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Observations on the neuromuscular blocking action of pipecuronium in the dog
Research in Veterinary Science 1987, 43, 101-103
Observations on the neuromuscular blocking action of pipecuronium in the dog R. S. JONES, Department of Anaesthesia, University of Liverpool, PO Box 147, Liverpool L69 3BX
Pipecuronium bromide is a nondepolarising muscle relaxant which is an analogue of pancuronium. Doses of O·025 and O·05 mg kg - 1 produced neuromuscular block in the anaesthetised dog. Previous work would suggest that the drug has minimal effects on the cardiovascular system. However, a dose of 0·05 mg kg- 1 produced a profound hypotension in one dog on one occasion. The neuromuscular blocking action of the drug would appear to be extremely variable as indicated by the wide range of the results. The neuromuscular block was readily reversible with neostigmine preceded by atropine. PIPECURONIUM (2f3, 16f3-bis-(4' dimethyl-l ' piperazino) 3 a, 17 f3 diacetoxy-5a-androstane dibromide) was synthesised in Hungary by Tuba (1980). It is an analogue of pancuronium with the quaternary nitrogen groups situated at the more remote nitrogen of the piperazino groups substituted at the 2 and 16 positions of the androstane skeleton. In isolated nerve-muscle preparations (rat phrenic nerve-diaphragm and chick biventer cervicis muscle) pipecuronium produced a pure non-depolarising block and demonstrated a potency of 1· 7 to 3 times that of pancuronium. The non-depolarising action was also demonstrated in vivo in cats, rabbits and dogs. Pipecuronium partial block was potentiated by pancuronium and could be reversed by cholinesterase inhibitors. It also showed typical characteristics of fade and post-tetanic facilitation following tetanic stimulation. In cats, rabbits and dogs the ED50 doses of pipecuronium were 9· 5 JJg kg - I, 5· 8 JJg kg - I and 3 · 7 lAg kg - I, respectively (Karpati and Biro 1980). The cardiovascular effects in dogs, including a dose related fall in blood pressure, heart rate, peripheral resistance and left ventricular dp/dt were seen at doses of 1· 5 to 5 mg kg - I, which is approximately 375 to 1250 times the EDSO (Karpati and Biro 1980). The initial clinical"data in the human subject have been reported by Boros et al (1980). They reported on the use of the drug in adult human patients undergoing a variety of clinical procedures. The ED95 of pipe. curonium bromide (0·05 mg kg-I) was studied with or without the. prior administration of suxa-
methonium and the results compared to those obtained with equipotent doses of pancuronium. To investigate the action of pipecuronium in the intact dog this series of experiments was carried out using doses of 0·05 mg kg-I and 0·025 mg kg- 1 administered by the intravenous route. Materials and methods The investigation was carried out on four mature female beagle dogs weighing between 12 and 14 kg. The technique used was similar to that described by Cullen et al (1980). After premedication with acepromazine 0·1 mg kg ' ! and atropine 0·044 mg kg- 1 anaesthesia was induced with 12 mg kg ' ' thiopentone and the trachea intubated. Anaesthesia was maintained with nitrous oxide and oxygen (2: 1)and ventilation was controlled using a technique similar to that previously described in the human subject (Snowdon et al 1975). Intermittent doses of thiopentone were also used to maintain anaesthesia. The animals were maintained in a state of moderate hyperventilation with a Paeo 2 in the region of 35 mm Hg. A Datex Normocap carbon dioxide/oxygen analyser (Vickers Medical) was used to monitor end tidal carbon dioxide and occasional checks of the accuracy were made by blood gas analysis of arterial blood samples taken from the femoral arterial catheter. The Peco, was controlled by adjusting the fresh gas flow to the circuit. 'The dogs were placed in left lateral recumbency and"the left hind leg was fixed in a well padded clamp. The left peroneal nerve was stimulated using steel needle electrodes in a similar manner to that described by Bowen (1969). Square wave stimuli of 0·3 ms duration were delivered from a Grass nerve stimulator (S48). The voltage was adjusted to 20 per cent above that required to produce a supramaximal response. Trainof-four stimuli of frequency 2 Hz were applied and repeated at 12 second intervals. The mechanical response of the paw was recorded by attaching a Grass force displacement transducer (Fr03) to the foot and recording the signal on a Devices two channel recorder.
101
Pipecuronium in the dog
102
Rectal temperature was monitored using a thermistor probe and the animal's temperature was maintained at 37· 5 ± 1°C by placing it on a heater pad. The femoral artery was cannulated with a 17· 5 gauge intravenous cannula (Wallace) to obtain a blood pressure record and to obtain arterial blood samples for blood-gas analysis. Arterial blood pressure was measured using a Bell and Howell pressure transducer (4/327 L221) and the signal recorded on the second channel of the recorder. Control readings were obtained for muscle activity and arterial blood pressure before the administration of pipecuronium. The drug was injected into a rapidly flowing drip of normal saline inserted into the right cephalic vein. Doses of 0·05 and 0·025 mg kg-I were used. The times to the first depression and to the disappearance of the train-of-four twitch were noted and continuous monitoring was performed through.. out the whole experiment. The times to the reappearance and to 10 per cent recovery of the train of four response were also noted. At the point when the height of the first twitch (A') of the train-of-four returned to 50 per cent of its original height atropine 0·6 mg was administered. This was followed one minute later by atropine 0·6 mg and neostigmine 2· 5 mg and again one minute later by a second dose of neostigmine 2· 5 mg. The observations were repeated once in each of the four dogs at intervals of not less than one week. Results The effect of the intravenous administration of O' 05 mg kg - 1 pipecuronium on the arterial blood pressure and train-of-four response is shown in Fig I. This is typical of the blood pressure traces obtained
200 150 ~"'IU"'.JUI.l.
100 50
o
mmHg
t
inj
o
+2 min
+1 min
FIG 2: The effect of the intravenous injection of pipecuronium 0-05 mg kg 1 on arterial blood pressure and on the train-of-four response. This illustrates the hypotension observed in one dog after 0-05 mg kg 1
from all the dogs except on a single occasion. Dog B on the first occasion on which it received a dose of 0·05 mg kg-I pipecuronium showed a profound hypotension and the arterial blood pressure fell from 175/130 to 50125. This was the first known exposure of the dog to pipecuronium. This is shown in Fig 2. However, this did not occur on the second occasion on which it received a dose of 0·05 mg kg-I of pipecuronium or on the occasions on which it received the two doses of 0'025 mg kg-I of the drug. The results of the effect of the pipecuronium administration are shown in Table 1. There are obvious differences between the effect of the two doses of pipecuronium on the various measured parameters. However, one of the most notable effects of the drug was the wide range of times observed. If, for example, the time to the maximum disappearance of the train-of-four for a dose of 0·05 mg kg- J is
TABLE 1: Mean times (with ranges) to first depression of the twitch response its disappearance and reappearance together with the time to the recovery of the initial response to 10 per cent of the control values. the time to 60 per cent of A and to full recovery of the traln-of-four response
Dose of pipecuronium
t
inj
a
+ 1 min
+2 min
FIG 1: The effect of the Intravenous injection of pipecuronium 0-05 mg kg 1 on arterial blood pressure and on the train-of-four response: a typical trace
Time to first depression of response (sl Time to disappearance of response (sl Time to reappearance of response (min) Time to 10 per cent recovery of initial twitch height (min) Time to 50 per cent of initial twitch height (min) Time to 100 per cent recovery of initial twitch height (min)
0·05 mg kg .. 1
30·25 (25-36) 494·4 (75-1800) 63·8
(40-97) 71·7
(48·6-109·4)
80·7 (59-9~114-1)
83 (63-116·9)
R. S. Jones
150,••••••••••• 200
100 • 50
o
mmHg
FIG 3: The effect on the arterial blood pressure and train-of-four response of the intravenous administration of atropine and neostigmine to reverse the neuromuscular block produced by pipecuronium
considered the mean figure is 494 -4 seconds with a range of 75 to 1800 seconds which is extremely wide. At 50 per cent return of the first twitch of the trainof-four atropine was administered by intravenous injection followed one minute later by atropine and neostigmine and followed a further minute later by a second dose of neostigmine. The effect of these drugs on the arterial blood pressure and the train-of-four response is shown in Fig 3.
Discussion The results of these experiments indicate that a dose of 0-025 mg-kg ' ! of pipecuronium will produce a neuromuscular block in the dog for a mean time of 46 minutes and 0·05 mg kg-I for 83 minutes. The time of onset of the drug was decreased from 41 to 30 seconds by doubling the dose. The ED50 for pipecuronium in the dog has, been shown to be 3· 7 lAg kg - I (Karpati and Biro 1980). This was demonstrated on the peroneal nerve-anterior tibialis muscle preparation under pentobarbitone anaesthesia using single twitches at a frequency of 0-1 Hz. In the conscious dog the dose for 'total relaxation' was found to be 40 lAg kg - I. These workers did not report a wide range in their results in direct contrast to the work described in this paper.
103
The main feature of the results obtained with this drug in the dog with both doses (0-025 and 0-05 mg kg-I) is the wide range in the times of onset and the duration of its action. This unpredictability would be one of the features which would mitigate against its use in clinical canine anaesthesia, In dogs anaesthetised with pentobarbitone it has been demonstrated that the effects of pipecuronium were only observed with excessive doses of 1· 5 to 5 mg kg - I which is a dose range approximately 375 to 1250 times the ED50. Effects on blood pressure. heart rate. peripheral resistance and left ventricular dp/dt were investigated. Ganglion blocking effects in chloralose/ pentobarbitone anaesthetised cats were only observed at doses in excess of 10 mg kg - I (Karpati and Biro 1980). Hence it is extremely difficult to explain the single case of hypotension observed in one of the dogs after a dose of 0-06 mg kg-I of pipecur onium. This is particularly so in view of the fact that this was the first exposure of the dog to pipecuronium and it received three subsequent doses of the drug during these experiments (that is. a further dose of 0·05 mg kg-I and two of 0-025 mg kg ' '). No degree of arterial hypotension was observed on these three occasions.
Acknowledgements The technical assistance of Mr P. Locke and Mr J. Yates is gratefully acknowledged. The author was in receipt of a Wellcome research leave fellowship.
References BOROS, M., SZENOHRADSZKY, J., MORASI, G. & TOTH, I. (1980) Arzneizmittet Forschung/Drug Research 30, 389-393 BOWEN, J. M. (1%9) American Journal of Veterinary Research 30, 857-859 CULLEN, L. K., JONES, R. S. & SNOWDON, S. L. (1980) British Veterinary Journal 136, 154-159 KARPATI, E. & BIRO, K. (1980) Arzneimittel Forschung/Drug Research 30, 346-354 SNOWDON, S. L., POWELL, D. L., FADL. E. T. & UTTING, J. E. (1975) Anaesthesia JO, 323-332 TUBA, Z. (1980) Arzneimittel Forschung/Drug Research 30, 342-346
Received April LS, 1986 Accepted August 11, 1986
Observations on the neuromuscular blocking action of pipecuronium in the dog R. S. JONES, Department of Anaesthesia, University of Liverpool, PO Box 147, Liverpool L69 3BX
Pipecuronium bromide is a nondepolarising muscle relaxant which is an analogue of pancuronium. Doses of O·025 and O·05 mg kg - 1 produced neuromuscular block in the anaesthetised dog. Previous work would suggest that the drug has minimal effects on the cardiovascular system. However, a dose of 0·05 mg kg- 1 produced a profound hypotension in one dog on one occasion. The neuromuscular blocking action of the drug would appear to be extremely variable as indicated by the wide range of the results. The neuromuscular block was readily reversible with neostigmine preceded by atropine. PIPECURONIUM (2f3, 16f3-bis-(4' dimethyl-l ' piperazino) 3 a, 17 f3 diacetoxy-5a-androstane dibromide) was synthesised in Hungary by Tuba (1980). It is an analogue of pancuronium with the quaternary nitrogen groups situated at the more remote nitrogen of the piperazino groups substituted at the 2 and 16 positions of the androstane skeleton. In isolated nerve-muscle preparations (rat phrenic nerve-diaphragm and chick biventer cervicis muscle) pipecuronium produced a pure non-depolarising block and demonstrated a potency of 1· 7 to 3 times that of pancuronium. The non-depolarising action was also demonstrated in vivo in cats, rabbits and dogs. Pipecuronium partial block was potentiated by pancuronium and could be reversed by cholinesterase inhibitors. It also showed typical characteristics of fade and post-tetanic facilitation following tetanic stimulation. In cats, rabbits and dogs the ED50 doses of pipecuronium were 9· 5 JJg kg - I, 5· 8 JJg kg - I and 3 · 7 lAg kg - I, respectively (Karpati and Biro 1980). The cardiovascular effects in dogs, including a dose related fall in blood pressure, heart rate, peripheral resistance and left ventricular dp/dt were seen at doses of 1· 5 to 5 mg kg - I, which is approximately 375 to 1250 times the EDSO (Karpati and Biro 1980). The initial clinical"data in the human subject have been reported by Boros et al (1980). They reported on the use of the drug in adult human patients undergoing a variety of clinical procedures. The ED95 of pipe. curonium bromide (0·05 mg kg-I) was studied with or without the. prior administration of suxa-
methonium and the results compared to those obtained with equipotent doses of pancuronium. To investigate the action of pipecuronium in the intact dog this series of experiments was carried out using doses of 0·05 mg kg-I and 0·025 mg kg- 1 administered by the intravenous route. Materials and methods The investigation was carried out on four mature female beagle dogs weighing between 12 and 14 kg. The technique used was similar to that described by Cullen et al (1980). After premedication with acepromazine 0·1 mg kg ' ! and atropine 0·044 mg kg- 1 anaesthesia was induced with 12 mg kg ' ' thiopentone and the trachea intubated. Anaesthesia was maintained with nitrous oxide and oxygen (2: 1)and ventilation was controlled using a technique similar to that previously described in the human subject (Snowdon et al 1975). Intermittent doses of thiopentone were also used to maintain anaesthesia. The animals were maintained in a state of moderate hyperventilation with a Paeo 2 in the region of 35 mm Hg. A Datex Normocap carbon dioxide/oxygen analyser (Vickers Medical) was used to monitor end tidal carbon dioxide and occasional checks of the accuracy were made by blood gas analysis of arterial blood samples taken from the femoral arterial catheter. The Peco, was controlled by adjusting the fresh gas flow to the circuit. 'The dogs were placed in left lateral recumbency and"the left hind leg was fixed in a well padded clamp. The left peroneal nerve was stimulated using steel needle electrodes in a similar manner to that described by Bowen (1969). Square wave stimuli of 0·3 ms duration were delivered from a Grass nerve stimulator (S48). The voltage was adjusted to 20 per cent above that required to produce a supramaximal response. Trainof-four stimuli of frequency 2 Hz were applied and repeated at 12 second intervals. The mechanical response of the paw was recorded by attaching a Grass force displacement transducer (Fr03) to the foot and recording the signal on a Devices two channel recorder.
101
Pipecuronium in the dog
102
Rectal temperature was monitored using a thermistor probe and the animal's temperature was maintained at 37· 5 ± 1°C by placing it on a heater pad. The femoral artery was cannulated with a 17· 5 gauge intravenous cannula (Wallace) to obtain a blood pressure record and to obtain arterial blood samples for blood-gas analysis. Arterial blood pressure was measured using a Bell and Howell pressure transducer (4/327 L221) and the signal recorded on the second channel of the recorder. Control readings were obtained for muscle activity and arterial blood pressure before the administration of pipecuronium. The drug was injected into a rapidly flowing drip of normal saline inserted into the right cephalic vein. Doses of 0·05 and 0·025 mg kg-I were used. The times to the first depression and to the disappearance of the train-of-four twitch were noted and continuous monitoring was performed through.. out the whole experiment. The times to the reappearance and to 10 per cent recovery of the train of four response were also noted. At the point when the height of the first twitch (A') of the train-of-four returned to 50 per cent of its original height atropine 0·6 mg was administered. This was followed one minute later by atropine 0·6 mg and neostigmine 2· 5 mg and again one minute later by a second dose of neostigmine 2· 5 mg. The observations were repeated once in each of the four dogs at intervals of not less than one week. Results The effect of the intravenous administration of O' 05 mg kg - 1 pipecuronium on the arterial blood pressure and train-of-four response is shown in Fig I. This is typical of the blood pressure traces obtained
200 150 ~"'IU"'.JUI.l.
100 50
o
mmHg
t
inj
o
+2 min
+1 min
FIG 2: The effect of the intravenous injection of pipecuronium 0-05 mg kg 1 on arterial blood pressure and on the train-of-four response. This illustrates the hypotension observed in one dog after 0-05 mg kg 1
from all the dogs except on a single occasion. Dog B on the first occasion on which it received a dose of 0·05 mg kg-I pipecuronium showed a profound hypotension and the arterial blood pressure fell from 175/130 to 50125. This was the first known exposure of the dog to pipecuronium. This is shown in Fig 2. However, this did not occur on the second occasion on which it received a dose of 0·05 mg kg-I of pipecuronium or on the occasions on which it received the two doses of 0'025 mg kg-I of the drug. The results of the effect of the pipecuronium administration are shown in Table 1. There are obvious differences between the effect of the two doses of pipecuronium on the various measured parameters. However, one of the most notable effects of the drug was the wide range of times observed. If, for example, the time to the maximum disappearance of the train-of-four for a dose of 0·05 mg kg- J is
TABLE 1: Mean times (with ranges) to first depression of the twitch response its disappearance and reappearance together with the time to the recovery of the initial response to 10 per cent of the control values. the time to 60 per cent of A and to full recovery of the traln-of-four response
Dose of pipecuronium
t
inj
a
+ 1 min
+2 min
FIG 1: The effect of the Intravenous injection of pipecuronium 0-05 mg kg 1 on arterial blood pressure and on the train-of-four response: a typical trace
Time to first depression of response (sl Time to disappearance of response (sl Time to reappearance of response (min) Time to 10 per cent recovery of initial twitch height (min) Time to 50 per cent of initial twitch height (min) Time to 100 per cent recovery of initial twitch height (min)
0·05 mg kg .. 1
30·25 (25-36) 494·4 (75-1800) 63·8
(40-97) 71·7
(48·6-109·4)
80·7 (59-9~114-1)
83 (63-116·9)
R. S. Jones
150,••••••••••• 200
100 • 50
o
mmHg
FIG 3: The effect on the arterial blood pressure and train-of-four response of the intravenous administration of atropine and neostigmine to reverse the neuromuscular block produced by pipecuronium
considered the mean figure is 494 -4 seconds with a range of 75 to 1800 seconds which is extremely wide. At 50 per cent return of the first twitch of the trainof-four atropine was administered by intravenous injection followed one minute later by atropine and neostigmine and followed a further minute later by a second dose of neostigmine. The effect of these drugs on the arterial blood pressure and the train-of-four response is shown in Fig 3.
Discussion The results of these experiments indicate that a dose of 0-025 mg-kg ' ! of pipecuronium will produce a neuromuscular block in the dog for a mean time of 46 minutes and 0·05 mg kg-I for 83 minutes. The time of onset of the drug was decreased from 41 to 30 seconds by doubling the dose. The ED50 for pipecuronium in the dog has, been shown to be 3· 7 lAg kg - I (Karpati and Biro 1980). This was demonstrated on the peroneal nerve-anterior tibialis muscle preparation under pentobarbitone anaesthesia using single twitches at a frequency of 0-1 Hz. In the conscious dog the dose for 'total relaxation' was found to be 40 lAg kg - I. These workers did not report a wide range in their results in direct contrast to the work described in this paper.
103
The main feature of the results obtained with this drug in the dog with both doses (0-025 and 0-05 mg kg-I) is the wide range in the times of onset and the duration of its action. This unpredictability would be one of the features which would mitigate against its use in clinical canine anaesthesia, In dogs anaesthetised with pentobarbitone it has been demonstrated that the effects of pipecuronium were only observed with excessive doses of 1· 5 to 5 mg kg - I which is a dose range approximately 375 to 1250 times the ED50. Effects on blood pressure. heart rate. peripheral resistance and left ventricular dp/dt were investigated. Ganglion blocking effects in chloralose/ pentobarbitone anaesthetised cats were only observed at doses in excess of 10 mg kg - I (Karpati and Biro 1980). Hence it is extremely difficult to explain the single case of hypotension observed in one of the dogs after a dose of 0-06 mg kg-I of pipecur onium. This is particularly so in view of the fact that this was the first exposure of the dog to pipecuronium and it received three subsequent doses of the drug during these experiments (that is. a further dose of 0·05 mg kg-I and two of 0-025 mg kg ' '). No degree of arterial hypotension was observed on these three occasions.
Acknowledgements The technical assistance of Mr P. Locke and Mr J. Yates is gratefully acknowledged. The author was in receipt of a Wellcome research leave fellowship.
References BOROS, M., SZENOHRADSZKY, J., MORASI, G. & TOTH, I. (1980) Arzneizmittet Forschung/Drug Research 30, 389-393 BOWEN, J. M. (1%9) American Journal of Veterinary Research 30, 857-859 CULLEN, L. K., JONES, R. S. & SNOWDON, S. L. (1980) British Veterinary Journal 136, 154-159 KARPATI, E. & BIRO, K. (1980) Arzneimittel Forschung/Drug Research 30, 346-354 SNOWDON, S. L., POWELL, D. L., FADL. E. T. & UTTING, J. E. (1975) Anaesthesia JO, 323-332 TUBA, Z. (1980) Arzneimittel Forschung/Drug Research 30, 342-346
Received April LS, 1986 Accepted August 11, 1986