INTERACTION BETWEEN PANCURONIUM BROMIDE AND VECURONIUM BROMIDE

Br. J. Anaesth. (1985), 57, 1063-1066

INTERACTION BETWEEN PANCURONIUM BROMIDE AND VECURONIUM BROMIDE O. M. RASHKOVSKY, S. AGOSTON AND J. M. KET

We investigated the practicability of such a technique, in a study of the possible interactions between pancuronium and vecuronium. Two alternative sequences of administration of the compounds were investigated: pancuronium followed by vecuronium, and vice versa.

O. M. RASHKOVSKY,

M.D.;

S. AGOSTON,

M.D.,

PH.D.;

J. M. KET;.Research Group of the Institutes of Anaesthesiology and Clinical Pharmacology, State University of Groningen, Oostersingel 59, 9713 EZ Groningen, The Netherlands. Correspondence to O.M.R.

SUMMARY The interaction between two non-depolarizing neuromuscular blocking agents, pancuronium bromide and vecuronium bromide, has been studied at standardized levels of neuromuscular blockade and alternating the sequence of their administration, in 40 surgical patients. The drug administered first appeared invariably to play a dominant role in influencing both the dose requirements and the duration of action of the subsequent neuromuscular blocker. This resulted in reduced dose requirements and significant prolongation of action of vecuronium administered after pancuronium and increased dose requirements and shortening of neuromuscular blocking action of pancuronium given during vecuronium-induced partial neuromuscular blockade. Possible mechanisms of such interaction are discussed.

PATIENTS AND METHODS

Forty adult surgical patients of either sex (ASA I or II) were studied after informed consent had been obtained from each. Premedication consisted of papaveretum 10-15 mg and atropine 0.5 mg given i.m. approximately 1 h before the start of anaesthesia. Anaesthesia was induced with droperidol 10-15 mg, fentanyl 0.4-0.6 mg and a "sleep dose" of thiopentone. The patients' lungs were ventilated with a mixture of 67% nitrous oxide in oxygen. Small increments of fentanyl (0.05—0.1 mg) were administered as needed for the maintenance of anaesthesia. Neuromuscular transmission was monitored continuously throughout the investigation by means of registration of the isometric twitch tension of the adductor pollicis muscle in response to indirect stimulation of the ulnar nerve at the wrist with square-wave supramaximal electrical stimuli of 0.2 ms duration at a rate of 0.1 Hz.

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Vecuronium is a non-depolarizing neuromuscular blocking agent which has recently been introduced to clinical practice. Although closely related chemically to its bisquatemary analogue, pancuronium, it has a considerably shorter duration of action and lacks the occasional undesirable cardiovascular side-effects of pancuronium (Agoston et al., 1980; Crul and Booij, 1980). These differences in clinical characterstics might confer some advantage in combining the two drugs in clinical practice: the alternate administration ofneuromuscular blockers with different durations of action might enable the anaesthetist to regulate to a finer degree the depth and duration of neuromuscular blockade during surgery, according to the stage of an operation and the clinical requirements. One possible application of such a combination of myoneural blockers with different durations of actions could be the administration of the shorter-acting drug for the closure of the peritoneum at the end of an abdominal operation. On the other hand, when a non-depolarizing agent is used, instead of suxamethonium, to provide blockade for intubation of the trachea, a shorter-acting drug like vecuronium, devoid of undesirable cardiovascular side effects, may be preferred. In such instances (dependent on the anticipated duration of the operation) the maintenance of blockade during surgery might be achieved using either the same drug or a longer acting compound, such as pancuronium.

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TABLE I. Combinations of neuromuscular blocking agents studied Blockers administered for 95% blockade N

Group

I II

III

VIII

patients

rtf initctinn of

5 5 5 5 5 5 5 5

First drug

Second drug

Pancuronium Pancuronium

Pancuronium Pancuronium Vecuronium Vecuronium Vecuronium Vecuronium Pancuronium

Pancuronium Pancuronium Vecuronjum Vecuronium Vecuronium Vecuronium

second drug (%) 25 50

25 50 25 50 25 50

Pancuronium

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IV V VI VII

Recovery at time

n

After the induction of anaesthesia and a control recording of the twitch tension, the first neuromuscular blocking drug was injected, in increments, to a fast running infusion until approximately 95 % blockade was obtained. The trachea was then intubated. By random allocation to groups, 20 patients (five in each of groups I-IV) received pancuronium as the first neuromuscular blocker administered, and another 20 patients (five in each of groups V-VIII) received vecuronium first. Table I shows the combinations of drugs studied subsequently: neuromuscular blockade was maintained during surgery using either the same drug as for initial blockade (groups I, II and V, VI) or the alternative drug (groups III, IV and VII, VIII), administered in increments at 25 % or 50 % recovery after the first drug, until a blockade of 95% was again obtained. The size of the increments was determined individually in each patient, according to the effect obtained, and with the aim of achieving the desired degree of blockade (95%) with the minimal number of increments in the shortest possible time. After this the blockade was allowed to recover spontaneously. The doses of pancuronium and vecuronium required for 95 % neuromuscular blockade as well as their time course of action (clinical duration and recovery index) were compared. Statistical analysis was with Student's r test. Differences were considered significant at P < 0.05.

and at 50% recovery of the neuromuscular blockade induced by the initial dose of pancuronium or vecuronium. At both stages of recovery after vecuronium the same magnitude of block could be produced only by using 35-40% larger maintenance doses, of either neuromuscular blocker, than were necessary after pancuronium. Understandably, at the more advanced (50 %) stage of recovery from the initial

RESULTS

FIG. 1. Maintenance doses (ugkg" 1 ) of vecuronium (open columns) and pancuronium (cross-hatched columns) required for production of approximately 95 % blockade at 25 % or 50% recovery from an initial block produced by pancuronium or by vecuronium. Mean values±SD. 'Significantly different from the corresponding value after pancuronium.

Figure 1 shows the mean values of the maintenance doses of pancuronium and vecuronium required, for reinforcement of the blockade to 95 % suppression of twitch height, given at 25 %

After At 25 L pancuronium

After vecuronium

— 40-,

5

\ I:

01 (0

n-

At 5 0 1

* „ 4O-|

•1*1

0)

3 8 o

20-

a

MYONEURAL BLOCKERS: INTERACTIONS At 25 1

After pancuronium

After vecuronium

eon

D

Rl

D

Rl

vecuronium. This difference was especially pronounced when the drugs were given at the less advanced stage of recovery (25%). Although the duration of action of pancuronium was always longer than that of the comparable dose of vecuronium, the differences (expressed as a percentage of the greater value in the pair) between comparable clinical durations and recovery indices observed after administration of the same initial blocker were not great, with the exception of drugs given at 50% recovery after vecuronium. DISCUSSION

Since the introduction of neuromuscular blocking drugs to anaesthesia, attempts have been made to At 50% use their different properties to advantage by combining them in clinical practice. Such com60-. bined use, however, has had only limited clinical application because the interactions between different blockers remain one of the least investi£ 40gated problems in modern anaesthesia. J Theoretically, the administration of two drugs, such as non-depolarizing neuromuscular blockers, which affect the same primary sites of action similarly, should result in a summation of their separate effects (addition). However, this proved 0not always to be true. It has been shown, in D Rl D Rl both clinical and experimental studies, that, while concomitant administration of some mixFIG. 2. Duration (min) to 25% recovery (D) and recovery indices (Rl) of maintenance doses of vecuronium (open tures of non-depolarizing neuromuscular blocking columns) and pancuronium (cross-hatched columns) adminiagents (pancuronium—alcuronium; tubocurarine stered at 25% or 50% recovery from an initial block induced —dimethylcurarine (metocurine); pancuronium— by pancuronium or vecuronium. Mean values ± S D . *Signivecuronium) does result in additive action, ficantly different from the corresponding value after pancuronium. other mixtures of non-depolarizing blockers (tubocurarine with gallamine, alcuronium, panblockade it was necessary to use larger maintenance curonium or vecuronium; metocurine—pancuronium) clearly demonstrate synergistic doses of either blocker. (super-additive), rather than additive, effects It can be seen from figure 1 that, in all (Wong, 1969; Ghoneim et al., 1972; Lebowitz et circumstances investigated, the dose requirements for pancuronium were 15—20% larger than the al., 1980; Ferres et al., 1983; Pollard and Jones, corresponding dose requirements for vecuronium. 1983; Gibson et al., 1984). These observations This can probably be attributed to the difference may be interpreted as indicating that combinations of structurally similar compounds exert only an in the relative potency of the two compounds. Figure 2 illustrates the duration of action of the additive action, while combinations of structurally maintenance doses of both drugs after pancuro- dissimilar substances produce a potentiating nium and after vecuronium, expressed as duration response, the latter effect reflecting different to 25 % twitch height recovery and recovery index mechanisms of action of structurally dissimilar (duration from 25 % to 75 % recovery). There was substances acting at pre- and postsynaptic, and a marked difference in the action of both drugs possibly other, binding sites in the neuromuscular according to which neuromuscular blocker was junction. administered first: after pancuronium both drugs The studies referred to above were carried out were effective for significantly longer than after using concomitant administration of different

•I

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jl

CM

1065

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CONCLUSIONS

Administration of the "short-acting" neuromuscular blocking drug, vecuronium, with the aim

of providing blockade of short duration in the final stages of an operation after pancuronium has been given earlier seems unjustified, since significant prolongation of the recovery, resembling the pattern of recovery from pancuronium, will ensue. When pancuronium is considered for administration to maintain neuromuscular blockade after the initial use of vecuronium, it should be realized that the desired degree of neuromuscular blockade would require an increased dose of pancuronium, and that its duration might be much shorter than expected. When using different non-depolarizing muscle relaxants in the course of anaesthesia, the anaesthetist should be aware of the possibility of interactions (sometimes unpredictable) between them, which depend not only on the specific drugs used, but also on the sequence of their administration. Monitoringof neuromuscular transmission in such instances is, therefore, advisable.

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non-depolarizing agents. The present study has clearly demonstrated that the results of the consecutive administration of such drugs depend on the sequence of their administration: after administration of pancuronium first, the maintenance dose requirements for pancuronium or for vecuronium were smaller, and the duration of blockade longer, than after administration of vecuronium first. The drug administered first obviously played a dominant role, and exerted a determining influence on both the dose and the duration of action of the blocking agent subsequently given. According to Paton and Waud (1967), the " margin of safety " of neuromuscular transmission accounts for 75-80 % of all receptors, which must be blocked before there is any decrease in the twitch response. This means that, at 25 % or 50 % twitch height recovery from the initial blockade, when the blockade is reinforced by the second drug, the great majority of the receptors are still occupied by the first drug. Consequently, the resulting summation of the effects of both drugs reflects mainly the effect of the first drug and, to a lesser extent, that of the second. This would explain the apparent prolongation of the action of a maintenance dose of (otherwise short-acting) vecuronium following initial blockade by (longeracting) pancuronium and a blockade of short duration following a maintenance dose of pancuronium after initial blockade by vecuronium. It is generally believed that the plasma clearance rate is an important factor in determining the duration of action of a muscle relaxant. Drugs that leave the plasma more rapidly have shorter durations of action, and vice versa. It is conceivable that the dose requirement for a drug subsequently given would depend on the plasma clearance rate of the one previously given: a drug with faster clearance will thus impose the requirement for a larger maintenance dose of any drug by which it is substituted than would a drug with a slower clearance. The total plasma clearance rate of vecuronium was shown to be three to five times greater than that for pancuronium (Bencini, 1982), which would thus explain the reduced maintenance dose requirements for both compounds after pancuronium, and the increased dose requirements after vecuronium.

REFERENCES Agoston, S., Salt, P., Newton, D., Bencini, A., Boomsma, P., and Erdmann, W. (1980). The neuromuscular blocking action of Org NC 45, a new pancuronium derivative, in anaesthetized patients. A pilot study. Br. J. Anaesth., 52, 53S. Bencini, A. (1982). Clinical pharmacokinetics of vecuronium bromide; in Clinical Experiences with Norcuron (ed. S. Agoston), p. 25. Amsterdam: Excerpta Medica. Crul, J. F., and Booij, L. H. D. J. (1980). First clinical experiences with Org NC 45. Br. J. Anaesth., 52, 49S. Ferres, C. J., Mirakhur, R. K., Clarke, R. S. J., and Pandit, S. K. (1983). Neuromuscular blocking effects of a combination of vecuronium and pancuronium. Br. J. Clin. Pharmacol, 16, 218P. Ghoneim, M. M., Urgena, R. B., Dretchen, R., and Long, P. (1972). The interaction between d-tubocurarinc and gallamine during halothane anaesthesia. Can. Anaesth. Soc.J., 19, 66. Gibson, F. M., Ferres, C. J., Clarke, R. S. J., and Mirakhur, R. K. (1984). Potcntiation of neuromuscular block with a combination of vecuronium and tubocurarine. Br. J. Clin. Pharmacol, 17, 223P. Lebowitz, P. W., Ramsey, F. M., Savarese, J. J., and Ali, H. A. (1980). Potentiation of neuromuscular blockade in man produced by combinations of pancuronium and metocurine or pancuronium and d-tubocurarine. Anesth. Analg., 59, 604. Pollard, B. J., and Jones, R. M. (1983). Interactions between tubocurarine, pancuronium and alcuronium demonstrated in the rat phrenic nerve-hemidiaphragm preparation. Br. J. Anaesth., 55, 1127. Paton, W. D. M., and Waud, D. R. (1967). The margin of safety of neuromuscular transmission. J. Physiol. (Lond.), 196, 59. Wongj K. C. (1969). Some synergistic effects of curare and gallamine. Fed. Proc., 28, 420.