Inhibitor Report for: Vecuronium

Recovery from the effects of muscle relaxants can occur either spontaneously by their metabolism in the body or by elimination via the normal excretion pathways, or by the administration of pharmacologic antagonists. The decision as to whether spontaneous recovery should be allowed to take place or pharmacologic reversal should be induced depends upon several factors, principal among them being the duration of action of the muscle relaxant used, its dose, and the time that is available. The recovery times of most relaxants, including atracurium and vecuronium, are such as to require antagonism if adequate recovery is to be attained quickly. An agent such as mivacurium may, however, allow complete spontaneous recovery to take place without the use of antagonists.

Mivacurium chloride (BW B1090U) is a new, short-acting non-depolarizing neuromuscular blocking agent. It is a synthetic bis-benzylisoquinolinium diester, which is hydrolysed rapidly by plasma cholinesterase. This study compares mivacurium, atracurium and vecuronium by continuous i.v. infusion. The duration of mivacurium infusion ranged from 29.5 to 286 min. The steady state infusion rates necessary to maintain 95 (SEM 4)% twitch suppression were: mivacurium 8.3 (0.7) micrograms kg-1 min-1; atracurium 7.9 (0.4) micrograms kg-1 min-1; vecuronium 1.2 (0.3) micrograms kg-1 min-1. Following infusions of mivacurium, various recovery times (for example: 25-75%, 6.9 (0.3) min; 25-95%, 11.0 (0.4) min; 5-95% 14.5 (0.4) min) did not differ significantly from those following single bolus doses. Recovery times following cessation of mivacarium infusions were approximately 50% of those for equivalent durations of infusion of atracurium (10.9 (0.3) min for 25-75% recovery and 26.6 (0.4) min for 5-95% recovery). For vecuronium, corresponding recovery times were 13.8 (0.9) and 32.0 (1.2) min, respectively. Comparative recovery times for mivacurium were 40-50% of those for vecuronium. There was a significant correlation between the infusion rate of mivacurium required to maintain 95% twitch depression and the plasma cholinesterase activity of individual subjects.

The interaction of three new non-depolarizing neuromuscular blocking agents--atracurium, vecuronium and Duador--on human red cell acetylcholinesterase (AChE; EC 3.1.1.7) and human plasma butyrylcholinesterase (BuChE; EC 3.1.1.8) was investigated. The binding of these neuromuscular blockers to human plasma proteins (protein binding) was also studied with a new method not requiring dialysis. For sake of comparison the protein binding and the interaction of tubocurarine and pancuronium with AChE and BuChE were observed also. None of the drugs studied was a substrate of AChE or BuChE. All had a relatively weak inhibitory effect on AChE (I50 greater than 10(-5) mol litre-1 in assay systems containing 5% haemolysed red cells). Of the three new neuromuscular blockers, vecuronium and Duador were relatively potent inhibitors of BuChE (I50 less than 10(-5) mol litre-1 in assay systems containing 5% plasma), but less potent than pancuronium (I50 = 6.1 X 10(-8) mol litre-1). All neuromuscular blocking drugs tested, especially vecuronium and pancuronium, were strongly (77-91%) bound to plasma proteins.

INTRODUCTION Recent developments in both the quantitative evaluation of neuromuscular blockade and new muscle relaxants are reviewed. With respect to nerve stimulation, neuromuscular recording, and definition of parameters, the results of the 1994 Copenhagen International Consensus Conference are highlighted. Future clinical studies should adhere to these standards. MUSCLE RELAXANTS: Rocuronium, cisatracurium, and mivacurium are new muscle relaxants that were released for clinical use in 1995/1996. Of these, rocuronium has the shortest time of onset, whereas its recovery characteristics closely resemble those of vecuronium. Rocuronium is five times less potent than vecuronium. Twice the ED95 of rocuronium provides good or excellent intubating conditions within 60 to 90 s. Slight vagolytic effects were reported following injection of 0.6 mg/kg rocuronium, while histamine release was not observed. Cisatracurium is one of the ten steroisomers of atracurium. It is five times as potent as the chiral mixture while having a similar pharmacodynamic and -kinetic profile. Up to eight times the ED95 did not cause significant histamine release or clinically relevant cardiovascular effects. Mivacurium is a short-acting nondepolarizing benzylisoquinoline muscle relaxant that undergoes rapid break-down by plasma cholinesterase (PChE). Its duration of action is about one-half as long as that of equipotent doses of atracurium and vecuronium and three times as long as succinylcholine. Mivacurium has a moderate histamine-releasing potential. In patients with atypical or reduced PChE activity, the duration of action of mivacurium is prolonged.

We studied the possible effects of repetitive (1-min interval) 50- and 100-Hz tetanic stimuli on 50-Hz and 100-Hz tetanic fade ratios (RF50HZ and RF100HZ). We also evaluated the sensitivity of the recorded responses to these two tests to assess residual neuromuscular block (isometric adductor pollicis mechanical activity), either during spontaneous recovery, or 15 min after neostigmine administration, in 22 adult anesthetized (thiopental, fentanyl, N2O/O2) patients receiving vecuronium. Two 50-Hz and two 100-Hz, 5-s duration, tetanic stimulations were randomly assessed at 1-min intervals: in a spontaneous (SPO) group (n = 11), when train-of-four (TOF) ratio spontaneously regained 0.7, and in a neostigmine (NEO) group (n = 11), 15 min after 40 micrograms/kg neostigmine was given intravenously at 25% return of control twitch tension. In the SPO group, when TOF ratio was 0.7, RF50HZ was 0.92 +/- 0.01 before and after subsequent tetanic stimulation, while RF100HZ was 0.48 +/- 0.05 and 0.47 +/- 0.05, respectively (not significant [NS]). In the NEO group, when TOF ratio was approximately 0.9, RF50HZ was 0.93 +/- 0.01 before and after subsequent tetanic stimulation, while RF100HZ was 0.80 +/- 0.02 and 0.78 +/- 0.02, respectively (NS). From patient to patient, both RF50HZ and RF100HZ were also identical. In conclusion, in patients receiving vecuronium, 1) 5-s, 50- and 100-Hz tetanic stimuli may be repeated without changes at 1-min intervals and, 2) in contrast to RF50HZ, recorded RF100HZ enables one to determine residual neuromuscular block during spontaneous recovery (P < 0.001) such as after neostigmine reversal (P < 0.05).

The duration of clinical relaxation induced by vecuronium and reversal by neostigmine was studied in 40 patients with renal failure (RF) and 40 patients with normal renal function (NL) under general anesthesia. Patients were premedicated with flunitrazepam, and anesthesia commenced with fentanyl 1-2 micrograms/kg, thiopental 5-8 mg/kg, and vecuronium 0.1 mg/kg. Anesthesia was maintained with 60% nitrous oxide in oxygen, isoflurane 0.3%-1.0% end-tidal concentration, and 1 microgram/kg fentanyl every 20-30 min. Neuromuscular block was reversed by the administration of intravenous neostigmine 40 mg/kg at the time of reappearance of either two or four responses to the train-of-four (TOF) stimulation. Monitoring of neuromuscular function consisted of supramaximal TOF stimulation of the ulnar nerve and the evoked thumb response was registered using a force transducer. Spontaneous recovery time, reversal time, and the time to recovery of TOF ratio to 0.7 were recorded. RF did not prolong the vecuronium neuromuscular blocking effect, reversal was achieved at the same rate in NL as in RF, and the duration of reversal of neuromuscular blocking effect of vecuronium was not influenced by the time of administration of neostigmine. Therefore, the neuromuscular blocking effect of a tracheal intubating dose of vecuronium can be reversed at the same rate in patients with end-stage RF as in patients with normal kidney function.

OBJECTIVE The depolarizing muscle relaxant succinylcholine (SCh) may cause several side effects including muscle fasciculations and postoperative myalgia. These can be attenuated or even prevented by prior administration of a non-depolarizing muscle relaxant. A study was conducted to detect any difference between clinically established approaches concerning the successful prevention of muscular side effects and the influence on the time profile of SCh action. METHODS: The study included 64 patients (ASA status I or II) who underwent elective surgery under general anesthesia. The patients were divided into four groups; the demographic data did not differ significantly between the groups (see table 1). Before the injection of SCh (1 mg/kg) for intubation, the control group received saline (K), the other groups 5 mg Atracurium (A), 1 mg Vecuronium (V), or 1 mg Pancuronium (P), respectively. Neuromuscular block was quantified after train-of-four (TOF) stimulation of the tibial nerve by accelerometry at the toe. The first response was used to determine the onset time, duration of effect, and recovery index. It was noted whether SCh led to muscular activity. Postoperatively, patients were asked whether they experienced any muscular sequelae. Statistical significance was assessed at the 5% probability level by the Mann-Whitney-U test and the CHi2 test (Fisher's exact test, if appropriate). RESULTS: SCh caused a complete neuromuscular block in all patients. Most patients in the control group exhibited muscular contractions than in the other groups (see table 2), but only two patients reported light myalgia. There was no statistically significant difference between the four groups in the onset time and the recovery index of SCh. The duration of the effect was significantly reduced by atracurium (7.5 min) or vecuronium (8.2 min) as compared to the placebo (11.8 min) and pancuronium (13.5 min) (see figure). CONCLUSION: The prolonged duration of the SCh effect after pancuronium is probably due to the known inhibition of cholinesterase by pancuronium. The short duration of action after Atracurium and Vecuronium can be explained by the competitive antagonism at the receptor causing an increased amount of unbound SCh. The duration of the SCh effect may be influenced according to clinical needs by the choice of the non-depolarizing muscle relaxant. The significantly reduced duration of complete neuromuscular block after Atracurium or Vecuronium as precurarizing agents may be advantageous in cases where a fast recovery of spontaneous breathing is essential. If a reduction of the SCh blockade has to be avoided, Pancuronium should be selected for prior administration.

We followed the recovery time course in 46 patients antagonized by neostigmine (0.036 mg kg-1) at different levels of vecuronium-induced neuromuscular blockade ranging from post-tetanic count 1 to train-of-four ratio 0.4 and in 15 patients during spontaneous recovery. Non-linear regression curve fit analyses showed that the optimal time for neostigmine administration was when the first twitch in the train of four (T1) was between 1% and 10%. Visual analyses of the scattergram in which the level of block, when neostigmine was given, was plotted against total recovery time (the time elapsed from administration of the last dose of vecuronium to train-of-four ratio 0.7) gave the same result. The reduction in total recovery time achieved by neostigmine was 32.6 min (SE diff. 6.0 min). To achieve the optimum effect, neostigmine must therefore be given 32.6 min plus the required time for peak effect of neostigmine (5.3-7.1 min), i.e. 37.9-39.7 min, before train-of-four ratio 0.7 is reached. During spontaneous recovery this corresponds to a T1 between 1% and 15%.

Recovery from the effects of muscle relaxants can occur either spontaneously by their metabolism in the body or by elimination via the normal excretion pathways, or by the administration of pharmacologic antagonists. The decision as to whether spontaneous recovery should be allowed to take place or pharmacologic reversal should be induced depends upon several factors, principal among them being the duration of action of the muscle relaxant used, its dose, and the time that is available. The recovery times of most relaxants, including atracurium and vecuronium, are such as to require antagonism if adequate recovery is to be attained quickly. An agent such as mivacurium may, however, allow complete spontaneous recovery to take place without the use of antagonists.

People with genetic variants of cholinesterase respond abnormally to succinylcholine, experiencing substantial prolongation of muscle paralysis with apnea rather than the usual 2-6 min. The structure of usual cholinesterase has been determined including the complete amino acid and nucleotide sequence. This has allowed identification of altered amino acids and nucleotides. The variant most frequently found in patients who respond abnormally to succinylcholine is atypical cholinesterase, which occurs in homozygous form in 1 out of 3500 Caucasians. Atypical cholinesterase has a single substitution at nucleotide 209 which changes aspartic acid 70 to glycine. This suggests that Asp 70 is part of the anionic site, and that the absence of this negatively charged amino acid explains the reduced affinity of atypical cholinesterase for positively charged substrates and inhibitors. The clinical consequence of reduced affinity for succinylcholine is that none of the succinylcholine is hydrolyzed in blood and a large overdose reaches the nerve-muscle junction where it causes prolonged muscle paralysis. Silent cholinesterase has a frame shift mutation at glycine 117 which prematurely terminates protein synthesis and yields no active enzyme. The K variant, named in honor of W. Kalow, has threonine in place of alanine 539. The K variant is associated with 33% lower activity. All variants arise from a single locus as there is only one gene for human cholinesterase (EC 3.1.1.8). Comparison of amino acid sequences of esterases and proteases shows that cholinesterase belongs to a new family of serine esterases which is different from the serine proteases.

Plasma cholinesterase activity was measured in patients following administration of pancuronium and vecuronium at dosages of 0.1 mg/kg. Both agents produced significant reduction in the plasma cholinesterase activity (P less than 0.01). No statistically significant difference between the inhibitory effects of these drugs was observed.

Mivacurium chloride (BW B1090U) is a new, short-acting non-depolarizing neuromuscular blocking agent. It is a synthetic bis-benzylisoquinolinium diester, which is hydrolysed rapidly by plasma cholinesterase. This study compares mivacurium, atracurium and vecuronium by continuous i.v. infusion. The duration of mivacurium infusion ranged from 29.5 to 286 min. The steady state infusion rates necessary to maintain 95 (SEM 4)% twitch suppression were: mivacurium 8.3 (0.7) micrograms kg-1 min-1; atracurium 7.9 (0.4) micrograms kg-1 min-1; vecuronium 1.2 (0.3) micrograms kg-1 min-1. Following infusions of mivacurium, various recovery times (for example: 25-75%, 6.9 (0.3) min; 25-95%, 11.0 (0.4) min; 5-95% 14.5 (0.4) min) did not differ significantly from those following single bolus doses. Recovery times following cessation of mivacarium infusions were approximately 50% of those for equivalent durations of infusion of atracurium (10.9 (0.3) min for 25-75% recovery and 26.6 (0.4) min for 5-95% recovery). For vecuronium, corresponding recovery times were 13.8 (0.9) and 32.0 (1.2) min, respectively. Comparative recovery times for mivacurium were 40-50% of those for vecuronium. There was a significant correlation between the infusion rate of mivacurium required to maintain 95% twitch depression and the plasma cholinesterase activity of individual subjects.

The interaction of three new non-depolarizing neuromuscular blocking agents--atracurium, vecuronium and Duador--on human red cell acetylcholinesterase (AChE; EC 3.1.1.7) and human plasma butyrylcholinesterase (BuChE; EC 3.1.1.8) was investigated. The binding of these neuromuscular blockers to human plasma proteins (protein binding) was also studied with a new method not requiring dialysis. For sake of comparison the protein binding and the interaction of tubocurarine and pancuronium with AChE and BuChE were observed also. None of the drugs studied was a substrate of AChE or BuChE. All had a relatively weak inhibitory effect on AChE (I50 greater than 10(-5) mol litre-1 in assay systems containing 5% haemolysed red cells). Of the three new neuromuscular blockers, vecuronium and Duador were relatively potent inhibitors of BuChE (I50 less than 10(-5) mol litre-1 in assay systems containing 5% plasma), but less potent than pancuronium (I50 = 6.1 X 10(-8) mol litre-1). All neuromuscular blocking drugs tested, especially vecuronium and pancuronium, were strongly (77-91%) bound to plasma proteins.

A steroid, the dibutyrate analogue of pancuronium bromide (9.8 X 10(-8)M), has been used as differential inhibitor in the study of the plasma cholinesterase variants. Pancuronium dibutyrate numbers have been measured for 190 individuals, and the mean values for six of the known genotypes, E1uE1u, E1uE1f, E1uE1a, E1fE1a, E1aE1a, and E1fE1f, have been calculated. Evidence is presented that a combination of the pancuronium dibutyrate number and the fluoride number give better resolution of the six genotypes than the combination of the pancuronium dibutyrate and the dibucaine number. This new differential inhibitor has real potential for revealing the probable existence of new genotypes.