F.J. Richardson and S. Agoston
F o r a review of the whole of this subject the reader is referred to SED 9 (pp. 1 9 1 212) and the previous Annuals. In the last year there have been few reports on side effects of muscle relaxants, but there has been a good review on the pharmacokinetics of non-depolarizing neuromuscular blocking agents by Ramzan et al. (1 R) and another on intravenous agents (including muscle relaxants) used in anesthetic practice by Duvaldestin (2R). Factors altering the normal pharmacokinetic patterns are also discussed in these 2 papers. In a volume devoted to anesthetic side effects and complications, Lebowitz and Savarese (3 R) review complications involving neuromuscular pharmacology. They provide a short, clinically-orientated fist o f unwanted side effects, sometimes controversial, o f neuromuscular blockers. An article emphasizing the role of the cyclic nucleotides in neuromuscular transmission is presented by Standaert and Dretchen (4R). These authors review the experimental evidence on the physiologic role o f cAMP, supporting the view that increased activity o f cAMP in the nerve endings will ultimately increase transmitter release. By the above mechanism a number of side effects and interactions with neuromuscular blocking drugs can be explained.
at frequencies o f 5 0 - 1 0 0 Hz be used to uncover fatigue.
Influence o f age
In a clinical study where no relaxants were used Crumrine and Yodlowski (5 c ) , employing the frequency sweep electromyogram (FSEMG), found that infants less than 12 weeks oM had significantly less pronounced FSEMG responses at high stimulation frequencies ( > 5 0 Hz) and that nitrous oxide reduced the response amplitudes. In older infants the responses were similar to those seen in adults. The authors concluded that myoneural function is different below this age and suggest that the younger infant is more susceptible to neuromuscular fatigue and has a smaller margin of safety for neuromuscular transmission. When testing neuromuscular function in infants they advise that tetanic stimulation
Effect o f hemodilution
The potency of both depolarizing (suxamethonium) and non-depolarizing (pancuronium, tubocurarine) neuromuscular blockers m a y be doubled, according to a paper by Schuh (6c), by pre-operative hemodilution (1 litre blood replaced by Rheornacrodex 10%). More scientific data are required before his hypotheses on the mechanisms involved can be accepted. The question remains how intra-operative hemodilution, with fluids of different composition, as regularly occurs in clinical practice, may affect the actions o f neuromuscular blockers.
DEPOLARIZING NEUROMUSCULAR BLOCKING AGENTS Suxamethonium (SED 9, 201; SEDA-4, 88;
SEDA-5, 134) Neurologic diseases as a risk factor It is well known that suxamethonium can be dangerous in patients with neurologic diseases (7Cr). In chronic or relapsing polyneuropathy the risk o f ventricular dysrhythmias, probably resulting from transient serum potassium elevation following the injection of suxarnethonium, is highlighted by Fergusson et al. (8C). Their 4 patients had neurologic symptoms o f long-standing duration, from 5 months to 5 years, with increasing weakness producing pulmonary problems. The danger of a substantial rise in serum potassium is usually said to be much less in patients who have had their neurologic disease for longer than 6 months. Cooperman (7Cr), however, added that this may n o t be so in disease of a progressive nature, and this was indeed the case in the patients reported on by Fergusson et al. While it also appears that the "vulnerable period' of suxamethonium hyperkalemia takes some 3 - 4 weeks to develop, there are
Muscle relaxants cases, such as transverse spinal lesions with tetraplegia, where it has been reported to begin at 2 4 - 4 8 hours; thus it seems advisable to avoid suxamethonium altogether in patients with denervation diseases or injuries. Perhaps the only indication for its use would be for 'crash' intubation directly after the denervating injury if the risk o f pulmonary problems from aspiration is great. Another case of hyperkalemia associated with suxamethonium has been reported by Gravlee (9 C) in a patient with Parkinson's disease. The disease was poorly controlled, therapy having been discontinued 6 days before, with increasing signs of parkinsonism becoming apparent as a result. He was given a large dose of suxamethonium (800 mg over 30 minutes by infusion). A further point worth noting is that 1 mg pancuronium was given prior to the suxamethonium. Nondepolarizers have been shown (SED 8, 282; 7 Cr) to be ineffective or unpredictable in preventing potassium rises secondary to suxamethonium injection. Geographic variations in sensitivity Prolonged apnea after suxamethonium has long been linked with genetic factors. There have been several reports in the past indicating geographic variations in response to suxamethonium and in the incidence of the various plasma cholinesterase genotypes (10 C, 11 C, 12 CR, 1 3 c - i 5 c, 16Or). Vergnes et al. (17 c r ) have reported on the genetic polymorphism in distinct Pyrenean communities (2400 subjects). They found a significant variation in the different areas studied, and briefly discuss the differences in incidences of the commoner genotypes reported in different world regions. It may be that among isolated communities, where there is little mixing with other groups, the incidence o f abnormal genotypes for plasma cholinesterase may be much different from that expected from published data on large 'mixed' population samples and this may produce differences in sensitivity to suxamethonium, which may be important clinically, even within the same racial group or large geographic area. Inter-racial differences with respect to plasma cholinesterase variants may be 10-fold or greater (12 CR) for example, plasma cholinesterase variants seem to be rare in Negroes, and the 'silent' gene has been found remarkably frequently in Eskimoes. It should be noted, however, that it may be misleading to compare older -
129 with newer data as cases may in the past have been assigned to the wrong genotype group as a result of the lack of more specific tests and comprehensive family studies (16Cr). Miscellaneous A group of 70 patients in Denmark who were all genotypically normal but whose plasma cholinesterase activities ranged from low to high (range 1 5 4 - 2 3 3 4 U/l; normal range 6 7 7 - 1 5 6 0 U/l) were examined by Viby-Mogensen (18Or). The duration of apnea and the times to recovery of twitch height after suxamethonium were found to bear linear relationships to the inverse plasma cholinesterase activity. In other words, 'for patients with the genotypically normal enzyme the duration o f suxamethonium action increases with decreasing plasma cholinesterase activity'. Esterase activity as low as 1 5 0 200 U/I caused, however, only moderate prolongation of recovery from suxamethonium (maximum time to 100% twitch recovery was 22 minutes). It is suggested that apnea of more than moderate duration occurring in such patients may be due to factors other than low plasma cholinesterase activity. Further experimental information on the phenomena of tachyphylaxis and phaseH block has been provided in a recent paper (19Cr). In a series of 22 children, aged 1 - 1 5 years, under halothane ( 1-1 89 N 2 0 anesthesia, it was found that suxamethonium given by infusion resulted in tachyphylaxis at a mean dose of 3 mg/kg and phase-II block (as defined by a train-of-four ratio of less than 50%) after a total of 4.1 mg/kg was given. The tachyphylaxis occurred 23 _+ 2 minutes and phase-II block in 29 _+ 5minutes (mean _+ SE). As adequate recovery (train-of-four ratio greater than 75%) was highly variable, taking from 4 - 8 1 minutes, the authors' conclusions would seem to be justified, namely, that extreme caution should be used when suxamethonium is given by infusion and that monitoring o f the trainof-four is extremely valuable especially when more than 3 mg/kg is necessary. It must not be expected that recovery from suxamethonium in such circumstances is 'instantaneous' time has to be allowed for adequate recovery. On the prevention of known suxamethonium side effects there have been several papers in the last year. The incidence o f dysrhythmias after a second dose o f suxamethonium, given 5 minutes after the first, was
130 found to be statistically the same when glycopyrrolate (0.0045 or 0.008 mg/kg) or atropine (0.009 mg/kg) was given intravenously before anesthesia (20C). The higher dose of glycopyrrolate, however, resulted in significantly higher heart rates over the 15 minutes of the study. Under similar circumstances (21C), pretreatment with pancuronium (0.01, 0.015 or 0.02 mg/kg) or gallamine (0.03 mg/kg) resulted in protection against suxamethonium-induced dysrhythmia. The highest dose of pancuronium caused an unacceptably high frequency of partial neuromuscular block. Pancuronium 0.01 mg/kg or gallamine 0.3 mg/kg appear to be equally effective. Atypical responses to such small doses of non-depolarizing neuromuscular blocking agents may occur (see section on non-depolarizing agents). Hypersensitivity to small doses of suxamethonium, as given in the i.v. regional suxamethonium test, may also lead to unexpected degrees of paralysis (22c). Suxamethonium produced a significant rise in intra-ocular pressure despite petreatment with tubocurarine 0.1 mg/kg (23c). As there appears to be no reliable method o f preventing this side effect (SEDA-2, 1 t 6 ; SEDA-5, 136) suxamethonium should not be used in cases, such as patients with open eye injuries, where a rise in lOP must not be allowed to occur.
NON-DEPOLARIZING NEUROMUSCULAR BLOCKING AGENTS Interactions The neuromuscular block p~t)duced by non-depolarizing agents may be affected by many drugs. Potentiation has been reported with antidysrhythmic agents such as lidocaine, procainamide and propranolol (SED 8, 269). Another antidysrhythmic drug, disopyramide was found by Healy et al. (24 C) to decrease neuromuscular transmission in experiments with the rat isolated phrenic nerve-diaphragm preparation. This effect was more marked in the presence of low concentrations of tubocurare and it is postulated that this drug may increase the residual impairment in neuromuscular transmission at the termination o f anesthesia. Trimetaphan has already been reported as having an anti-piasma cholinesterase action (SED 9, 205) and as having contributed to prolonged
F. J. Richardson and S. Agoston paralysis in a case where both suxamethonium and tubocurarine had been used (SEDA-I, 114). This hypotensive agent may have produced a non-depolarizing block in a complicated case reported by Nakamura (25c), although there were several other factors which could have played a role. The block produced by the new relaxant vecuronium (Org NC 45) may be potentiated, as is the case with pancuronium and tubocurarine, by the previous administration of suxamethonium (26c). Cholestasis as a risk factor A paper by Westra et al. (27Cr), examining the changes induced in the pharmacokinetics and -dynamics of pancuronium and gallamine in patients with extrahepatic cholestasis, suggests that in such patients neuromuscular blockers partially cleared by the liver may have prolonged elimination half-lives and duration of action, possibly due to elevated levels of bile salts which, according to animal experiments (28 Cr, 29 C, 30c), may reduce hepatic uptake of the relaxant. Precurarization Small doses ofpancuronium (0.014 mg/kg) given to volunteers were found to decrease pulmonary function (31C). F o u r out of 15 volunteers developed dyspnea and one had to be artificially ventilated. In view of the atypical responses which are not infrequently seen using small doses of non-depolarizing agents to reduce the side effects o f suxamethonium ventilation should be carefully monitored at all times. Alcuronium (SED 9,200; SEDA-5, 132)
Ho et al. studied the placental transfer of alcuronium in 12 patients undergoingelective or emergency cesarean section. The drug appeared to cross the placenta rapidly and in measurable concentration, but no adverse effects on the neonates were evident, as judged by measurement of Apgar scores (55c).
NEW NEUROMUSCULAR BLOCKING DRUGS As far as new drugs are concerned Savarese, in a recent editorial (32r), concludes that new non-depolarizers which meet the m o d e m high demands of anesthesiologists will soon be on the market. The need for
Muscle relaxants non-depolarizers of intermediate duration, virtually non-cumulative and lacking cardiovascular side effects, seems to be met by vecuronium (Org NC 45) and atracurium (SEDA-5, 134; 33 c , 34 c ) and BWA 444U (so far no published data). The long-acting relaxant pipecurium is fully reviewed in SEDA5 (p. 133). Non-depolarizers of short duration (comparable to suxamethonium) are still awaited. Vecuronium (Org NC 45) (SEDA-5, 132,
134) Interactions between vecuronium (Org NC 45) and many anesthetic, analgesic and antimicrobial agents have been examined in cats by Mclndewar and Marshall (35c). Methoxyflurane at 0.3% significantly potentiated the neuromuscular block, as did halothane and enflurane (but only at 2% concentration). These agents also significantly increased the 2 5 - 7 5 % recovery time for twitch height. Nitrous oxide had no effect. Intravenous anesthetic drugs (althesin, etomidate, ketamine, methohexitone, propanidid, thiopentone and sodium oxybate) potentiated the degree of block but did not prolong the recovery times (ketamine did slightly). In general, at the lower end of the dosage range there was only minor potentiation. Diazepam, morphine and fentanyl/droperidol were without effect. The potentiating effect of crystamycin (benzylpeniciUin together with streptomycin) was thought most likely to be the result o f the streptomycin - as with other relaxants. An interesting finding was that metronidazole potentiated vecuronium. Previously this drug has been reported as facilitating neuromuscular transmission and partially antagonizing tubocurare in rats (36). The potentiation was only seen after a delay and it is suggested that a metabolite of metronidazole might be responsible for altering the distribution or metabolism of vecuronium (pancuronium was n o t potentiated). These comprehensive interactions, like those investigated by Krieg et al. (37), were, it must be emphasized, found in animal experiments. It remains to be seen if they are confirmed in man. So far Foldes et al. (38) and ~)rding and Viby-Mogensen (39 C) have reported on the potentiation of vecuronium by halothane in man. The latter paper indicates that under halothane anesthesia vecuronium is 1.4 times as potent as pancuronium, whereas the 2 drugs are roughly equipotent
131 under neuroleptanesthesia. Duvaldestin (personal communication) and the present authors have seen prolongation of vecuronium block in patients who were receiving metronidazole, although in man definite proof of a direct association is not yet available. Dioxonium Dioxonium is a neuromuscular blocking agent popular with Soviet anesthetists. Salmenper~ and Tammisto (40 c , 41 c ) have reported their initial experiences with this agent. It produces a dep6larizing block initially which changes to one with non-depolarizing characteristics (dose-dependent?) rather like the development of phase-II block after suxamethonium. In higher doses reversal with neostigmine is unpredictable. It would appear to have no obvious advantages. SKELETAL MUSCLE RELAXANTS A review of many of the relaxants used in rehabilitation medicine has been given by Gy~Sry (42R). He describes sites of action, indications and doses as well as side effects, and gives a guide to the choice of management in different spastic conditions. Dantrolene (SED 9, 206; SEDA-4, 89, 282; SEDA-5, 137) Dantrolene and malignant hyperthermia (MH) Dantrolene is established as the treatment of choice in MH and is currently recommended for prophylactic use when patients suspected of being susceptible to MH have to be anesthetized (SEDA-5, 139). It is, therefore, disquieting to read the case history reported by Fitzgibbons (49 C) where MH
occurred in a patient prophylactically given dantrolene (3.3 mg/kg/24 hr for 48 hr) and who was not exposed to any known triggering agents during anesthesia. Intravenous dantro- ' lene, 1 mg/kg, was successful in conjunction with other measures in aborting the 2 episodes of MH which occurred. The features of this case, however, do n o t allow the diagnosis o f MH to be made with absolute certainty. Servoflurane is reported as triggering MH in swine (50 C) and may, therefore, be hazardous in susceptible patients. Conflicting conclusions are reached in further studies examining the relationship, if any, between MH susceptibility and an
132 increased frequency of the fluoride-resistant plasma cholinesterase variant (E 1f) (51 - 53). Any conclusion on this fine of enquiry would be premature. A full review on the subject of MH has been presented by Gronert (54R). The side effects of dantrolene and recommended precautions in long-term use are given in SEDA-5 (p. 137).
Other drugs DS 1 0 3 - 2 8 2
(see also SEDA-5, 137)This drug is reported to have produced a fall in blood pressure, 45 minutes after 6 mg orally, in a patient receiving methyldopa (43c), and allergic urticaria in another (44e), leading to the drug's withdrawal after 14 days' treatment. Unfortunately, details are lacking and these side effects are n o t discussed. Baelofen Sudden withdrawal of baclofen is reported, in a paper on the drug's usefulness in trigeminal neuralgia (45 c), to have resulted in hallucinations and status epilepticus (treated successfully by phenytoin sodium) in one patient. Hallucinations on sudden withdrawal have been reported several times with this drug, as has worsening of epilepsy (SED 9, 206; SEDA-3, 114; SEDA-5, 137). This patient had had one seizure in the past. Sudden withdrawal is contraindicated, and use of baclofen in patients with a history of seizures
F.J. Richardson and S. Agoston is to be avoided. Five cases of deterioration in liver function tests after administration of baclofen tablets have been documented from Japan; changes in liver function with this drug have in the past been poorly documented (56c). Cyclobenzaprine (Flexeril) This drug appears capable of precipitating Raynaud's phenomenon ( 1 case; 46 c r). This is supported by the observation that Raynaud's phenomen o n has also been associated with the administration of the tricyclic antidepressants, which have a similar chemical structure. A proposed mechanism is that arteriolar vasoconstriction is produced by the accumulation of noradrenaline in the synaptic cleft as a result of prevention of neuronal uptake by tricyclic drugs. Cyclobenzaprine was formerly used in psychiatry in much higher dosage, tachycardia and orthostatic hypotension being reported (SED 9, 208; SEDA-3, 115). It seems quite likely that patients receiving this drug may share with the tricychc antidepressants the interaction with pancuronium and halothane (and enflurane to a lesser extent) which may result in severe tachydysrhythmias under anesthesia (47c). Another paper on cyclobenzaprine summarizes its efficiency and side effects in 6311 patients in a post-marketing surveillance program (48).
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134 49. Fitzgibbons, D.C. (1981): Malignant hyperthermia following preoperative oral administration of dantrolene. Anesthesiology, 54, 73. 50. Shulman, M., Braverman, B., Ivankovich, A. D. et al. (1981): Servoflurane triggers malignant hyperthermia in swine. Anesthesiology, 54,259. 51. Whittaker, M. and Britten, J. J. (1981): Malignant hyperthermia and the fluoride resistant gene. Brit. J. Anaesth., 53, 241. 52. Evans, R.T., Iqbal, J., Ellis, F.R. et al. (1981): Collaborative study of the frequency of the fluoride resistant cholinesterase variant in patients with malignant hyperthermia. Brit. J.
F. J. Richardson and S. Agoston Anaesth., 53, 245. 53. 0rding, H., Hanel, H. H. and Viby-Mogensen, J. (1981): Plasma cholinesterase and malignant hyperthermia. Brit. J.. Anaesth., 53, 317. 54. Gronert, G.A. (1980): Malignant hyperthermia. Anesthesiology, 53, 395. 55. Ho, P.C., Stephens, I.D. and Triggs, E.J. (1981): Caesarean section and placental transfer of alcuronium. Anaesth. intens. Care., 9, 113. 56. Anonymous (1981): Abnormal hepatic function test results due to baclofen (publication of the Japanese Ministry of Health and Welfare). Jap. reed. Gaz. , May 20, 12.