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Muscle relaxants
S. Agoston
13
Muscle relaxants
NON-DEPOLARIZING NEUROMUSCULAR BLOCKING AGENTS
obstructive pulmonary disease and mild hypertension who had been treated for the last few years with methyldopa, furosemide, prednisone and theophylline. On the eighth hospital day the patient developed respiratory distress with symptoms of progressive hypoxia which necessitated endotracheal intubation and artificial ventilation. During the first eight days of hospitalization the patient's blood pressure had ranged from 130/50 to 150/70 mm Hg. Within five minutes of the administration of 0.057 mg kg-x of pancuronium, the blood pressure rose to 280/130 mm Hg and remained elevated for two hours. Six hours after the first dose the blood pressure had returned to 140/70 mm Hg but the patient then received another 0.027 mg kg-1 of pancuronium since she had begun to resist the ventilator at that time. Following this small maintenance dose her blood pressure rose again to 270/130 mm Hg and then gradually fell to 140/60 mm Hg over the next five hours. During the further course of treatment diazepam 10 mg i.v. was given prior to each next dose of pancuronium and this prevented the rise in blood pressure subsequent to pancuronium. The hypertensive reaction after the first two doses of pancuronium could have been due either to an interaction between one of the drugs employed and pancuronium, or to elevated catecholamine levels induced by fear, increasing respiratory distress and hypoxia, all of which could have interacted with pancuronium. At all events it is important to know that severe hypertensive reactions due to pancuronium may be prevented or counteracted by diazepam.
New information on the adverse effects of muscle relaxants from the past year is virtually limited to the two most frequently used agents, i.e. pancuronium and suxamethonium. For more information on the side effects of the muscle relaxants in general the reader is referred to SED 9 and SEDA-1, 2 and 3. Pancuroniumbromide Reports, mainly on cardiovascular side effects and new types of interactions of this compound, continue to appear. In order to establish a dose-effect relationship Parmentier and Dagnelie (1 c ) investigated the effect of graded doses of pancuronium on the h e a r t r a t e i n patients undergoing elective surgery under nitrous oxide/oxygen anaesthesia supplemented with either fentanyl alone (0.003 mg kg-1) or fentanyl 0.003 mg kg -1 plus droperidol 0.15 mg kg-x. In this study pancuronium induced a dose-dependent increase of the heart rate. The tachycardia was more marked following the administration of droperidol. Since no differences were found in the control heart rate between the subgroups receiving fentanyl alone and those receiving fentanyl and droperidol it is likely that the tachycardia observed was induced by pancuronium. Although the greatest change in mean heart rate in this study (a 15% increase) was statistically significant, the question remains whether an increase in the heart rate to this extent is clinically relevant in all cases. A slight increase in the mean systolic b l o o d p r e s s u r e together with a moderate increase in the pulse rate is generally known to occur with the use of pancuronium as pointed out in earlier volumes in this series. More recently Fraley e t al. (2 c) have, however, described a drastic increase in blood pressure associated with pancuronium in a newly hospitalized patient with a history of chronic
Interactions A few years ago Standaert and his associates (3) demonstrated the involvement of the cyclic nucleotide/phosphodiesterase system in the transmitter release at the motor nerve ending. Subsequently Dretchen e t al. (4) described the antagonistic action of a z a t h i o p r i n e -- a n immunosuppressive agent - on the neuromuscular blocking effects of pancuronium, d-tubocurarine and
88
gallamine in the cat. In contrast to its effect on the blockade produced by non-depolarizing blocking agents, azathioprine potentiated the neuromuscular blockade caused by suxamethonium. The most likely explanation for the neuromuscular effects of azathioprine, in full agreement with the findings of Standaert et al. (3), must be sought in its phosphodiesterase-inhibiting activity. The same authors have found that the neuromuscular effects of azathioprine were similar to those of a known phosphodiesterase inhibitor, theophylline. More recently Doll and Rosenberg (5 C) described a patient with marked resistance to pancuronium. The patient suffered smoke inhalation and hypoxic brain injury several days before her admission to the intensive care unit. Because of severe bronchospasm, aminophylline was infused at a rate of 1.55 mg kg -1 hr -1 for 48 hours. At this infusion rate her plasma theophylline level was 35 mg 1-1. Other medications included hydrocortisone 100mg every six hours and cimetidine 300 mg given intravenously every six hours. Further deterioration of the patient's respiratory status required controlled mechanical ventilation, and 0.13 mg kg -1 pancuronium was therefore administered. Since there was no apparent effect of this dose and the patient showed sustained tetanic stimulation of the ulnar nerve even after some minutes, an additional dose of 0.35 mg kg-1 pancuronium was given without any change in respiratory status or response to nerve stimulation over the next 20 minutes. Finally the patient was paralyzed by giving 100 mg suxamethonium. This marked resistance to the neuromuscular effects of pancuronium might have been caused not only by the high plasma theophylline levels but also by the corticosteroid present in the patient's medication (6). Another interesting and possibly clinically relevant finding concerns the interaction between pancuronium and nitroglycerin. Glisson et al. (7) recently described a significant delay in the recovery rate of neuromuscular blockade produced by pancuronium in the presence of a nitroglycerin infusion of 1 //g kg -1 min. -1 in the cat. Under identical experimental conditions nitroglycerin did not alter the recovery rate of the block produced by d-tubocurarine or suxamethonium, or the magnitude of the pancuronium-induced block in the isolated rat diaphragm preparation. These observations strongly suggest a pharmacokinetic inter-
S. Agoston
action specific to pancuronium and nitroglycerin. Marked tachy-arrhythmias were observed by Edwards et al. (8) in two patients treated with imipramine after the administration of pancuronium bromide during halothane anaesthesia. This observation led the authors to investigate this phenomenon in animals more extensively. They studied the occurrence of cardiac arrhythmias due to pancuronium in dogs under halothane or enflurane anaesthesia either after acute administration of increasing doses of imipramine or in animals pretreated with this tricyclic antidepressant for 15 days. The arrhythmias in dogs chronically treated with imipramine were more severe than those in animals receiving acute doses of this compound and were more prone to occur during halothane than during enfiurane anaesthesia, which strongly suggests that halothane in combination with pancuronium and long-lasting pretreatment with imipramine increases the likelihood of cardiac arrhythmias. Both long-lasting tricyclic antidepressant administration ( 9 ) a n d pancuronium (SEDA-3) may inhibit norepinephrine re-uptake by adrenergic nerve endings, resulting in elevated concentrations of norepinephrine in cardiac tissue. Since elevated levels of epinephrine are known to facilitate the action of halothane in predisposing the myocardium to arrhythmias (10 C ) the administration of pancuronium to patients under chronic tricyclic antidepressant therapy anaesthetized with halothane should be avoided. The interaction of pancuronium and other non-depolarizing neuromuscular blocking agents with various antibiotics is well recognized (SEDA-2, 113), but it should be borne in mind that this can be of great clinical importance. Giala and Paradelis from Greece have recently described two cases in which such an interaction (induced by colistin in one case and streptomycin in another) resulted in severe respiratory depression (18c); the effect was terminated by injections of calcium gluconate.
DEPOLARIZING NEUROMUSCULAR BLOCKING AGENTS Suxamethonium The most frequently reported side effects of suxamethonium are muscle fasciculations
89
Muscle relaxants
and muscle pain, particularly in patients who are ambulatory a short time after operation. Although many reports have in the past appeared regarding the possible causes, frequency, severity and prevention of suxamethonium-induced muscle fasciculation, little information is available on more objective methods than simple rating for the assessment of the extent and intensity of muscle response either to suxamethonium or to drugs that interact with succinylcholine. Jansen and H a n s e n ( l l C) have described a method of electrical fasciculation counting by which variations in the circumference of an upper arm were recorded by a strain gauge, Philips Minilog Amplifier and a fourtrack tape recorder. In clinical use the method appeared to be highly sensitive, especially in quantifying hardly visible fasciculations of low amplitude and high frequency. There are reasons to consider that by using this method more meaningful data can be collected in the future regarding the fasciculations induced by suxamethonium. Elsenberg et al. (12 C) investigated the effects of low doses (0.05 mg kg -1) of diazepam pretreatment on suxamethonium-induced muscle pain and fasciculations, increases in potassium and creatine phosphokinase levels. They found that pretreatment with diazepam did not alter the suxamethonium-induced neuromuscular blockade, or prevent the rise in creatine phosphokinase levels; however, it reduced the incidence of post-operative muscle pain as well as the usual increase of serum potassium levels. Since the neuromuscular effects of suxamethonium remained uninfluenced by this low dose of diazepam, it seems that this drug is to be preferred over non-depolarizing relaxants in the prevention of suxamethoniuminduced muscle pain and fasciculations. Prolonged muscle paralysis lasting about three hours was described (13 c ) following the administration of 100 mg and a few minutes later 40 mg of suxamethonium to a patient weighing 61 kg with carcinoma of the prostate on diethylstilboestrol therapy. Markedly decreased qualitatively normal pseudocholinesterase levels were detected in this patient in the recovery room and on the first post-operative day. A few weeks later the diethylstilboestrol therapy was discontinued, following which the plasma pseudocholinesterase levels rose, but still remained under the lower limit of normal. The acquired plasma cholinesterase deficiency in
this patient was probably caused by diethylstilboestrol, since oestrogens are known to depress hepatic synthesis or release of pseudocholinesterase ( 1 4 c ; SED 9). However, a number of other factors, such as hormonal effects due to prior orchiectomy, or the presence of mild liver disease, may all have contributed to the deficiency of the enzyme in this patient. At all events diethylstilboestrol should be considered as a factor which may cause plasma pseudocholinesterase deficiency. Apparent resistance to 50, 40 and 40 mg suxamethonium given at 2 - 3 minute intervals was observed (15 c) in a psychiatric patient with markedly elevated levels of qualitatively normal pseudocholinesterase. In the absence of any other factors, related to other drugs or to the patient's disease, which might explain this unusual reaction, it is probable that the elevated levels of otherwise normal pseudocholinesterase found in this patient produced an unusually rapid breakdown of suxamethonium, resulting in apparent resistance. In practice this type of reaction occurs more often than the reports in the literature would suggest and usually the hospital pharmacy or the manufacturer is blamed for the delivery of an 'inactive' drug. In cases showing the above type of resistance it would be wise to determine the plasma levels and the type of the enzyme, since in such individuals not o n l y the effects of suxamethonium, but also those of other compounds such as the ester-type local anaesthetics hydrolyzed by this enzyme may be affected. A hyperkalaemic response to suxamethonium with serum potassium levels raised from 3.8 mEq[t to 7.1 mEq/1 and transient ventricular dysrhythmia has been reported (16 c ) in a patient without known neurological deficits, but with muscle wasting secondary to chronic arterial insufficiency. Patients with advanced arteriosclerotic disease with muscle wasting thus represent an additional group of individuals susceptible to suxamethonium-induced hyperkalaemia.
SKELETAL MUSCLE RELAXANTS This group of agents comprises dantrolene sodium, baclofen, cyclobenzaprine and diazepam. They are used either for long-or for short-term management of muscle spasticity. During the past year no facts regarding their
90 side effects were reported which had n o t already been described in the past and discussed in earlier volumes in this series. However, the trend to use dantrolene for the prophylaxis or treatment of the malignant hyperpyrexic syndrome (SED 9) still continues. The poor solubility of the drug has in the past prevented its intravenous use in man, but recently this limitation has been overcome by the manufacturer. Friesen et al. (17 C) reported the first successful i.v. use of dantrolene sodium in the treatment of malignant hyperthermia in one patient. After developing the first signs of this potentially fatal condition, the malignant hyperthermia protocol was instituted, consisting of the administration of iced intravenous solution, surface cooling with ice and the administration of chlorpromazine. Subsequently the patient was given a total of 250 mg dantrolene by rapid intravenous infusion. Within ten minutes the patient's temperature returned to 36.5~ Apart from some in-
S. Agoston crease in temperature (38~ during five days observation in the Intensive Care Unit, the patient made an uneventful recovery and was discharged. Three months later he was re-admitted for operation. This time dantrolene 300 mg was given by m o u t h five hours before the operation. No side effects were reported following the intravenous dose, but after the oral dose on the second occasion the patient experienced dizziness and nausea, both of which are known side effects o f this compound. During the second operation none o f the signs of malignant hyperthermia appeared, but this is not surprising, since the operation was performed under regional anaesthesia. Although it would be premature to form a view of the drug's adverse effects after intravenous administration the possibility cannot be excluded that the known side effects of dantrolene sodium are related at least in part to the pharmaceutical form used for oral administration.
REFERENCES 1. Parmentier, P. and Dagnelie, P. (1979): Dose related tachycardia induced by pancuronium during balanced anaesthesia with and without droperidol. Brit. J. Anaesth., 51, 157. 2. Fraley, D.S., Lemoncelli, G.L. and Coleman, A. (1978): Severe hypertension associated with pancuronium bromide. Anesth. Analg., 57, 265. 3. Standaert, F.G., Dretchen, K.L., Skirboll, L. R. et al. (1976): Effects of cyclic nueleotides on mammalian motor nerve terminals. J. Pharmacol. exp. Ther., 199, 544. 4. Dretchen, K.L., Morgenroth, V.H., Standaert, F. G. et al. (1976): Azathioprine: effects on neuromuscular transmission. Anesthesiology, 45, 604. 5. Doll, D. C. and Rosenberg, H. (1979): Antagonism of neuromuscular blockage by theophylline. Anesth. Analg., 58, 139. 6. Meyers, E.F. (1977): Partial recovery from pancuronium neuromuscular blockade following hydrocortisone administration. Anesthesiology, 46, 148. 7. Glisson, S.N., E1-Etr, A.A. and Lim, R. (1979): Prolongation of pancuronium-induced neuromuscular blockade by intravenous infusion of nitroglycerin. Anesthesiology, 51, 47. 8. Edwards, R. P., Miller, R. D., Roizen, M. F. et al. (1979): Cardiac responses to finipramine and pancuronium during anesthesia with halothane or enflurane. Anesthesiology, 50, 421.
9. Byck, R. (1975): Drugs and the treatment of psychiatric disorders. In: The Pharmacological Basis of Therapeutics, Fifth Edition. pp. 174-179. Editors: L.S. Goodman and A. Gilman. MacMillan, New York. 10. Johnston, R. R., Eger II, E. I. and Wildon, C. (1976): A comparative interaction of epinephrine with enflurane, isoflurane and halothane ial man. Anesth. Analg., 55, 709. 11. Jansen, E. C. and Hansen, P. H. (1979): Objective measurement of succinylcholine-induced fasciculations and the effect of pretreatment with pancuronium or gallamine. Anesthesiology, 51, 159. 12. Eisenberg, M., Balsley, S. and Katz, R. L. (1979): Effects of diazepam on succinylcholineinduced myalgia, potassium increase, creatine phosphokinase elevation, and relaxation. Anesth. Analg., 58, 314. 13. Archer, T.L. and Janowsky, E.C. (1978): Plasma pseudocholinesterase deficiency associated with diethylstilboestrol therapy. Anesth. Analg., 57, 726. 14. Robertson, G. S. (1967): Serum protein and cliolinesterase changes in association with contraceptive pills. Lancet, I, 232. 15. Spurgeon, M. J. (1979): Apparent resistance to succinylcholine. Anesth. Analg., 58, 57. 16. Rao, T.L.K. and Shanmugam, M. (1979): Succinylcholine administration - another contraindication? Anesth. Analg., 58, 61.
Muscle relaxants 17. Friesen, C.M., Brodsky, J.B. and Dillingham, M. F. (1979): Successful use of dantrolene sodium in human malignant hyperthermia syndrome: a case report. Canad. Anaesth. Soc. J., 26, 319.
91 18. Giala, M. M. and Paradelis, A. G. (1979): Two cases of prolonged respiratory depression due to interaction of pancuronium with colistin and streptomycin. J. antimicrob. Chemother., 5,234.
13
Muscle relaxants
NON-DEPOLARIZING NEUROMUSCULAR BLOCKING AGENTS
obstructive pulmonary disease and mild hypertension who had been treated for the last few years with methyldopa, furosemide, prednisone and theophylline. On the eighth hospital day the patient developed respiratory distress with symptoms of progressive hypoxia which necessitated endotracheal intubation and artificial ventilation. During the first eight days of hospitalization the patient's blood pressure had ranged from 130/50 to 150/70 mm Hg. Within five minutes of the administration of 0.057 mg kg-x of pancuronium, the blood pressure rose to 280/130 mm Hg and remained elevated for two hours. Six hours after the first dose the blood pressure had returned to 140/70 mm Hg but the patient then received another 0.027 mg kg-1 of pancuronium since she had begun to resist the ventilator at that time. Following this small maintenance dose her blood pressure rose again to 270/130 mm Hg and then gradually fell to 140/60 mm Hg over the next five hours. During the further course of treatment diazepam 10 mg i.v. was given prior to each next dose of pancuronium and this prevented the rise in blood pressure subsequent to pancuronium. The hypertensive reaction after the first two doses of pancuronium could have been due either to an interaction between one of the drugs employed and pancuronium, or to elevated catecholamine levels induced by fear, increasing respiratory distress and hypoxia, all of which could have interacted with pancuronium. At all events it is important to know that severe hypertensive reactions due to pancuronium may be prevented or counteracted by diazepam.
New information on the adverse effects of muscle relaxants from the past year is virtually limited to the two most frequently used agents, i.e. pancuronium and suxamethonium. For more information on the side effects of the muscle relaxants in general the reader is referred to SED 9 and SEDA-1, 2 and 3. Pancuroniumbromide Reports, mainly on cardiovascular side effects and new types of interactions of this compound, continue to appear. In order to establish a dose-effect relationship Parmentier and Dagnelie (1 c ) investigated the effect of graded doses of pancuronium on the h e a r t r a t e i n patients undergoing elective surgery under nitrous oxide/oxygen anaesthesia supplemented with either fentanyl alone (0.003 mg kg-1) or fentanyl 0.003 mg kg -1 plus droperidol 0.15 mg kg-x. In this study pancuronium induced a dose-dependent increase of the heart rate. The tachycardia was more marked following the administration of droperidol. Since no differences were found in the control heart rate between the subgroups receiving fentanyl alone and those receiving fentanyl and droperidol it is likely that the tachycardia observed was induced by pancuronium. Although the greatest change in mean heart rate in this study (a 15% increase) was statistically significant, the question remains whether an increase in the heart rate to this extent is clinically relevant in all cases. A slight increase in the mean systolic b l o o d p r e s s u r e together with a moderate increase in the pulse rate is generally known to occur with the use of pancuronium as pointed out in earlier volumes in this series. More recently Fraley e t al. (2 c) have, however, described a drastic increase in blood pressure associated with pancuronium in a newly hospitalized patient with a history of chronic
Interactions A few years ago Standaert and his associates (3) demonstrated the involvement of the cyclic nucleotide/phosphodiesterase system in the transmitter release at the motor nerve ending. Subsequently Dretchen e t al. (4) described the antagonistic action of a z a t h i o p r i n e -- a n immunosuppressive agent - on the neuromuscular blocking effects of pancuronium, d-tubocurarine and
88
gallamine in the cat. In contrast to its effect on the blockade produced by non-depolarizing blocking agents, azathioprine potentiated the neuromuscular blockade caused by suxamethonium. The most likely explanation for the neuromuscular effects of azathioprine, in full agreement with the findings of Standaert et al. (3), must be sought in its phosphodiesterase-inhibiting activity. The same authors have found that the neuromuscular effects of azathioprine were similar to those of a known phosphodiesterase inhibitor, theophylline. More recently Doll and Rosenberg (5 C) described a patient with marked resistance to pancuronium. The patient suffered smoke inhalation and hypoxic brain injury several days before her admission to the intensive care unit. Because of severe bronchospasm, aminophylline was infused at a rate of 1.55 mg kg -1 hr -1 for 48 hours. At this infusion rate her plasma theophylline level was 35 mg 1-1. Other medications included hydrocortisone 100mg every six hours and cimetidine 300 mg given intravenously every six hours. Further deterioration of the patient's respiratory status required controlled mechanical ventilation, and 0.13 mg kg -1 pancuronium was therefore administered. Since there was no apparent effect of this dose and the patient showed sustained tetanic stimulation of the ulnar nerve even after some minutes, an additional dose of 0.35 mg kg-1 pancuronium was given without any change in respiratory status or response to nerve stimulation over the next 20 minutes. Finally the patient was paralyzed by giving 100 mg suxamethonium. This marked resistance to the neuromuscular effects of pancuronium might have been caused not only by the high plasma theophylline levels but also by the corticosteroid present in the patient's medication (6). Another interesting and possibly clinically relevant finding concerns the interaction between pancuronium and nitroglycerin. Glisson et al. (7) recently described a significant delay in the recovery rate of neuromuscular blockade produced by pancuronium in the presence of a nitroglycerin infusion of 1 //g kg -1 min. -1 in the cat. Under identical experimental conditions nitroglycerin did not alter the recovery rate of the block produced by d-tubocurarine or suxamethonium, or the magnitude of the pancuronium-induced block in the isolated rat diaphragm preparation. These observations strongly suggest a pharmacokinetic inter-
S. Agoston
action specific to pancuronium and nitroglycerin. Marked tachy-arrhythmias were observed by Edwards et al. (8) in two patients treated with imipramine after the administration of pancuronium bromide during halothane anaesthesia. This observation led the authors to investigate this phenomenon in animals more extensively. They studied the occurrence of cardiac arrhythmias due to pancuronium in dogs under halothane or enflurane anaesthesia either after acute administration of increasing doses of imipramine or in animals pretreated with this tricyclic antidepressant for 15 days. The arrhythmias in dogs chronically treated with imipramine were more severe than those in animals receiving acute doses of this compound and were more prone to occur during halothane than during enfiurane anaesthesia, which strongly suggests that halothane in combination with pancuronium and long-lasting pretreatment with imipramine increases the likelihood of cardiac arrhythmias. Both long-lasting tricyclic antidepressant administration ( 9 ) a n d pancuronium (SEDA-3) may inhibit norepinephrine re-uptake by adrenergic nerve endings, resulting in elevated concentrations of norepinephrine in cardiac tissue. Since elevated levels of epinephrine are known to facilitate the action of halothane in predisposing the myocardium to arrhythmias (10 C ) the administration of pancuronium to patients under chronic tricyclic antidepressant therapy anaesthetized with halothane should be avoided. The interaction of pancuronium and other non-depolarizing neuromuscular blocking agents with various antibiotics is well recognized (SEDA-2, 113), but it should be borne in mind that this can be of great clinical importance. Giala and Paradelis from Greece have recently described two cases in which such an interaction (induced by colistin in one case and streptomycin in another) resulted in severe respiratory depression (18c); the effect was terminated by injections of calcium gluconate.
DEPOLARIZING NEUROMUSCULAR BLOCKING AGENTS Suxamethonium The most frequently reported side effects of suxamethonium are muscle fasciculations
89
Muscle relaxants
and muscle pain, particularly in patients who are ambulatory a short time after operation. Although many reports have in the past appeared regarding the possible causes, frequency, severity and prevention of suxamethonium-induced muscle fasciculation, little information is available on more objective methods than simple rating for the assessment of the extent and intensity of muscle response either to suxamethonium or to drugs that interact with succinylcholine. Jansen and H a n s e n ( l l C) have described a method of electrical fasciculation counting by which variations in the circumference of an upper arm were recorded by a strain gauge, Philips Minilog Amplifier and a fourtrack tape recorder. In clinical use the method appeared to be highly sensitive, especially in quantifying hardly visible fasciculations of low amplitude and high frequency. There are reasons to consider that by using this method more meaningful data can be collected in the future regarding the fasciculations induced by suxamethonium. Elsenberg et al. (12 C) investigated the effects of low doses (0.05 mg kg -1) of diazepam pretreatment on suxamethonium-induced muscle pain and fasciculations, increases in potassium and creatine phosphokinase levels. They found that pretreatment with diazepam did not alter the suxamethonium-induced neuromuscular blockade, or prevent the rise in creatine phosphokinase levels; however, it reduced the incidence of post-operative muscle pain as well as the usual increase of serum potassium levels. Since the neuromuscular effects of suxamethonium remained uninfluenced by this low dose of diazepam, it seems that this drug is to be preferred over non-depolarizing relaxants in the prevention of suxamethoniuminduced muscle pain and fasciculations. Prolonged muscle paralysis lasting about three hours was described (13 c ) following the administration of 100 mg and a few minutes later 40 mg of suxamethonium to a patient weighing 61 kg with carcinoma of the prostate on diethylstilboestrol therapy. Markedly decreased qualitatively normal pseudocholinesterase levels were detected in this patient in the recovery room and on the first post-operative day. A few weeks later the diethylstilboestrol therapy was discontinued, following which the plasma pseudocholinesterase levels rose, but still remained under the lower limit of normal. The acquired plasma cholinesterase deficiency in
this patient was probably caused by diethylstilboestrol, since oestrogens are known to depress hepatic synthesis or release of pseudocholinesterase ( 1 4 c ; SED 9). However, a number of other factors, such as hormonal effects due to prior orchiectomy, or the presence of mild liver disease, may all have contributed to the deficiency of the enzyme in this patient. At all events diethylstilboestrol should be considered as a factor which may cause plasma pseudocholinesterase deficiency. Apparent resistance to 50, 40 and 40 mg suxamethonium given at 2 - 3 minute intervals was observed (15 c) in a psychiatric patient with markedly elevated levels of qualitatively normal pseudocholinesterase. In the absence of any other factors, related to other drugs or to the patient's disease, which might explain this unusual reaction, it is probable that the elevated levels of otherwise normal pseudocholinesterase found in this patient produced an unusually rapid breakdown of suxamethonium, resulting in apparent resistance. In practice this type of reaction occurs more often than the reports in the literature would suggest and usually the hospital pharmacy or the manufacturer is blamed for the delivery of an 'inactive' drug. In cases showing the above type of resistance it would be wise to determine the plasma levels and the type of the enzyme, since in such individuals not o n l y the effects of suxamethonium, but also those of other compounds such as the ester-type local anaesthetics hydrolyzed by this enzyme may be affected. A hyperkalaemic response to suxamethonium with serum potassium levels raised from 3.8 mEq[t to 7.1 mEq/1 and transient ventricular dysrhythmia has been reported (16 c ) in a patient without known neurological deficits, but with muscle wasting secondary to chronic arterial insufficiency. Patients with advanced arteriosclerotic disease with muscle wasting thus represent an additional group of individuals susceptible to suxamethonium-induced hyperkalaemia.
SKELETAL MUSCLE RELAXANTS This group of agents comprises dantrolene sodium, baclofen, cyclobenzaprine and diazepam. They are used either for long-or for short-term management of muscle spasticity. During the past year no facts regarding their
90 side effects were reported which had n o t already been described in the past and discussed in earlier volumes in this series. However, the trend to use dantrolene for the prophylaxis or treatment of the malignant hyperpyrexic syndrome (SED 9) still continues. The poor solubility of the drug has in the past prevented its intravenous use in man, but recently this limitation has been overcome by the manufacturer. Friesen et al. (17 C) reported the first successful i.v. use of dantrolene sodium in the treatment of malignant hyperthermia in one patient. After developing the first signs of this potentially fatal condition, the malignant hyperthermia protocol was instituted, consisting of the administration of iced intravenous solution, surface cooling with ice and the administration of chlorpromazine. Subsequently the patient was given a total of 250 mg dantrolene by rapid intravenous infusion. Within ten minutes the patient's temperature returned to 36.5~ Apart from some in-
S. Agoston crease in temperature (38~ during five days observation in the Intensive Care Unit, the patient made an uneventful recovery and was discharged. Three months later he was re-admitted for operation. This time dantrolene 300 mg was given by m o u t h five hours before the operation. No side effects were reported following the intravenous dose, but after the oral dose on the second occasion the patient experienced dizziness and nausea, both of which are known side effects o f this compound. During the second operation none o f the signs of malignant hyperthermia appeared, but this is not surprising, since the operation was performed under regional anaesthesia. Although it would be premature to form a view of the drug's adverse effects after intravenous administration the possibility cannot be excluded that the known side effects of dantrolene sodium are related at least in part to the pharmaceutical form used for oral administration.
REFERENCES 1. Parmentier, P. and Dagnelie, P. (1979): Dose related tachycardia induced by pancuronium during balanced anaesthesia with and without droperidol. Brit. J. Anaesth., 51, 157. 2. Fraley, D.S., Lemoncelli, G.L. and Coleman, A. (1978): Severe hypertension associated with pancuronium bromide. Anesth. Analg., 57, 265. 3. Standaert, F.G., Dretchen, K.L., Skirboll, L. R. et al. (1976): Effects of cyclic nueleotides on mammalian motor nerve terminals. J. Pharmacol. exp. Ther., 199, 544. 4. Dretchen, K.L., Morgenroth, V.H., Standaert, F. G. et al. (1976): Azathioprine: effects on neuromuscular transmission. Anesthesiology, 45, 604. 5. Doll, D. C. and Rosenberg, H. (1979): Antagonism of neuromuscular blockage by theophylline. Anesth. Analg., 58, 139. 6. Meyers, E.F. (1977): Partial recovery from pancuronium neuromuscular blockade following hydrocortisone administration. Anesthesiology, 46, 148. 7. Glisson, S.N., E1-Etr, A.A. and Lim, R. (1979): Prolongation of pancuronium-induced neuromuscular blockade by intravenous infusion of nitroglycerin. Anesthesiology, 51, 47. 8. Edwards, R. P., Miller, R. D., Roizen, M. F. et al. (1979): Cardiac responses to finipramine and pancuronium during anesthesia with halothane or enflurane. Anesthesiology, 50, 421.
9. Byck, R. (1975): Drugs and the treatment of psychiatric disorders. In: The Pharmacological Basis of Therapeutics, Fifth Edition. pp. 174-179. Editors: L.S. Goodman and A. Gilman. MacMillan, New York. 10. Johnston, R. R., Eger II, E. I. and Wildon, C. (1976): A comparative interaction of epinephrine with enflurane, isoflurane and halothane ial man. Anesth. Analg., 55, 709. 11. Jansen, E. C. and Hansen, P. H. (1979): Objective measurement of succinylcholine-induced fasciculations and the effect of pretreatment with pancuronium or gallamine. Anesthesiology, 51, 159. 12. Eisenberg, M., Balsley, S. and Katz, R. L. (1979): Effects of diazepam on succinylcholineinduced myalgia, potassium increase, creatine phosphokinase elevation, and relaxation. Anesth. Analg., 58, 314. 13. Archer, T.L. and Janowsky, E.C. (1978): Plasma pseudocholinesterase deficiency associated with diethylstilboestrol therapy. Anesth. Analg., 57, 726. 14. Robertson, G. S. (1967): Serum protein and cliolinesterase changes in association with contraceptive pills. Lancet, I, 232. 15. Spurgeon, M. J. (1979): Apparent resistance to succinylcholine. Anesth. Analg., 58, 57. 16. Rao, T.L.K. and Shanmugam, M. (1979): Succinylcholine administration - another contraindication? Anesth. Analg., 58, 61.
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