THE NEUROMUSCULAR BLOCKING PROPERTIES OF A NEW STEROID COMPOUND, PANCURONIUM BROMIDE A Pilot Study in Man

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1 Brit. J. Anaesth. (1967), 39, 775 THE NEUROMUSCULAR BLOCKING PROPERTIES OF A NEW STEROID COMPOUND, PANCURONIUM BROMIDE A Pilot Study in Man BY W. L. M. BAIRD AND A. M. REID Department of Anaesthetics, Royal Infirmary, Glasgow, Scotland SUMMARY The action of a new steroid compound, pancuronium bromide (NA97) on the myoneural junction in man has been studied. The drug was shown to produce myoneural blockade which was reversible with neostigmine. A -mg dose of pancuronium bromide produced a degree of blockade similar in intensity and duration to that of mg of tubocurarine. Electromyography showed a rapid fall-off in tetanus followed by post-tetanic facilitation. These facts would point to the blockade being of the non-depolarizing or curariform type. On intravenous injection of the drug there were no changes in pulse rate or systolic blood pressure. Further investigation of the effects of pancuronium bromide in man would seem to be indicated. The compound /3, 16/J-Dipiperidino-5a-androstane-3a,17/3-diol diacetate dimethobromide, known as pancuronium bromide (NA97), was first synthesized in 1964 by Hewett and Savage (1966, personal communication). The chemical structure is shown in figure 1. It is a bisquatemary ammonium steroid compound and, as such, has the two quaternary ammonium groups separated by the 17-carbon atom ring structure common to all the steroid group of drugs. As in tubocurarine and most other myoneural blocking drugs, the presence of two quaternary ammonium groups OOC.CH Br CHCOO FIG. 1 /5, 16/3-Dipiperidino-5a-androstane-3o, 170-diol diacetate dimethobromide.

2 776 BRITISH JOURNAL OF ANAESTHESIA thus situated was a good indication that this drug would also possess neuromuscular blocking properties. The pharmacological action of this drug has been studied extensively in animals by Buckett and Bonta (1966) and Bonta et al. (1966) who showed it to have a neuromuscular blocking action in the mouse, rat, rabbit, cat, dog, frog and chicken. This action was particularly powerful in the cat, rabbit and dog, the blockade being of the non-depolarizing or curariform type. The drug produced slight hypertension in the cat and this was thought to be due to a cardiac vagolytic action. This was the only undesirable side effect noted. It possessed only one-tenth of the potency of hexamethonium as a ganglion blocker. In cats pancuronium bromide is a non-depolarizing myoneural blocker of about ten times the potency, and of about the same duration of action, as tubocurarine. While there is a marked species variation in the effects of neuromuscular blocking drugs, the effects produced in cats are usually most closely reflected in man. The purpose of this investigation was merely to establish whether or not pancuronium bromide produced any neuromuscular blockade in man and, if it did, to determine the type and duration of the blockade and to see if the blockade was easily reversed by neostigmine. The occurrence of any side effects, particularly cardiovascular side effects, was also obviously of prime importance. In order to obtain a quantitative measure of the degree and duration of any myoneural blockade produced, an electromyograph was employed to record the action potentials elicited from the hypothenar muscles in response to supramaximal stimulation of the ulnar nerve at the elbow. It has been shown (Katz, 1965) that under such conditions the height of the action potential is closely related to the degree of paralysis or reduction in muscle tension of the muscle group under study. METHOD Six healthy female patients, with ages ranging from 3 to 51 years, who were undergoing minor gynaecological procedures were studied. Premedication was given approximately 1 hour pre-operatively and consisted of pethidine 50 mg, promethazine 5 mg, and atropine mg (three cases), or sodium phenobarbitone 00 mg and atropine mg (three cases). Anaesthesia was induced with thiopentone and thereafter maintained with nitrous oxide, oxygen and halothane. In five patients the larynx was sprayed with 4 per cent lignccaine and an endotracheal tube passed without using any muscle relaxant. The systolic blood pressure and pulse rate were recorded at 1-minute intervals. The action of the drug on the myoneural junction was recorded by a Medelec Electromyograph Model MNC.l. The supinated forearm was secured on an arm board. The skin over the hypothenar eminence was cleaned with ether and then smeared with Mastisol solution. The recording electrodes (two small silver button-type electrodes such as are used in electroencephalography) were secured on to the skin. An earth-plate was placed on the forearm. The stimulating electrodes, two metal hemispheres set cm apart in a Seton tourniquet strap with a Velcro fastening, were secured in position on the skin over the ulnar nerve behind the elbow. To ensure good electrical contact, the skin had been previously smeared with electrode jelly. The rate of stimulation was 1/sec, the duration of stimulation 0.1 m.sec, and the voltage was the smallest that produced supramaximal stimulation, usually about 80 V. For tetanic stimulation, a rate of 50/sec was used. The impulses from the recording electrodes were fed to two oscilloscopes, one for visual monitoring of the twitch height, the other for photographing with a Cossor cine-camera, the motor speed of which was set at 1 inch/sec. Before injection of the drug, a calibration signal of 1 mv was recorded for a few moments. When the systolic blood pressure and pulse rate were steady, a recording was made of the action potentials at twitch rate prior to injection of the drug. The height of this twitch on the oscilloscope was measured using a pair of dividers. The drug was then injected via a Mitchell needle on the opposite hand, the dose being washed in with about 5 ml sterile water. A stopwatch was started immediately and systolic blood pressure and pulse rate were recorded every minute. At this stage the e.m.g. was continuously scrutinized for signs of myoneural blockade. The time taken to produce diminution of the twitch height and also the time taken to produce

3 NEUROMUSCULAR BLOCKING PROPERTIES OF NEW COMPOUND 777 total disappearance of the twitch height were noted. Thereafter, during the period of a "flat-line" tracing the stimulator was switched on every 3 minutes, to detect the point of return of electromyographic activity. The gradual return of the twitch height to normal was followed. During this phase, at about the point of onethird return, the stimulation rate was increased to 50/sec, and after a short tracing of the tetanus was obtained the stimulation was discontinued until, after a 5-sec interval, a single twitch was recorded to demonstrate the presence or absence of post-tetanic facilitation. The end-point of the myoneural blockade was taken as that point at which the twitch height had returned to the same height as that measured with the dividers before the injection of the drug. The effect of another short burst of tetanus was also a guide as to whether or not the myoneural blockade had ended. In cases 4, 5 and 6, the blockade was reversed by injection of neostigmine and atropine. During the time of the myoneural blockade ventilation was assisted where necessary. At the end of the study, when all signs of myoneural block, both clinical and electromyographic, had passed, anaesthesia was discontinued. The patient, having regained consciousness, was returned to the ward where a careful watch was kept for any after-effects. RESULTS Table I shows the ages, body weights, premedications, doses of thiopentone and of pancuronium bromide administered to the six patients, and summarizes the results obtained. No. 1 received pancuronium bromide 0.5 mg and showed no electromyographic evidence of myoneural blockade, the height of the action potentials remaining constant throughout the period of observation. No. received 1 mg. No real evidence of myoneural blockade was seen, although after about 3 minutes the height of the action potential may have been marginally less for about minutes. No. 3, having received mg of the drug, showed signs of commencing fall in action potential height at 1 minute 30 seconds. By 3 minutes, the electromyograph tracing was a flat line. The tracing remained a flat line until at 17 minutes a slight twitch reappeared. After 8 minutes the twitch height had returned to about one-third of its original height. At this point a rapid fall-off in tetanus followed by marked post-tetanic facilita- 1 Age (years) 33 Approximate weight (stones) 8.5 (kg) 54 Premedication (mg) Pethidine 50 Promethazine 5 Atropine Na-phenobarbitone Induction Thiopentone (mg) 350 Dose of pancuronium bromide (mg) 0.5 Time of onset (seconds) Per cent block produced Time of reappearance of twitch (minutes) Duration of action to complete recovery (minutes) TABLE I *After neostigmine and atropine * * *

778 BRITISH JOURNAL OF ANAESTHESIA B C D FIG. Electromyogram from No. 5. A Before injection of pancuronium bromide B minutes after injection of pancuronium mg.

4 778 BRITISH JOURNAL OF ANAESTHESIA B C D FIG. Electromyogram from No. 5. A Before injection of pancuronium bromide B minutes after injection of pancuronium mg. me bromide mg. me. C 74 minutes after injection of pancuronium D 3 minutes after C, following the injection of bromide mg. atropine mg and neostigmine 1.5 mg.

5 NEUROMUSCULAR BLOCKING PROPERTIES OF NEW COMPOUND 779 tion was demonstrated. The duration of action of this -mg dose was followed until at 55 minutes the twitch height had returned to the same height as before the injection of the drug. Tetanus was now well maintained and there was no posttetanic facilitation. No. 4 also received mg, which produced commencing myoneural blockade at 45 seconds, and a flat-line electromyograph at 1 minute 30 seconds. This time the twitch did not reappear until the nd minute. At 6 minutes atropine 1. mg was given intravenously, followed at 31 minutes by neostigmine 1.5 mg. By the 36th minute the twitch height was not yet back to normal, and so neostigmine 1.5 mg was repeated. The twitch had returned to its original height by 39 minutes, and at 4 minutes tetanus was well maintained and there was no post-tetanic facilitation. No. 5 was also given mg (see fig. ). Twitch height depression commenced at 50 seconds and was complete at minutes. The progress ; ve return of the twitch height was followed after its reappearance at the 30th minute but, since the twitch had not yet completely returned to its original height by 75 minutes, atropine mg and neostigmine 1.5 mg were given. By 77 minutes the twitch had returned to its original height and again tetanus was well maintained and was not followed by facilitation. No. 6 was given 3 mg. Within 0 seconds depression of the twitch height was seen and the tracing was flat at 55 seconds. At 1 minute 30 seconds direct laryngoscopy was performed, the cords were well relaxed, and the patient gave only a slight cough on the passage of an endotracheal tube. Thereafter, the patient became completely apnoeic and intermittent positive pressure ventilation was instituted. At 30 minutes there was still no evidence of returning twitch, and so atropine 1. mg and neostigmine.5 mg were given. This produced the return of clinically adequate spontaneous ventilation, but only a very small twitch height. Atropine mg was given at 4 minutes, and neostigmine 1.5 mg at 46 minutes and again at 49 minutes. The twitch height was back to its original at 51 minutes. Tetanus was now well maintained and there was no post-tetanic facilitation. Throughout each investigation, the injection of pancuronium bromide caused no change in pulse rate or systolic blood pressure. There was no evidence of histamine release such as the formation of skin weals or bronchospasm. DISCUSSION The need for a rapidly acting, non-depolarizing mynoneural blocker, the duration of which is short relative to tubocurarine and which is free from undesirable side effects, has long been recognized. Although it was anticipated from the animal experiments that the duration of action of pancuronium bromide would be about the same as tubocurarine, it was its relative freedom from undesirable side effects, such as tachycardia and hypotension, which led us to undertake this pilot study in man. Mushin and Mapleson (1964) tested a steroid bisquaternary ammonium salt (dipyrandium chloride) as a myoneural blocker, using conscious volunteers and some anaesthetized patients, but found that the time of recovery from the blockade, relative to gallamine, was very variable. The present study of pancuronium bromide suggests that the drug is about five times as potent as tubocurarine and has similar duration of action. The blockade is reversed by neostigmine and the e.m.g. shows a poorly sustained tetanus followed by post-tetanic facilitation. It is therefore reasonable to assume that the blockade is of the nondepolarizing type. The rapid onset of action of pancuronium bromide in cases 4, 5 and 6 would enable early intubation to be carried out, and might obviate any need for the use of suxamethonium. None of the six pulse or systolic blood pressure recordings showed any change on injection of pancuronium bromide although all of these patients received halothane (0.5 per cent) throughout the investigation. The drug has two features which if corroborated in a much larger series of cases might give it advantages over tubocurarine. These are that it has a more rapid onset of action and that there is a complete absence of cardiovascular side effects when used with halothane. Obviously much more investigation in man of the effects of pancuronium bromide as a myoneural blocker is required before further conclusions can be drawn.

6 780 BRITISH JOURNAL OF ANAESTHESIA ACKNOWLEDGEMENTS We are indebted to Dr. W. R. Buckett of Organon Laboratories Ltd., for his help in the preparation of this study, and also for help with the publication of the results. Dr. W. Norris rendered constructive criticism of the paper, for which we are extremely grateful. Organon Laboratories Ltd. very kindly supplied the drug pancuronium bromide (NA97). REFERENCES Bonta, I. L., Buckett, W. R., Lewis, J. J., and Vargaftig, B. B. (1966). /3, 16 -Dipiperidino-5aandrostane-3a, 17/3-diol diacetate dimethobromide, a potent neuromuscular blocking steroid. Proceedings of nd International Congress on Hormonal Steroids. Amsterdam: Excerpta Medica. Buckett, W. R., and Bonta, I. L. (1966). Pharmacological studies with NA97 (, 16/S-Dipiperidine-5aandrostane-3a, 17/8-diol diacetate dimethobromide). Fed. Proc, 5, 718. Katz, R. L. (1965). Comparison of electrical and mechanical recording of spontaneous and evoked muscle activity: the clinical value of continuous recording as an aid to the rational use of muscle relaxants during anesthesia. Anesthesiology, 6,, 04. Mushin, W. W., and Mapleson, W. W. (1964). Relaxant action in man of dipyrandium chloride (M&B 9105A) (a steroid bis-quaternary ammonium salt). Brit. J. Anaesth., 36, 761. LES PROPRIETES DE BLOCAGE NEURO- MUSCULAIRE D'UNE NOUVELLE SUBSTANCE STEROIDE: UNE ETUDE PRELIMINAIRE CHEZ L'HOMME SOMMAIRE L'action de la nouvelle substance stiroide pancuronium bromure (NA.97) sur la fonction myoneurale de l'hoinme a <5te 6tudiee. On a prouve que le medicament provoque un blocage myoneural, reversible par neostigmine. Une dose de mg de pancuronium bromure causait un degr de blocage similaire en intensity et duree, a celui provoqui par mg de tubocurarine. L'electromyographie montrait une rapide reduction en titanie, suivie par une tendance posttitanique accrue. Ces donnfes semblent indiquer que le block est du type non-d6polarisant ou curarifonne. Apres injection intraveineuse du midicament, la frequence du pouls ou la pression sanguine systolique ne subissaient aucun changemenl Des Etudes plus etendues des effets de pancuronium bromure chez l'homme semblent indiquees. DIE NEUROMUSKULAR BLOCKIERENDEN EIGENSCHAFTEN EINER NEUEN STEROID- VERBINDUNG: EINE RICHTUNGWEISENDE UNTERSUCHUNG BEIM MENSCHEN ZUSAMMENFASSUNG Die Wirkung der neuen Steroidverbindung Pancuronium Bromid (NA.97) auf die neuromuskulare Uberleitung beim Menschen wurde untersucht. Es wurde festgestellt, dafi die Substanz eine neuromuskulare Blockade verursacht, die sich mit Neostigmin wieder aufheben lafit, Eine Dosis von mg Pancuronium Bromid crgab eine Blockade, die an Intensitat und Dauer der von mg Tubocurarin entsprach. Die Elektromyographie zeigte einen raschen Abfall der tetanischen Kontraktion mit posttetanischer Entspannung. Diese Befunde wiirden darauf hinweisen, dao die Blockade dem nicht-depolarisierenden oder curareartigen Typ zuzuordnen isl Nach der intravenosen Injektion der Substanz wurden keine Veranderungen der Pulsfrequenz oder des systolischen Blutdruckes beobachtet. Es schiene angezeigt, dafi die Wirkungen von Pancuronium Bromid beim Menschen weiter untersucht werden. "ANAESTHETIC PROBLEMS FACING THE DEVELOPING COUNTRIES" Copies of the Proceedings of the Symposium held at Addenbrooke's Hospital on June 10, 1967, may be obtained from the Secretary of the Medical School, Tennis Court Road, Cambridge. Price 10s. (including postage).

MUSCLE relaxants are used to provide better operating conditions for

MUSCLE relaxants are used to provide better operating conditions for CLEVELAND CLINIC QUARTERLY Copyright 1970 by The Cleveland Clinic Foundation Volume 37, July 1970 Printed in U.S.A. Pancuronium bromide A new non-depolarizing muscle relaxant Preliminary in fifty patients