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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.

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.

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)

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)

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.

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)

The effect of temperature on the potencies of neuromuscular blocking agents remains unclear. This study was undertaken to examine the effects of different neuromuscular blocking agents at 37 and 27 degrees C at a constant carbon dioxide content (alpha stat principle). The effect of neostigmine 1 mumol litre-1 induced antagonism of these agents was also investigated. Phrenic nerve-hemidiaphragm preparations of rats were mounted in modified Krebs solution, maintained at 37 degrees C and aerated with a 5% carbon dioxide-95% oxygen gas mixture, and at 27 degrees C with 4% carbon dioxide to maintain the carbon dioxide content of the solution constant. Phrenic nerves were stimulated with 0.1-Hz supra-maximal impulses of 0.2-ms duration and the elicited tension of the diaphragm recorded. The potencies of the steroidal neuromuscular blocking agents (rocuronium, vecuronium, pancuronium and pipecuronium) increased significantly at 27 degrees C (P0.05), while the potencies of the benzylisoquinolinium agents (tubocurarine and dimethyltubocurarine) did not change. Neostigmine-induced antagonism of the steroidal agents did not differ significantly between each other but differed significantly from the benzylisoquinolinium agents (P0.05) at both temperatures. The ratios of IC50 (inhibitory concentration, 50%) with and without neostigmine at hypothermia were slightly higher for the steroidal agents, indicating slight enhancement of antagonism by neostigmine at 27 degrees C. In contrast, the ratios were significantly greater at 27 degrees C (P0.05) for isoquinolinium agents, implying significant enhancement of antagonism. Our results indicate that at 27 degrees C the potency of all steroidal agents increased and neostigmine-induced antagonism was slightly enhanced.(ABSTRACT TRUNCATED AT 250 WORDS)

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

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

The pharmacokinetics of pipecuronium 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.

Neuromuscular blocking drugs are not as notorious for producing adverse reactions as the i.v. induction agents; nevertheless, to a varying degree they all produce unfavourable or harmful effects. The newer non-depolarizing neuromuscular blockers, atracurium and vecuronium, have been developed in an attempt to overcome the disadvantages of the earlier drugs, but although much more specific agents, they are not completely free from side-effects. The adverse effects of the neuromuscular blocking drugs available in Great Britain today will be discussed in this paper. Those which are not available in this country (such as pipecuronium and metocurine), and obsolete agents (such as decamethonium) will not be discussed. Although what follows is concerned mainly with the non-depolarizing agents, suxamethonium is included where appropriate, whilst what might be regarded as the unique features of the drug are discussed later in the article.

We have studied the effects of pipecuronium and pancuronium on myocardial contractility and heart rate in two different animal preparations. Pipecuronium and pancuronium produced no change in isometric contraction of rabbit atria. The chronotropic effects of pipecuronium, pancuronium and vecuronium were investigated using acetylcholine as an agonist in isolated perfused rabbit heart. Pancuronium but not pipecuronium or vecuronium, produced a significant degree of antagonism to the bradycardia produced by acetylcholine.

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.