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ADVERSE EFFECTS OF NEUROMUSCULAR BLOCKING DRUGS · PDF fileADVERSE EFFECTS OF NEUROMUSCULAR BLOCKING DRUGS ... blockers, atracurium and ... Ganglion Sympathetic Vagolytic Vagal Histamine

Sep 06, 2018




  • Br. J. Anaesth. (1987), 59, 46-60


    J. M. HUNTER

    Neuromuscular blocking drugs are not as notori-ous for producing adverse reactions as the i.v.induction agents; nevertheless, to a varying degreethey all produce unfavourable or harmful effects.The newer non-depolarizing neuromuscularblockers, atracurium and vecuronium, have beendeveloped in an attempt to overcome the disad-vantages of the earlier drugs, but although muchmore specific agents, they are not completely freefrom side-effects. The adverse effects of theneuromuscular blocking drugs available in GreatBritain today will be discussed in this paper.Those which are not available in this country(such as pipecuronium and metocurine), andobsolete agents (such as decamethonium) will notbe discussed. Although what follows is concernedmainly with the non-depolarizing agents, suxa-methonium is included where appropriate, whilstwhat might be regarded as the unique features ofthe drug are discussed later in the article.


    With the possible exception of vecuronium, all theneuromuscular blocking drugs have some effecton the cardiovascular system. Such effects are

    JENNIFER M. HUNTER, M.B., F.F.A.R.C.S., University Depart-ment of Anaesthesia, Royal Liverpool Hospital, Prescot Street,P.O. Box 147, Liverpool L63 3BX.

    described usually in terms of the degree ofganglionic blockade, sympathetic stimulation,vagal stimulation and vagolytic effect, and aresummarized in table I. It must be emphasized,however, that histamine release caused by admini-stration of a blocking agent may well have a muchgreater effect on the cardiovascular system thanany direct effect of the drug itself; this isparticularly pertinent in the case of tubocurarine.

    The ganglionic blockade caused by tubocura-rine and the synthetic derivative of tubocurarine,alcuronium, results in a decrease in peripheralvascular resistance and hence a reduction inarterial pressure. This effect is dose related and isprobably of clinical significance only when usinglarger doses of the drugs (such as tubocurarine0.6 mg kg"1) and in a hypovolaemic patient. Astubocurarine also releases histamine to a signifi-cant degree, the two unrelated effects maycombine, even when using smaller doses of thisdrug to produce a decrease in arterial pressure, aneffect which is often used to clinical advantagewhen hypotension is desired.

    The sympathomimetic effect characteristic ofsome neuromuscular blocking drugs is thought tobe an indirect response attributable to release ofnoradrenaline from adrenergic nerve endings inthe heart; it has been demonstrated with bothgallamine (Brown and Crout, 1970) and pancuro-nium (Nana, Cardan and Domokos, 1973). The

    TABLE I. The pharmacological effects of each of the nturomuscular blocking drugs which producecardiovascular changes. (From Norman (19S5))

    Ganglion Sympathetic Vagolytic Vagal Histamineblockade stimulation effect stimulation releate

    Suxamethonium + +Vecuronium Atracurium +Alcuronium + +Gallamine + + + + + +Tubocurarine + + + + +Pancuronium + + + +


    subsequent development of tachycardia andhypertension is potentiated by the vagolytic effectof these two drugs, for they also produce anatropine-like blockade of the cardiac muscarinicreceptors (Goat and Feldman, 1972).

    In contrast, of all the neuromuscular blockingdrugs, suxamethonium is most likely to produce areduction in heart rate as a result of stimulation ofthe cholinergic receptors in the heart, eitherdirectly or indirectly from reflex activity followingstimulation of peripheral sensory receptors in thecarotid body. There has been much discussion inthe literature over these alternative mechanismsand the relative importance of each is still not clear(Goat, 1972). Bradycardia and asystole have beendescribed clinically after a single dose of suxa-methonium (Sorenson et al., 1984), but this effecton muscarinic receptors is more pronounced afterrepeated dosage, in the presence of an inhalationagent and in the younger patient (Leigh et al.,1957). In such circumstances, the resultantbradycardia frequently necessitates the use of ananticholinergic drug such as atropine.

    In a patient with severe cardiovascular diseasethe cardiovascular effects produced by a neuro-muscular blocker can be of clinical importance: forinstance gallamine might be contraindicatedbecause the combination of a vagolytic effect withsympathetic stimulation may cause an unaccept-able increase in heart rate and hence cardiacrate-pressure product (Stoelting, 1973). The sameeffect, to a lesser extent, may also be seen withpancuronium.

    Atracurium and vecuronium are free fromdirect cardiovascular effects within the clinicaldose range (Crul and Booji, 1980; Sokoll et al.,1983), although the histamine releasing propertiesof atracurium may produce some degree ofhypotension and tachycardia, especially whenused in large bolus doses, greater than 0.6 mg kg"1

    (Hughes and Payne, 1983). Only when very largedoses (2 mg kg"1) were used in animal work has avagolytic effect been reported with atracurium(Hughes and Chappie, 1980). Because of thepossibility of histamine release with atracurium,vecuronium is the neuromuscular blocking agentcausing the least cardiovascular side effects. It istherefore the best drug when considering the mostsuitable form of anaesthesia for the patient withsevere myocardial disease.

    The virtual absence of direct cardiovasculareffects associated with vecuronium and atracur-ium, however, does allow other anaesthetic agents

    such as halothane and the opioid analgesics toexert an unopposed effect on the myocardium. Inaddition, surgical manoeuvres which result invagal stimulation such as peritoneal traction orcervical stimulation may lead to an unopposedreduction in heart rate. These factors probablyexplain the occurrence of bradycardia which hasbeen reported during the use of both atracurium(Carter, 1983) and vecuronium (Robertson, et al.,1983) which provoked much debate in theliterature (Madden, 1983; Macrae, 1985). It ispertinent that a similar case of sinus arrest duringperitoneal traction has also recently been reportedwhen tubocurarine was the neuromuscular block-ing agent used (Nandi and Astley, 1985); thereis always the possibility of a bradycardia duringvagal traction, whatever the anaesthetic techniqueused.


    Most neuromuscular blocking agents cause hista-mine release and the results of this release are seenin three ways: first, by a local erythematousreaction, like nettle rashing, sometimes accom-panied by a widespread flush but without areduction in arterial pressure; second by systemiceffects such as tachycardia and hypotension, whichmay well be of clinical importance; and third,and rarely, as a life threatening anaphylactic oranaphylactoid reaction.

    Basic compounds are more disruptive of mastcells, and thus more prone to release histaminethan are acidic substances. Of the neuromuscularblocking agents, tubocurarine is the most potentin this respect: the free hydroxyl groups on themolecule are thought to enhance histaminerelease. Atracurium (Hilgenberg, 1983), alcuron-ium and gallamine have only about one-third ofthe histamine releasing potency of tubocurarine.However, several severe anaphylactic reactions toall these agents have now been described (Salem,Kim and El Etr, 1968; Fisher, 1978; Fisher,Hallowes and Wilson, 1978; Mercer, 1984).Although pancuronium and vecuronium, whichare acidic compounds, are relatively free fromhistamine releasing properties, cardiovascularcollapse has been reported following the admini-stration of pancuronium, as has an incident ofacute bronchospasm following administration ofthe drug (Heath, 1973; Mishima and Yamamura,1984). More recently, localized histamine release


    has been reported after an injection of vecuronium(Spence and Barnetson, 1985).

    It has been suggested that atracurium does notcause histamine release when doses of less than0.6 mg kg"1 are used. It has also been demon-strated that histamine liberation is less likely tobecome evident when the speed of administrationof atracurium is reduced and when pretreatmentwith Hx and Hj-receptor antagonists is used;cimetidine 4 mg kg"1 and chlorpheniramine0.1 mg kg"1 i.v. were given successfully for thispurpose (Scott et al., 1985). It is probable that thesame histamine antagonists would have .similarbeneficial effects with the other histaminereleasing neuromuscular blockers, especiallytubocurarine.

    The incidence of the localized erythema andurticaria occasionally produced when atracuriumis injected to a peripheral vein may be reduced byinjecting the drug separately from the inductionagent, either by flushing the needle used withsaline between the administration of two drugs orby injecting them both to a free flowing peripherali.v. infusion. This observation suggests that theprecipitate formed by the mixture of the two drugsis responsible at least in part for the localizedresponse (Hughes, 1985).

    There is some evidence that allergic crossreactivity between different myoneural blockerscan develop, exposure to a second blocker morecommonly producing any abnormal reaction whensensitivity to another relaxant has already oc-curred (Harle, Baldo and Fisher, 1985).

    There are isolated reports of anaphylactoidreactions to suxamethonium (Assem, Frost andLevis, 1981; Royston and Wilkes, 1978), but theseare generally considered to be much less commonthan with tubocurarine (Lim and Churchill-Davidson, 1981).


    Any pathological process which impairs the routeof metabolism or excretion of a neuromuscularblocking drug may result, not only in prolongationof the effect of the

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