ABSTRACT
PURPOSE: This study was conducted to elucidate the mechanism of enhancement of volatile anesthetics by neuromuscular blocking agents in rats and to consider the relevance of this enhancement to clinical anesthesia. METHODS: Male Sprague-Dawley rats were used. After confirming a movement in response to tail clamping under 1.1 % isoflurane anesthesia, response was determined when the tail clamp was applied at several points after microinjection of pancuronium into the lateral ventricle. Arousal responses to microinjection of nicotine into the lateral ventricle were assessed with or without pretreatment with intraventricular pancuronium. The intravenous 50 % effective dose (ED50) and 95 % effective dose (ED95) for neuromuscular blockade with pancuronium administered in a cumulative fashion at 1.1 % isoflurane were calculated. RESULTS: Intraventricular pancuronium dose-dependently reduced the response to tail clamping, and the dose required to show immobilization of 50 % of rats (intraventricular ED50) was 1.62 µg/kg. Pretreatment with pancuronium at 6 µg/kg significantly reduced the effect of awakening by nicotine under isoflurane anesthesia (P = 0.044). The intravenous ED50 and ED95 for neuromuscular blockade were 63 µg/kg (90 % confidence interval [CI] 52-75 µg/kg) and 133 µg/kg (90 % CI 109-158 µg/kg), respectively. The ratio of intraventricular ED50 to intravenous ED50 was 0.026. CONCLUSION: Pancuronium microinjection into the lateral ventricle dose-dependently enhances the depth of isoflurane anesthesia, which might be caused by inhibition of neuronal nicotinic acetylcholine receptor transmission in the cerebrum. Intravenous injection of pancuronium at high doses might increase the cerebrospinal concentration to a level at which an effect can be observed.
Subject(s)
Isoflurane/administration & dosage , Neuromuscular Blockade/methods , Neuromuscular Blocking Agents/administration & dosage , Pancuronium/administration & dosage , Anesthesia/methods , Anesthetics/administration & dosage , Animals , Male , Neuromuscular Blocking Agents/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, Nicotinic/drug effectsABSTRACT
1. The 2 Hz train-of-four ratio (TOF(ratio)) is used to monitor the degree of patient curarization. Using a rat phrenic nerve-hemidiaphragm preparation, we showed that antinicotinic agents, such as hexamethonium, d-tubocurarine and pancuronium, but not cisatracurium, decreased contractions produced by physiological nerve activity patterns (50 Hz) more efficiently than those caused by 2 Hz trains. Uncertainty about the usefulness of the TOF(ratio) to control safe recovery from curarization prompted us to investigate the muscarinic and adenosine neuromodulation of tetanic (50 Hz) fade induced by antinicotinic agents at concentrations that cause a 25% reduction in the TOF(ratio) (TOF(fade)). 2. Tetanic fade caused by d-tubocurarine (1.1 µmol/L), pancuronium (3 µmol/L) and hexamethonium (5.47 mmol/L) was attenuated by blocking presynaptic inhibitory muscarinic M(2) and adenosine A(1) receptors with methoctramine (1 µmol/L) and 1,3-dipropyl-8-cyclopentylxanthine (2.5 nmol/L), respectively. These compounds enhanced rather than decreased tetanic fade induced by cisatracurium (2.2 µmol/L), but they consistently attenuated cisatracurium-induced TOF(fade). The effect of the M(1) receptor antagonist pirenzepine (10 nmol/L) on fade produced by antinicotinic agents at 50 Hz was opposite to that observed with TOF stimulation. Blockade of adenosine A(2A) receptors with ZM 241385 (10 nmol/L) attenuated TOF(fade) caused by all antinicotinic drugs tested, with the exception of the 'pure' presynaptic nicotinic antagonist hexamethonium. ZM 241385 was the only compound tested in this series that facilitated recovery from tetanic fade produced by cisatracurium. 3. The data suggest that distinct antinicotinic relaxants interfere with fine-tuning neuromuscular adaptations to motor nerve stimulation patterns via activation of presynaptic muscarinic and adenosine receptors. These results support the use of A(2A) receptor antagonists together with atropine to facilitate recovery from antinicotinic neuromuscular blockade.
Subject(s)
Adenosine A2 Receptor Antagonists/pharmacology , Neuromuscular Blocking Agents/pharmacology , Neuromuscular Junction/drug effects , Nicotinic Antagonists/pharmacology , Animals , Diaphragm/drug effects , Diaphragm/physiology , Drug Synergism , Electric Stimulation/methods , Hexamethonium/pharmacology , Male , Muscle Contraction/drug effects , Muscle Contraction/physiology , Neuromuscular Junction/physiology , Pancuronium/pharmacology , Phrenic Nerve/drug effects , Phrenic Nerve/physiology , Rats , Rats, Wistar , Receptor, Adenosine A2A/metabolism , Receptor, Muscarinic M1/metabolism , Receptor, Muscarinic M2/metabolism , Refractory Period, Electrophysiological/drug effects , Tubocurarine/pharmacologyABSTRACT
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.
Subject(s)
Muscle, Skeletal/metabolism , Neuromuscular Blocking Agents/pharmacology , Nicotinic Antagonists/pharmacology , Receptors, Nicotinic/metabolism , Acetylcholine/pharmacology , Androstanols/pharmacology , Animals , Atracurium/analogs & derivatives , Atracurium/pharmacology , Binding Sites , Binding, Competitive , Cell Line , Clone Cells , Dose-Response Relationship, Drug , Drug Synergism , Humans , Inhibitory Concentration 50 , Kidney/cytology , Mice , Pancuronium/pharmacology , Patch-Clamp Techniques , Receptors, Nicotinic/drug effects , Rocuronium , Transfection , Tubocurarine/analogs & derivatives , Tubocurarine/pharmacology , Vecuronium Bromide/pharmacologyABSTRACT
Curare was clinically used in a patient with acute appendicitis by Griffith and Johnson in January 1942. From the day on, the development of new muscle relaxants went on in the world. Since pancuronium was synthesized by Savage in 1964, it was widely used in clinical cases because it provided sufficient muscle relaxation during operation. At present, pancuronium, vecuronium and rocuronium are routinely used in the world. In the future, we expect development of new muscle relaxants with rapid onset, intermediate duration of action, rapid recovery and without side effects.
Subject(s)
Drug Design , Neuromuscular Blocking Agents , Androstanols , Animals , Humans , Neuromuscular Blocking Agents/adverse effects , Neuromuscular Blocking Agents/pharmacokinetics , Neuromuscular Blocking Agents/pharmacology , Pancuronium , Rocuronium , Succinylcholine , Vecuronium BromideABSTRACT
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.
Subject(s)
Neuromuscular Blocking Agents/pharmacology , Pancuronium/pharmacology , Receptor, Muscarinic M2/metabolism , Vecuronium Bromide/pharmacology , Allosteric Regulation/drug effects , Animals , Atropine/pharmacology , Binding, Competitive/drug effects , CHO Cells , Cricetinae , Cricetulus , Gallamine Triethiodide/pharmacology , Humans , Kinetics , Muscarinic Antagonists/pharmacology , N-Methylscopolamine/metabolism , Pancuronium/metabolism , Radioligand Assay , Receptor, Muscarinic M2/antagonists & inhibitors , Receptor, Muscarinic M2/genetics , Recombinant Proteins/metabolism , TritiumABSTRACT
Organophosphorus (OP) pesticides or nerve agents cause severe intoxication by inhibition of acetylcholinesterase, finally resulting in death due to respiratory failure. The phrenic nerve diaphragm preparation is considered as the classic model to investigate the effect of OP intoxications and oxime treatment at the neuromuscular junction. However, this preparation is unsuitable for larger species or for muscle strips from biopsies where no nerve is available for stimulation. An alternative technique is the indirect field stimulation of muscles containing intramuscular nerve branches only. The proposed method by Wolthuis et al. [Wolthuis, O.L., Vanwersch, R.A.P., Van Der Wiel, H.J., 1981. The efficacy of some bis-pyridinium oximes as antidotes to soman in isolated muscles of several species including man. Eur. J. Pharmacol. 70, 355-369] was modified and experimentally reevaluated in isolated mouse diaphragms. To confirm that electrical field stimulation technique induced muscle contraction only via the neuromuscular endplate the nicotinic antagonists pancuronium or d-tubocurarine (1microM) were given. In the presence of a nicotinic antagonist hardly any contraction was blocked after indirect field stimulation technique with very short pulses (5micros, <0.6A), in contrast to direct muscle stimulation (broader pulse width, or higher amplitude >0.6A). During paraoxon circumfusion (20min, 1micromol/l) muscle force generation by indirect stimulation was almost completely blocked. Restoration of paralyzed muscle function to 80% of initial values could be achieved after paraoxon wash out (20min) and circumfusion with obidoxime (1micromol/l, 20min). This data correspond quite well to data shown earlier when using conventional nerve stimulation techniques.
Subject(s)
Muscle Contraction/drug effects , Oximes/pharmacology , Paraoxon/poisoning , Animals , Diaphragm/drug effects , Diaphragm/innervation , Electric Stimulation , In Vitro Techniques , Male , Mice , Mice, Inbred Strains , Neuromuscular Blocking Agents/pharmacology , Pancuronium/pharmacology , Tubocurarine/pharmacologyABSTRACT
STUDY OBJECTIVE: The present report investigates the rate of arousal following remifentanil-based anesthesia associated with the coadministration of pancuronium, which inhibits butyrylcholinesterase, or cisatracurium, which is partially metabolized by nonspecific esterases, versus vecuronium that is eliminated independently of ester hydrolysis. DESIGN, SETTING AND PATIENTS: Sixty patients, ASA I-II, scheduled for elective abdominal surgeries were enrolled in a double-blinded prospective study. In fact, patients were equally divided into three Groups with each Group receiving remifentanil and either one of the following three muscle relaxants: pancuronium, vecuronium or cisatracurium. MEASUREMENTS: The rate of arousal following discontinuation of anesthesia was assessed by Modified Aldrete Score. Time to eye opening on verbal command, tracheal extubation, Modified Aldrete Score >9, and time to discharge from the recovery room were recorded. MAIN RESULTS: Time to eye opening on verbal command, tracheal extubation, Modified Aldrete Score >9, and time to discharge from the recovery room were not significantly different between the three groups. CONCLUSION: The results suggest that recovery following remifentanil-based anesthesia is not delayed by the coadministration of pancuronium, cisatracurium versus vecuronium; and by the use of neostigmine for reversal of neuromuscular blockade.
Subject(s)
Anesthesia Recovery Period , Anesthetics, Intravenous , Atracurium/analogs & derivatives , Neuromuscular Blocking Agents/pharmacology , Neuromuscular Nondepolarizing Agents/pharmacology , Pancuronium/pharmacology , Piperidines , Abdomen/surgery , Adult , Atracurium/pharmacology , Double-Blind Method , Female , Humans , Male , Middle Aged , RemifentanilABSTRACT
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.
Subject(s)
Light , Neuromuscular Blocking Agents/pharmacology , Pupil/drug effects , Pupil/radiation effects , Adult , Anesthesia , Female , Humans , Male , Middle Aged , Pancuronium/pharmacology , Vecuronium Bromide/pharmacologyABSTRACT
1. Rats were anaesthetized with sodium pentobarbitone and maximal twitches of a tibialis anterior muscle were evoked by stimulation of the motor nerve. 2. Suramin, injected intravenously in a series of cumulative bolus doses, each 15 mg kg-1, completely reversed a 90% depression of twitches maintained by a continuous intravenous infusion of pancuronium. The cumulated dose necessary to restore twitches to 50% of their control amplitude was 35 mg kg-1. Suramin did not modify a similar degree of block produced by suxamethonium, nor did it affect the amplitude of control maximal twitches, even in cumulative doses up to 150 mg kg-1. 3. The effects of bolus doses of suramin (85 mg kg-1), neostigmine (0.03 mg kg-1) and 4-aminopyridine (1.2 mg kg-1), calculated to restore pancuronium-blocked twitches to 95% of control amplitude, were compared. Suramin produced the most rapid reversal (1.1 +/- 0.5 min), but its duration of action was the shortest (9.4 +/- 1.6 min). Suramin was without effect on heart rate or blood pressure in the doses used. 4. The results showed that suramin reversed neuromuscular block produced by nondepolarizing blocking drug, pancuronium, but was without effect on a block produced by the depolarizing blocking drug, suxamethonium. Its short duration of action suggests that suramin would probably not be of value clinically as a reversal agent. However, it is possible that it might serve as a starter compound for the synthesis and development of a new class of reversal agents for use in anaesthetic practice.
Subject(s)
Neuromuscular Blocking Agents/antagonists & inhibitors , Pancuronium/antagonists & inhibitors , Suramin/pharmacology , 4-Aminopyridine/pharmacology , Anesthesia , Animals , Electric Stimulation , Isometric Contraction/drug effects , Male , Neostigmine/pharmacology , Neuromuscular Blocking Agents/pharmacology , Pancuronium/pharmacology , Rats , Rats, Wistar , Succinylcholine/pharmacologyABSTRACT
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.
Subject(s)
Neuromuscular Blocking Agents/pharmacology , Receptors, Muscarinic/drug effects , Analysis of Variance , Androstanols/pharmacology , Animals , Binding, Competitive , CHO Cells , Cricetinae , Cyclic AMP/metabolism , Humans , Pancuronium/pharmacology , Receptors, Muscarinic/genetics , Recombinant Proteins/genetics , Recombinant Proteins/pharmacology , Rocuronium , Transfection , Vecuronium Bromide/pharmacologyABSTRACT
1 A new in vivo experimental method is described whereby the liver can be temporarily excluded from the general circulation by means of a portocaval shunt operation. The influence of this manoeuvre upon the effects of pancuronium and Org 6368 was investigated using the tibialis muscle preparation of anaesthetized cats. 2 The procedure also allowed intraportal injections of the drugs to be made so that the effect of first-passage uptake by the liver could be compared with hapatic exclusion in the same animal. 3 Hepatic exclusion greatly increased the duration of action of both drugs. Whereas intraportal injection did not significantly alter the effect of pancuronium on the tibialis muscle, the effect of Org 6368 was greatly diminished when given by this route. 4 The liver appears to tolerate short periods of hepatic exclusion and it is concluded that this technique may become a useful tool for studying the handling of drugs by this organ.
Subject(s)
Liver/metabolism , Pharmaceutical Preparations/metabolism , Anesthesia , Animals , Cattle , Injections, Intravenous , Muscle Contraction/drug effects , Neuromuscular Blocking Agents/administration & dosage , Neuromuscular Blocking Agents/metabolism , Neuromuscular Blocking Agents/pharmacology , Pancuronium/administration & dosage , Pancuronium/analogs & derivatives , Pancuronium/metabolism , Pancuronium/pharmacology , PharmacologyABSTRACT
The neuromuscular blocking agents tubocurarine, atracurium and pancuronium have been tested for their ability to inhibit receptor-mediated increases in the K+ permeability of intestinal smooth muscle. All three agents, as well as the bee venom peptide apamin, reduced both the resting efflux of 86Rb and the increase in efflux caused by the application of either bradykinin (1 microM) or an alpha 1-adrenoceptor agonist, amidephrine (20 microM), to depolarized strips of guinea-pig taenia caeci. This suggested that like apamin, the neuromuscular blocking agents inhibit the Ca2+-dependent K+ permeability (PK(Ca] mechanism which in this tissue is activated by a variety of membrane receptors. The concentrations (IC50S) of atracurium, pancuronium and (+)-tubocurarine which reduced the effect of amidephrine on 86Rb efflux by 50% were 12, 37 and 67 microM respectively. Also in keeping with an ability to block PK(Ca), the neuromuscular blockers and apamin reduced the inhibition by amidephrine and bradykinin of physalaemin-mediated contractions of the taenia caeci. The IC50 values were 15, 31 and 120 microM for atracurium, tubocurarine and pancuronium respectively, and 2.3 nM for apamin. Each of the neuromuscular blockers, and apamin, increased the spontaneous contractions of the rabbit duodenum and blocked the inhibitory effect of amidephrine thereon. It is concluded that the PK(Ca) mechanism in the longitudinal smooth muscle of the intestine It is concluded that the PK(Ca) mechanism in the longitudinal smooth muscle of the intestine resembles that of hepatocytes and sympathetic ganglion cells in its susceptibility to inhibition by neuromuscular blocking agents, as well as by apamin.
Subject(s)
Muscle, Smooth/drug effects , Neuromuscular Blocking Agents/pharmacology , Potassium Channels , Potassium/metabolism , Adrenergic alpha-Agonists/pharmacology , Animals , Apamin/pharmacology , Atracurium , Bradykinin/pharmacology , Calcium/physiology , Cecum/drug effects , Cecum/physiology , Drug Interactions , Duodenum/drug effects , Duodenum/physiology , Ethanolamines/pharmacology , Guinea Pigs , In Vitro Techniques , Isoquinolines/pharmacology , Muscle Contraction/drug effects , Muscle, Smooth/physiology , Pancuronium/pharmacology , Physalaemin/pharmacology , Rabbits , Receptors, Neurotransmitter , Tubocurarine/pharmacologyABSTRACT
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.
Subject(s)
Histamine N-Methyltransferase/antagonists & inhibitors , Methyltransferases/antagonists & inhibitors , Neuromuscular Blocking Agents/pharmacology , Neuromuscular Nondepolarizing Agents/pharmacology , Androstane-3,17-diol/analogs & derivatives , Androstane-3,17-diol/pharmacology , Animals , Atracurium/pharmacology , Gallamine Triethiodide/pharmacology , Kidney/enzymology , Pancuronium/pharmacology , Pipecuronium , Piperazines/pharmacology , Rats , Tubocurarine/analogs & derivatives , Tubocurarine/pharmacology , Vecuronium Bromide/pharmacologyABSTRACT
Neuromuscular blocking drugs have a high affinity for muscarinic acetylcholine receptors in the heart atria and ileal smooth muscle. In experiments on homogenates, alcuronium, gallamine, pancuronium, tercuronium and ritebronium inhibited the binding of the muscarinic antagonist (3H)quinuclidinyl benzilate (QNB) to rat heart atria with IC50 values of 0.15-0.53 mumol X 1(-1) and to ileal longitudinal muscles with IC50 values of 0.12-0.45 mumol X 1(-1). d-Tubocurarine and decamethonium inhibited (3H)QNB binding to these tissues with IC50 values of 6.2-8.5 mumol X 1(-1). For each neuromuscular blocking drug, the IC50 values were virtually identical for (3H)QNB displacement in the homogenates of the atria and of the ileal muscle. Alcuronium and gallamine differed from the other blocking agents in that they produced less steep (3H)QNB displacement curves both in the atria and the ileal muscle; Hill coefficients for the binding of alcuronium and gallamine to atrial and ileal homogenates were lower than unity. On isolated atria, gallamine, pancuronium, ritebronium and tercuronium antagonized the inhibition of tension development caused by the muscarinic agonist, methylfurmethide, with Kd values which were of the same order of magnitude as the IC50 values for the displacement of (3H)QNB binding to homogenates; the Kd of alcuronium was 12.5 times higher. d-Tubocurarine and decamethonium did not antagonize the effects of methylfurmethide at concentrations up to 100 mumol X 1(-1). On isolated ileal longitudinal muscle, gallamine and pancuronium antagonized the effects of methylfurmethide with Kd values that were 53 times and 100 times higher than their respective Kd values in the atria.(ABSTRACT TRUNCATED AT 250 WORDS)
Subject(s)
Heart/drug effects , Muscle, Smooth/drug effects , Neuromuscular Blocking Agents/pharmacology , Receptors, Cholinergic/drug effects , Alcuronium/pharmacology , Animals , Binding, Competitive/drug effects , Decamethonium Compounds/pharmacology , Female , Gallamine Triethiodide/pharmacology , Ileum/drug effects , In Vitro Techniques , Kinetics , Muscle, Smooth/metabolism , Myocardium/metabolism , Neuromuscular Blocking Agents/metabolism , Pancuronium/pharmacology , Piperidines/metabolism , Piperidines/pharmacology , Quaternary Ammonium Compounds/metabolism , Quaternary Ammonium Compounds/pharmacology , Quinuclidinyl Benzilate , Rats , Rats, Inbred Strains , Tubocurarine/pharmacologyABSTRACT
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.
Subject(s)
Anesthesia, General , Hemodynamics/drug effects , Isoflurane , Neuromuscular Blocking Agents/pharmacology , Neuromuscular Junction/drug effects , Adolescent , Adult , Androstane-3,17-diol/analogs & derivatives , Androstane-3,17-diol/pharmacology , Atracurium/pharmacology , Blood Pressure/drug effects , Female , Heart Rate/drug effects , Humans , Male , Middle Aged , Neuromuscular Junction/physiology , Pancuronium/pharmacology , Pipecuronium , Piperazines/pharmacology , Time Factors , Vecuronium Bromide/pharmacologyABSTRACT
The effect of atracurium on intraocular pressure was studied by comparing it with pancuronium in a randomised controlled trial. The intraocular pressure was measured in patients undergoing cataract surgery before administration of the muscle relaxant, at 1, 3, and 5 minutes after its administration, and at 1 minute after tracheal intubation. Atracurium was found to decrease intraocular pressure to a significantly greater degree than pancuronium. The intraocular pressure after tracheal intubation was found to be significantly higher than that measured immediately after induction of anaesthesia. The authors conclude that atracurium provides an acceptable alternative to pancuronium for ophthalmic surgery but does not overcome the ocular hypertensive effect of tracheal intubation.
Subject(s)
Intraocular Pressure/drug effects , Isoquinolines/pharmacology , Neuromuscular Blocking Agents/pharmacology , Aged , Anesthesia, General , Atracurium , Cataract Extraction , Clinical Trials as Topic , Female , Humans , Intubation, Intratracheal , Male , Middle Aged , Pancuronium/pharmacology , Random AllocationABSTRACT
This study consists of the synthesis, separation, and stereochemical analysis of oximino ethers, followed by a preliminary pharmacological evaluation for neuromuscular blockade. Synthesis of the compounds began with the double oximation of progesterone, which yielded EE and ZE dioximes as major products. Both stereoisomers were separated and purified by chromatography followed by crystallization. The diether of each dioxime was prepared by O-alkylation with 2-dimethylaminoethyl chloride hydrochloride, using a mixture of potassium tert-butoxide and sodium hydride as base. The diethers were separated from the monoethers by vacuum chromatography. Configurational assignments of all compounds were based on 1HNMR and 13CNMR spectroscopy. Quaternization with methyl bromide yielded the salts which were purified via fractional crystallization. A preliminary pharmacological evaluation was conducted by using mice on a treadmill apparatus. Structure-activity relationships are discussed on the basis of similarities to succinylcholine.
Subject(s)
Neuromuscular Blocking Agents/chemical synthesis , Progesterone/analogs & derivatives , Alkylation , Animals , Crystallization , Female , Magnetic Resonance Spectroscopy , Male , Mice , Neostigmine/pharmacology , Neuromuscular Blocking Agents/chemistry , Neuromuscular Blocking Agents/pharmacology , Pancuronium/pharmacology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The effect of trimetaphan alone and in combination with pancuronium, tubocurarine or metocurine (dimethyl tubocurarine) has been examined on the rat phrenic nerve diaphragm preparation. Trimetaphan alone produced neuromuscular blockade in an all-or-none fashion once a concentration of between 2.39 X 10(-4) and 3.00 X 10(-4) M had been exceeded. Concentrations of trimetaphan below this threshold produced a dose-dependent potentiation of all three non-depolarizing relaxants studied. This potentiation was equal for tubocurarine and metocurine, but less for pancuronium.
Subject(s)
Neuromuscular Blocking Agents , Trimethaphan/pharmacology , Animals , Dose-Response Relationship, Drug , Drug Therapy, Combination , In Vitro Techniques , Neuromuscular Blocking Agents/pharmacology , Neuromuscular Nondepolarizing Agents/pharmacology , Pancuronium/pharmacology , Phrenic Nerve/drug effects , Rats , Rats, Inbred Strains , Tubocurarine/analogs & derivatives , Tubocurarine/pharmacologyABSTRACT
Org 6368 is a homologue of pancuronium bromide. Its interactions with other agents in the cat sciatic nerve-gastrocnemius muscle preparation revealed that paralysis was of the non-depolarizing type. This was confirmed in experiments using avian muscle. Org 6368 is a potent muscle relaxant being 2-4 times as potent as (+)-tubocurarine in the cat. Paralysis in the cat is rapid in onset and of appreciably shorter duration than that of pancuronium and (+)-tubocurarine. Repeated injections of the same dose of Org 6368 show no cumulative effect. Muscle relaxant doses generally cause a slight increase in both blood pressure and heart rate. Although its histamine-releasing capacity is greater than that of pancuronium it is less than that of (+)-tubocurarine. Org 6368 shares with pancuronium a very weak effect on both the muscarinic receptor and ganglionic transmission. Differences in the muscle relaxant profiles of Org 6368 and pancuronium are discussed.
Subject(s)
Neuromuscular Blocking Agents/pharmacology , Pancuronium/analogs & derivatives , Animals , Autonomic Fibers, Preganglionic/physiology , Cats , Chickens , Electric Stimulation , Female , Gallamine Triethiodide/pharmacology , Ganglia, Spinal/drug effects , Guinea Pigs , Hexamethonium Compounds/pharmacology , Histamine Release/drug effects , In Vitro Techniques , Male , Muscles/drug effects , Neuromuscular Junction/drug effects , Pancuronium/pharmacology , Parasympatholytics/pharmacology , Phrenic Nerve/physiology , Sciatic Nerve/physiology , Synaptic Transmission/drug effects , Tubocurarine/pharmacologyABSTRACT
Neuromuscular blockade frequently is employed to facilitate mechanical ventilation and other therapeutic interventions in adults and children. In recent years it has been suggested that the use of neuromuscular blockade in the management of premature infants who are ventilated for respiratory distress will reduce the incidence of barotrauma and intracranial hemorrhage. Subsequently, neuromuscular blocking agents have become some of the most commonly used medications in the intensive care nursery. A discussion of these drugs is included in this article to improve the understanding of their pharmacology, the indications and consequence of their use, and their potential side effects. Additionally, the recent introduction of new, shorter-acting agents warrants a review of current practice.