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INTERACTIONS BETWEEN TUBOCURARINE, PANCURONIUM AND ALCURONIUM DEMONSTRATED IN THE RAT PHRENIC NERVE-HEMIDIAPHRAGM PREPARATION
Br. J. Anaesth. (1983), 55,1127
INTERACTIONS BETWEEN TUBOCURARINE, PANCURONIUM AND ALCURONIUM DEMONSTRATED IN THE RAT PHRENIC NERVE-HEMIDIAPHRAGM PREPARATION B. J. POLLARD AND R. M. JONES SUMMARY
MATERIALS AND METHODS Mixtures of competitive neuromusciilar blocking drugs are used clinically because greater cardiovas- Wistar rats weighing between 280 and 350 g were cular stability can be obtained with the mixture than sacrificed and both hemidiaphragms dissected out, with the individual drugs (Hill et al.,, 1981). How- together with their accompanying phrenic nerves. ever, interactions between certain of the neuromus- These were transferred to a dish containing oxygecular blocking drugs have been reported. Mixtures nated Krebs solution at room temperature. The of pancuronium with tubocurarine and pan- preparations were attached to carrier assemblies and curonium with di-methyl tubocurarine are synergis- placed in identical organ baths of 50 ml capacity ticinman(Lebowitzetal., 1980), while a mixture of containing oxygenated Krebs solution maintained at pancuronium with alcuronium does not display this 37 °C. The hemidiaphragms were stimulated indiphenomenon (Shanks, 1982). Mixtures of gallamine rectly through the nerve and directly across the with tubocurarine may also exhibit synergy (Wong, muscle using supramaximal square wave stimuli. 1969; Ghoneim et al., 1972). Direct and indirect stimuli were administered alterWe have studied the neuromuscular blocking nately with an overall frequency of 0.5 Hz. effects of tubocurarine, pancuronium, alcuronium, The muscle twitch was recorded using an isometand the three two-component mixtures of these ric force transducer and displayed on a Grass multidrugs in an isolated neuromuscular preparation (the channel polygraph. The tension on the muscle was rat phrenic nerve-hemidiaphragm), so as to investi- maintained at 1.5 g. The agents under investigation gate further aspects of the phenomenon of synergy were added to the bath in a volume of 0.5 ml, to and to elucidate the possible mechanism for this o(btain the desired final concentration. A contact effect. time of 5 min was chosen since this was found to give repeatable, reliable, maximal responses. The wash time was 15 min, with a further 20 min wash cycle BRIAN J. POLLARD,* BJHARM., F.F.A.RX.S.; RONALD M. JONES,* allowed between different agents. Preliminary exF.F-A.RX.S.; Anaesthesia Research Laboratories, University of Nottingham Medical School, Queen's Medical Centre, Clifton periments in our laboratory had shown that cumulation did riot occur when using this technique. The Boulevard, Nottingham. Present addresses: depression of twitch height was measured and ex'University of Michigan Hospitals, Anesthesiology Depart- pressed as a percentage with respect to the twitch ment, 1405 E. Ann, Room A6061, Ann Arbor, MI. 48109, height before the addition of the agent. The order of U.S.A. administration of the drugs and mixtures was varied ^Department of Anaesthetics, Guy's Hospital, London SE1 in a random manner throughout. 9RT. Correspondence to B. J. P. Preliminary log dose-response curves were conAn abstract of this study was presented at the 1982 American structed for pancuronium, tubocurarine and alSociety of Anesthesiologists Annual Scientific Meeting in Las curonium (n = 5) and the concentrations required to Vegas, U.S.A. © The Macmillan Press Ltd 1983
Downloaded from http://bja.oxfordjournals.org/ at Georgetown University on August 22, 2015
The interactions between tubocurarine, pancuronium and alcuronium on neuromuscular transmission have been studied in an isolated neuromusciilar preparation (the rat phrenic nerve-hemidiaphragm). Mixtures of tubocurarine and pancuronium, and tubocurarine and alcuronium were found to have a more potent effect than the additive effects of the individual agents when given alone, that is, mixtures were synergisuc. Mixtures of alcuronium and pancuronium did not exhibit this phenomenon. Possible mechanisms for these findings are discussed.
1128
BRITISH JOURNAL OF ANAESTHESIA
Downloaded from http://bja.oxfordjournals.org/ at Georgetown University on August 22, 2015
depress twitch height by 50% (ED*,) defined as one TABLE I. Tubocurarint, pancuronium and mixture—EDX expressed in dose units dose unit. One dose unit of pancuronium was 6 1 2.7 x 10~ mol litre" , one dose unit of tubocurarine Experiment was 1 x 10~6 mol litre"1, and one dose unit of al- number Pancuronium Tubocurarine Mixture 6 1 curonium was 1.4 x 10~ mol litre" . Mixtures of pancuronium with tubocurarine, pancuronium with 1 1.07 1.03 0.84 0.86 0.76 2 1.00 alcuronium, and alcuronium with tubocurarine 1.03 0.84 3 0.90 were prepared. Each combination was mixed in the 1.03 4 1.03 0.80 following proportions: 1.14 1.26 5 0.80 (1) 0.3 dose units of each (total 0.6 dose units). 0.93 1.07 6 1.02 7 0.95 1.05 0.86 (2) 0.4 dose units of each (total 0.8 dose units). 1.03 8 1.20 0.80 (3) 0.5 dose units of each (total 1.0 doseunits). 9 1.08 1.00 0.88 Using suitable concentrations, log dose-response 1.20 0.82 10 0.90 curves (with a minimum of three points each) were 1.03 0.91 11 0.90 plotted for the individual drugs and for the mixtures 12 1.02 0.76 1.01 13 0.87 1.21 0.84 in the above proportions. In the case of pan0.98 14 0.94 1.00 curonium with tubocurarine this was repeated on 20 1.06 0.87 0.98 15 separate phrenic nerve-hemidiaphragm prepara16 0.82 1.01 0.91 tions and in the cases of tubocurarine with al17 0.84 0.75 1.00 curonium and pancuronium with alcuronium, on 12 18 1.05 0.85 0.95 0.91 19 0.88 0.80 separate phrenic nerve-hemidiaphragm prepara0.90 0.88 20 0.95 tions. The EDJO expressed in dose units was recorded. The results for each mixture were then 1.03 ±0.02 0.85±0.02 Mean±SEM 0.97 ±0.02 compared with those of each of its components using Student's ttest. the two individual drugs. In figure 2, the log dose-response curves constructed by regression RESULTS analysis from all of the individual data for The ED,o for tubocurarine, pancuronium and their tubocurarine, alcuronium and their mixture are mixture are shown in table I. The mean for the shown. The curve for the mixture was displaced mixture was lower than that for either drug alone. towards the left from the position occupied by the This difference was significant at the P <0.001 level 100between pancuronium and the mixture and also between tubocurarine and the mixture. There was no significant difference between the results for the two individual drugs. The log dose-response curves 80drawn from the means of the individual results for tubocurarine, pancuronium and their mixture are shown in figure 1. The lines have been constructed £ 60by regression analysis. The log dose-response l curves for the two individual agents can be seen to be close together, while that for the mixture is dis»_ _« Pancuronium S 40placed towards the left. The log dose-response Q. X K Tubocurarine curve for tubocurarine appears less steep than that o—o Mixture for pancuronium, but this difference was not statistically significant. 20The data for tubocurarine, alcuronium and their mixture are given in table II. The mean ED*, of the mixture was lower than that for either drug alone, 0- 1 I I and this difference was significant at the i'<0.001 1.0 2.0 0.5 level between tubocurarine and the mixture, and Dose of relaxant (Dose Units) also between alcuronium and the mixture. There FIG. 1. Log dose-response relationship for tubocurarine, panwas no significant difference between the results for curonium and their mixture (± SEM).
TUBOCURARINE, PANCURONIUM AND ALCURONIUM INTERACTIONS
1129
TABLE II. Alcuronium, tubocurarine and mixture—EDX expressed TABLE HI. Pancuronium, alcuronium and in dose units expressed in dose units Experiment number
Tubocurarine
Mixture
1 2 3 4 5 6 7 8 9 10 11 12
1.11 0.98 1.20 0.90 1.11 0.86 1.00 0.86 0.80 0.92 1.08 1.08
1.00 0.81 1.02 1.03 0.95 1.03 0.80 0.86 0.86 1.00 0.95 0.84
0.60 0.63 0.74 0.69 0.71 0.71 0.62 0.62 0.63 0.76 0.75 0.69
Mean±SEM
0.9910.04
0.93 ±0.03
0.6810.02
two individual agents. The log dose-response curve for tubocurarine appears less steep than that for alcuronium, but this difference was not statistically significant. The ED50 values for pancuronium, alcuronium and their mixture are shown in table III. There were no significant differences between either of the drugs and the mixture, or between the agents themselves. The log dose - response curves constructed by regression analysis from all of the individual data for pancuronium, alcuronium and their mixture are shown in figure 3. The three almost parallel lines are
Experiment number
Pancuronium
Alcuronium
Mixture
6 7 8 9 10 11 12
1.22 1.08 1.13 0.9O 1.09 0.82 0.92 1.03 0.95 0.96 0.86 0.80
1.17 0.88 1.10 1.12 0.95 0.98 1.01 1.07 1.00 1.00 0.91 0.97
1.03 0.88 1.12 1.14 0.98 0.86 0.99 0.93 1.00 0.95 0.90 0.90
MeanlSEM
0.9810.04
1.0110.03
0.9710.03
1 2 3 4
5
positioned close together with no evidence of any displacement. There were no statistically significant differences between the slopes of the curves. DISCUSSION
The results demonstrate clearly synergy between pancuronium and tubocurarine, and between alcuronium and tubocurarine, but not between pancuronium and alcuronium. Thus, support for previously reported findings (Lebowitz et al., 1980; Shanks, 1982) is evident. In the intact animal, any of a multiplicity of
100 -1
100 -I
80-
80-
•6 a 60-
60-
2 2 40-
-A Alcuronium -K Tubocurarine —o Mixture
20-
• Pancuronium * Alcuronium — —o Mixture
3 40-
20-
0-1
0-1 0.5
1.0 Dote of relaxant (Dose Uniti)
2.0
FIG. 2. Log dose—response relationship for alcuronium, tubocurarine and their mixture ( 1 SEM).
0.5
1.0 Do« of relaxant (Dote Units)
20
FIG. 3. Log dose-response relationship for pancuronium, alcuronium and their mixture ( 1 SEM).
Downloaded from http://bja.oxfordjournals.org/ at Georgetown University on August 22, 2015
Alcuronium
mixture—EDX
1130
log dose-response curve for tubocurarine and those for alcuronium and pancuronium may indicate differing mechanisms of action. Furthermore, the structural similarity between the alcuronium and pancuronium molecules is greater than between either of these and tubocurarine. We conclude that specific junctional effects are an important mechanism for the phenomenon of synergy between competitive neuromuscular blocking drugs, and that simultaneous pre- and post^ junctional blockade is a theory of synergy which is compatible with our own observations, and those of other workers. REFERENCES
Bowman, W. C. (1980). Prejunctional and postjunctional cholinoceptors at the neuromuscular junction. Atusth. Analg., 59,935. (1982). Non-relaxant properties of neuromusculflr blocking drugs. Br. J. Aruusth., 54,147. Galindo, A. (1972). Curare and pancuronium compared: Effects on previously undepressed mammalian myoneural junctions. Scieiux, 178, 753. Ghoneim.M. M.,Urgena, R. B.,Dretchen, K., and Long, J.P. (1972). The interaction between d-tubocurarine and gallamine during halothanc anaesthesia. Can. Anaesth. Soc. / . , 19, 66. Hill, A. B., Muller, B.J., Smith, M., Knight, P. R., and Jones, R. M. (198i). Optimum relaxant for high dose fentanyl induction. Aiusthaiology, 55, A208. Hubbard, J. I., Wilson, D. F., and Miyamoto, M. (1969). Reduction of transmitter release by tubocurarine. Namrt (Land.), 223, 531. Lebowitz.P. W., Ramsey, F. M., Savarese, J. J.,and Ali, H. H. (1980). Potentiation of neuromuscular blockade in man produced by combinations of pancuronium and metocurine or pancuronium and d-tubocurarine. Anath. Analg., 59,604. Shanks, C. A. (1982). Dose-response curves for alcuronium and pancuronium alone and in combination. Aruusth. Inltni. Can, 10,248. Standaert, F. G. (1964). The action of d-tubocurarine on the motor nerve terminal. / . Pharmacol. Exp. Ther., 143, 181. Wong, K. C. (1969). Some synergistic effects of curare and gallamine. Fed. Proc., 28, 420.
Downloaded from http://bja.oxfordjournals.org/ at Georgetown University on August 22, 2015
pharmacokinetic factors may be implicated in the formation of drug interactions, for example variations in protein binding and in distribution. Alterations in muscle blood flow have been shown not to be implicated (GhoneimetaL, 1972). In this isolated preparation, the majority of these factors are not operable, yet synergy was observed. Thus, it appears that this phenomenon is produced primarily by actions taking place within the neuromuscular junction itself. Neuromuscular blocking drugs act on at least four sites in the neuromuscular junction, namely the preand post-junctional acetylcholine receptor sites and their corresponding ion channels (Bowman, 1980). The post-junctional receptors are those classically implicated in neuromuscular transmission and their stimulation by pre-junctionally released acetylcholine initiates the excitation-contraction coupling mechanism of the muscle. The pre-junctional cholinoceptors are regarded as being more concerned with transmitter mobilization and release (Bowman, 1980). In addition, they appear to resemble the nicotinic receptors in autonomic ganglia (Bowman, 1980). Standaert (1964), has emphasized that a decrease in pre-junctional stimulus and an increase in postjunctional threshold should reinforce each other. Tubocurarine has been shown to decrease the release of acetylcholine (Hubbard, Wilson and Miyamoto, 1969; Galindo, 1972) and, in addition, has significant autonomic ganglion blocking activity which pancuronium and alcuronium lack (Bowman, 1982). Therefore pancuronium and alcuronium are predominantly post-synaptic blockers, while tubocurarine does have pre-synaptic effects. Consequently, when a combination of pancuronium and tubocurarine is administered, simultaneous preand post-junctional receptor blockade will lead to a reinforcement of the block (that is the mixtures will display synergy). When administering a mixture of alcuronium and pancuronium, synergy will not occur, since neither agent decreases pre-junctional stimulus. While this proposal may explain satisfactorily the reported interactions between the three drugs under investigation, it is likely that each possesses its own spectrum of activity which includes both pre-and post-junctional effects, the emphasis varying between the different agents. Additional support for this proposal may be gained from an inspection of the log dose-response curves. While statistical significance was not evident, the apparent differences in slope between the
BRITISH JOURNAL OF ANAESTHESIA
TUBOCURARINE, PANCURONIUM AND ALCURONIUM INTERACTIONS
1131
INTERACTIONS ENTRE TUBOCURARINE, PANCURONIUM ET ALCURONIUM MISES EN EVIDENCE SUR UNE PREPARATION NERF PHRENIQUE-HEMIDIAPHRAGME CHEZ LE RAT RESUME
INTERAKTIONEN ZWISCHEN TUBOCURARIN, PANCURONIUM UND ALCURONIUM— DEMONSTRIERT AM PHRENICUSNERV DER RATTE BEI HEMIDIAPHRAGMALER PRAPARATION ZUSAMMEKFASSUNG
An einem isolierten neuromuskularen Praparat (hemidiaphragmaler Phrenicusnerv der Ratte) wurden Interakdonen zwiscben Tubocurarin, Pancuronium und Alcuronium auf die neuromuskulare Ubertragung untersucht. Mischungen von Tubocurarin und Pancuronium als auch von Tubocurarin und Alcuronium zeigten einen potenteren Effekt als die additiven Effekte der einzelnen Substanzen allein gegeben, das beifit, die Mischungen waren synergistisch. Mischungen von Pancuronium und Alcuronium wtesen dieses Phanomen nicht auf. Mogliche Ursachen dieser Ergebniise werden diskunert.
INTERACCIONES ENTRE LA TUBOCURARINA, EL PANCURONIO Y EL ALCURONIO DEMONSTRADAS EN LA PREPARACION DE NERVIO FRENICO-HEMIDIAFRAGMA DE LA RATA SUMARIO
En una preparaci6n neuromuscular aislada (nervio frenicohemidiafragma de la rata), se estudiaron las interacciones entre la tubocurarina, el pancuronio y el alcuronio sobre la transmision neuromuscular. Se observo que las mezclas de tubocurarina y de pancuronio y de tubocurarina y alcuronio tenian un efecto mas potente que los efectos aditivos de los agentes individuales administrados por separado, es decir, las mezclas eran sinergisticas. Las mezclas de alcuronio y de pancuronio no produjeron dicho fenomeno. Se discute de los posibles mecanismos que dan estos resultados.
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Nous avons itudie les interactions entre tubocurarine, pancuronium et alcuronium BUT la transmission neuromusculaire grace a unc preparation neuromusculaire isolee (hemidiaphragme de nerf phrenique de rat). Nous avons trouve que les melanges de tubocurarine et de pancuronium ainsi que de tubocurarine et d'alcuronhim avaient un effet phis puissant que les effets additionnea des agents pris isolement, c'est-a-dire que ces melanges etaicnt synergiques. II n'en ctait pas de mane avec les melanges d'alcuronium et de pancuronium. Les mecanismes possibles qui sous-en tendent ces resultats sont discutes.
INTERACTIONS BETWEEN TUBOCURARINE, PANCURONIUM AND ALCURONIUM DEMONSTRATED IN THE RAT PHRENIC NERVE-HEMIDIAPHRAGM PREPARATION B. J. POLLARD AND R. M. JONES SUMMARY
MATERIALS AND METHODS Mixtures of competitive neuromusciilar blocking drugs are used clinically because greater cardiovas- Wistar rats weighing between 280 and 350 g were cular stability can be obtained with the mixture than sacrificed and both hemidiaphragms dissected out, with the individual drugs (Hill et al.,, 1981). How- together with their accompanying phrenic nerves. ever, interactions between certain of the neuromus- These were transferred to a dish containing oxygecular blocking drugs have been reported. Mixtures nated Krebs solution at room temperature. The of pancuronium with tubocurarine and pan- preparations were attached to carrier assemblies and curonium with di-methyl tubocurarine are synergis- placed in identical organ baths of 50 ml capacity ticinman(Lebowitzetal., 1980), while a mixture of containing oxygenated Krebs solution maintained at pancuronium with alcuronium does not display this 37 °C. The hemidiaphragms were stimulated indiphenomenon (Shanks, 1982). Mixtures of gallamine rectly through the nerve and directly across the with tubocurarine may also exhibit synergy (Wong, muscle using supramaximal square wave stimuli. 1969; Ghoneim et al., 1972). Direct and indirect stimuli were administered alterWe have studied the neuromuscular blocking nately with an overall frequency of 0.5 Hz. effects of tubocurarine, pancuronium, alcuronium, The muscle twitch was recorded using an isometand the three two-component mixtures of these ric force transducer and displayed on a Grass multidrugs in an isolated neuromuscular preparation (the channel polygraph. The tension on the muscle was rat phrenic nerve-hemidiaphragm), so as to investi- maintained at 1.5 g. The agents under investigation gate further aspects of the phenomenon of synergy were added to the bath in a volume of 0.5 ml, to and to elucidate the possible mechanism for this o(btain the desired final concentration. A contact effect. time of 5 min was chosen since this was found to give repeatable, reliable, maximal responses. The wash time was 15 min, with a further 20 min wash cycle BRIAN J. POLLARD,* BJHARM., F.F.A.RX.S.; RONALD M. JONES,* allowed between different agents. Preliminary exF.F-A.RX.S.; Anaesthesia Research Laboratories, University of Nottingham Medical School, Queen's Medical Centre, Clifton periments in our laboratory had shown that cumulation did riot occur when using this technique. The Boulevard, Nottingham. Present addresses: depression of twitch height was measured and ex'University of Michigan Hospitals, Anesthesiology Depart- pressed as a percentage with respect to the twitch ment, 1405 E. Ann, Room A6061, Ann Arbor, MI. 48109, height before the addition of the agent. The order of U.S.A. administration of the drugs and mixtures was varied ^Department of Anaesthetics, Guy's Hospital, London SE1 in a random manner throughout. 9RT. Correspondence to B. J. P. Preliminary log dose-response curves were conAn abstract of this study was presented at the 1982 American structed for pancuronium, tubocurarine and alSociety of Anesthesiologists Annual Scientific Meeting in Las curonium (n = 5) and the concentrations required to Vegas, U.S.A. © The Macmillan Press Ltd 1983
Downloaded from http://bja.oxfordjournals.org/ at Georgetown University on August 22, 2015
The interactions between tubocurarine, pancuronium and alcuronium on neuromuscular transmission have been studied in an isolated neuromusciilar preparation (the rat phrenic nerve-hemidiaphragm). Mixtures of tubocurarine and pancuronium, and tubocurarine and alcuronium were found to have a more potent effect than the additive effects of the individual agents when given alone, that is, mixtures were synergisuc. Mixtures of alcuronium and pancuronium did not exhibit this phenomenon. Possible mechanisms for these findings are discussed.
1128
BRITISH JOURNAL OF ANAESTHESIA
Downloaded from http://bja.oxfordjournals.org/ at Georgetown University on August 22, 2015
depress twitch height by 50% (ED*,) defined as one TABLE I. Tubocurarint, pancuronium and mixture—EDX expressed in dose units dose unit. One dose unit of pancuronium was 6 1 2.7 x 10~ mol litre" , one dose unit of tubocurarine Experiment was 1 x 10~6 mol litre"1, and one dose unit of al- number Pancuronium Tubocurarine Mixture 6 1 curonium was 1.4 x 10~ mol litre" . Mixtures of pancuronium with tubocurarine, pancuronium with 1 1.07 1.03 0.84 0.86 0.76 2 1.00 alcuronium, and alcuronium with tubocurarine 1.03 0.84 3 0.90 were prepared. Each combination was mixed in the 1.03 4 1.03 0.80 following proportions: 1.14 1.26 5 0.80 (1) 0.3 dose units of each (total 0.6 dose units). 0.93 1.07 6 1.02 7 0.95 1.05 0.86 (2) 0.4 dose units of each (total 0.8 dose units). 1.03 8 1.20 0.80 (3) 0.5 dose units of each (total 1.0 doseunits). 9 1.08 1.00 0.88 Using suitable concentrations, log dose-response 1.20 0.82 10 0.90 curves (with a minimum of three points each) were 1.03 0.91 11 0.90 plotted for the individual drugs and for the mixtures 12 1.02 0.76 1.01 13 0.87 1.21 0.84 in the above proportions. In the case of pan0.98 14 0.94 1.00 curonium with tubocurarine this was repeated on 20 1.06 0.87 0.98 15 separate phrenic nerve-hemidiaphragm prepara16 0.82 1.01 0.91 tions and in the cases of tubocurarine with al17 0.84 0.75 1.00 curonium and pancuronium with alcuronium, on 12 18 1.05 0.85 0.95 0.91 19 0.88 0.80 separate phrenic nerve-hemidiaphragm prepara0.90 0.88 20 0.95 tions. The EDJO expressed in dose units was recorded. The results for each mixture were then 1.03 ±0.02 0.85±0.02 Mean±SEM 0.97 ±0.02 compared with those of each of its components using Student's ttest. the two individual drugs. In figure 2, the log dose-response curves constructed by regression RESULTS analysis from all of the individual data for The ED,o for tubocurarine, pancuronium and their tubocurarine, alcuronium and their mixture are mixture are shown in table I. The mean for the shown. The curve for the mixture was displaced mixture was lower than that for either drug alone. towards the left from the position occupied by the This difference was significant at the P <0.001 level 100between pancuronium and the mixture and also between tubocurarine and the mixture. There was no significant difference between the results for the two individual drugs. The log dose-response curves 80drawn from the means of the individual results for tubocurarine, pancuronium and their mixture are shown in figure 1. The lines have been constructed £ 60by regression analysis. The log dose-response l curves for the two individual agents can be seen to be close together, while that for the mixture is dis»_ _« Pancuronium S 40placed towards the left. The log dose-response Q. X K Tubocurarine curve for tubocurarine appears less steep than that o—o Mixture for pancuronium, but this difference was not statistically significant. 20The data for tubocurarine, alcuronium and their mixture are given in table II. The mean ED*, of the mixture was lower than that for either drug alone, 0- 1 I I and this difference was significant at the i'<0.001 1.0 2.0 0.5 level between tubocurarine and the mixture, and Dose of relaxant (Dose Units) also between alcuronium and the mixture. There FIG. 1. Log dose-response relationship for tubocurarine, panwas no significant difference between the results for curonium and their mixture (± SEM).
TUBOCURARINE, PANCURONIUM AND ALCURONIUM INTERACTIONS
1129
TABLE II. Alcuronium, tubocurarine and mixture—EDX expressed TABLE HI. Pancuronium, alcuronium and in dose units expressed in dose units Experiment number
Tubocurarine
Mixture
1 2 3 4 5 6 7 8 9 10 11 12
1.11 0.98 1.20 0.90 1.11 0.86 1.00 0.86 0.80 0.92 1.08 1.08
1.00 0.81 1.02 1.03 0.95 1.03 0.80 0.86 0.86 1.00 0.95 0.84
0.60 0.63 0.74 0.69 0.71 0.71 0.62 0.62 0.63 0.76 0.75 0.69
Mean±SEM
0.9910.04
0.93 ±0.03
0.6810.02
two individual agents. The log dose-response curve for tubocurarine appears less steep than that for alcuronium, but this difference was not statistically significant. The ED50 values for pancuronium, alcuronium and their mixture are shown in table III. There were no significant differences between either of the drugs and the mixture, or between the agents themselves. The log dose - response curves constructed by regression analysis from all of the individual data for pancuronium, alcuronium and their mixture are shown in figure 3. The three almost parallel lines are
Experiment number
Pancuronium
Alcuronium
Mixture
6 7 8 9 10 11 12
1.22 1.08 1.13 0.9O 1.09 0.82 0.92 1.03 0.95 0.96 0.86 0.80
1.17 0.88 1.10 1.12 0.95 0.98 1.01 1.07 1.00 1.00 0.91 0.97
1.03 0.88 1.12 1.14 0.98 0.86 0.99 0.93 1.00 0.95 0.90 0.90
MeanlSEM
0.9810.04
1.0110.03
0.9710.03
1 2 3 4
5
positioned close together with no evidence of any displacement. There were no statistically significant differences between the slopes of the curves. DISCUSSION
The results demonstrate clearly synergy between pancuronium and tubocurarine, and between alcuronium and tubocurarine, but not between pancuronium and alcuronium. Thus, support for previously reported findings (Lebowitz et al., 1980; Shanks, 1982) is evident. In the intact animal, any of a multiplicity of
100 -1
100 -I
80-
80-
•6 a 60-
60-
2 2 40-
-A Alcuronium -K Tubocurarine —o Mixture
20-
• Pancuronium * Alcuronium — —o Mixture
3 40-
20-
0-1
0-1 0.5
1.0 Dote of relaxant (Dose Uniti)
2.0
FIG. 2. Log dose—response relationship for alcuronium, tubocurarine and their mixture ( 1 SEM).
0.5
1.0 Do« of relaxant (Dote Units)
20
FIG. 3. Log dose-response relationship for pancuronium, alcuronium and their mixture ( 1 SEM).
Downloaded from http://bja.oxfordjournals.org/ at Georgetown University on August 22, 2015
Alcuronium
mixture—EDX
1130
log dose-response curve for tubocurarine and those for alcuronium and pancuronium may indicate differing mechanisms of action. Furthermore, the structural similarity between the alcuronium and pancuronium molecules is greater than between either of these and tubocurarine. We conclude that specific junctional effects are an important mechanism for the phenomenon of synergy between competitive neuromuscular blocking drugs, and that simultaneous pre- and post^ junctional blockade is a theory of synergy which is compatible with our own observations, and those of other workers. REFERENCES
Bowman, W. C. (1980). Prejunctional and postjunctional cholinoceptors at the neuromuscular junction. Atusth. Analg., 59,935. (1982). Non-relaxant properties of neuromusculflr blocking drugs. Br. J. Aruusth., 54,147. Galindo, A. (1972). Curare and pancuronium compared: Effects on previously undepressed mammalian myoneural junctions. Scieiux, 178, 753. Ghoneim.M. M.,Urgena, R. B.,Dretchen, K., and Long, J.P. (1972). The interaction between d-tubocurarine and gallamine during halothanc anaesthesia. Can. Anaesth. Soc. / . , 19, 66. Hill, A. B., Muller, B.J., Smith, M., Knight, P. R., and Jones, R. M. (198i). Optimum relaxant for high dose fentanyl induction. Aiusthaiology, 55, A208. Hubbard, J. I., Wilson, D. F., and Miyamoto, M. (1969). Reduction of transmitter release by tubocurarine. Namrt (Land.), 223, 531. Lebowitz.P. W., Ramsey, F. M., Savarese, J. J.,and Ali, H. H. (1980). Potentiation of neuromuscular blockade in man produced by combinations of pancuronium and metocurine or pancuronium and d-tubocurarine. Anath. Analg., 59,604. Shanks, C. A. (1982). Dose-response curves for alcuronium and pancuronium alone and in combination. Aruusth. Inltni. Can, 10,248. Standaert, F. G. (1964). The action of d-tubocurarine on the motor nerve terminal. / . Pharmacol. Exp. Ther., 143, 181. Wong, K. C. (1969). Some synergistic effects of curare and gallamine. Fed. Proc., 28, 420.
Downloaded from http://bja.oxfordjournals.org/ at Georgetown University on August 22, 2015
pharmacokinetic factors may be implicated in the formation of drug interactions, for example variations in protein binding and in distribution. Alterations in muscle blood flow have been shown not to be implicated (GhoneimetaL, 1972). In this isolated preparation, the majority of these factors are not operable, yet synergy was observed. Thus, it appears that this phenomenon is produced primarily by actions taking place within the neuromuscular junction itself. Neuromuscular blocking drugs act on at least four sites in the neuromuscular junction, namely the preand post-junctional acetylcholine receptor sites and their corresponding ion channels (Bowman, 1980). The post-junctional receptors are those classically implicated in neuromuscular transmission and their stimulation by pre-junctionally released acetylcholine initiates the excitation-contraction coupling mechanism of the muscle. The pre-junctional cholinoceptors are regarded as being more concerned with transmitter mobilization and release (Bowman, 1980). In addition, they appear to resemble the nicotinic receptors in autonomic ganglia (Bowman, 1980). Standaert (1964), has emphasized that a decrease in pre-junctional stimulus and an increase in postjunctional threshold should reinforce each other. Tubocurarine has been shown to decrease the release of acetylcholine (Hubbard, Wilson and Miyamoto, 1969; Galindo, 1972) and, in addition, has significant autonomic ganglion blocking activity which pancuronium and alcuronium lack (Bowman, 1982). Therefore pancuronium and alcuronium are predominantly post-synaptic blockers, while tubocurarine does have pre-synaptic effects. Consequently, when a combination of pancuronium and tubocurarine is administered, simultaneous preand post-junctional receptor blockade will lead to a reinforcement of the block (that is the mixtures will display synergy). When administering a mixture of alcuronium and pancuronium, synergy will not occur, since neither agent decreases pre-junctional stimulus. While this proposal may explain satisfactorily the reported interactions between the three drugs under investigation, it is likely that each possesses its own spectrum of activity which includes both pre-and post-junctional effects, the emphasis varying between the different agents. Additional support for this proposal may be gained from an inspection of the log dose-response curves. While statistical significance was not evident, the apparent differences in slope between the
BRITISH JOURNAL OF ANAESTHESIA
TUBOCURARINE, PANCURONIUM AND ALCURONIUM INTERACTIONS
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INTERACTIONS ENTRE TUBOCURARINE, PANCURONIUM ET ALCURONIUM MISES EN EVIDENCE SUR UNE PREPARATION NERF PHRENIQUE-HEMIDIAPHRAGME CHEZ LE RAT RESUME
INTERAKTIONEN ZWISCHEN TUBOCURARIN, PANCURONIUM UND ALCURONIUM— DEMONSTRIERT AM PHRENICUSNERV DER RATTE BEI HEMIDIAPHRAGMALER PRAPARATION ZUSAMMEKFASSUNG
An einem isolierten neuromuskularen Praparat (hemidiaphragmaler Phrenicusnerv der Ratte) wurden Interakdonen zwiscben Tubocurarin, Pancuronium und Alcuronium auf die neuromuskulare Ubertragung untersucht. Mischungen von Tubocurarin und Pancuronium als auch von Tubocurarin und Alcuronium zeigten einen potenteren Effekt als die additiven Effekte der einzelnen Substanzen allein gegeben, das beifit, die Mischungen waren synergistisch. Mischungen von Pancuronium und Alcuronium wtesen dieses Phanomen nicht auf. Mogliche Ursachen dieser Ergebniise werden diskunert.
INTERACCIONES ENTRE LA TUBOCURARINA, EL PANCURONIO Y EL ALCURONIO DEMONSTRADAS EN LA PREPARACION DE NERVIO FRENICO-HEMIDIAFRAGMA DE LA RATA SUMARIO
En una preparaci6n neuromuscular aislada (nervio frenicohemidiafragma de la rata), se estudiaron las interacciones entre la tubocurarina, el pancuronio y el alcuronio sobre la transmision neuromuscular. Se observo que las mezclas de tubocurarina y de pancuronio y de tubocurarina y alcuronio tenian un efecto mas potente que los efectos aditivos de los agentes individuales administrados por separado, es decir, las mezclas eran sinergisticas. Las mezclas de alcuronio y de pancuronio no produjeron dicho fenomeno. Se discute de los posibles mecanismos que dan estos resultados.
Downloaded from http://bja.oxfordjournals.org/ at Georgetown University on August 22, 2015
Nous avons itudie les interactions entre tubocurarine, pancuronium et alcuronium BUT la transmission neuromusculaire grace a unc preparation neuromusculaire isolee (hemidiaphragme de nerf phrenique de rat). Nous avons trouve que les melanges de tubocurarine et de pancuronium ainsi que de tubocurarine et d'alcuronhim avaient un effet phis puissant que les effets additionnea des agents pris isolement, c'est-a-dire que ces melanges etaicnt synergiques. II n'en ctait pas de mane avec les melanges d'alcuronium et de pancuronium. Les mecanismes possibles qui sous-en tendent ces resultats sont discutes.