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The systemic anti-inflammatory effect induced by antidromic sensory nerve stimulation was investigated in rats and guinea-pigs. In atropine-pretreated rats, bilateral antidromic stimulation of vagal afferent fibres (8 Hz, 20 min, at C-fibre strength) inhibited plasma extravasation induced by 1% mustard oil on the acutely denervated hindlegs by 36.45+/-3.95%. Both the prevention of this inhibitory effect by cysteamine pretreatment and the stimulation-evoked rise of plasma somatostatin-like immunoreactivity in the two species suggest a mediator role of neural somatostatin. Since this response was blocked by systemic capsaicin pretreatment and slightly reduced after subdiaphragmal vagotomy, participation of thoracic capsaicin-sensitive afferents is indicated. In guinea-pigs pretreated with guanethidine and pipecuronium, antidromic sciatic nerve stimulation induced 45.46+/-5.08% inhibition on the contralateral leg and increased plasma somatostatin-like immunoreactivity. It is concluded that somatostatin released from the activated vagal capsaicin-sensitive sensory nerve terminals of the rat and somatic nerves of the guinea-pigs exerts a systemic humoral function.

We have studied the effect of non-depolarizing neuromuscular blocking agents, at concentrations present in serum during anaesthesia, on release of [3H]-norepinephrine ([3H]NE) from superfused atrial appendage obtained during cardiac surgery from 48 patients. Three of the neuromuscular blocking agents (pancuronium, gallamine and rocuronium), which are known to cause an increase in heart rate during anaesthesia, increased stimulation-evoked release of [3H]NE. In contrast, (+)tubocurarine and pipecuronium, neuromuscular blocking agents that do not cause tachycardia, did not affect release of NE. Org 9487 significantly enhanced release while SZ1677 was ineffective, even at concentrations higher than those expected after administration of a 2 x ED95 dose. Atropine enhanced release. These data suggest that the axon terminals of sympathetic nerves in human heart have muscarinic heteroreceptors whose activation by acetylcholine (ACh) released from the vagal nerve reduces release of NE. This action contributes to lowering of heart rate. Therefore, any neuromuscular blocking agent with antimuscarinic actions and capable of increasing the release of NE may produce tachycardia.

The potential effects of propofol emulsion (Diprivan) on the neuromuscular transmission and muscular contraction were studied using in vitro and in vivo nerve-muscle preparations of rats. The contractions of the isolated rat diaphragm elicited by either indirect or direct electrical stimulation were inhibited by propofol emulsion at threshold concentrations of 42 and 112 μmol l −1 , respectively. Similarly, the gastrocnemius muscle contractions induced by either indirect or direct electrical stimulation in vivo were inhibited by propofol emulsion administration as a bolus injection of 2.5 mg kg −1 intravenously, followed by intravenous infusion of 150 μg kg −1 min −1 for 1 h into rats. The inhibitory effects of propofol in both preparations were greater with indirect rather than direct stimulation. Propofol emulsion was found to be capable of enhancing the paralysis of the indirectly stimulated rat diaphragm in vitro and gastrocnemius muscle in vivo induced by either pipecuronium or succinylcholine. The combination of propofol and pipecuronium led to a synergistic inhibition of the neuromuscular transmission, while the combination of propofol and succinylcholine led to additive inhibition. Pretreatment with propofol emulsion at these threshold concentrations markedly inhibited the stimulant effects of aminophylline and digoxin on the indirectly and directly induced diaphragmatic contractions. Also, the enhancement effects of aminophylline on the indirectly and directly and of digoxin on indirectly induced rat gastrocnemius muscle contractions were markedly inhibited by propofol emulsion administration to rats. Pretreatment with propofol emulsion at the threshold concentrations enhanced the inhibitory effects of verapamil on diaphragmatic contractions elicited either indirectly or directly and enhanced the inhibitory effect of adenosine on the contractions elicited indirectly. Similarly, the inhibitory effects of verapamil on the indirectly and directly and of adenosine on indirectly induced rat gastrocnemius muscle contractions were markedly potentiated by propofol emulsion administration to rats. In addition, doubling the concentration of calcium in the bathing fluid produced no change in the inhibitory effects of propofol emulsion on either indirectly or directly elicited diaphragmatic contractions, while doubling the concentration of external magnesium potentiated the propofol effects. Pretreatment with 4-aminopyridine suppressed the inhibitory effects of propofol emulsion on diaphragmatic contractions elicited either indirectly or directly. These results suggest that propofol acts presynaptically to inhibit the neuromuscular transmission and acts at the muscle membrane to inhibit the muscular contraction.

Study Objective To compare dose-response relationship and maintenance requirement of pipecuronium in anesthetized infants, children, and adults. Design Prospective, consecutive sample trial. Setting Operating room at a university hospital. Patients: 15 infants (1–11 months), 15 children (3–10 years), and 15 adults (35–50 years) of ASA physical status I and II. Interventions Anesthesia was induced and maintained with N 2 O:O 2 2:1 and 1 minimum alveolar concentration end-tidal halothane. The neuromuscular function was recorded by adductor pollicis electromyogram evoked by a train-of-four ulnar nerve stimulation at 20 second intervals. An individual cumulative log-probit dose-response curve was established and maintenance requirement of pipecuronium determined. Between-group comparisons were made by analysis of variance and Scheffe F-test. Measurements and Main Results Dose-response curves were parallel with a doserequirement of pipecuronium similar in infants and adults (ED 95 of 40–42 μg/kg) and greater in children (ED 95 of 52 μg/kg). After 30 minutes of surgical neuromuscular block, pipecuronium was required in each age group at a rate oj 0.6 to 0. 7 individual ED 95 doses per hour to maintain an 85 % to 95% neuromuscular block. Conclusions Bolus dose requirement of pipecuronium is greatest in children. Maintenance requirement is related to potency in each age group studied.

We have determined the relative potency of rocuronium, pancuronium, pipecuronium and vecuronium, and examined the nature of the interaction of rocuronium with the other three steroidal neuromuscular blocking drugs. We studied the dose-response relationships of each drug and their combination with rocuronium in 200 ASA I or II patients during propofol-fentanyl-nitrous oxide-oxygen anaesthesia. Neuromuscular block was recorded as the evoked thenar mechanomyographic response to single twitch stimulation of the ulnar nerve at 10-s intervals. The dose-response curves were determined by probit analysis. Isobolographic and algebraic (fractional) analyses were used to assess the combined effect of equipotent doses of rocuronium and vecuronium, pipecuronium or pancuronium and to define the type of interaction between these drugs. The isobolograms were constructed by plotting single-drug ED50 points on the dose co-ordinates, and a combined ED50 point in the dose field. The calculated doses producing 50% depression (ED50) of the twitch height for rocuronium, pancuronium, pipecuronium and vecuronium were 144.8 (95% confidence intervals 140.4-149.3), 32.4 (31.7-32.9), 27.1 (26.5-27.6) and 23.7 (22.7-24.8) micrograms kg-1, respectively. Corresponding doses producing 95% depression (ED95) of twitch height were, respectively, 322.1 (307.5-337.3), 58.1 (56.2-60.1), 48.7 (46.9-50.5) and 39.9 (38.4-41.4) micrograms kg-1. Based on the estimate of ED50, the relative potency was 1:4.5:5.4:6, respectively. The interaction between rocuronium and vecuronium, pipecuronium or pancuronium was found to be additive.

We have compared the antagonism of neuromuscular block produced by pipecuronium with pancuronium in 80 anaesthetized surgical patients using mechanomyography and electromyography. Pancuronium 0.1 mg kg-1 or pipecuronium 0.07 mg kg-1 was given after induction of anaesthesia and neuromuscular block was adjusted to 75% twitch depression at the time of antagonism. The following regimens were used: edrophonium 0.5 and 1.0 mg kg-1, neostigmine 0.04 mg kg-1, pyridostigmine 0.3 mg kg-1 and edrophonium 0.25 mg kg-1 with pyridostigmine 0.15 mg kg-1. Antagonism was evaluated also by the head lift test. There was no difference between the reversibility of neuromuscular block produced by pancuronium or pipecuronium. Edrophonium produced a significantly faster antagonism than neostigmine or pyridostigmine but onset of action was not significantly faster than that of edrophonium with pyridostigmine. All regimens produced 100% (or near 100%) antagonism of twitch response within 15 min. However, TOF fade antagonism was more complete with pyridostigmine, neostigmine and edrophonium 1.0 mg kg-1 than with edrophonium 0.5 mg kg-1. The head lift test indicated somewhat less antagonism with edrophonium 0.5 and 1.0 mg kg-1. Using five monitoring methods, the rank order of reversal potency was: pyridostigmine approximately neostigmineedrophonium 1.0 mg kg-1edrophonium+pyridostigmineedrophonium 0.5 mg kg-1.

Summary In a little over 10 years, six new muscle relaxants have been introduced into clinical practice. The first two, the intermediate-duration vecuronium and atracurium were outstanding drugs and clearly an advance over the long-acting drugs which had been available previously. The next two, the long-acting doxacurium and pipecuronium were relics of an earlier era, and have made little clinical impact. Mivacurium created a new class, the short-acting nondepolarizer, and caused succinylcholine to be reclassified as an ultrashort-acting drug. However, mivacurium has neither the rapid onset nor the ultrashort duration of succinylcholine and is to some extent still trying to establish a significant clinical role. Rocuronium is the first non-depolarizer to have an onset approaching that of succinylcholine, and has spurred the development of drugs of low potency. It is likely that we will see the introduction of at least two more drugs, ORG 9487 and 51W89 by the end of this decade, but the goal of a nondepolarizing relaxant which is a complete replacement for succinylcholine still seems some distance in the future.

T HIS ARTICLE reviews the complications of muscle relaxants in clinical practice. Their introduction more than 50 years ago revolutionized the practice of anesthesia but was also associated with a new set of anesthetic-induced complications. Much of the development of new compounds has been with the aim of avoiding or reducing these effects, some of which contributed to postoperative morbidity and mortality. This review emphasizes the complications that have attracted recent attention, and is restricted to those agents in current use and to the recently introduced compounds, doxacurium, mivacurium, pipecuronium, and rocuronium. It should be considered an update of the article published in this journal 10 years ago. ~ Complications of muscle relaxants can be unwanted effects of the normal action of the drugs at the neuromuscular junction, actions at other sites, abnormal or idiosyncratic responses, or result from their use in unusual situations. Some of the complications are common to all relaxants (general complications), eg, slow recovery from block or residual blockade, anaphylaxis, etc, others are restricted to a few or single drugs (specific complications), eg, prolonged block after succinylcholine or mivacurium from a decrease in plasma cholinesterase activity. This review has less emphasis on succinylcholine, in part because most of its specific complications are well recognized but also because it is now used much less frequently than the estimate 10 years ago of its use in 75% of all anesthetics.

We have studied in seven healthy conscious volunteers the correlation between the electro-myographic (EMG) and clinical criteria used to identify adequate recovery from sub-paralysing doses of pipecuronium. Pipecuronium (mean dose 1.88 (range 0.92–3.16) mg) was administered to reach a T4/T1 ratio of 0.5; full recovery to 1.0 was produced in a mean time of 25.3 (14–39) min. During recovery from neuromuscular block, we measured tidal volume, forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1) negative inspiratory pressure (NIP), peak expiratory flow rate (PEFR), mid-expiratory flow rate (MEFR) and 5-s head lift. The assessments were started when the train-of-four (TOF) ratio reached 0.5 ± 0.001 and repeated at each 0.1 ± 0.001 increase up to a ratio of 1.0. All volunteers showed ptosis and diplopia after the first dose and difficulty in swallowing with subsequent doses. They also experienced a pleasant, relaxing sedative sensation. All could sustain head lift for 5 s at a TOF ratio of 0.5 and higher, except for one subject who could not lift his head only at a ratio of 0.5. There was a statistically significant decrease in FVC, FEV, and PEFR with a nonsignificant decrease in other pulmonary measurements, except for NIP which only decreased significantly at a ratio of 0.5. These changes are probably of no clinical importance. All the measured respiratory variables returned to control values at a TOF ratio of 0.9. (Br.J. Anaesth. 1995; 74: 16–19)

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

Summary Four new non-depolarizing drugs offer advantages in different clinical situations. Pipecuronium and doxacurium are long-acting compounds with a relatively slow onset and a variable duration of action. Their main advantage is a lack of cardiovascular side-effects. Their use is likely to be confined to prolonged surgical procedures. Mivacurium has an onset of action similar to atracurium and vecuronium and a duration of action midway between these drugs and suxamethonium. It is metabolized by plasma cholinesterase and may not require to be routinely antagonized by anticholinesterases. Rocuronium (Org 9426) has a duration of action similar to atracurium and vecuronium but a more rapid onset of action. Whether it can replace suxamethonium in the rapid sequence induction requires further clinical assessment, but it would appear to be the drug of choice for rapid intubation where suxamethonium is contraindicated.

Hemodynamic responses to pipecuronium bromide or doxacurium chloride were compared in patients undergoing valvular heart surgery. Thirty ASA class III-IV patients of either sex, mean age 62 +/- 3 years (+/- SD), weight 70 +/- 3 kg, were randomly selected to receive either doxacurium (0.08 mg/kg) or pipecuronium (0.15 mg/kg). Hemodynamic parameters were determined at preinduction, induction, 2 minutes and 6 minutes following administration of the muscle relaxant. Anesthetic induction consisted of midazolam, 0.10 mg/kg, followed by fentanyl, 5 micrograms/kg. Measured or calculated parameters were as follows: mean arterial pressure, heart rate, cardiac index, mean pulmonary artery pressure, systemic vascular resistance index, central venous pressure, pulmonary capillary wedge pressure, stroke volume index, left and right stroke work indices, and pulmonary vascular resistance index. Awake patients who had been randomly assigned to the pipecuronium group had significantly higher pulmonary capillary wedge pressures (22 +/- 2 v 15 +/- 2 mmHg; P < 0.05) and heart rates (86 +/- 3 v 64 +/- 5 beats/min; P < 0.05) than awake patients in the doxacurium group. Following induction, both wedge pressure and heart rate were not significantly different between the two groups. Compared to hemodynamics at induction, there were no clinically significant changes following administration of pipecuronium or doxacurium.

We have studied the neuromuscular effects of pipecuronium, vecuronium and their combination in 130 ASA group I or II patients. Patients were anaesthetized with 0.8% halothane and 60% nitrous oxide in oxygen. Neuromuscular block was recorded as the evoked thenar mechanomyographic response to train-of-four stimulation of the ulnar nerve (2Hz at 10-s intervals). The dose-response curves were determined by probit analysis. The calculated doses producing 50% depression of the first twitch height were 15.6, 16.9 and 15.0 μg kg−1 for the pipecuronium, vecuronium and pipecuronium-vecuronium combination groups, respectively. Isobolo graphic and algebraic (fractional) analyses were used to assess quantitatively the combined neuromuscular effect of pipecuronium and vecuronium and to define the type of interaction between these drugs. The interaction between pipecuronium and vecuronium was found to be additive. (Br. J. Anaesth. 1993; 71: 556–560)

Study Objective : To measure the interaction of two antibiotics (clindamycin and colistin) on neuromuscular blockade induced by Pipecuronium bromide (a new long-acting, steroidal, nondepolarizing neuromuscular blocking drug). Design : Prospective, randomized, placebo-controlled study. Setting : Inpatient gynecologic and gastroenterologic service at a university Medical center. Patients : Three groups of 20 ASA physical status 1 and II patients with normal kidney and liver function, taking no medication, and undergoing elective surgery under general anesthesia. Interventions : Anesthesia was induced with propofol and alfentanil intravenously (IV) and maintained with a propofol infusion and 60% nitrous oxide in oxygen. Pipecuronium bromide 50 μg/kg was administered after reaching a stable baseline of single-twitch response. At 25% recovery of Pipecuronium-induced neuromuscular blockade, patients received one of two antibiotics, clindamycin 300 mg or colistin 1 million I U, or a placebo. Measurements and Main Results : The recovery index (RI, defined as time from 25% to 75% recovery of neuromuscular blockade) was measured using the single-witch response of the adductor pollicis muscle with supramaximal stimulation of the ulnar nerve at the wrist. RI after administration of an antibiotic (given at 25% recovery) was measured and compared with RI of the control group using Student's unpaired t -test. Statistical analyses of the results showed a significant prolongation of the recovery time (from 25% to 75% recovery) of 40 minutes for colistin. Conclusions : When this type of antibiotic is used during anesthesia with pipecuronium as a muscle relaxant, one must be aware of a significant prolongation of an already long-acting neuromuscular blockade and (although not observed in this study) possible problems in antagonism.

We have investigated the effects of adenosine i.v. on neuromuscular block induced by rocuronium, vecuronium and pipecuronium in an in vivo guinea-pig sciatic nerve-tibialis anterior preparation. The ED50 of each neuromuscular blocker was determined from cumulative log dose-response regression lines (n = 14). In separate experiments, adenosine 0.1 mg kg-1 min-1 or the same volume of 0.9% NaCl was given i.v. via a constant infusion and the ED50 of each neuromuscular blocking agent was then administered (n = 24). Adenosine 0.1 mg kg-1 min-1 increased significantly maximal block induced by the ED50 of these neuromuscular blockers (55-72%, 49-73% and 60-96%, respectively, for rocuronium, vecuronium and pipecuronium; P0.05). Time to maximal block after rocuronium was significantly prolonged by adenosine (1.4-2.1 min; P0.05) and time to maximal block after vecuronium and pipecuronium was unchanged by adenosine. Time to maximal recovery of twitch tension after administration of the ED50 of all neuromuscular blocking agents was prolonged significantly by adenosine (4.5-10.7 min, 8.2-15.8 min and 47.0-128.7 min, respectively, for rocuronium, vecuronium and pipecuronium; P0.05). We conclude that continuous infusion of adenosine 0.1 mg kg-1 min-1 potentiated the effects of neuromuscular blocking agents in this in vivo guinea-pig preparation.

Study Objective : To determine the incubating conditions following the administration of pipecuronium bromide in doses of two (0.07 mg/kg) or three (0.1 mg/kg) times ED 95 (average dose that gives 95% block of the first twitch). Design : To compare intubating conditions at 1 tl2 and 21/2 minutes in 41 patients receiving balanced anesthesia. Setting : Surgical patients at Thomas Jefferson University Hospital. Patients : Forty-one patients undergoing surgical procedure who received general anesthesia. Interventions : After obtaining a stable baseline of train-of f our (TOF), 41 patients r randomly received either 0.07 mg/kg or 0.1 mg/kg of pipecuronium as a single intravenous (IV) bolus dose, and the trachea was intubated either at 112 or 212 minutes. minutes. Measurements and Main Results : Intubating conditions at 212 minutes appeared significantly better than those at 12 minutes, regardless of the pipecuronium dose. The mean time for TI (first twitch of TOF) to reach 50% and 90% suppression was 1.36 ± 0.51 minutes and 2.29 ± 0.8 minutes, respectively, for the 0.07 mg/kg dose and 1.07 ± 0.27 minutes and 1.72 ± 0.45 minutes, respectively, for the 0.1 mglkg dose. This did not make a significant difference in intubating conditions at either time. The time to 25% recovery of TI was 68.2 ± 22 minutes for the 0.07 mg/kg dose and 121.5 ± 49 minutes for the 0.1 mg/kg dose. In patients who had spontaneous recovery of T1 to between 10% and 25% of control, administration of neostigmine or edrophonium resulted in identical recovery in 10 minutes. However, in patients with less than 10% spontaneous recovery of T1, neostigmine appeared to be superior to edrophonium. Conclusion : Pipecuronium has a relatively rapid onset. The trachea could be intubated successfully in 112 minutes with a dose of either 0.07 mg/kg or 0.1 mg/kg. If the clinical situation requires perfect relaxation with no movement or bucking, we recommend waiting at least 212 minutes.

The usefulness of the joint application of HPLC and NMR spectroscopy in drug impurity profiling is demonstrated by the following examples: (1) identification of Z and E isomers of 17α-ethynyl-4-oestrene-3β,17-diol-3- acetate-17-(3′-acetoxy-2′-butenoate) in ethynodiol diacetate; (2) identification of the p -tolyl analogue as the impurity of enalapril maleate; (3) identification and quantification of 2′-dehydro-pipecuronium bromide in pipecuronium bromide. The possibilities of utilizing NMR spectroscopy for the identification and quantification of the impurities with and without their isolation are discussed.

Interaction of the steroidal neuromuscular blocking drugs pancuronium, pipecuronium, rocuronium and vecuronium with cardiac muscarinic receptors in rat hearts was investigated in vitro by a tritiated N-methyl hyoscine binding assay. We showed an interaction with cardiac muscarinic receptors with a rank order of potency pancuronium > vecuronium > pipecuronium > rocuronium and demonstrated complex binding characteristics for pancuronium, vecuronium and rocuronium, with "Hill coefficient" of less than unity. We conclude that the haemodynamic differences seen during the use of these neuromuscular blocking drugs may be a result of their interactions with cardiac M2 muscarinic receptors.

We have examined the prolongation of a maintenance dose of vecuronium after an intubating dose of pipecuronium in 45 patients who received either pipecuronium 70 μg kg-1 or vecuronium 200 μg kg-1 i.v. for tracheal intubation, followed by either pipecuronium 10 μg kg-1 or vecuronium 15 μg kg-1 for maintenance of neuromuscular block. The duration of the vecuronium maintenance dose was greater after pipecuronium (40 (so 12) min) than after vecuronium (29 (9) min) (P = 0.02). The duration of pipecuronium after pipecuronium (49 (15) min) was similar to that of vecuronium after pipecuronium. We conclude that the duration of action of vecuronium is prolonged by prior administration of pipecuronium. (Br. J. Anaesth. 1993; 70: 446–448)

Acute respiratory and metabolic acidosis as well as metabolic alkalosis increased (by 11, 11, 21%) whereas respiratory alkalosis antagonized (by 10%) the partial steady state block produced by pipecuronium infusion on the anterior tibialis muscle of the cat. The duration of neuromuscular block following six successive doses of pipecuronium was prolonged 1.4-fold during long-lasting metabolic alkalosis while this parameter was shortened to half of that in control cats during acidosis. Pipecuronium block could be fully antagonized by neostigmine.

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

A sensitive and specific capillary gas chromatographic (GC) assay was developed for the quantitation of the quaternary ammonium steroidal neuromuscular blocking drugs pancuronium (PANC), vecuronium (VEC) and pipecuronium (PIP), as well as the metabolites 3-desacetylpancuronium (3-desPANC) and 3-desacetylvecuronium (3-desVEC) in plasma, bile and urine; the putative metabolite 3-desacetylpipecuronium (3-desPIP) was extracted and quantitated only in urine. The procedure employed a single dichloromethane extraction of the iodide ion-pairs of the monoquaternary or bisquaternary ammonium compounds (including internal and external standards) from acidified, ether-washed biological fluid followed by the formation of stable O- tert .-butyldimethylsilyl derivatives at the 3-hydroxy steroidal position of the metabolites. An automated capillary GC system fitted with a nitrogen-sensitive detector and an integrator was then used to analyze and quantitate both parent compounds and their derivatized metabolites. Optimal extraction, derivatization and GC conditions, as well as short-term stability and recoveries of these drugs and metabolites in plasma, are reported. Electron ionization mass spectrometry combined with GC was used to confirm the identities of compounds eluted from the column. The assay demonstrated a 10 3 -fold linear range up to 5000 ng/ml for PANC, VEC, 3-desVEC and PIP, and lower limits of detection with adequate precision of 2 ng/ml for PANC, VEC and PIP, and 4 ng/ml for 3-desVEC; 3-desPANC was linear from 8 to 500 ng/ml while 3-desPIP was linear from 25 to 1000 ng/ml. The precision (coefficient of variation) of the calibration curves for underivatized drugs and their derivatized metabolites over the linear ranges was 2–20% and the reproducibility of the assay over a range of clinical concentrations of these drugs found in human plasma was 5–16% for PANC, 2–4% for VEC and 6–11% for PIP. No interferences were detected in the assay of plasma samples from 106 surgical patients.

The non-depolarising muscle relaxant vecuronium (0·2 mg kg−1) was administered to four dogs. At 50 per cent return of neuromuscular activity, as measured by the train-of-four technique, the depolarising muscle relaxant suxamethonium (0·3 mg kg−1) was injected intravenously. At 50 per cent return of neuromuscular activity reversal of the block was achieved with atropine and neostigmine. The duration of action of suxamethonium was reduced by the prior administration of vecuronium. In the second series of experiments the order of administration of the suxamethonium and vecuronium was reversed. Suxamethonium (0·3 mg kg−1) was administered first and at 50 per cent recovery vecuronium (0·2 mg kg−1) was given. At 50 per cent recovery of the twitch response after vecuronium administration the block was reversed with atropine and neostigmine. The previous administration of suxamethonium prolonged the duration of the vecuronium induced neuromuscular block.

Pipecuronium bromide is a nondepolarising muscle relaxant which is an analogue of pancuronium. Doses of 0·025 and 0·05 mg kg –1 produced neuromuscular block in the anaesthetised dog. Previous work would suggest that the drug has minimal effects on the cardiovascular system. However, a dose of 0·05 mg kg –1 produced a profound hypotension in one dog on one occasion. The neuromuscular blocking action of the drug would appear to be extremely variable as indicated by the wide range of the results. The neuromuscular block was readily reversible with neostigmine preceded by atropine.

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.