Vecuronium bromide and its advanced intermediates: A crystallographic and spectroscopic study.

Vecuronium bromide (Piperidinium, 1-[(2ß,3α,5α,16ß,17ß)-3,17-bis(acetyloxy)-2-(1-piperidinyl)androstan-16-yl]-1-methyl-, bromide; Norcuron®) has been extensively used in anesthesiology practice as neuromuscular blocking agent since its launch on the market in 1982. However, a detailed crystallographic and NMR analysis of its advanced synthetic intermediates is still lacking. Hence, with the aim of filling this literature gap, vecuronium bromide was prepared starting from the commercially available 3ß-hydroxy-5α-androstan-17-one (epiandrosterone), implementing some modifications to a traditional synthetic procedure. A careful NMR study allowed the complete assignment of the 1H, 13C, and 15N NMR signals of vecuronium bromide and its synthetic intermediates. The structural and stereochemical characterization of 2ß,16ß-bispiperidino-5α-androstane-3α,17ß-diol, the first advanced synthetic intermediate carrying all the stereocenters in the final configuration, was described by means of single-crystal X-ray diffraction and Hirshfeld surface analysis, allowing a detailed conformational investigation.

Neuroactive steroids, WIN-compounds and cholesterol share a common binding site on muscarinic acetylcholine receptors.

Endogenous neurosteroids and their synthetic analogues-neuroactive steroids-have been found to bind to muscarinic acetylcholine receptors and allosterically modulate acetylcholine binding and function. Using radioligand binding experiments we investigated their binding mode. We show that neuroactive steroids bind to two binding sites on muscarinic receptors. Their affinity for the high-affinity binding site is about 100 nM. Their affinity for the low-affinity binding site is about 10 µM. The high-affinity binding occurs at the same site as binding of steroid-based WIN-compounds that is different from the common allosteric binding site for alcuronium or gallamine that is located between the second and third extracellular loop of the receptor. This binding site is also different from the allosteric binding site for the structurally related aminosteroid-based myorelaxants pancuronium and rapacuronium. Membrane cholesterol competes with neurosteroids/neuroactive steroids binding to both high- and low-affinity binding site, indicating that both sites are oriented towards the cell membrane..

Quantitative Structure-Activity Relationship (QSAR) Model for the Severity Prediction of Drug-Induced Rhabdomyolysis by Using Random Forest.

Drug-induced rhabdomyolysis (DIR) is a rare and potentially life-threatening muscle injury that is characterized by low incidence and high risk. To our best knowledge, the performance of the current predictive models for the early detection of DIR is suboptimal because of the scarcity and dispersion of DIR cases. Therefore, on the basis of the curated drug information from the Drug-Induced Rhabdomyolysis Atlas (DIRA) database, we proposed a random forest (RF) model to predict the DIR severity of the marketed drugs. Compared with the state-of-art methods, our proposed model outperformed extreme gradient boosting, support vector machine, and logistic regression in distinguishing the Most-DIR concern drugs from the No-DIR concern drugs (Matthews correlation coefficient (MCC) and recall rate of our model were 0.46 and 0.81, respectively). Our model was subsequently applied to predicting the potentially serious DIR for 1402 drugs, which were reported to cause DIR by the postmarketing DIR surveillance data in the FDA Spontaneous Adverse Events Reporting System (FAERS). As a result, 62.7% (94) of drugs ranked in the top 150 drugs with the Most-DIR concerns in FAERS can be identified by our model. The top four drugs (odds ratio >30) including acepromazine, rapacuronium, oxyphenbutazone, and naringenin were correctly predicted by our model. In conclusion, the RF model can well predict the Most-DIR concern drug only based on the chemical structure information and can be a facilitated tool for early DIR detection.

Sugammadex reverses neuromuscular block induced by 3-desacetyl-vecuronium, an active metabolite of vecuronium, in the anaesthetised rhesus monkey.

BACKGROUND AND OBJECTIVE: 3-Desacetyl-vecuronium is an active metabolite of the neuromuscular blocking agent (NMBA) vecuronium, which might lead to residual paralysis after prolonged administration of vecuronium in critically ill patients with renal failure. This study investigated the ability of sugammadex to reverse 3-desacetyl-vecuronium-induced neuromuscular block (NMB) in the anaesthetised rhesus monkey. METHODS: Experiments were performed in anaesthetised female rhesus monkeys. After bolus intravenous injection of vecuronium (n = 8) or 3-desacetyl-vecuronium (n = 8) 10 µg kg(-1) (ED90), a continuous infusion of the same NMBA was started to maintain the first twitch of the train-of-four (TOF) at 10% of baseline value. The infusion was stopped and NMB recovered spontaneously. The procedure was repeated, but immediately after stopping the infusion, an intravenous bolus dose of sugammadex 0.5 or 1.0 mg kg(-1) was given. For each NMBA, four placebo experiments were performed, in which the second recovery from NMB was also spontaneous. For all experiments, time to recovery of the TOF ratio to 90% was retrieved. RESULTS: After administration of sugammadex for reversal of 3-desacetyl-vecuronium-induced NMB, recovery was significantly faster than spontaneous recovery. Mean time to recovery of TOF to 90% was 3.2 min (sugammadex 0.5 mg kg(-1)) and 2.6 min (1.0 mg kg(-1)), compared to spontaneous recovery (17.6 min). For vecuronium-induced NMB, mean time to recovery of TOF to 90% was 17.1 min (0.5 mg kg(-1)) and 4.6 min (1.0 mg kg(-1)), compared to spontaneous recovery (23.4 min). CONCLUSION: Sugammadex rapidly and effectively reversed 3-desacetyl-vecuronium-induced NMB in the rhesus monkey, at a lower dose than that needed to reverse vecuronium-induced NMB.

Determining the potency of neuromuscular blockers: are traditional methods flawed?

BACKGROUND: Traditionally, the clinical potency of neuromuscular blocking drugs has been measured using linear regression analysis (LRA) after log dose and probit or logit data transformation. However, probit and logit analyses are meant to handle only quantal responses with binomial error distributions, not continuous data such as per cent of maximal response. Some statisticians now consider this approach outmoded and assert that non-linear regression (NLR) is the preferred way to analyse sigmoidal dose-response relationships. We were interested in the degree to which the method of regression analysis alters calculated ED(50) and ED(95) values. METHODS: We analysed raw data for succinylcholine, rocuronium, rapacuronium, and cisatracurium from previously published studies using both LRA and NLR to determine the ED(50) and ED(95) values and the respective slopes of the dose-response relationships. We also estimated drug potency using the Hill equation (HE) using the slopes obtained from LRA and NLR. RESULTS: ED(50) values calculated by NLR, LRA, or the HE were interchangeable. LRA resulted in ED(95) values that were 13-18% lower than those determined by NLR. The 95% confidence limits (CL) for the ED(50) did not exceed +/-8% of the estimated value no matter how it was calculated vs +/-20-30% for the ED(95). CONCLUSIONS: The ED(50) is a very robust parameter. When comparing the potency of neuromuscular blockers, it is this value rather than the ED(95) that should be used. The CL for the ED(95), regardless of how it is calculated, are so wide that this parameter must be viewed, at best, as an approximation.

Gantacurium and CW002 do not potentiate muscarinic receptor-mediated airway smooth muscle constriction in guinea pigs.

BACKGROUND: Neuromuscular blocking agents are an integral component of general anesthesia. In addition to their intended pharmacologic target on skeletal muscle nicotinic receptors, undesirable airway effects (i.e., bronchoconstriction) can result from neuromuscular blocking agents' affinity for airway muscarinic receptors. We questioned whether two new members of a bisquaternary nondepolarizing muscle relaxant family, gantacurium and CW002, demonstrated detrimental effects of airway muscarinic receptors using an in vivo model in guinea pig airways. METHODS: Urethane-anesthetized male guinea pigs were ventilated through a tracheostomy with continuous digital recordings of pulmonary inflation pressure and heart rate. The dose for 95% twitch suppression for gantacurium, CW002, cisatracurium, and rapacuronium was defined in the guinea pig. Transient and reproducible changes in pulmonary inflation pressure and heart rate were recorded after vagal nerve stimulation or intravenous injection of acetylcholine before and after pretreatment with cumulatively increasing concentrations of gantacurium, CW002, cisatracurium or a single concentration of rapacuronium. RESULTS: The doses for 95% twitch suppression for gantacurium, CW002, cisatracurium, and rapacuronium were 0.064 +/- 0.006, 0.012 +/- 0.0006, 0.10 +/- 0.003, and 0.31 +/- 0.05 mg/kg, respectively. Gantacurium, CW002, and cisatracurium were without effects on baseline pulmonary inflation pressures and were devoid of significant interactions with M2 and M3 muscarinic receptors in vivo. CONCLUSION: These findings suggest that gantacurium and CW002 are devoid of significant effects at airway muscarinic receptors particularly M3 receptors on bronchial smooth musculature at doses several fold higher than those required for functional muscle paralysis.

Divergence of allosteric effects of rapacuronium on binding and function of muscarinic receptors.

BACKGROUND: Many neuromuscular blockers act as negative allosteric modulators of muscarinic acetylcholine receptors by decreasing affinity and potency of acetylcholine. The neuromuscular blocker rapacuronium has been shown to have facilitatory effects at muscarinic receptors leading to bronchospasm. We examined the influence of rapacuronium on acetylcholine (ACh) binding to and activation of individual subtypes of muscarinic receptors expressed in Chinese hamster ovary cells to determine its receptor selectivity. RESULTS: At equilibrium rapacuronium bound to all subtypes of muscarinic receptors with micromolar affinity (2.7-17 microM) and displayed negative cooperativity with both high- and low-affinity ACh binding states. Rapacuronium accelerated [3H]ACh association with and dissociation from odd-numbered receptor subtypes. With respect to [35S]GTPgammaS binding rapacuronium alone behaved as an inverse agonist at all subtypes. Rapacuronium concentration-dependently decreased the potency of ACh-induced [35S]GTPgammaS binding at M2 and M4 receptors. In contrast, 0.1 microM rapacuronium significantly increased ACh potency at M1, M3, and M5 receptors. Kinetic measurements at M3 receptors showed acceleration of the rate of ACh-induced [35S]GTPgammaS binding by rapacuronium. CONCLUSIONS: Our data demonstrate a novel dichotomy in rapacuronium effects at odd-numbered muscarinic receptors. Rapacuronium accelerates the rate of ACh binding but decreases its affinity under equilibrium conditions. This results in potentiation of receptor activation at low concentrations of rapacuronium (1 microM) but not at high concentrations (10 microM). These observations highlight the relevance and necessity of performing physiological tests under non-equilibrium conditions in evaluating the functional effects of allosteric modulators at muscarinic receptors. They also provide molecular basis for potentiating M3 receptor-mediated bronchoconstriction.

Quantitative analysis of the aminosteroidal non-depolarizing neuromuscular blocking agent vecuronium by LC-ESI-MS: A Postmortem Investigation.

The apparent recreational use of an aminosteroidal non-depolarizing neuromuscular blocking agent, vecuronium, is reported in this postmortem investigation. A quantitative method for the analysis of vecuronium and its active metabolite, 3-desacetylvecuronium, in blood and tissue samples was developed using liquid chromatography-electrospray ionization mass spectrometry operated in positive selected ion monitoring mode. Chromatographic separation was performed on a Gemini 5-microm C18 column using a mobile phase of 0.1% formic acid/acetonitrile at 0.700 mL/min. The method was linear from 0.01 to 1.00 mg/L with correlation coefficients of 0.999 and greater for both compounds. The limits of detection and quantitation were determined in blood to be 0.005 and 0.010 mg/L, respectively. The coefficients of variation were less than 10% for both intra- and interday assays. Vecuronium was quantitated in blood at 0.070 mg/L and in the kidney, liver, and spleen at 0.224, 0.045, and 0.080 mg/kg, respectively. The active metabolite 3-desacetylvecuronium was quantitated in blood at 0.100 mg/L, in the urine at 0.040 mg/L and in the kidney, liver, spleen, and lung at 0.271, 0.100, 0.082, and 0.164 mg/kg, respectively.

Performance of an iterative two-stage bayesian technique for population pharmacokinetic analysis of rich data sets.

PURPOSE: To test the suitability of an Iterative Two-Stage Bayesian (ITSB) technique for population pharmacokinetic analysis of rich data sets, and to compare ITSB with Standard Two-Stage (STS) analysis and nonlinear Mixed Effect Modeling (MEM). MATERIALS AND METHODS: Data from a clinical study with rapacuronium and data generated by Monte Carlo simulation were analyzed by an ITSB technique described in literature, with some modifications, by STS, and by MEM (using NONMEM). The results were evaluated by comparing the mean error (accuracy) and root mean squared error (precision) of the estimated parameter values, their interindividual standard deviation, correlation coefficients, and residual standard deviation. In addition, the influence of initial estimates, number of subjects, number of measurements, and level of residual error on the performance of ITSB were investigated. RESULTS: ITSB yielded best results, and provided precise and virtually unbiased estimates of the population parameter means, interindividual variability, and residual standard deviation. The accuracy and precision of STS was poor, whereas ITSB performed better than MEM. CONCLUSIONS: ITSB is a suitable technique for population pharmacokinetic analysis of rich data sets, and in the presented data set it is superior to STS and MEM.

Simultaneous determination of pancuronium, vecuronium and their related compounds using LC-ESI-MS.

A simultaneous determination method of quaternary amino steroidal muscle relaxants, pancuronium (PAN), vecuronium (VEC), and 17-monodesacetyl pancuronium (17-OH-PAN), 3,17-bisdesacetyl pancuronium (3,17-OH-PAN), 3-monodesacetyl vecuronium (3-OH-VEC), 3,17-bisdesacetyl vecuronium (3,17-OH-VEC) in human serum was developed using liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS). The weak cation exchange cartridge was useful for the extraction of these compounds. Under optimized LC-ESI-MS conditions, these compounds were almost fully separated within 6.5 min. Linear responses over the concentration range 0.25-50.0 ng/mL were demonstrated for each compound. The developed method successfully detected VEC, 3-OH-VEC and 3,17-OH-VEC in serum intravenously administered with VEC. The level of 3-OH-VEC was higher than other compounds. This suggested that 3-OH-VEC was useful as a forensic probe in VEC administration.

Rapacuronium augments acetylcholine-induced bronchoconstriction via positive allosteric interactions at the M3 muscarinic receptor.

BACKGROUND: Neuromuscular blocking agents' detrimental airway effects may occur as a result of interactions with muscarinic receptors, allergic reactions, or histamine release. Rapacuronium, a nondepolarizing muscle relaxant, was withdrawn from clinical use because of its association with fatal bronchospasm. Despite its withdrawal from clinical use, it is imperative that the mechanism by which bronchospasm occurred is understood so that new muscle relaxants introduced to clinical practice do not share these same detrimental airway effects. METHODS: Airway smooth muscle force was measured in guinea pig tracheal rings in organ baths exposed to muscle relaxants with or without subthreshold concentrations of acetylcholine. Antagonism of muscarinic, histamine, neurokinin, leukotriene receptors, or blockade of L-type calcium channels or depletion of nonadrenergic, noncholinergic neurotransmitters was performed. Muscle relaxants' potentiation of acetylcholine-stimulated inositol phosphate synthesis and allosteric interactions on the kinetics of atropine-induced [3H]N-methylscopolamine dissociation were measured in cells expressing recombinant human M3 muscarinic receptors. RESULTS: Rapacuronium, within clinically achieved concentrations, contracted tracheal rings in the presence but not in the absence of subthreshold concentrations of acetylcholine. This effect was prevented or reversed only by atropine. The allosteric action of rapacuronium was demonstrated by the slowing of atropine-induced dissociation of [3H]N-methylscopolamine, and positive cooperativity was demonstrated by potentiation of acetylcholine-induced inositol phosphate synthesis. CONCLUSION: Many muscle relaxants have allosteric properties at muscarinic receptors; however, positive cooperativity at the M3 muscarinic receptor within clinically relevant concentrations is unique to rapacuronium. These findings establish novel parameters that should be considered in the evaluation of airway safety of any newly synthesized neuromuscular blocking agents considered for clinical practice.

Antiemetics of the 5-hydroxytryptamine 3A antagonist class inhibit muscle nicotinic acetylcholine receptors.

Antagonists of the serotonergic 5-hydroxytryptamine 3A receptor (5-HT(3A)R) and muscle nicotinic acetylcholine receptors (nAChR) are widely used in anesthesia practice. Both 5-HT(3A)R and nAChR are ligand-gated ion channels with known pharmacological overlap between some of their agonists and antagonists. We studied the actions of clinically used 5-HT(3A)R antagonist antiemetics and nondepolarizing muscle blockers on ionic currents elicited by the activation of mammalian 5-HT(3A)R and muscle nAChR, expressed in Xenopus laevis oocytes. Currents were recorded using a whole-cell two-electrode voltage clamp technique. Dolasetron, ondansetron, and granisetron reversibly inhibited 5-HT(3A)R function at nanomolar concentrations with 50% inhibitory concentrations (IC(50)) of 11.8, 6.4, and 0.2 nM; the rank order of inhibition correlated well with their clinical antiemetic potencies. The principal metabolite of dolasetron, hydrodolasetron, was 40 times more potent than the parent compound on 5-HT(3A)R (IC(50) = 0.29 nM). The potency of the nondepolarizing muscle blocker d-tubocurarine in blocking 5-HT(3A)R was similar to that of the antiemetics and significantly more than vecuronium and rapacuronium (IC(50) = 11.4 nM, 18.9 microM, 60.5 microM). Conversely, ondansetron, dolasetron, and granisetron also reversibly inhibited nAChR currents in a dose-dependent manner with IC(50)s of 14.2, 7.8, and 4.4 microM for the adult nAChR and 16.0, 18.6, and 13.9 microM for the embryonic nAChR. Again, hydrodolasetron showed significantly (10 times) more inhibitory potency on the adult nAChR than the parent compound dolasetron. These results indicate that drugs that target specific ligand-gated ion channels may also affect other ion channel types.

Rapacuronium preferentially antagonizes the function of M2 versus M3 muscarinic receptors in guinea pig airway smooth muscle.

BACKGROUND: Rapacuronium, a nondepolarizing muscle relaxant that was proposed as a replacement for succinylcholine for rapid intubation, was withdrawn from clinical use as a result of fatal bronchospasm, but the mechanism of this effect is not known. Preferential antagonism of presynaptic M2 muscarinic receptors versus postsynpatic M3 muscarinic receptors can facilitate bronchoconstriction. The authors questioned whether rapacuronium preferentially antagonized M2 versus M3 muscarinic receptors in intact airway. METHODS: Guinea pig tracheal rings were suspended in organ baths and muscle relaxants' antagonism of prejunctional M2 muscarinic autoreceptors was evaluated by augmentation of muscle contraction elicited by electrical field stimulation. Muscle relaxants' antagonism of postjunctional M3 muscarinic receptors was assessed by attenuation of muscle contraction elicited by acetylcholine. RESULTS: Rapacuronium displayed a 50-fold higher affinity for antagonism of the M2 versus M3 muscarinic receptor. Moreover, its affinity for the M2 but not the M3 receptor was within concentrations achieved clinically. In addition, rapacuronium caused an increase in baseline tone of airway smooth muscle that was antagonized by atropine but not by previous depletion of nonadrenergic noncholinergic neurotransmitters or by inhibitors of histamine receptors, tachykinin receptors, leukotriene receptors, or calcium channels. CONCLUSION: These findings are consistent with the hypothesis that rapacuronium may precipitate bronchoconstriction by selective antagonism of the M2 muscarinic receptor on parasympathetic nerves, enhancing acetylcholine release to act upon unopposed M3 muscarinic receptors on airway muscle. An additional mechanism of rapacuronium-induced bronchoconstriction is suggested by increases in baseline muscle tension.

Influence of chronic phenytoin administration on the pharmacokinetics and pharmacodynamics of vecuronium.

BACKGROUND: The duration of action of vecuronium is reduced in patients receiving phenytoin. In this study, the authors examined, simultaneously, the influence of phenytoin on both the pharmacokinetics and the pharmacodynamics of vecuronium. METHODS: This study was approved by the institutional review board of the University of California, San Francisco, and patients gave written informed consent. Twenty-two patients, 11 taking phenytoin and all scheduled to undergo prolonged neurosurgical procedures with general anesthesia, participated in the study. In 12 patients (6 phenytoin, 6 control), vecuronium was infused at 7.5 microg x kg(-1) x min(-1) until the first response (T1) of each train-of-four decreased by 50%; in the remaining 10 patients (5 phenytoin, 5 control), 200 microg/kg vecuronium was infused over 10 min. Arterial blood samples were drawn at intervals over the next 5-7 h. Plasma concentrations of vecuronium and 3-desacetylvecuronium were measured by capillary gas chromatography. Pharmacokinetic and pharmacodynamic modeling was used to characterize the disposition of vecuronium and patient responses to it in the two groups. RESULTS: Clearance was typically increased by 138% (95% confidence interval, 93-183%) in patients taking phenytoin. The effect of vecuronium was well described using a sigmoid Emax model. The concentration of vecuronium giving 50% twitch depression was increased 124% (45-202%) in patients taking phenytoin. CONCLUSIONS: Chronic phenytoin therapy reduces the effect of vecuronium by mechanisms that include both increased vecuronium metabolism and reduced sensitivity of the patient to circulating concentrations of vecuronium.

Edrophonium effectively antagonizes neuromuscular block at the laryngeal adductors induced by rapacuronium, rocuronium and cisatracurium, but not mivacurium.

PURPOSE: To examine the efficacy of antagonism of rapacuronium-, mivacurium-, rocuronium- and cisatracurium-induced neuromuscular block at the laryngeal adductors (LA). METHODS: One hundred four patients were randomly assigned to one of eight study groups. They either received rapacuronium 1.5 mg x kg(-1), mivacurium 0.25 mg x kg(-1), rocuronium 0.9 mg x kg(-1) or cisatracurium 0.15 mg x kg(-1). Patients in each treatment group either received edrophonium (0.5 mg x kg(-1)) at 10% recovery of the first twitch (T1) of train-of-four (TOF) at the LA or were allowed to recover spontaneously from neuromuscular block. The effect of antagonism on speed of recovery of neuromuscular function at the LA was evaluated. RESULTS: The time to recovery to a TOF ratio of 0.9 at the LA, when compared to the spontaneous recovery group, was significantly shortened by the administration of edrophonium in patients receiving rapacuronium [19.2 +/- 7.8 vs 26.2 +/- 4.9 (mean +/- SD) min], rocuronium (24.7 +/- 14.3 vs 44.4 +/- 13.0 min) and cisatracurium (24.2 +/- 5.7 vs 35.1 +/- 7.6 min). Edrophonium administration did not shorten complete recovery from mivacurium-induced block (15.7 +/- 8.0 vs 17.6 +/- 6.1 min). CONCLUSION: Recovery from rapacuronium-, rocuronium- or cisatracurium- induced neuromuscular block to a TOF ratio of 0.9 as measured at the LA was shortened by the administration of edrophonium, when compared to spontaneous recovery.

[The time-course of action of rapacuronium and mivacurium after early reversal following equally lasting relaxation]. / Spontane und induzierte neuromuskuläre Erholung nach gleich langer Relaxierung mit Rapacuronium und Mivacurium.

This study was designed to compare the time course of action and the safety profile of Rapacuronium and Mivacurium in day case dental surgery. After Ethics Committee approval 61 healthy adult patients, scheduled for dental day case surgery, were randomised in an assessor-blinded manner to receive either 1.5 mg/kg Rapacuronium with and without 0.05 neostigmine 5 min later (19 patients each) or a total of 0.25 mg/kg Mivacurium (n = 16). Anaesthesia was induced using Propofol 2 - 5.1 mg/kg and Remifentanil 24 - 73 mcg/kg/h and maintained with Desflurane in N2O/O2 (2/1). Endotracheal intubation was performed when maximum blockade was achieved and scored by a blinded intubator. Neuromuscular block was monitored using the train-of-four response to supramaximal stimuli at the ulnar nerve every 15 seconds using acceleromyography (TOF Watch SX). Onset time, clinical duration (reappearance of the third twitch of a TOF-stimulation) and recovery to T4/T1 > 0.9 were recorded. Speed of recovery was evaluated by the time difference between reappearance of the third twitch and T4/T1 > 0.9. The intubating conditions at the time of maximum block revealed no statistically significant differences between the three groups. Changes in blood pressure, heart rate and airway pressure were not significant. Onset time in subjects who received Rapacuronium (99 +/- 29 s) was faster compared to the onset time in those who received Mivacurium (157 +/- 36 s). Also clinical duration was significantly shorter following Rapacuronium without reversal (12 +/- 4 min) as well as with reversal (9 +/- 1 min) compared with Mivacurium (21 +/- 5 min)). Patients treated with Rapacuronium and reversal recovered faster (14 +/- 8 min)) compared to the other two groups (Mivacurium: 20 +/- 6 min, Rapacuronium without reversal: 31 +/- 9 min). The fraction of clinical duration of the total duration was highest following Mivacurium (51 %) when compared with Rapacuronium/Neostigmine (43 %) and Rapacuronium (28 %).

Does the choice of intravenous induction drug affect intubation conditions after a fast-onset neuromuscular blocker?

STUDY OBJECTIVES: To compare intubation conditions and hemodynamic effects resulting from thiopental-rapacuronium, propofol-rapacuronium, and etomidate-rapacuronium intravenous (IV) induction. DESIGN: Randomized, blinded study. SETTING: Operating suites of a large university-affiliated medical center. PATIENTS: 60 ASA physical status I and II adult patients without airway abnormalities, who were scheduled for elective surgery requiring endotracheal intubation. Patients were randomly allocated to receive IV thiopental sodium 5 mg/kg (Group 1), propofol 2 mg/kg (Group 2), or etomidate 0.3 mg/kg (Group 3) followed by rapacuronium 1.5 mg/kg. Fifty seconds later, an anesthesiologist, who had no knowledge of the induction drug used, entered the operating room and attempted laryngoscopy and intubation. MEASUREMENTS: Intubation conditions were graded as excellent, good, poor, or impossible according to Good Clinical Research Practice criteria. Arterial blood pressure and heart rate changes accompanying both induction techniques were also monitored and recorded. MAIN RESULTS: All patients were intubated within 55 to 70 seconds. Clinically acceptable intubation conditions were not statistically different among the three groups. Moderate tachycardia after induction was seen in all three groups, and blood pressure was significantly lower in Group 2 than in Groups 1 or 3. CONCLUSIONS: Clinically acceptable intubation conditions are similar after either thiopental, propofol, or etomidate when a fast-onset neuromuscular blocking drug (rapacuronium 1.5 mg/kg) is used to facilitate tracheal intubation.

A mechanism for rapacuronium-induced bronchospasm: M2 muscarinic receptor antagonism.

BACKGROUND: A safe and effective ultra-short-acting nondepolarizing neuromuscular blocking agent is required to block nicotinic receptors to facilitate intubation. Rapacuronium, which sought to fulfill these criteria, was withdrawn from clinical use due to a high incidence of bronchospasm resulting in death. Understanding the mechanism by which rapacuronium induces fatal bronchospasm is imperative so that newly synthesized neuromuscular blocking agents that share this mechanism will not be introduced clinically. Selective inhibition of M2 muscarinic receptors by muscle relaxants during periods of parasympathetic nerve stimulation (e.g., intubation) can result in the massive release of acetylcholine to act on unopposed M3 muscarinic receptors in airway smooth muscle, thereby facilitating bronchoconstriction. METHODS: Competitive radioligand binding determined the binding affinities of rapacuronium, vecuronium, cisatracurium, methoctramine (selective M2 antagonist), and 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP; selective M3 antagonist) for M2 and M3 muscarinic receptors. RESULTS: Rapacuronium competitively displaced 3H-QNB from the M2 muscarinic receptors but not from the M3 muscarinic receptors within clinically relevant concentrations. Fifty percent inhibitory concentrations (mean +/- SE) for rapacuronium were as follows: M2 muscarinic receptor, 5.10 +/- 1.5 microm (n = 6); M3 muscarinic receptor, 77.9 +/- 11 microm (n = 8). Cisatracurium and vecuronium competitively displaced 3H-QNB from both M2 and M3 muscarinic receptors but had affinities at greater than clinically achieved concentrations for these relaxants. CONCLUSIONS: Rapacuronium in clinically significant doses has a higher affinity for M2 muscarinic receptors as compared with M3 muscarinic receptors. A potential mechanism by which rapacuronium may potentiate bronchoconstriction is by blockade of M2 muscarinic receptors on prejunctional parasympathetic nerves, leading to increased release of acetylcholine and thereby resulting in M3 muscarinic receptor-mediated airway smooth muscle constriction.

Priming rapacuronium: a comparison with rocuronium and mivacurium.

The aim of this study is to present the pharmacodynamics of the priming principle using rapacuronium and a comparison with rocuronium and mivacurium. After induction, 120 patients were randomly allocated to six similar groups. Groups 1 and 2 received rapacuronium 1000 micrograms.Kg-1 as a bolus or primed with 100 micrograms.Kg-1. To groups 3 and 4, rocuronium 400 micrograms.Kg-1 were given as a bolus or primed with 60 micrograms.Kg-1, finally mivacurium 100 micrograms.Kg-1 was used for groups 5 and 6 by bolus or primed with 10 micrograms.Kg-1. Neuromuscular function was monitored by electromyography and it was demonstrated that time to 80% blockade, is significantly shorter after priming: 137 (bolus) vs 101 seconds (priming) for rapacuronium, 160 vs 90 for rocuronium and 196 vs 118 for mivacurium. Onset time was also statistically accelerated by priming: 229 seconds vs 183, 289 vs 203 and 298 vs 252 respectively. No significant change was noticed in maximal blockade and clinical duration due to priming. During early onset, only the mivacurium patients showed a statistical difference in train of four fade between bolus and priming. In conclusion, priming hasten early and maximal effect produced by rapacuronium, rocuronium and mivacurium without any change in maximal blockade and clinical duration. Pre-synaptic effect does not explain consistently the mode of action of priming.