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PubMed1980

Comparison of the cardiovascular actions of ORG NC 45 with those produced by other non-depolarizing neuromuscular blocking agents in experimental animals.

The cardiovascular actions of 1- [(2 beta,3 alpha, 16 beta,17 beta)-3,17-bis(acetyloxy)-2-(1-piperidinyl)-androstan-16-yl]-1-methyl-piperidinium bromide (Org NC 45) are reviewed and compared with those of other non-depolarizing neuromuscular blocking drugs. Results obtained in anaesthetized cats and dogs have demonstrated that, in contrast to other neuromuscular blocking drugs, Org NC 45, even in doses 20 times greater than those required for neuromuscular block, has no effects on heart rate, arterial pressure, autonomic ganglia, adrenoceptors or baroreceptors activity. Studies in pithed rats and on guineapig atria have further shown that Org NC 45 has little effect on cardiac muscarinic receptors or on noradrenaline re-uptake mechanisms. These results suggest that Org NC 45 possesses significant advantages over presently used non-depolarizing neuromuscular blocking drugs, since its clinical use should not be associated with cardiovascular side-effects.

Anesthesia, General↗
PubMed1982

Comparison of the effects of Org NC 45 and pancuronium bromide on heart rate and arterial pressure in anaesthetized man.

The effects of Org NC 45 and pancuronium bromide on heart rate and arterial pressure were studied in anaesthetized man. A bolus of either Org NC 45 0.1 mg kg-1 or pancuronium 0.1 mg kg-1 was administered to lightly anaesthetized unstimulated subjects. Following Org NC 45 heart rate decreased in the majority of subjects (mean and SEM 3.78 +/- 1.36), whereas after pancuronium heart rate was increased (mean and SEM 11.91 +/- 1.9). The changes in mean arterial pressure observed were minimal. The effect of endotracheal intubation on mean arterial pressure was then studied. Increase of mean arterial pressure was observed in all subjects. The increase was more marked in those patients who had received pancuronium and was significantly higher than in those patients who had received Org NC 45 (P less than 0.01). We conclude that Org NC 45 is devoid of vagal blocking action, and that the difference in response to the stimulus of endotracheal intubation is a result of the different effects exerted on the sympathetic nervous system by Org NC 45 and pancuronium.

Adult↗
PubMed1999

A pharmacodynamic explanation for the rapid onset/offset of rapacuronium bromide.

BACKGROUND: Nondepolarizing muscle relaxants differ in their time course at the laryngeal adductors and the adductor pollicis, a result of differences in equilibration delays between plasma and effect sites, the sensitivity of each muscle to the relaxant, and the steepness of the concentration-effect relation at each muscle (the Hill factor). To determine whether similar differences exist for rapacuronium, a muscle relaxant with rapid onset and offset, the authors determined its pharmacodynamic characteristics. METHODS: The twitch tensions of the adductor pollicis and the laryngeal adductors (via a tracheal tube cuff positioned at the vocal cords) were measured in 10 volunteers who were anesthetized with propofoL Rapacuronium, 1.5 mg/kg, was given and blood samples were collected. A semiparametric effect compartment pharmacodynamic model was fit to values for rapacuronium plasma concentrations and twitch tension of the adductor pollicis and laryngeal adductors. RESULTS: Equilibration between the rapacuronium plasma concentration and both effect sites was rapid (typical values for the rate constant for equilibration between plasma and the effect site are 0.405 per min for the adductor pollicis and 0.630 per min for the laryngeal adductors) and was more rapid at the laryngeal adductors than at the adductor pollicis (ratio, 1.59+/-0.16; mean +/- SD). The steady state rapacuronium plasma concentration that depressed twitch tension by 50% and the Hill factor were similar for the two muscles. CONCLUSIONS: The rapid onset and offset of rapacuronium can be explained by the rapid equilibration between concentrations in plasma and at the effect site. Unlike the finding for other nondepolarizing muscle relaxants, the laryngeal muscles are not resistant to rapacuronium.

Adult↗
PubMed1999

Influence of renal failure on the pharmacokinetics and neuromuscular effects of a single dose of rapacuronium bromide.

BACKGROUND: Because renal function affects the elimination of muscle relaxants, each new muscle relaxant must be evaluated in patients with renal failure. Accordingly, the neuromuscular effects and pharmacokinetics of rapacuronium were identified in patients with renal failure. METHODS: Rapacuronium (1.5 mg/kg) was administered to 10 healthy volunteers and 10 patients with renal failure who were undergoing non-transplant surgery, were 18-45 yr old, and were anesthetized with propofol. The adductor pollicis muscle twitch tension was monitored. Plasma samples were obtained frequently for a period of 8 h to measure the concentrations of ORG9487 and its metabolite, ORG9488. Pharmacokinetic parameters were determined using mixed-effects modeling. RESULTS: One patient was excluded from analysis because he was taking phenytoin chronically. Twitch depression at 1 min was less in patients than in healthy volunteers (median values: 92% in patients, 99% in volunteers). The times to 90% and peak twitch depression; to 10%, 25%, and 75% twitch recovery; and to 70% and 80% train-of-four ratios were similar in volunteers and patients. Rapacuronium's clearance was 32% less in patients with renal failure; in both groups, clearance decreased 0.909% per year of age compared with the value in a 30 yr old. The steady state distribution volume was 14% less in women than in men and 16% less in patients than in volunteers. For ORG9488, clearance was 85% less in patients than in volunteers. CONCLUSIONS: The neuromuscular effects of a single dose of rapacuronium are affected minimally by renal failure. However, the decreased clearance of rapacuronium and its potent metabolite in renal failure suggests that repeated dosing of rapacuronium may lead to prolonged effects in patients with renal failure.

Adolescent↗
PubMed2002

Pharmacokinetics and pharmacodynamics of rapacuronium bromide.

Rapacuronium is an aminosteroidal nondepolarising neuromuscular blocking agent (NMBA). Its neuromuscular blocking effects have a different time course to those of most currently available agents. It also has lower potency than many of the other NMBAs. In doses consistent with short to medium duration of action, rapacuronium has rapid and complete onset. In some doses it gives tracheal intubating conditions that compare favourably with those produced by suxamethonium (succinylcholine) during rapid sequence induction of anaesthesia. Tracheal intubating conditions improve as dose increases, but adverse effects (including potentially severe bronchospasm) become more prominent. Rapacuronium has an active metabolite that is at least as potent as the parent compound and is eliminated much less efficiently. Consequently, the time course of action of rapacuronium is prolonged after multiple doses or an infusion. Its potency is similar across age ranges and its time course after single doses is little altered in patients with hepatic or renal insufficiency. At least in part because of its active metabolite, rapacuronium is highly cumulative in renal failure. In keeping with its rapid onset and short to medium duration of action, rapacuronium has a more rapid clearance than most other NMBAs. Values for clearance are in the range 0.26-0.67 L/h/kg, with most studies giving a value of approximately 0.45 L/h/kg. There is some evidence that clearance declines marginally with advanced age, and it is also reduced in children. A typical value for steady-state volume of distribution is 0.3 L/kg. This is similar to that of many other NMBAs, but is small compared with many other drugs, as expected with a highly polar compound. Pharmacokinetic parameters do not appear to differ markedly in hepatic insufficiency, but clearance is reduced by approximately 30% in renal failure. Rapacuronium equilibrates very rapidly between the plasma and the site of effect. This is the principal explanation behind its unusually rapid onset. It also appears to have a similar potency at the larynx compared with the adductor pollicis; most other NMBAs are less effective at the larynx. Because it gives rapid onset in a dose consistent with brief duration of action, it was hoped that rapacuronium might be a suitable alternative to suxamethonium. It does not have the problems associated with suxamethonium, but its use is associated with bronchospasm, the incidence of which is dose-related. Rapacuronium has been withdrawn from sale because of this adverse effect, and its future availability is uncertain.

Age Factors↗
PubMed1986

Quantitative estimation of quaternary ammonium neuromuscular blocking agents in serum by direct insertion probe chemical ionization mass spectrometry.

A new method based on selected ion monitoring chemical ionization mass spectrometry was developed to measure the quaternary ammonium neuromuscular blocking agents, pancuronium and vecuronium, in serum. An ion-pair extraction procedure is utilized to separate the compounds of interest from biological fluids. The intensities of the ion currents produced by the bisamines formed from the drugs and the corresponding deuterated internal standards through thermolytic dequaternization are monitored. The assay shows good linearity over the range of 1-500 ng/ml. This assay has been utilized in a variety of clinical pharmacokinetic studies involving surgical pediatric, geriatric and obstetric patients requiring anesthesia.

Chemical Phenomena↗
PubMed1998

Contribution of the murine mdr1a P-glycoprotein to hepatobiliary and intestinal elimination of cationic drugs as measured in mice with an mdr1a gene disruption.

In the mouse, both the mdr1a and the mdr1b gene encode drug-transporting P-glycoproteins. The mdr1a P-glycoprotein is expressed in epithelial cells of, among others, the liver and the intestine. Furthermore, the mdr1b gene product is found in the liver but is not detectable in the intestine. To establish the potential involvement of P-glycoprotein in the elimination of cationic amphiphilic drugs from the body, we investigated biliary, intestinal, and urinary excretion in mice with a homozygous disruption of the mdr1a gene (mdr1a(-/-) mice). These mice are fully viable under laboratory conditions and have normal bile flow. Cumulative biliary excretion (expressed as percent of the intravenously administered dose excreted over a 1-hour period) of several cationic compounds was decreased as follows in mdr1a(-/-) mice compared with the wild-type animals: tri-n-butylmethylammonium (TBuMA), 0.7% versus 2.1%; azidoprocainamide methoiodide (APM), 3.8% versus 7.6%; and vecuronium, 22.7% versus 41.3%. The luminal secretion of both TBuMA and APM in the small intestine was profoundly decreased, respectively 4.6-fold (1.8% vs. 8.2% in the wild-type) and 7.9-fold (1.6% vs. 10.3% in the wild-type) in mdr1a(-/-) mice. Thus mdr1a P-glycoprotein contributes substantially to the removal of a wide variety of cationic agents from the body through intestinal and hepatobiliary secretion, but it evidently acts in concert with other transport system(s). These processes probably provide a protective mechanism limiting the overall rate of absorption as well as the bioavailability of potentially toxic organic amines.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMedDate not supplied

Vecuronium: a new nondepolarizing neuromuscular-blocking agent. Clinical pharmacology, pharmacokinetics, cardiovascular effects and use in special clinical situations.

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

Adolescent↗
PubMed2001

Stimulated single fiber electromyography in the mouse: techniques and normative data.

As the number of new transgenic mouse models of human neuromuscular disease continues to increase, the development of sophisticated electrophysiologic techniques for assessing the peripheral nervous system in these models has become important. Neuromuscular junction (NMJ) dysfunction, in particular, is often not detectable by morphologic or other techniques. To enable sensitive testing of murine NMJ function, we developed and tested a method for stimulated single fiber electromyography (S-SFEMG) in the gastrocnemius muscles of anesthetized mice. Jitter was assessed by measuring the mean consecutive latency difference (MCD) of single fiber responses to sciatic nerve stimulation at 2 HZ. Mean MCD values in normothermic mice were in the range of 6-8 micros for different strains, with no MCD values exceeding 25 micros. Reduced core temperature (to 29 degrees--30 degrees C) resulted in increased jitter, whereas intubation and mechanical ventilation of mice did not alter these values. Intraperitoneal and intravenous injection of vecuronium, however, resulted in progressively increased jitter followed by blocking in continuously monitored fibers. These observations validate the utility of S-SFEMG in mice as an index of NMJ function under a variety of physiologic conditions, and suggest that a high safety factor for neuromuscular transmission exists at mouse NMJs.

Animals↗
PubMed1991

Myopathy with thick filament (myosin) loss following prolonged paralysis with vecuronium during steroid treatment.

A 20-year-old female hospitalized with status asthmaticus was treated with bronchodilators, antibiotics, and high-dose corticosteroids, and was paralyzed with vecuronium for 10 days to facilitate mechanical ventilation. When this was discontinued, she was found to have a flaccid quadriplegia with areflexia and 4-fold elevation in serum creatine kinase. A muscle biopsy showed extensive loss of thick (myosin) myofilaments, sometimes in core-like distribution, with relative preservation of thin (actin) filaments and Z-discs. Muscle strength returned to normal after 2 months. The pathological lesion in this patient's muscle fibers resemble those in rats treated with high doses of corticosteroids following denervation.

Adult↗
PubMed1994

Acute necrotizing myopathy of intensive care: electrophysiological studies.

A series of recent reports have identified cases of a quadriplegic myopathy characterized by myofiber necrosis and loss of myosin filaments associated with the use of nondepolarizing muscle blocking agents and glucocorticoids. We report electrophysiological findings in 7 intensive care unit patients who developed evidence of an acute myopathy in association with the use of nondepolarizing muscle blocking agents. Several important features were identified: (i) a neuromuscular transmission deficit was observed in 3 patients up to 7 days following withdrawal of vecuronium; (ii) motor M potentials were of low amplitude, there was mild abnormal spontaneous activity on needle electromyography, and sensory conduction was relatively preserved; (iii) not all patients received glucocorticoids or were asthmatic; (iv) 2 patients given vecuronium had very high creatine kinase levels and developed acute renal failure associated with myoglobinuria; and (v) rises in motor M potentials accompanied clinical recovery. This complication of intensive care may be severe, but is reversible and possibly avoidable. Our findings implicate nondepolarizing muscle blocking agents in the development of the myopathy. Electrophysiological studies provide important prognostic guidance.

Action Potentials↗
PubMed1994

Prolonged paralysis due to nondepolarizing neuromuscular blocking agents and corticosteroids.

The long-term use of nondepolarizing neuromuscular blocking agents (ND-NMBA) has recently been implicated as a cause of prolonged muscle weakness, although the site of the lesion and the predisposing factors have been unclear. We report 3 patients (age 37-52 years) with acute respiratory insufficiency who developed prolonged weakness following the discontinuation of ND-NMBAs. Two patients also received intravenous corticosteroids. Renal function was normal but hepatic function was impaired in all patients, and all had acidosis. Electrophysiologic studies revealed low amplitude compound motor action potentials, normal sensory studies, and fibrillations. Repetitive stimulation at 2 Hz showed a decremental response in 2 patients. The serum vecuronium level measured in 1 patient 14 days after the drug had been discontinued was 172 ng/mL. A muscle biopsy in this patient showed loss of thick, myosin filaments. The weakness in these patients is due to pathology at both the neuromuscular junction (most likely due to ND-NMBA) and muscle (most likely due to corticosteroids). Hepatic dysfunction and acidosis are contributing risk factors.

Adrenal Cortex Hormones↗
PubMed1995

AAEM case report #29: Prolonged paralysis after neuromuscular blockade.

Nondepolarizing neuromuscular blocking agents (NMBA) are being used with increasing frequency in critically ill patients. Recently, many centers have described patients with prolonged muscle weakness after long-term use of these agents, either alone or in combination with other agents or disorders. Brief weakness lasting several hours to several days is probably the result of prolonged neuromuscular blockade, while more prolonged weakness lasting several weeks to months is, in all likelihood, caused by a myopathy. Patients with this myopathic disorder have flaccid paralysis with intact cognition and sensation. Electrodiagnostic findings include decreased M-wave amplitudes, positive waves and fibrillations, and rapid recruitment of small amplitude short duration, polyphasic motor unit potentials. Muscle biopsy findings include atrophy of type I and type II fibers, myofiber necrosis, and selective loss of thick myofilaments. The myopathy is believed to be related to the prolonged use of NMBA either alone or in combination with other disorders or medications, particularly corticosteroids. The weakness experienced by these patients leads to additional respiratory compromise, difficulty weaning from the ventilator, and prolonged hospitalization.

Adrenal Cortex Hormones↗
PubMed2006

Adverse effects of neuromuscular blocking agents based on yellow card reporting in the U.K.: are there differences between males and females?

BACKGROUND: Adverse drug reactions (ADRs) are known to occur during anaesthesia; in the U.K. such ADRs may be reported through the Yellow Card Scheme (YCS). Our aim was to determine the demographics of ADRs to neuromuscular blocking drugs without formal causality assessment. METHODS: A retrospective analysis of ADRs to seven neuromuscular blocking drugs reported via the YCS during a greater than 30-year period was performed. Sex and age were analysed in order to identify at risk groups. RESULTS: Of 998 reports, 969 included gender. Non-allergic suspected reactions occurred with almost the same frequency as those with an allergic component. The majority occurred in females 676 (70%), and significant sex differences were measured between drugs. Males were more likely to have suffered an ADR to atracurium (p = 0.01) whilst females experienced more ADRs to suxamethonium (p = 0.01). ADRs proved fatal in 81 (9%) of the 950 reports for single drugs. Mortality following suxamethonium was significantly higher in males at 22% compared with 9% females (p < 0.001). More women than men were reported to have allergic reactions, 73% (362/499) compared with 27% (137/499) respectively. The female:male ratio for ADRs was reversed for subjects < 10 years compared with peak ADR reports during the decade from 31-40 years. CONCLUSIONS: Sex differences in mortality exist in this analysis. The unexpected high frequency of non-allergic ADRs suggests that morbidity and mortality from reactions to established drugs is twice that expected from allergic reactions alone. Standards and guidance for the reporting of ADRs warrant urgent development.

Adolescent↗
PubMed2002

Spatial effects in modeling pharmacokinetics of rapid action drugs.

We develop a model to describe the time course of plasma concentration of neuromuscular blocking agents used as anesthetics during surgery. This model, which overcomes the limitations of the classical compartment models routinely used in pharmacokinetics, incorporates spatial effects due to heterogeneity in the circulation: it takes the form of a dispersion equation on a circular domain, with a time-dependent leakage term. This term is fitted to the functional form desired once first-stage transients have died out. Comparisons are made with clinical data by adjusting three parameters in the model.

Body Fluid Compartments↗
PubMed1997

Natural and imposed astigmatism and their relation to emmetropization in the chick.

This study investigated the ocular response of young chicks to astigmatic errors imposed by spectacle lenses and as a related issue, we examined the nature and prevalence of astigmatism in young chicks, and its relation to corneal development and natural emmetropization. Normal hatchling chicks exhibited significant against-the-rule refractive astigmatism (approx. 8 D) of which 60-90% was corneal. Both types of astigmatism decreased in magnitude with normal corneal development as part of emmetropization. The apparent association with corneal growth is consistent with two further observations: (1) that smaller corneas, induced by constant light rearing, had higher than normal astigmatism (1.5 D greater at 15 days), (ii) that enlarged corneas, due to form deprivation, had reduced astigmatism (2.4 D less). When astigmatism was artificially imposed with (+/-10 DC spectacle lenses), altered ocular growth patterns were observed, although the changes were not consistent with the chicks having emmetropized to the imposed astigmatism. Irrespective of the axis setting used in positioning the lenses (45 degrees, 90 degrees, 180 degrees), eyes became hyperopic with +10 DC lenses (+8.8 +/- 1.3 D), and became slightly myopic with 10 DC lenses (-1.8 +/- 1.9 D). These refractive changes are consistent with the chicks having emmetropized to the more myopic meridian rather than the equivalent mean spherical error imposed (responses of control groups to +5 D and -5 D spherical lenses were +5.2 +/- 1.0 D and -5.1 +/- 0.8 D resp.). The same was true for chicks first prevented from accommodating by prior ciliary nerve section, except for one group wearing the 10 DC lens at 45 degrees axis where astigmatic changes consistent with partial compensation were seen, although this may represent an artefact of the surgery. These results argue against 'astigmatic emmetropization' as a normal phenomenon. Also consistent with this finding was the lack of significant astigmatic changes with accommodation-stimulating and inhibiting drugs (nicotine and vercuronium resp.), for normal chicks. These results imply that accommodation, while the most likely mechanism for astigmatic emmetropization, has little capacity to compensate for imposed astigmatic focussing errors.

Accommodation, Ocular↗