Haemodynamic differences between pancuronium and vecuronium in an experimental pig model.

OBJECTIVE: To compare baseline cardiovascular function in anesthetised pigs using either pancuronium or vecuronium as a neuromuscular blocker. STUDY DESIGN: Retrospective, non-randomized comparison. ANIMALS: Norwegian Land Race pigs (Sus scrofa domesticus) weighing mean 42 ± SD 3 kg. METHODS: One hundred and sixteen animals from four different research protocols premedicated with identical doses of ketamine, diazepam, atropine and isoflurane, and anaesthetised with pentobarbital, fentanyl, midazolam and N(2)O were arranged into three uniform groups with respect to neuromuscular blocking agent: pancuronium bolus of 0.063 mg kg(-1) followed by 0.14 mg kg(-1) hour(-1) (n = 54), low-dose vecuronium 0.4 mg kg(-1) /0.2 mg kg(-1) hour(-1) (n = 29) and high-dose vecuronium 0.6 mg kg(-1) /0.3 mg kg(-1) hour(-1) (n = 33). RESULTS: The majority of cardiovascular parameters demonstrated no significant differences between groups. For heart rate, there was an overall group difference, p = 0.036. Dromotropy was low in the pancuronium group, with an increased normalised PR-interval compared to the high-dose vecuronium group, median 0.200 interquartile range (0.190, 0.215) versus 0.182 (0.166, 0.199), p < 0.05. Left ventricular compliance was increased in pancuronium-treated animals, demonstrated as a reduction in the nonlinear end-diastolic pressure volume relationship ß compared to both vecuronium groups, 0.021 (0.016, 0.025) versus 0.031 (0.025, 0.046) and 0.031 (0.022, 0.048), p < 0.05. The linear end-diastolic pressure volume relationship EDPVR(lin) was reduced as well in the pancuronium group, compared to the low-dose vecuronium group, 0.131 (0.116, 0.169) versus 0.181 (0.148, 0.247), p < 0.05. CONCLUSIONS: There are only minor haemodynamic differences when using pancuronium compared to vecuronium in the fentanyl-pentobarbital-midazolam-N(2)O anesthetised domestic pigs. Furthermore, increasing doses of vecuronium have minimal haemodynamic effects. CLINICAL RELEVANCE: Experimental studies in pigs using either pancuronium or vecuronium as a neuromuscular blocking agent are comparable with regard to cardiac and haemodynamic performance.

Presynaptic facilitatory adenosine A2A receptors mediate fade induced by neuromuscular relaxants that exhibit anticholinesterase activity.

1. Pancuronium, cisatracurium and vecuronium are antinicotinic agents that, in contrast with d-tubocurarine and hexamethonium, exhibit anticholinesterase activity. Pancuronium-, cisatracurium- and vecuronium-induced fade results from blockade of facilitatory nicotinic receptors on motor nerves, but fade produced by such agents also depends on the presynaptic activation of inhibitory muscarinic M2 receptors by acetylcholine released from motor nerve terminals and activation of inhibitory adenosine A1 receptors by adenosine released from motor nerves and muscles. The participation of presynaptic facilitatory A2A receptors in fade caused by pancuronium, cisatracurium and vecuronium has not yet been investigated. In the present study, we determined the effects of ZM241385, an antagonist of presynaptic facilitatory A2A receptors, on fade produced by these neuromuscular relaxants in the rat phrenic nerve-diaphragm (PND) preparation. 2. The muscles were stimulated indirectly at 75±3Hz to induce a sustained tetanizing muscular contraction. The lowest concentration at which each antinicotinic agent produced fade without modifying initial tetanic tension (presynaptic action) was determined. 3. d-Tubocurarine-induced fade occurred only at 55 nmol/L, a concentration that also reduced maximal tetanic tension (post-synaptic action). At 10 nmol/L, ZM 241385 alone did not produce fade, but it did attenuate pancuronium (0.32 µmol/L)-, cisatracurium (0.32 µmol/L)- and vecuronium (0.36 µmol/L)-induced fade. 4. The fade induced by the 'pure' antinicotinic agents d-tubocurarine (55 nmol/L) and hexamethonium (413 µmol/L) was not altered by 10 nmol/L ZM 241385, indicating that presynaptic adenosine A2A receptors play a significant role in the fade produced by antinicotinic agents when such agents have anticholinesterase activity.

Site selectivity of competitive antagonists for the mouse adult muscle nicotinic acetylcholine receptor.

The muscle-type nicotinic acetylcholine receptor has two nonidentical binding sites for ligands. The selectivity of acetylcholine and the competitive antagonists (+)-tubocurarine and metocurine for adult mouse receptors is known. Here, we examine the site selectivity for four other competitive antagonists: cisatracurium, pancuronium, vecuronium, and rocuronium. We rapidly applied acetylcholine to outside-out patches from transfected BOSC23 cells and measured macroscopic currents. We have reported the IC(50) of the antagonists individually in prior publications. Here, we determined inhibition by pairs of competitive antagonists. At least one antagonist was present at a concentration producing > or =67% receptor inhibition. Metocurine shifted the apparent IC(50) of (+)-tubocurarine in quantitative agreement with complete competitive antagonism. The same was observed for pancuronium competing with vecuronium. However, pancuronium and vecuronium each shifted the apparent IC(50) of (+)-tubocurarine less than expected for complete competition but more than expected for independent binding. The situation was similar for cisatracurium and (+)-tubocurarine or metocurine. Cisatracurium did not shift the apparent IC(50) of pancuronium or vecuronium, indicating independent binding of these two pairs. The data were fit to a two-site, two-antagonist model to determine the antagonist binding constants for each site, L(alphaepsilon) and L(alphadelta). We found L(alphaepsilon)/L(alphadelta) = 0.22 (range, 0.14-0.34), 20 (9-29), 21 (4-36), and 1.5 (0.3-2.9) for cisatracurium, pancuronium, vecuronium, and rocuronium, respectively. The wide range of L(alphaepsilon)/L(alphadelta) for some antagonists may reflect experimental uncertainties in the low affinity site, relatively poor selectivity (rocuronium), or possibly that the binding of an antagonist at one site affects the affinity of the second site.

Investigation of the relaxant effects of pancuronium, rocuronium, vecuronium and mivacurium on rat thoracic aorta.

BACKGROUND AND OBJECTIVE: Pancuronium, vecuronium, mivacurium and rocuronium are nondepolarizing neuromuscular blocking agents, which are competitive antagonists against acetylcholine at nicotinic receptors, and considered to have no direct actions on vascular smooth muscle. We aimed to investigate the relaxant effects and possible underlying mechanisms of these agents on isolated rat thoracic aorta. METHODS: The preparations were precontracted with prostaglandin F2alpha (10(-7) mol l(-1)) and pancuronium (10(-7)-10(-4) mol l(-1)), rocuronium (10(-7)-10(-4) mol l(-1)), vecuronium (10(-7)-10(-4) mol l(-1)) and mivacurium (10(-7)-10(-4) mol l(-1)) added at cumulative concentrations in the presence or absence of a prostaglandin synthesis inhibitor, indomethacin (10(-6) M), and a nitric oxide synthesis inhibitor, N(omega)-nitro-L-arginine methylester (3 x 10(-5)). The same protocol was applied to both endothelia (+) and endothelia (-) aortic rings. The preparations precontracted with prostaglandin F2alpha (10(-7) mol l(-1)) were stimulated with electrical field stimulation at a frequency of 10 Hz as square-wave pulses of 50 V (0.2 ms) in the presence of a noradrenaline reuptake inhibitor desipramine (10(-7) mol l(-1)) and a nonselective beta-blocker propranolol (10(-6) mol l(-1)). Drugs were added at ineffective concentration of 10(-7) mol l(-1). Tetrodotoxin (10(-7) mol l(-1)) was added to test whether the changes were dependent on the neuronal response. RESULTS: Pancuronium and rocuronium relaxed aortic rings precontracted by prostaglandin F2alpha in a dose-dependent manner, but vecuronium and mivacurium did not. The relaxation effect of pancuronium and rocuronium was endothelium independent because there was not a significant response difference from the endothelium-denuded group. CONCLUSION: In conclusion, their relaxation effect may be due to an increase in prostaglandin synthesis. The increased relaxation effect of these agents at electrical field stimulation may be by the decreasing effect of noradrenaline reuptake from nerve endings because a noradrenaline reuptake inhibitor desipramine did not change this effect. Also, these neuromuscular agents may affect beta-receptors, because a nonselective beta-blocker agent, propranolol, decreased their electrical field stimulation-induced relaxations.

Allosteric interaction of the neuromuscular blockers vecuronium and pancuronium with recombinant human muscarinic M2 receptors.

Neuromuscular blocking drugs produce muscle weakness by interaction with nicotinic-acetylcholine receptors. Cardiovascular side effects have been reported. In this study the neuromuscular blocking drug vecuronium and the controls gallamine and pancuronium slowed the rate of atropine induced [(3)H]N-methylscopolamine dissociation from Chinese hamster ovary cells expressing recombinant human muscarinic M2 receptors K(off) values min(-1); vecuronium (125 nM), atropine 0.45+/-0.07+blocker 0.04+/-0.02; gallamine (21 nM), atropine 0.42+/-0.05+blocker 0.15+/-0.04; pancuronium(21 nM), atropine 0.36+/-0.03+blocker 0.03+/-0.01). These data indicate that vecuronium, gallamine and pancuronium interact with an allosteric site on the muscarinic M2 receptor (located on the heart) and this may explain some of their cardiac side effects.

Neuromuscular blocking drugs do not alter the pupillary light reflex of anesthetized humans.

OBJECTIVE: To test the hypothesis that systemically administered neuromuscular blocking drugs acutely alter resting pupil size or the direct reflex response to light in anesthetized humans. DESIGN: Patients were randomized to receive an intravenous injection of saline (0.15 mL/kg), pancuronium bromide (0.1 mg/kg), or vecuronium bromide (0.15 mg/kg) after induction of general anesthesia and tracheal intubation. SETTING: The University of California, San Francisco, Moffitt-Long Hospitals. PATIENTS: Healthy adults (American Society of Anesthesiologists physical status I or II) of either sex scheduled for elective surgery requiring general anesthesia, tracheal intubation, and muscle relaxation of an anticipated duration of 2 or more hours. MAIN OUTCOME MEASURES: Measurements of resting pupil size, direct reflex response to light, and constriction velocity were obtained in double-blinded fashion using infrared pupillometry. RESULTS: Pupillary size, reflex amplitude, and constriction velocity were not altered by the presence of either vecuronium or pancuronium. Tetanic stimuli and concomitant isoflurane administration respectively increased and decreased pupillary light reflex amplitude, indicating that pupillary responses were not fixed. CONCLUSIONS: We conclude that systemically administered neuromuscular blocking drugs (vecuronium and pancuronium) do not acutely affect the pupillary light reflex in healthy, anesthetized patients.

Interaction of neuromuscular blocking drugs with recombinant human m1-m5 muscarinic receptors expressed in Chinese hamster ovary cells.

1. Neuromuscular blocking drugs (NMBD's) are known to produce cardiovascular side effects manifesting as brady/tachycardias. In this study we have examined the interaction of a range of steroidal NMBD's with recombinant human m1-m5 muscarinic receptors expressed in Chinese hamster ovary cells. Our main hypothesis is that NMBD's may interact with m2 (cardiac) muscarinic receptors. 2. All binding studies were performed with cell membranes prepared from CHO m1-m5 cells in 1 ml volumes of 20 mM HEPES, 1 mM MgCl2 at pH 7.4 for 1 h. Muscarinic receptors were labelled with [3H]-NMS and displacement studies were performed with pancuronium, vecuronium, pipecuronium, rocuronium and gallamine. In addition a range of muscarinic receptor subtype selective reference compounds were included. In order to determine the nature of any interaction the effects of pancuronium, rocuronium and vecuronium on methacholine inhibition of forskolin stimulated cyclic AMP formation in CHO m2 cells was examined. Cyclic AMP formation was assessed in whole cells using a radioreceptor assay. All data are mean +/- s.e.mean (n > or = 5). 3. The binding of [3H]-NMS was dose-dependent and saturable in all cells tested. Bmax and Kd values in m1-m5 cells were 2242+/-75, 165+/-13, 1877+/-33, 458+/-30, 127+/-2 fmol mg(-1) protein and 0.11+/-0.02, 0.15+/-0.01, 0.12+/-0.01, 0.12+/-0.01, 0.22+/-0.01 nM respectively. 4. The binding of [3H]-NMS was displaced dose dependently (pK50) by pirenzepine in CHO m1 membranes (7.97+/-0.04), methoctramine in CHO m2 membranes (8.55+/-0.1), 4-diphenylacetoxy-N-methyl piperidine methiodide (4-DAMP) in CHO m3 membranes (9.38+/-0.03), tropicamide in CHO m4 membranes (6.98+/-0.01). 4-DAMP, pirenzepine, tropicamide and methoctramine displaced [3H]NMS in CHO m5 membranes with pK50 values of 9.20+/-0.14, 6.59+/-0.04, 6.89+/-0.05 and 7.22+/-0.01 respectively. These data confirm homogenous subtype expression in CHO m1-m5 cells. 5. [3H]NMS binding was displaced dose-dependently (pK50) by pancuronium (m1, 6.43+/-0.12; m2, 7.68+/-0.02; m3, 6.53+/-0.06; m4, 6.56+/-0.03; m5, 5.79+/-0.10), vecuronium (m1, 6.14+/-0.04; m2, 6.90+/-0.05; m3, 6.17+/-0.04; m4, 7.31+/-0.02; m5, 6.20+/-0.07), pipecuronium (m1, 6.34+/-0.11; m2, 6.58+/-0.03; m3, 5.94+/-0.01; m4, 6.60+/-0.06; m5, 4.80+/-0.03), rocuronium (m1, 5.42+/-0.01; m2, 5.40+/-0.02; m3, 4.34+/-0.02; m4, 5.02+/-0.04; m5, 5.10+/-0.03) and gallamine (m1, 6.83+/-0.05; m2, 7.67+/-0.04; m3, 6.06+/-0.06; m4, 6.20+/-0.03; m5, 5.34+/-0.03). 6. Cyclic AMP formation was inhibited dose dependently by methacholine in CHO m2 cells pEC50 for control and pancuronium (300 nM) treated cells were 6.18+/-0.34 and 3.57+/-0.36 respectively. Methacholine dose-response curves in the absence and presence of rocuronium (1 microM) and vecuronium (1 microM) did not differ significantly. Pancuronium, vecuronium and rocuronium did not inhibit cyclic AMP formation alone indicating no agonist activity. 7. With the exception of rocuronium there was a significant interaction with m2 muscarinic receptors with all NMBD's at clinically achievable concentrations suggesting that the brady/tachycardias associated with these agents may result from an interaction with cardiac muscarinic receptors. Furthermore pancuronium at clinically achievable concentrations antagonised methacholine inhibition of cyclic AMP formation in CHO m2 cells further suggesting that the tachycardia produced by this agent results from muscarinic antagonism. The mechanism of the bradycardia produced by vecuronium is unclear.

Inhibition of histamine N-methyltransferase (HNMT) in vitro by neuromuscular relaxants.

There have been reports of hypotension and flushing following vecuronium administration. The etiology of these symptoms, which are similar to those of histamine release, is not clear. The steroidal neuromuscular relaxants (NMRs), unlike muscle relaxants structurally similar to curare, have been shown not to cause histamine release after the administration of typical clinical doses. Histamine levels in plasma reflect a balance between release and catabolism. In humans, histamine N-methyl-transferase (HNMT) is the enzyme primarily degrading for histamine. Therefore, we performed in vitro kinetic studies of purified HNMT to determine the effects of the steroidal and curare-like NMRs and also of gallamine on histamine catabolism. We demonstrated that all NMRs tested were inhibitors of HNMT in vitro. The inhibition was competitive with respect to the cosubstrate S-adenosyl-L-[3H-methyl] methionine, and noncompetitive with respect to histamine. The rank order of inhibition was vecuronium greater than pancuronium greater than gallamine greater than d-tubocurarine greater than metocurine greater than atracurium greater than pipecuronium, with Ki values ranging from 1.2 to 44.8 microM. Our data suggest that HNMT-based radioenzymatic assays for histamine should be susceptible to inhibition by concurrent use of NMRs, particularly vecuronium.

Isobolographic analysis of non-depolarising muscle relaxant interactions at their receptor site.

Administration of certain combinations of non-depolarising muscle relaxants produces greater than expected neuromuscular blockade. Synergistic effects may be explained by drug interactions with the postsynaptic muscle nicotinic acetylcholine receptor. To investigate this hypothesis, the adult mouse muscle nicotinic acetylcholine receptor (alpha(2)beta delta epsilon) was heterologously expressed in Xenopus laevis oocytes and activated by the application of acetylcholine (10 microM). The effects of five individually applied muscle relaxants and six combinations of structurally similar and dissimilar compounds were studied. Drug combinations containing equipotent concentrations of two agents were tested and dose-response curves were determined. All compounds tested alone and in combination produced rapid and readily reversible, concentration-dependent inhibition. Isobolographic and fractional analyses indicated additive interactions for all six tested combinations. These findings suggest that synergistic neuromuscular blocking effects, observed for the administration of certain combinations of muscle relaxants, do not result from purely postsynaptic binding events at the muscle nicotinic acetylcholine receptor, but rather from differential actions on pre- and postsynaptic sites.

The actions of muscle relaxants at nicotinic acetylcholine receptor isoforms.

The pharmacological diversity of the different isoforms of the nicotinic acetylcholine receptor arises from the diversity of the subunits that assemble to form the native receptors. The aim of this study was to investigate the actions of the muscle relaxants d-tubocurarine, pancuronium and vecuronium on different isoforms of nicotinic acetylcholine receptors (mouse foetal muscle, mouse adult muscle and a rat neuronal), using the Xenopus oocyte expression system. Oocytes were injected with cRNAs for alpha, beta, gamma, delta subunits (the native foetal muscle subunit combination), or with cRNAs for alpha, beta, epsilon, delta subunits (the native adult muscle subunit combination), or with cRNAs for alpha4beta2 subunits (a putative native neuronal subunit combination). Acetylcholine had a similar potency at all three subunit combinations (EC50 11.6, 17.4 and 19.1 microM, respectively). At all three receptor types, d-tubocurarine and pancuronium blocked the responses elicited by acetylcholine in a reversible manner. Furthermore, the inhibition of the acetylcholine currents for the foetal and adult nicotinic acetylcholine receptor by pancuronium and d-tubocurarine was independent of the holding voltage over the range -100 to -40 mV. In oocytes expressing the foetal muscle nicotinic acetylcholine receptors the inhibition of the current in response to 100 microM acetylcholine by 10 nM d-tubocurarine was 29 +/- 5% (mean +/- S.E.M.; n = 7), and the inhibition by 10 nM pancuronium was 39 +/- 6% (mean +/- S.E.M.; n = 8; P > 0.05 vs. d-tubocurarine). However, in the adult form of the muscle nicotinic acetylcholine receptor, 10 nM d-tubocurarine and 10 nM pancuronium were both more effective at blocking the response to 100 microM acetylcholine compared to the foetal muscle nicotinic acetylcholine receptor, with values of 55 +/- 5% (P < 0.01; n = 12) and 60 +/- 4% (P < 0.001; n = 10), respectively. Thus the developmental switch from the gamma to the epsilon subunit alters the antagonism of the nicotinic acetylcholine receptor for both pancuronium and d-tubocurarine. Vecuronium was more potent than pancuronium. One nM vecuronium reduced the response to 100 microM acetylcholine by 71 +- 6% (n = 10) for foetal and 63 +/- 5% (n = 4) for adult nicotinic acetylcholine receptors. In the alpha4beta2 neuronal nicotinic acetylcholine receptor combination, 10 nM pancuronium was a more effective antagonist of the response to 100 microM acetylcholine (69 +/- 6%, n = 6) than 10 nM d-tubocurarine (30 +/- 5%; n = 6; P < 0.05 compared to pancuronium). This is in contrast to the adult muscle nicotinic acetylcholine receptor, where pancuronium and d-tubocurarine were equieffective. The expression of the beta2 subunit with muscle alpha, epsilon and delta subunits formed a functional receptor which was blocked by pancuronium and d-tubocurarine in a similar manner to the alphabeta1epsilondelta subunit consistent with the hypothesis that the beta subunit is not a major determinant in the action of this drug at the adult muscle nicotinic acetylcholine receptor.

Inhibition by vecuronium of carbachol-induced influx of 22Na+, 45Ca2+ and secretion of catecholamines in cultured bovine adrenal medullary cells.

In cultured bovine adrenal medullary cells, vecuronium, pancuronium and D-tubocurarine reduced carbachol-induced 45Ca2+ influx and catecholamine secretion by inhibiting 22Na+ influx via nicotinic receptor-ion channel complex with IC50 values of 0.43, 7.6 and 3.9 mumol/l, respectively. IC50 values of pancuronium and D-tubocurarine observed in adrenal medulla were one order of magnitude higher than the plasma concentrations of these muscle relaxants reported to produce 50% neuromuscular blockade, while IC50 of vecuronium was quite close between adrenal medulla and skeletal muscle.

Prolonged neuromuscular blockade in two critically ill patients treated with atracurium.

Recent literature suggests that the risk of prolonged neuromuscular blockade associated with atracurium compared with other nondepolarizing neuromuscular blocking agents may be minimal. Two patients experienced prolonged weakness associated with the administration of atracurium. Both received atracurium 0.5-0.7 mg/kg/hour in combination with methylprednisolone 500-600 mg/day. Electromyographic results and creatine kinase levels were suggestive of muscular weakness in both patients. Despite high-dose corticosteroid therapy, the electromyographic evidence supporting prolonged weakness did not suggest typical corticosteroid myopathy. Although some clinicians advocate routine administration of atracurium in critically ill patients due to the relative lack of reports of prolonged weakness, this may be premature. Although there are fewer reports of atracurium-associated prolonged weakness compared with pancuronium and vecuronium, the patients we describe suggest that it may occur.

Comparative evaluation of the neuromuscular and cardiovascular effects of pipecuronium, pancuronium, atracurium, and vecuronium under isoflurane anesthesia.

The neuromuscular and cardiovascular effects of intubating doses of pipecuronium 80 micrograms/kg, pancuronium 100 micrograms/kg, atracurium 500 micrograms/kg, and vecuronium 100 micrograms/kg were compared in 62 patients under isoflurane (end-tidal concentration = 0.5-1%) anesthesia. Pipecuronium, pancuronium, and vecuronium had no significant effect on systolic or diastolic blood pressure. In one patient the administration of atracurium resulted in significant hypotension. Heart rate was significantly increased only after the administration of pancuronium. The neuromuscular-blocking effect of pipecuronium and pancuronium appears to be twice as long as that of vecuronium and atracurium. Administration of neostigmine resulted in significantly faster recovery of muscle function in patients receiving vecuronium or atracurium. Although pipecuronium's neuromuscular-blocking effect is similar to that of pancuronium, its lack of cardiovascular effects more closely resembles that of vecuronium.

Cholinesterase inhibition by vecuronium and pancuronium in human airways.

Vecuronium (100 microM) but not pancuronium (100 microM) increased the sensitivity of human isolated bronchial preparations (HBP) to exogenous acetylcholine (ACh). The pD2 values obtained from concentration-dependent contractions were: control, 4.59 +/- 0.29 vecuronium, 5.86 +/- 0.31. Vecuronium or pancuronium (100 microM) significantly decreased (50%) the neostigmine contractions in HBP. In addition, vecuronium was more potent than pancuronium in preventing exogenous ACh degradation. These results suggest that vecuronium and pancuronium may have physiological effects in human airways by inhibiting both the tissue cholinesterases and muscarinic (M3) receptors.

Pancuronium, vecuronium, and heart rate during anesthesia for aortocoronary bypass operations.

To determine the effects of pancuronium and vecuronium on heart rate, 90 patients scheduled for aortocoronary bypass were randomly assigned to one of three groups (30 patients each) which received vecuronium 100 micrograms[sdot]kg-1, pancuronium 100 micrograms[sdot]kg-1, or a mixture of vecuronium (50 micrograms[sdot]kg-1) and pancuronium (50 micrograms[dot]kg-1) in a double-blind fashion during induction of anesthesia. All patients were premedicated with lorazepam prior to surgery, hence avoiding the effects of scopolamine. Our results showed no significant increase in heart rate from the administration of pancuronium, following administration of this drug the heart rate increased by only four beats per minute. The heart rate was unchanged after the mixture, but decreased by twelve beats per minute after vecuronium (P < 0.05). The heart rate response differed by 16 beats per minute between pancuronium and vecuronium. All patients who received either of the neuromuscular relaxants and who were on beta blockers showed a decrease in heart rate. In this study, the administration of pancuronium after an adequate induction dose of fentanyl did not cause tachycardia. We therefore feel that pancuronium still has a role in cardiac anesthesia, especially as the newer muscle relaxants such as vecuronium, pipecuronium and doxacurium are significantly more expensive.

Cardio-vascular effects of vecuronium & pancuronium in patients undergoing elective closed mitral valvotomy.

Vecuronium, a monoquaternary analogue of pancuronium, the neuromuscular blocker, was compared with pancuronium in 50 patients undergoing elective closed mitral valvotomy. The patients were randomly divided into two groups of 25 each, and the muscle relaxants were administered in a dose of 0.1 mg/kg body weight. Both the agents produced identical intubating conditions at 3 min. Vecuronium showed a significantly shorter onset of action, as compared to pancuronium. The latter significantly increased the heart rate throughout the period of study whereas vecuronium significantly decreased the heart rate, 25 min after administration. There was significant increase in the mean arterial pressure (MAP) at tracheal intubation in both the groups, which persisted throughout the period of study in pancuronium group. There was a significant fall in MAP at 30 min after relaxant in vecuronium group. The incidence of arrythmias was similar and significant in both the groups. Vecuronium, thus showed a quicker onset of action with minimal haemodynamic effects, as compared to pancuronium in patients undergoing closed mitral valvotomy.

Interaction of sevoflurane, isoflurane, enflurane and halothane with non-depolarizing muscle relaxants and their prejunctional effects at the neuromuscular junction.

The interaction of four inhalational anesthetics (sevoflurane, isoflurane, enflurane and halothane) with pancuronium and vecuronium and also their prejunctional actions at the neuromuscular junction were quantitatively studied using rat phrenic nerve-hemidiaphragm preparations. To investigate the prejunctional effects of inhalational anesthetics, a train-of-four ratio (T4/T1) and the tetanus ratio (the ratio of the final response to the initial response during tetanus) were evaluated. All four inhalational anesthetics markedly potentiated the neuromuscular blockade of twitch response caused by either pancuronium or vecuronium with halothane and enflurane being the most potent both on a % concentration basis and on a MAC (minimum alveolar concentration) basis. Although none of the four inhalational anesthetics had any effects on the T4/T1 ratio, they produced variable effects on the tetanus ratio. Sevoflurane had little effect on the tetanus ratio, whereas 1 and 2% isoflurane and 1, 2 and 3% enflurane increased the tetanus ratio and 5% halothane and 5% enflurane significantly reduced the tetanus ratio. Halothane and enflurane had the most potent depressant action of the four inhalational anesthetics both on the % concentration basis and on the MAC basis. These results indicate that the main site of action of inhalational anesthetics is a postjunctional site at the neuromuscular junction and that they do not seem to act on prejunctional sites at the concentrations used in clinical situations.

The effect of non-depolarizing neuromuscular blocking agents on the release of acetylcholine from the right atrium of the guinea pig.

The effect of various non-depolarizing neuromuscular blocking agents (gallamine, pancuronium, vecuronium, d-tubocurarine, metocurine, atracurium and pipecuronium) on [3H]acetylcholine release in the response to field electrical stimulation was investigated in vitro in preparations of the guinea pig right atrium. In this preparation, atropine enhanced and oxotremorine, a muscarinic agonist, reduced the release of [3H] acetylcholine. Atropine reversed the inhibitory effect of oxotremorine in a concentration dependent manner, indicating that there is negative feedback modulation of acetylcholine release from the vagal nerve. While pancuronium, gallamine and atracurium enhanced the release of [3H]acetylcholine, d-tubocurarine, metocurine, vecuronium and pipecuronium did not affect it. Pancuronium and gallamine also reduced the inhibitory effect of oxotremorine and the Kd value of pancuronium for muscarinic receptors located on cholinergic nerve terminals was 2.31 microM. These findings indicate that pancuronium and gallamine enhanced the release of acetylcholine from the atrial parasympathetic nerve, probably by inhibiting presynaptic muscarinic receptors.

Comparative use of various mydriatic drugs in kestrels (Falco tinnunculus).

The mydriatic effect of 3 curare-like neuromuscular blocking agents was tested in European kestrels (Falco tinnunculus) after topical application. Alcuronium chloride (5 mg/ml) was found to be effective at a dose of 1 drop (20 drops = 1 ml) administered twice at a 15-minute interval. Mydriasis was achieved at t = 26 +/- 11 minutes, maximal effect was reached at t = 60 +/- 39 minutes, and sufficient mydriasis ended at t = 364 +/- 134 minutes. Nevertheless, side effects, including temporary full paralysis in 1 bird, indicated that this drug should not be used. Pancuronium bromide (2 mg/ml) had an inconsistent effect on each bird at a dose of 2 drops administered twice at 15-minute intervals, and total mydriasis was not reached in 5 of 8 birds. Mydriasis was achieved at t = 34 +/- 11 minutes, maximal effect was reduced and reached at t = 43 +/- 13 minutes, and sufficient mydriasis ended at t = 90 +/- 39 minutes. Vecuronium bromide (4 mg/ml) was administered at a dose of 2 drops, 3 times, at 15-minute intervals. Mydriasis was achieved at t = 23 +/- 8 minutes, maximal effect was reached at t = 65 +/- 12 minutes, and sufficient mydriasis ended at t = 253 +/- 65 minutes. Side effects were not detected. Vecuronium bromide should be used in raptorial birds whenever retinal examination requires fundoscopy.

Effects of mydriatic agents in cockatoos, African gray parrots, and Blue-fronted Amazon parrots.

OBJECTIVE: To compare, in psittacines, the mydriatic effects of several topically applied curariform, sympathomimetic, and parasympatholytic drugs with and without the addition of surface-acting penetrating agents. DESIGN: Prospective, randomized controlled trial. ANIMALS: 10 adult cockatoos (Cacatua sulphurea subspecies), 2 adult African gray parrots (Psittacus erithacus), and 3 adult Blue-fronted Amazon parrots (Amazona aestiva). PROCEDURE: Three curariform drugs (d-tubocurarine, pancuronium, and vecuronium bromide) and 2 autonomic drugs (atropine and phenylephrine hydrochloride) were evaluated. Drugs were tested with and without the addition of a surface-acting penetrating agent, either saponin or benzalkonium chloride. The agent that resulted in the most significant change in pupillary diameter with the fewest systemic side effects in the cockatoos then was evaluated for its effects in the African gray parrots and the Blue-fronted Amazon parrots. During each drug trial, 1 eye was randomly selected to receive the control drug (0.9% NaCl), and the opposite eye was selected to receive the test drug. Each pupil was videotaped 5 (cockatoos only), 15, 30, 45, 60, and 75 minutes after treatment. Pupil diameters were measured by use of a computerized image analysis system. Data for pupil size were analyzed by means of repeated measures ANOVA. RESULTS: Vecuronium without the addition of a surface-acting penetrating agent produced the most consistent and greatest pupillary dilatation in all 3 species with the fewest systemic side effects. CLINICAL IMPLICATIONS: Vecuronium is potentially a clinically useful, topical mydriatic agent for use in avian species. Documented differences in the prevalence of systemic side effects between species suggests that caution should be applied when applying this drug bilaterally.