SUXAMETHONIUM-NEOSTIGMINE INTERACTION IN PATIENTS WITH NORMAL OR ATYPICAL CHOLINESTERASE

Br.J. Anaesth. (1977), 49, 479

SUXAMETHONIUM-NEOSTIGMINE INTERACTION IN PATIENTS WITH NORMAL OR ATYPICAL CHOLINESTERASE A. BARAKA SUMMARY

Baraka (1975a) has shown that the interaction of suxamethonium with hexafluorenium, a selective plasma cholinesterase inhibitor, differs in normal patients from that in patients with atypical plasma cholinesterase activity. In normal patients, hexafluorenium results in marked potentiation of suxamethonium block, while in patients with the atypical enzyme there is no potentiation or even a diminution of the response. Neostigmine is an inhibitor of both plasma- and acetylcholinesterases (Irwin and Smith, 1960). Therefore, the suxamethonium-neostigmine interaction might differ also in patients with normal plasma cholinesterase activity from that in patients with the atypical enzyme. This report compares the suxamethonium-neostigmine interaction in patients with normal and atypical esterase. METHODS

Fifteen patients undergoing elective surgical procedures were investigated. Ten had normal plasma cholinesterase activity while the other five were atypical cholinesterase homozygotes. The relative plasma cholinesterase activity and the dibucaine number were measured in the patients investigated. The cholinesterase activity was measured by the method of Michel (1949), while the dibucaine number was estimated by the method described by Kalow and Genest (1957). In the normal patients, the relative cholinesterase activity was 80-110% of normal while the dibucaine number ranged from 74 to 81. ANIS BARAKA, M.D., Department of Anesthesiology, American University of Beirut, Beirut, Lebanon.

In the atypical homozygotes, the relative cholinesterase activity was 13-19% of normal, while the dibucaine number ranged from 22 to 30. Anaesthesia was maintained with nitrous oxide in oxygen (2 : 1) and halothane 0.5%. The ulnar nerve was stimulated with a Block-Aid monitor at 0.25 Hz. The resultant thumb adduction was monitored by a Grass force displacement transducer (FT 03) connected to a Grass polygraph. After a steady twitch response was obtained, the following observations were made. Normal esterase homozygotes. In five normal adult patients, a bolus of suxamethonium 0.1 mg/kg was injected i.v. and the neuromuscular block was recorded. After complete recovery of neuromuscular transmission, a mixture of neostigmine 0.05 mg/kg and atropine 0.02 mg/kg was injected and followed 1 min later by the same dose of suxamethonium (0.1 mg/kg). The resultant block was compared with the control response. In a second group of five normal adult patients, suxamethonium 0.1% was infused continuously to produce a twitch response about 25% of the control. The type of block was determined by the response to tetanic stimulation. When desensitization block was established, a mixture of neostigmine 0.05 mg/kg and atropine 0.02 mg/kg was injected i.v. and the effect on the suxamethonium block was observed. Atypical esterase homozygotes. In the five patients who were atypical esterase homozygotes (one child and four adults), a bolus of suxamethonium was injected and its effect on the twitch response was observed. During recovery of neuromuscular transmission, a mixture of neostigmine 0.05 mg/kg and atropine 0.02 mg/kg was injected i.v. and its effect on

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The effect of neostigmine 0.05 mg/kg on the neuromuscular block produced by suxamethonium was investigated in 10 normal patients and in five patients with atypical plasma cholinesterase activity, by recording the twitch response to ulnar nerve stimulation. In the normal patients, neostigmine potentiated the block produced by suxamethonium whether it was of the depolarizing or desensitizing type. On the other hand, in patients with atypical plasma cholinesterase activity, neostigmine potentiated the depolarizing phase of suxamethonium block, while antagonizing the desensitizing phase. The degree of antagonism was not related to the magnitude of neuromuscular block, but was proportional to the degree of desensitization at the time of antagonism.

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tization at the time of reversal, as assessed by tetanic fade and post-tetanic facilitation. In one of these patients the injection of suxaRESULTS methonium 0.1 mg/kg produced complete neuromuscular block which was of the depolarizing type, Normal patients Suxamethonium bolus injection. In five normal as indicated by maintained tetanus and absence of patients, suxamethonium 0.1 mg/kg produced partial post-tetanic facilitation (fig. 3A). After 20 min, reand transient depolarizing neuromuscular block covery started and was associated with early desensiwhich was characterized by a sustained response to tization shown by partial tetanic fade. The injection tetanus and absence of post-tetanic facilitation. When of neostigmine at that time potentiated the block and the same dose of suxamethonium was repeated after delayed recovery (fig. 3B). In the second and third patients in this group, neostigmine 0.05 mg/kg, a marked potentiation of the block and delay of recovery were observed suxamethonium 0.5 mg/kg produced complete neuromuscular block. Recovery started after 45 min and (fig- I)Suxamethonium infusion. In the other five normal was associated with moderate desensitization. Neopatients, the infusion of suxamethonium 0.1% was stigmine 0.05 mg/kg partially reversed the block adjusted to produce about 75% block. Initially, the (fig. 4). In the fourth and fifth patients, suxamethonium block was depolarizing in nature as indicated by maintained tetanus and absence of post-tetanic 1 mg/kg produced complete neuromuscular block. facilitation. Gradually, desensitization started to After 90 min, recovery started and was associated develop, as shown by an increasing tetanic fade and with marked desensitization with complete tetanic post-tetanic facilitation. After 40-60 min, when fade and marked post-tetanic facilitation. Neostigmine desensitization block was established fully, the injec- 0.05 mg/kg produced an immediate and effective tion of neostigmine 0.05 mg/kg potentiated the block antagonism of the block (fig. 5). in all five patients. Cessation of the infusion was DISCUSSION followed by recovery of neuromuscular transmission Suxamethonium is a quatenary ammonium com(fig. 2). pound which is hydrolysed rapidly by plasma cholinesterase. The drug, consisting of two acetylcholine Atypical esterase homozygotes In the five patients with atypical plasma cholin- molecules linked together (Paton, 1959), can compete esterase activity, the effect of neostigmine on the with acetylcholine for the cholinergic receptors and, neuromuscular block provided by suxamethonium like acetylcholine, will depolarize the end-plate. showed marked variations. The response differed Initially, the depolarizing activity predominates. according to the type of block and degree of desensi- However, with increasing dose or time, or both, (Crul the block was observed at different degrees of desensitization.

SUXAMETHONIUM ( 0 1 mg/kg)

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FIG. 1. Tracing of the twitch response to ulnar nerve stimulation at 0.25 Hz showing the neuromuscular block produced in a normal patient by a bolus of suxamethonium 0.1 mg/kg before and after neostigmine 0.05 mg/kg. The block was depolarizing in nature and was potentiated by the pre-injection of neostigmine.

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FIG. 2. The twitch response to ulnar nerve stimulation at 0.25 Hz during the continuous infusion of suxamethonium 0.1%. About 75% neuromuscular block was maintained. The block was initially depolarizing in nature as indicated by maintained response to tetanic stimulation and no post-tetanic facilitation. Gradual desensitization occurred, with increasing tetanic fade and post-tetanic facilitation. After 45 min, desensitization block was established fully. However, the injection of neostigmine 0.05 mg/kg potentiated the block. Cessation of the infusion was followed by recoverv.

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FIG. 3. The twitch response to ulnar nerve stimulation at 0.25 Hz in an atypical esterase homozygote. The injection of suxamethonium 0.1 mg/kg produced complete neuromuscular block, depolarizing in nature as shown by maintained tetanus and no post-tetanic facilitation (A). Recovery started after 20 min and was associated with partial desensitization. The injection of neostigmine at that stage potentiated the block and delayed recovery (B).

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t NEOSTIGMINE (2.5 mg)

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FIG. 4. Tracing of the twitch response to ulnar nerve stimulation at 0.25 Hz in an atypical esterase homozygote. The injection of suxamethonium 0.5 mg/kg produced complete neuromuscular block. After 45 min, recovery occurred associated with evidence of moderate desensitization. Neostigmine 0.05 mg/kg produced a moderate increase of the twitch response.

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FIG. 5. Tracing of the twitch response to ulnar nerve stimulation at 0.25 Hz in an atypical esterase homozygote. The injection of suxamethonium 1 mg/kg produced complete neuromuscular block. After 90 min, recovery started and was associated with marked desensitization, shown by complete tetanic fade and marked post-tetanic facilitation. Neostigmine 0.05 mg/kg produced a marked reversal of the block.

et al., 1966), desensitization occurs gradually (Thesleff, Neostigmine can inhibit both plasma- and acetyl1955) and the competitive nature of the molecule is cholinesterase enzymes (Irwin and Smith, 1960). manifested. Receptor desensitization, which may Therefore its interaction with suxamethonium block begin at the moment of application of the drug and in may vary not only according to the type of block, but parallel with depolarization, becomes apparent later also to the plasma cholinesterase activity of the in time because it has a slow rate of development patient. (Gissen and Nastuk, 1970). The present report has shown, in the patients with The present report confirms previous investigations normal plasma cholinesterase activity, that neostigshowing that desensitization can follow absolute mine always potentiates suxamethonium block overdosage in patients with normal plasma cholin- whether it is depolarizing or desensitizing. In normal esterase activity whether produced by repetitive doses patients, suxamethonium is hydrolysed by plasma or by an infusion of suxamethonium; or it may follow cholinesterase rapidly (Kalow, 1959). Injection of relative overdosage in patients with atypical esterase neostigmine under such conditions will inhibit the (homozygotes) (Churchill-Davidson and Christie, plasma cholinesterase, delay the hydrolysis of suxa1959; Churchill-Davidson, Christie and Wise, 1960; methonium and potentiate its neuromuscular blocking Katz, Wolf and Papper, 1963; Vickers, 1963). There- effect even when desensitization is established fully. fore desensitization block is not a cause but a result Gissen and others (1966) have investigated the of prolonged suxamethonium block whether because effect of neostigmine on desensitization block followof continuous administration of suxamethonium in ing i.a. infusion of suxamethonium. They concluded normal patients or its delayed hydrolysis in atypical that the response of the muscle to anticholinesterases homozygotes. in patients with normal, and perhaps atypical, plasma

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SUXAMETHONIUM-NEOSTIGMINE INTERACTION

acetylcholine at the neuromuscular junction and hence potentiate the depolarizing phase of suxamethonium while antagonizing the desensitizing phase. The degree of reversal is proportional to the degree of desensitization. REFERENCES

Baraka, A. (1972). Neuromuscular block in different species. Acta Anaesthesiol. Scand., 16, 132. (1975a). Hexafluorenium-suxamethonium interaction in patients with normal versus atypical cholinesterase. Br. J. Anaesth., 47, 885. (1975b). Potentiation of suxamethonium blockade by neostigmine in patients with atypical cholinesterase. Br. J. Anaesth., 47, 416. Churchill-Davidson, H. C , and Christie, T. H. (1959). The diagnosis of neuromuscular block in man. Br.J. Anaesth., 31, 290. Wise, R. P. (1960). Dual neuromuscular block in man. Anesthesiology, 21, 144. Katz, P. L. (1966). Dual, Phase II, or desensitization block. Anesthesiology, 27, 536. Crul, J. F., Long, G. J., Brunner, E. A., and Coolen, J. M. W. (1966). The changing pattern of neuromuscular blockade caused by succinylcholine in man. Anesthesiology, 27, 729. Gissen, A. J., Katz, R. L., Karis, J. H., and Papper, E. M. (1966). Neuromuscular block in man during prolonged arterial infusion with succinylcholine. Anesthesiology, 27, 242. Nastuk, W. L. (1966). Mechanisms underlying neuromuscular block following prolonged application of the depolarizing compounds. Ann. N.Y. Acad. Set., 135, 184. (1970). Succinylcholine and decamethonium: Comparison of depolarization and desensitization. Anesthesiology, 33, 611. Irwin, R. L., and Smith, H. J. m (1960). Cholinesterase inhibition by galanthamine and lycoramine. Biochem. Pharmacol., 3, 174. Kalow, W. (1959). The distribution, destruction and elimination of muscle relaxants. Anesthesiology, 20,505. Genest, K. (1957). A method for the detection of atypical forms of human serum cholinesterase: determination of dibucaine numbers. Can. J. Biochem., 35, 339. Katz, R. L., Wolf, C. E., and Papper, E. M. (1963). The non-depolarizing neuromuscular blocking action of succinylcholine in man. Anesthesiology, 24, 784. Michel, H. (1949). An electrometric method for the determination of red blood cell and plasma cholinesterase activity. J. Lab. Clin. Med., 34, 1564. Nastuk, W. L., and Gissen, A. J. (1965). Actions of acetylcholine and other quaternary ammonium compounds at the muscle postjunctional membrane; in Symposium on Muscle (eds W. M. Paul and E. C. Daniel), p. 389. Oxford, England: Pergamon Press Ltd. Paton, W. D. M. (1959). The effects of muscle relaxants other than muscular relaxation. Anesthesiology, 20, 453. Thesleff, S. (1955). The mode of neuromuscular block caused by acetylcholine, nicotine, decamethonium and succinylcholine. Acta Physiol. Scand., 34,218.

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cholinesterase enzymes depends on the presence or absence of suxamethonium in the blood. Neostigmine will not antagonize a desensitization block if suxamethonium is still present in the circulation (ChurchillDavidson and Katz, 1966). The present investigation, however, suggests that these findings apply only to patients with normal plasma cholinesterase activity and not to those who are homozygous for the atypical esterase. In patients with atypical plasma cholinesterase activity, the enzyme plays no part in the elimination of suxamethonium since there is virtually no hydrolysis of the drug at the pH of blood and in the concentrations used clinically (Kalow, 1959). Under such conditions, the antiplasmacholinesterase action of neostigmine will not change the rate of hydrolysis of suxamethonium. However, the anti-acetylcholinesterase action of neostigmine will effectively increase the concentration of acetylcholine at the neuromuscular junction by decreasing its rate of hydrolysis (Nastuk and Gissen, 1965). Such an effect will potentiate the depolarizing phase of suxamethonium and yet will reverse its desensitization phase. In atypical patients, suxamethonium produced a depolarizing block initially, followed by gradual desensitization. The present report confirms the in vitro findings of Gissen and Nastuk (1966, 1970), showing that the degree of desensitization is directly proportional to the drug concentration used. The resulting neuromuscular block will be determined by a balance between the initial depolarization and the degree of desensitization. There must be a broad spectrum where different proportions of both mechanisms co-exist (Baraka, 1972). The early use of neostigmine when depolarization predominates will potentiate the block despite the evidence of partial desensitization (Baraka, 1975b). However, when desensitization is established fully, the block can be reversed with neostigmine. The degree of reversal is not related to the magnitude of neuromuscular block, but is proportional to the degree of desensitization at the time of reversal. It can be concluded that neostigmine may affect suxamethonium block by inhibiting both plasma and acetylcholinesterase activity. In normal patients, the inhibition of plasma cholinesterase predominates, and the block of suxamethonium whether depolarizing or desensitizing will be potentiated as a result of delayed hydrolysis. On the other hand, in patients inheriting atypical plasma cholinesterase, the anti-acetylcholinesterase activity of neostigmine will predominate. This can effectively increase the concentration of

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484 Vickers, M. D. A. (1963). The mismanagement of suxamethonium apnoea. Br. J. Anaesth., 35, 260. INTERACTION DU SUXAMETHONIUM ET DE LA NEOSTIGMINE SUR LES MALADES AYANT UNE CHOLINESTERASE NORMALE OU ATYPIQUE RESUME

ZUSAMMENFASSUNG

Untersucht wurde die Wirkung von 0,05 mg/kg Neostigmin auf die durch Suxamethonium hervorgerufene neuromuskulare Blockierung bei 10 normalen Patienten und bei fttnf Patienten mit atypischer Plasma-Cholinesterase, indem man die Zuckungsreaktion bei Stimulierung des Ulnarnervs aufzeichnete. Bei den normalen Patienten verstarkte Neostigmin die Suxamethonium-Blockierung, gleichgUltig ob diese depolarisierender oder unempfindlichmachender Art war. Bei den Patienten mit atypischer Cholinesterase hingegen verstarkte Neostigmin die depolarisierende Phase der Suxamethonium-Blockierung, wahrend der unempfindlichmachenden Phase entgegengewirkt wurde. Das Ausmass dieser Gegenwirkung war unabhangig von der Starke der neuromuskularen Blockierung, war jedochproportionalzum Ausmass der Unempfindlichkeit zum Zeitpunkt der Gegenwirkung. INTERACCION DE SUXAMETONIO— NEOSTIGMINA EN PACIENTES CON COLINESTERASA NORMAL O ATIPICA SUMARIO

El efecto de neostigmina 0,05 mg/kg sobre el bloqueo neuromuscular producido por suxametonio fue investigado en 10 pacientes normales y en cinco pacientes con actividad atipica de colinesterasa plasmatica, mediante el registro de la respuesta de contracci6n a la estimulacion del nervio ulnar. En los pacientes normales, la neostigmina potencializa el bloqueo producido por el suxametonio tanto si era del tipo despolarizante o desensibilizante. Por otra parte, en pacientes con actividad atipica de colinesterasa plasmatica, la neostigmina potencializo la fase despolarizante del bloqueo con suxametonio, mientras que antagonizaba a la fase desensibilizante. El grado de antagonismo no estaba relacionado con la magnitud del bloqueo neuromuscular, pero era proporcional al grado de desensibilizacion en el momento del antagonismo.

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On a etudie sur 10 malades normaux et sur cinq malades ayant vine activite de cholinesterase atypique du plasma, 1'efTet de la neostigmine a raison de 0,05 mg/kg sur le blocage neuromusculaire produit par le suxamethonium, en enregistrant la crispation se produisant en reponse a la stimulation du nerf ulnaire. Sur les malades normaux, la neostigmine a rendu possible le blocage produit par le suxamethonium qu'il soit du type depolarisant ou du type desensibilisant. Par contre, sur les malades ayant une activite de cholinesterase atypique du plasma, la neostigmine a rendu possible la phase de depolarisation du blocage par le suxamethonium, tout en contrariant la phase de desensibilisation. Le degre d'antagonisme n'a pas ete relie a l'importance du blocage neuromusculaire, mais il a ete proportionnel au degre de desensibilisation au moment de l'antagonisme.

WECHSELWIRKUNG ZWISCHEN SUXAMETHONIUM UND NEOSTIGMIN BEI PATIENTEN MIT NORMALER ODER ATYPISCHER CHOLINESTERASE