1 X min-1; mean +/- SD) and a shorter elimination half-life (71 +/- 20 min) as compared with pancuronium (1.8 +/- 0.4 ml X kg-1 X min-1; 140 +/- 25 min). No other pharmacokinetic differences were found between the drugs. Pharmacodynamic analysis showed that the plasma concentration at steady state which produced a 50% neuromuscular blockade (Cpss 50) was similar for vecuronium and pancuronium. The authors conclude that the drugs are equivalent in their onset and potency; however, the more rapid clearance and shorter elimination half-life for vecuronium provides a kinetic basis for its shorter duration of neuromuscular blockade as compared with pancuronium.

The binding of [3H]quinuclidinyl benzilate ([3H]QNB) to cardiac muscarinic receptors was inhibited not only by classical muscarinic antagonists but also by nicotinic blocking agents and inhibitors of acetylcholinesterase. Gallamine, pancuronium, ambenonium, and decamethonium were the most potent of these agents examined. All of the nicotinic antagonists with significant muscarinic receptor activity had two or three quaternary nitrogens, and the potency of a series of these compounds was a function of the distance between quaternary nitrogens. The effects of gallamine and pancuronium were studied in detail because these neuromuscular blocking agents showed heterogeneity in their binding to cardiac muscarinic receptors, whereas classical muscarinic antagonists such as QNB and atropine did not. Gallamine did not compete for all of the [3H]QNB binding sites on atrial membranes, but left at least 20% of [3H]QNB binding unaffected. Curves of pancuronium competition for [3H]QNB binding were shallow, consistent with two binding sites for pancuronium, with approximately 20% having low affinity. Additionally, in the presence of gallamine or pancuronium, [3H]QNB binding sites were no longer homogeneous, and Scatchard plots became nonlinear. Guanine nucleotides did not alter the effect of gallamine or pancuronium on [3H]QNB binding. Gallamine and pancuronium showed no agonist activity but, like atropine, completely antagonized muscarinic receptor-mediated inhibition of cyclic AMP formation. However, differences in the behavior of gallamine and atropine suggested that gallamine was not a purely competitive antagonist. Gallamine did not protect against receptor alkylation by propylbenzilylcholine mustard, and [3H]QNB dissociation was apparently slowed by gallamine. We interpret our data to suggest that gallamine not only competes for [3H]QNB binding sites, but also binds at a secondary site on the receptor, forming a ternary complex with [3H]QNB. Heterogeneity in ligand binding is proposed to result from the dual actions of gallamine and pancuronium as ligands at both primary and secondary sites on the cardiac muscarinic receptor.

Muscle relaxants are of great benefit to the anaesthetist as adjuncts to anaesthesia. These drugs are used to facilitate endotracheal intubation and to reduce muscle tone during surgery, and may also find application in assisting ventilator care in the intensive care situation. The pharmacological effect of the relaxants may be readily assessed by the anaesthetist by means of a variety of techniques to quantify muscular activity in response to electrical stimulation. A number of factors may modify the effects of the muscle relaxants including anaesthetic agents, hypothermia, patient age and disease status and a variety of drugs. The disposition kinetics of the muscle relaxants have been well characterised although information on protein binding and placental transfer is somewhat scanty. A common characteristic of their pharmacokinetics is multicompartmental behaviour. Clearance of the relaxants ranges from total elimination by the kidneys (gallamine) to substantial hepatic clearance (fazadinium), and thus their clearance may be adversely affected by renal or hepatic disease. Dosage regimens have been designed using knowledge of the disposition kinetics of the relaxants to provide for continuous adequate relaxation during prolonged surgical procedures. With the use of sophisticated pharmacokinetic and pharmacodynamic models good relationships have been demonstrated between plasma concentrations of the relaxants throughout the entire range of relaxant response.

This retrospective study examines the indications and the effects of 119 doses of succinylcholine or pancuronium given in the emergency department during a 24-month period to patients considered to have immediately life-threatening emergencies. The most common indication for succinylcholine was to accomplish tracheal intubation (20 of 25 patients). Indications for pancuronium included computerized tomography of the head (60 of 94), control of agitation (40 of 94), facilitation of tracheal intubation (20 of 94), control of ventilation (12 of 94), and control of seizure unresponsive to anticonvulsants (4 of 94). Deterioration following succinylcholine occurred in three cases. These included two involving bradycardia and one involving ventricular tachycardia. Major complications following pancuronium included four incidences of ventricular arrhythmias. Intubation failure requiring surgical airway occurred in one patient given succinylcholine, two patients given pancuronium, and one patient who received both succinylcholine and pancuronium. Inadequate documentation of neurological examination prior to blockade was noted in six of 25 succinylcholine and nine of 94 pancuronium cases. Failure to sedate patients who might be aware of paralysis occurred in three of 25 succinylcholine and eight of 94 pancuronium uses. Neuromuscular blocking agents facilitate expeditious management of selected critical patients in the ED. Their prudent use requires anticipation of potential complications, preparation for surgical airway should intubation fail, documentation of physical examination before paralysis, and prior sedation when the patient responds to pain.

Plasma concentrations of pancuronium following single dose administration in six patients, and following multiple dose administration in four patients, all undergoing renal transplantation surgery, were measured using a fluorimetric method. A two-compartment open model was used in the pharmacokinetic analysis of the data. Comparison of the pharmacokinetic findings with data previously obtained for patients undergoing elective surgery but having normal renal function indicated that the clearance of the drug was reduced significantly in the patients with renal failure, and that in these individuals the half-life was increased significantly. Measurement of the evoked mechanical twitch response concurrently with plasma concentration monitoring of pancuronium confirmed that the prolongation of half-life in the patients with renal failure was often but not always associated with an extended duration of neuromuscular blockade and furthermore that the rate of recovery from block might also be prolonged. The clinical implications of these findings are discussed.

Antagonism by neostigmine of neuromuscular blockade produced by pancuronium or its metabolites was studied in the cat anterior or tibialis muscle-peroneal nerve preparation using constant infusions of muscle relaxants. The ED50 of neostigmine (dose which caused a 50% antagonism) was 16, 11, 29, and 26 micrograms/kg for pancuronium, 3-hydroxypancuronium, 17-hydroxypancuronium, and 3, 17-hydroxypancuronium, respectively. Times of onset of neostigmine action were shorter when antagonizing 17-hydroxypancuronium neuromuscular blockade. Duration of neostigmine action when antagonizing 17- or 3, 17-hydroxypancuronium blockade was shorter than with pancuronium or 3-hydroxypancuronium. We conclude that more neostigmine is required to antagonize 17- or 3,17-hydroxypancuronium neuromuscular blockade than is required to antagonize pancuronium. Conversely, less neostigmine was required to antagonize 3-hydroxypancuronium blockade.

The effect and plasma concentrations of vecuronium bromide were measured in normal patients after an intravenous dose of 50, 100, or 150 micrograms/kg and in patients with renal failure after 50 or 100 micrograms/kg. Urinary excretion of vecuronium was studied in normal patients after the 150 micrograms/kg dose. Pharmacokinetic parameters of patients with or without renal failure were similar. No metabolites of vecuronium were found in the plasma. Twenty percent of vecuronium was excreted unchanged in the urine; 5% as the 3-hydroxy derivative. No other metabolites of vecuronium were found in the urine. Increasing doses of vecuronium shortened the onset, but prolonged the duration of action and the recovery rate, to a similar extent in patients with or without renal failure. It was concluded that the disposition of vecuronium was best described by a three compartment model. Both the disposition and the effect of vecuronium are only marginally disturbed by renal failure.

The disposition of vecuronium bromide has been investigated in six normal cats (group I) and in six cats with ligated renal pedicles (group II). A combined fluorimetric and chromatographic technique was used to determine the concentrations of vecuronium and its metabolites in biological material. After i.v. injection of 0.6 mg kg-1, vecuronium disappeared rapidly from the plasma of the normal cat. Concentrations decreased bi-exponentially with half-lives of 4.6 and 31 min, respectively. The steady state volume of distribution was 0.23 litre kg-1 and the clearance 11 ml min-1 kg-1. Seventy percent of an i.v. dose of vecuronium (or its metabolites) was recovered: 15% in the urine, 40% in the bile and 15% in the liver. Only 3.8% of this consisted of the 3-hydroxy metabolite. There were no significant differences in pharmacokinetic data or in the amounts of vecuronium and its metabolites recovered in cats with ligated renal pedicles. The 15% of vecuronium normally excreted by the kidney was compensated for by increased hepatic and biliary concentration of vecuronium.

Vecuronium kinetics and dynamics were determined in five infants (3 to 11 months old) and five children (1 to 5 years old) during anesthesia with 70% nitrous oxide and 0.9 MAC halothane. Vecuronium was infused intravenously at a rate of 2.5 micrograms/kg/min while twitch tension of the adductor pollicis muscle was recorded and venous blood samples were drawn for determination of vecuronium concentrations by mass spectrometry. The elimination t1/2 was determined by linear regression of the log postdistribution concentration-time data; these values and noncompartmental techniques were used to calculate total plasma clearance (Cl), volume of distribution at steady state (Vdss), and mean residence time. The steady-state plasma concentration resulting in 50% depression of twitch tension (Cpss50) was determined by an effect compartment and a sigmoid concentration vs. paralysis model. Vdss was larger in infants (357 +/- 70 ml/kg; mean +/- SD) than in children (204 +/- 116 ml/kg), and Cl was of the same order for infants and children (5.6 +/- 1.0 and 5.9 +/- 2.4 ml/kg/min). Mean residence time was longer in infants (66.3 +/- 22.9 minutes) than in children (34.3 +/- 8.0 minutes). Cpss50 was lower in infants (57 +/- 18 ng/ml) than in children (110 +/- 28 ng/ml). The quantity of vecuronium in the body at steady state at 50% depression of twitch tension (Vdss X Cpss50) was similar in infants and children (21.2 +/- 9.9 and 19.0 +/- 3.3 micrograms/kg). During comparable nitrous oxide-halothane anesthesia, age-related changes in Vdss, Cl, and Cpss50 were much like those found for d-tubocurarine.(ABSTRACT TRUNCATED AT 250 WORDS)

The pharmacodynamics and pharmacokinetics of Org NC-45 and each of its metabolites were studied in anaesthetized dogs. Only Org NC-45 and C3-deacetylated NC-45 produced neuromuscular blockade at the doses studied. The plasma half-lives varied from 3 to 15 min, and are about one third of that of the structurally-related compound pancuronium. Renal excretion was of the order 5-20% and the biliary excretion 7-20% 6 h after administration of each of the 4 compounds. The apparent volume of distribution after a 1 1/2 h infustion was of the same order as the extracellular fluid volume. It seems that no significant entero-hepatic recirculation occurs. Thus, long term continuous infusions of Org NC-45 may be safe.

Plasma concentrations and the degree of neuromuscular blockade after a 2-min infusion of 0.1 mg/kg of vecuronium bromide or pancuronium bromide (equipotent doses) were studied in 12 gynecologic patients. The plasma concentrations of both drugs declined in a triphasic manner. The difference between the intercepts and rate constants of the two drugs was not significant. Vecuronium was removed faster from the plasma than pancuronium; this was reflected in a significantly larger plasma clearance rate for vecuronium (4 ml X min-1 X kg-1 vs 1.1 ml X min-1 X kg-1 for pancuronium). The effective plasma concentrations at 50% recovery of the twitch height were 0.11 +/- 0.02 (vecuronium) and 0.2 +/- 0.03 microgram/ml (pancuronium). The disposition kinetics were adequately described by a three-compartment model. An effect compartment was added to the model to correlate the neuromuscular effects and plasma concentrations of both drugs. The ratio between concentrations of vecuronium and pancuronium in the effect compartment at 50% twitch height was 0.83. In spite of its greater potency, vecuronium has a shorter duration of action than pancuronium.

Vecuronium provides additional flexibility to the clinician using neuromuscular-blocking drugs. Its shorter duration of action, lack of significant cardiovascular effects and lack of dependence on the kidney for elimination provide clinical advantages over, or alternatives to, currently available, nondepolarizing neuromuscular-blocking drugs.

Vecuronium and pancuronium were compared for placental transfer, pharmacokinetic variables, and neonatal effects during cesarean section under general anesthesia. Eighteen women underwent rapid-sequence intravenous induction using d-tubocurarine, succinylcholine, thiopental, and oxygen. Immediately after tracheal intubation, an intravenous injection of vecuronium (n = 11) or pancuronium (n = 7), 0.04 mg/kg, was given. Maternal venous blood samples were obtained before induction and at frequent intervals for 4 h after administration of vecuronium or pancuronium. Also, maternal venous and umbilical-cord arterial and venous blood samples were obtained at delivery. To describe placental transfer and maternal pharmacokinetics of the drugs, serum drug concentrations were determined using single-ion-monitoring mass spectrometry. The Apgar score and Neurologic and Adaptive Capacity Score (NACS) were used to evaluate neonatal condition. Both drugs crossed the placenta, as demonstrated by low concentrations of vecuronium (8.5-26.4 ng/ml) or pancuronium (12.2-34.2 ng/ml) found in umbilical venous blood. At delivery, the ratio of the drug concentration in umbilical venous blood to that in maternal venous blood was 0.11 +/- 0.02 for vecuronium and 0.19 +/- 0.03 for pancuronium. Vecuronium had a more rapid clearance (6.4 +/- 0.4 ml X kg-1 X min-1, mean +/- SE) and a shorter elimination half-life (36 +/- 1.8 min) than pancuronium (3.0 +/- 0.1 ml X kg-1 X min-1 and 72 +/- 6 min, respectively). No other pharmacokinetic differences were found between the drugs. Neonatal outcome was not affected adversely by either muscle relaxant, as assessed by Apgar scores and NACSs . The short duration of action, the minimal placental transfer, and the apparent lack of clinical neuromuscular effects on the newborn suggest that vecuronium should be a useful muscle relaxant for cesarean section.

The serum and urinary concentrations of pancuronium were measured in 14 surgical patients with cirrhosis and 12 patients free from liver disease undergoing abdominal surgery. A two-compartment open model was used in the pharmacokinetic analysis of the data. A two-fold increase in both the distribution half-life (T 1/2 alpha) from 11 min to 24 min and in the elimination half-life (T 1/2 beta) from 114 min to 208 min was observed in patients with cirrhosis. In these individuals, the total apparent volume of distribution of pancuronium was increased by 50%. Plasma clearance of pancuronium was decreased by 22%. No significant difference was found in the urinary excretion and biotransformation pattern of pancuronium. These results suggest that there is a risk of prolonged duration of action of pancuronium in patients with cirrhosis. In these patients, the initial dose to achieve adequate muscle relaxation is high and simultaneously there is slow disappearance of pancuronium from plasma. These alterations are mainly a consequence of the increase in the distribution volume of pancuronium in patients with cirrhosis.

The urinary excretion of ORG NC 45 (Vecuronium) and of pancuronium was studied in unanesthetized rats and the biliary excretion was studied in anesthetized rats. Urine and bile were analyzed for unchanged drug by a new and specific mass spectrometric assay. Pancuronium was eliminated primarily in the urine (85% +/- 6% of the dose in 12 hours), but little ORG NC 45 appeared in the urine (3.5% +/- 1.1% in 12 hours). Biliary excretion accounted for 46% +/- 4% of the ORG NC 45 dose in 7 hours, but only 7.5% +/- 5.3% of an injected dose of pancuronium appeared in the bile. Thus, it appears that ORG NC 45 (a monoquaternary ammonium compound) has a higher biliary clearance than pancuronium (a bisquaternary ammonium compound). The different biodisposition of these two compounds may be due to the greater lipophilicity and concomitant enhanced permeability into the hepatocyte of ORG NC 45. We conclude that in the rat elimination of pancuronium is primarily via the kidney whereas elimination of ORG NC 45 is dependent on nonrenal mechanisms.

This review is an attempt to bring together the pharmacokinetic data on d-tubocurarine and pancuronium with clinical observations on relaxant dosage and effect. The modelling techniques used here represent an oversimplification of the relationships between relaxant plasma concentration and response as they do not predict either the time of onset of paralysis or its peak intensity. However, they do enable calculation of a bolus dose of relaxant required to achieve a particular intensity of paralysis for the average patient once pseudo-distribution equilibrium has been achieved. This has been further extended to predict the cumulation of the relaxants with subsequent dosage in average patients. Suggested regimens incorporating bolus and infusion doses of the relaxants to achieve continuous neuromuscular blockade have been calculated also. Averaged pharmacokinetic parameters derived from patients with renal or hepatic dysfunction have been used to predict the likely duration and intensities of paralysis for the relaxants.