SEMINARS IN NEUROLOGY-VOLUME

10, N O . 1 MARCH 1990

Adverse Drug Effects on Neuromuscular Transmission

It is widely recognized that various pharmacologic agents routinely used in the practice of medicine can produce, albeit uncommonly, significant aberrations of neuromuscular transmission resulting in muscle weakness. In all instances there is a reduction in the safety factor of'neuromuscular transmission by one mechanism or another (see Pascuzzi, this issue of Seminars). Categorically, there are four clinical situations encountered in which these drugs produce a worsening of neuromuscular function. First, the direct and augmented deleterious effects of the drug on synaptic transmission in an otherwise apparently normal person; second, those related to a drug-induced disturbance of the immune system with the resulting development of myasthenia gravis (MG); third, the unmasking of subclinical MG or the worsening of muscle strength in patients with MG or the 1,ambert-Eaton myasthenic syndrome (LEMS); and fourth, those with delayed recovery of strength, particularly respiratory function, following general anesthesia during which neuromuscular blocking agents may or may not have been used. In the first situation there may be preexisting circumstances such as altered drug clearance due to renal or hepatic disease, concomitant drug administration, electrolyte disturbances, or direct toxicity that predispose the patient to neuromuscular weakness. Such an example would be the patient with chronic renal failure, undergoing a surgical procedure during which he or she was given a neuromuscular blocking agent and an aminoglycoside antibiotic. The second situation is most commonly encountered in D-penicillamine (DP)-induced rnyasthenia, and there are scattered reports of himilar occur-

rences in patients receiving tiopronine, pyrithioxin, hydantoin drugs, trimethadione, and possibly chloroquine. In the third situation, the failure of the neuromuscular manifestations to resolve following the discontinuation of the drug implies that the disorder was subclinical and brought forth by the use of the pharmacologic agent. The adverse reaction of drugs on synaptic transmission may be classified either as acting presynaptically, with a reduction in acetylcholine (ACh) release secondary to local anesthetic-like activity on the nerve terminal, alteration or impairment of calcium flux into the nerve terminal, or a hemicholinium effect; postsynaptically, with antibody blockade of ACh receptors (AChR), curarelike effects or potentiation of depolarizing or nondepolarizing neuromuscular blocking agents; or, in varying degrees, both. Each of these pharmacologic interactions may result in any of the situations just described. Since the publication of the summaries of Argov and Mastaglia,' Swift,' and Kaeser3 describing disorders of neuromuscular transmission occurring as the result of adverse drug reactions, many more reports have appeared, adding to the list of potentially dangerous agents. Unfortunately, much of the literature is anecdotal and there are only a few comprehensive in vitro evaluations of selected drugs on the effects of neuromuscular transmission in animal or human nerve-muscle preparations. The potential adverse effects of these medications must be taken into consideration when deciding which drugs to use in treating other diseases in patients who also have disorders of synaptic transmission. These problems are uncommon: the literature

Laboratory fbr Myasthenia Gravis Research, the Department of Neurology, T h e University of North Carolina School of Medicine, Chapel Hill, North Carolina Reprint requests: Dr. Howard, Dcpartment of Neurology, 751 Clinical Sciences Bldg., CB#7025, T h e University of North Carolina at Chapel Hill, NC 27599-7025 Copyright O 1990 by Thiemc Medical Publishers, Inc., 381 Park Avenue South, New York, N Y 100 16. All rights reserved.

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James F. Howard, Jr., M.D.

SEMINARS IN NEUROLOGY

go

who had routinely administered the inhalation anesthetic methoxyflurane.13 Fatigue, weakness, and ptosis occurred repeatedly on exposure to the anesthetic and would wane in severity 2 to 3 hours following the cessation of exposure. Similar symptoms produced by a direct challenge to the agent were readily reversed by neostigmirie. Experimental studies have shown that inhalation anesthetics will alter the postjunctional sensitivity to ACh, alter ionic conductances, and cause a shortening of channel open time following activation by ACh.14

LOCAL ANESTHETICS

Local anesthetics in and of then~selvesare unlikely to cause neuromuscular weakness in otherANALGESICS wise normal persons. However, intravenous injections of lidocaine, procaine, and similar local T h e narcotic analgesics, in therapeutic con- anesthetic agents are capable of potentiating the centrations, do not appear to depress neuromus- effects of neuromuscular blocking agents. T h e cular transmission directly in myasthenic m u ~ c l e . ~ mechanisms .~ of action appear varied, with both We have routinely used morphine sulfate for an- pres~napticand postsynaptic effects, and may be algesia in our post-thymectomy patients, without ascribed to an impairment of the propagation of difficulty. However, narcotics should be used with the nerve action potential in the nerve terminal extreme care, given their potential for respiratory with a reduction in ACh release.'"n addition, othdepression. Cholinesterase inhibitors may poten- ers have demonstrated a reduction in the sensitivtiate the analgesic effects of morphine, hydromor- ity of the postjunctional membrane to ACh.16 phone, codeine, and opium alkaloids.%rob7 has Procaine has been reported to produce an reported sudden death within hours of receiving acute myasthenic crisis,'' although this has been morphine sulfate. contested by others.18 I have observed an acute myasthenic crisis in a young woman who underwent a brachial plexus block in which large amounts of GENERAL ANESTHETICS lidocaine were used as the anesthetic for shunt placement. There are no controlled studies addressing the advantages or disadvantages of' the use of various general anesthetics in patients with disorders of ANTIBIOTICS neuromuscular transmission. There niay be a potentiation of neuromuscular blocking agents in paThe earliest report of antibiotic-induced tients with MG.' The current practice of pretreat- neuromuscular blockade in man was in 1956,'"ling the myasthenic patient with, for example, though in 1941 it was demonstrated that tyrothricorticosteroids, plasma exchange,"" or both, to cin, one of the first antibiotics, produced respiraachieve a state of marked improvement or remis- tory weakness in animals." Pridgen reported four sion prior to surgery has obviated much of the ear- patients without prior evidence of neuromuscular lier concern about prolonged postoperative venti- disease who developed apnea (resulting in death in latory failure. In our experience the majority of two) when given intraperitoneal neomycin sulpatients receive combinations of isoflurane and ni- fate.'" To date, there are several hundred case retrous oxide without the use of neuromuscular ports of purported neurornuscular weakness blocking agents. It is the very rare patient who re- resulting from antibiotic effects on the neuromusquires postoperative ventilation; the majority of cular junction in otherwise normal patients, those patients are extubated in the operating room or receiving neuromuscular blocking agents, those the recovery room when fully awake. T h e reader with MG, those with other diseases that alter the is referred to Foldes and McNall12 for a dated but phar~nacokirieticsof the drug, and those patients comprehensive review of this topic. receiving other drugs known to be toxic to the neuThere is a single case report of the unmasking romuscular j~nction."-~" of a subclinical case of MG in a nurse anesthetist As a group, the aminoglycoside antibiotics are

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suggests that the situation most often encountered is prolonged postoperative muscle weakness and respiratory embarrassment although it is my experience, in dealing with a large neuromuscular population, that the problem most frequently encountered is acute worsening of the strength of patients with MG caused by aminoglycoside antibiotics and beta-adrenergic blocking agents. This summary will review the adverse reactions of major classes of drugs on synaptic transmission. An extensive bibliography is provided so that the reader may have access to the anecdotal experiences of others. It is beyond the scope of this review to address in detail the anesthetic complications of synaptic transmission.

VOLUME 10, NUMBER 1 MARCH 1990

well recognized for producing neuromuscular weak- neuromuscular blocking effects of lincomycin may ness irrespective of the route of a d m i n i ~ t r a t i o n . ~be ~ reversed by increasing the calcium concentraThe weakness is related to dose and the serum lev- tion or by administering one of the aminopyriels and is reversible in part by cholinesterase inhib- dines.48Cholinesterase inhibitors may worsen the itors, calcium infusion, and the arnin~pyridines.*~-'" effect. Clindamycin appears to block muscle conExperimental nerve-muscle preparations have tractility directly, as well as having a local anesthetic demonstrated that these drugs act presynaptically, action.49 postsynaptically, or in both locations. For example, Polymyxin B, colistimethate, and colistin have tobramycin has predominantly presynaptic effects also been reported to produce neuromuscular similar to those reported with high concentrations weakness, particularly in those patients with renal of magnesium, with inhibition of ACh release; ne- disease or when used in combination with other tilmicin is predominantly postsynaptic in its effect, antibiotics or neuromuscular blocking a g e n t ~ . ~ O - ~ ~ with blocking of ACh binding to receptor similar Experimental studies have shown the effects of to that produced by Neuromuscular these drugs to be mixed, with a reduction in ACh toxicity data exist for several of the antibiotics, in- release and, to a lesser degree, a postjunctional cluding a m i k a ~ i n , ~g' .e~n~t a m i ~ i n ,k~a~n. ~a ~m y ~ i n , ~block ~ ~ ~of the AChR.49,56,57 Decker and F i n ~ h a m re-~ ~ n e ~ m ~ c i nn,e~t i~l m . ~i ~~i n , s~ t~r,e~p~t ~ m ~ c i nand , ~ ~ . ~port ~ acute ventilatory failure in a myasthenic pat ~ b r a m ~ c i nOf . ~ ~the , ~ group, ~ neomycin is the tient given a single intramuscular injection of colmost toxic, tobramycin the least.30 istimethate. Colistin is also reported to exacerbate Clinically, only gentamicin, kanamycin, neo- the weakness of myasthenic patients acutely.5g rnycin, tobramycin, and streptomycin have been Tetracycline analogues, oxytetracycline and implicated in producing muscle weakness in non- rolitetracycline, have also been reported to exacmyasthenic patient^.^ The weakness of infant bot- erbate MG, although the mechanism is ~ n c l e a r . ~ ~ . ~ ' ulism is potentiated by these d r ~ g s . ~T~h e, ~first ' It has been suggested that magnesium in the dicases of myasthenic exacerbation by antibiotics were luent causes a reduction in ACh release from the described in 1964 by Hokkanen and T~ivakka,~' nerve terminaL6' Others have reported no adverse who cited the acute deterioration of' strength in pa- reactions with tetracycline6' or alteration of neutients receiving a variety of aminoglycoside anti- romuscular transmission in nerve-muscle preparabiotics. The weakness varied from minimal to ven- t i o n ~ . ~ ~ tilatory failure. Occasionally, I have interviewed More recently, it has been suggested that ammyasthenic patients given erythromycin who re- picillin may aggravate the weakness of patients port a mild exacerbation of their weakness; de- with MG or worsen the decrement of repetitive tailed physiologic examinations have not been nerve stimulation in rabbits with experimental carried out. Erythromycin therapy in normal autoimmune myasthenia gravkfi3 Girlanda and volunteers demonstrated a facilitatory response coworkersfi4have demonstrated changes in synapwith repetitive nerve stimulation suggestive of a tic transmission in healthy volunteers by singlepresynaptic neuromuscular although this fiber electromyography (SFEMG), the most sensihas not yet been confirmed with more sensitive tive technique to assess synaptic efficacy.65 T h e techniques to assess synaptic transmission. mechanism of the neuromuscular block is not Neuromuscular blockade is not limited to the known; bath application of this antibiotic to nerveaminoglycoside antibiotics. T h e polypeptide and muscle preparations has not produced an abnormonobasic amino acid antibiotics, penicillins, mality of neuromuscular t r a n s m i ~ s i o n . ~ ~ sulfonamides, tetracyclines, and fluoroquinolones There is a single case report suggesting that have been reported to cause transient worsening of ciprofloxacin, a fluoroquinolone, acutely worsened myasthenic weakness, to potentiate the weakness the strength of a patient with MG." The mechaof neuromuscular blocking agents, or to have the- nism of this reaction is not known. oretical reasons to block synaptic transmission. L i n c ~ m y c i nand ~ ~ ~ l i n d a m y c i nmonobasic ,~~ amino acid antibiotics, are slightly different in structure ANTICONVULSANTS from the aminoglycosides but differ considerably in their effects on synaptic transmission. Both Phenytoin has been shown to depress both drugs can cause neuromuscular block that is not presynaptic and postsynaptic mechanisms of readily reversible with cholinesterase inhibitors. neuromuscular transmission in experimental sysBoth have pre- and postjunctional effects causing tems."7."8ymptomatic MG has been reported to reductions in frequency of miniature endplate po- occur in previously asymptomatic patients receivtentials (MEPP), evoked transmitter release, and ing a variety of anticonvulsant medications, includpostjunctional acetylcholine s e n s i t i ~ i t y . ~T~h,e~ ~ ing phenyt~in,"~~%ephen~toin,'~ and trimetha- 91

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EFFECTS O F DRUGS O N NEUROMUSCULAR TRANSMISSION-HOWARD

V O L U M E 10, NUMBER 1 MARCH 1990

d i ~ n e . ' ' .In ~ ~some patients weakness has reversed 101, propranolol, practolol, and timolol have been following discontinuation of the drug, suggesting reported to potentiate weakness in patients with that there is a direct neuroniuscular blocking effect MG.X'-8Webers%ites several cases of transient dipof these drugs. Experimentally, phenytoiri has lopia in patients receiving a variety of P-blockers, been demonstrated to reduce quantal release of although extensive evaluation of neuromuscular ACh from the nerve terminal and simultaneously transmission was not performed. In .my experito increase spontaneous neurotransmitter release ence, two patients given timolol maleate, one pa(MEPPs). This has been explained by a reduction tient given betaxolol for treatment of glauconia, in the amplitude of the nerve action potential or and one patient given pindolol for hypertension an antagonism of calcium influx into the nerve ter- experienced abrupt worsening of their strength. minal and its intracellular sequestration. In addi- Furthermore, the onset of myasthenic symptoms tion phenytoin also exerts postsynaptic effects, coincided with the initiation of drug therapy with reducing the amplitude of MEPPs, presumably the P-blockers propranolol and riadolol in four by desensitizing the e n d ~ l a t e . ' Osserman ~ and other patients whom I observed. Genkins7%lso reported that barbiturates could ag?b date, much of the experimental work has gravate myasthenic weakness. Experimentally, it has examined the effects of various P-blockers on been shown that barbiturates and ethosuximide changes in muscle twitch tension.8i-" 'There is only produce postsynaptic neuromuscular blo~k,~~,~%and one comprehensive study that has used intracellucarbamazepine exerts most of its effects presynapt- lar electrophysiologic techniques to measure the i c a l l y . ' ~ odate, there have been no clinical reports effects of P-blockers on the presynaptic and postof adverse reactions to ethosuximide or carbama- synaptic mechanisms of neuromuscular transmiszepine. sion. Atenolol, labetolol, rnetoprolol, riadolol, proIt has been suggested that trimethadione may pranolol, arid tirnolol cause a dose-dependent induce an autoimmune disorder directed toward reduction in the efficacy of neuromuscular transthe neuromuscular junction. This is suggested by rriission in normal rat skeletal muscle^" and human the development of other autoimmune diseases myasthenic intercostal muscle biopsies (unpub(systemic lupus erythemat~sus,~~ nephrotic syn- lished personal observations). Different P-blockers d r ~ m e in ~~ patients ) receiving this drug; the dem- have reproducibly different presynaptic and postonstration of other autoantibodies against skeletal synaptic effects on neuromuscular transmission at muscle, nuclear antigens, and thymic tissue, and motor endplates. T h e reduction in MEPP amplithe prolonged recovery following discontinuation tude caused by all of these drugs suggests a postof these agents."?" synaptic site of action. Additional presynaptic efIn my experience, there has been no acute fects of these drugs are suggested by the relatively worsening of strength in those few patients who large reductions in endplate potential (EPP) amplihave required phenytoin therapy for seizures. tude compared with MEPP amplitude reduction, drug-induced alterations in MEPP frequency caused by all of the P-blockers other than timolol, CARDIOVASCULAR DRUGS and the reduction in quantal content caused by rnetoprolol and propranolol. Propranolol is the PMany cardiovascular drugs have been irnpli- blocker that most effectively impairs neuromuscucated in adversely affecting the strength of patients lar transmission. Of these drugs, atenolol has the with MG and IXMS, and they, along with the an- least effect on neuroniuscular transmission. tibiotics, account for the majority of adverse drug T h e molecular rnechanisrns of P-blockerreactions in patients with neuromuscular disor- induced neuromuscular blockade have yet to be ders. Certain of them, including quinine, have elucidated. One possibility is that these drugs spebeen used as a diagnostic test for MG in the cifically block P-adrenergic receptors whose actipast.79,80 vation is important for neuromuscular transmission. Another source of natural adrenergic BETA-BLOCKERS agonists may be the motor nerve terminals themBeta-adrenergic blocking agents, despite their selves. I t has been shown that enzymes responsible clinical usefulness, may cause serious side effects for the synthesis of catecholamines are present in and, in particular, some are implicated in causing human and rat nerve terminal^.^' Beta-receptor symptomatic worsening of strength in patients stimulation has been implicated in having irnporwith MG. Even those drugs instilled topically on tant functional roles in neuromuscular transniisthe cornea are capable of producing such weakness ~ i o n . ~Epinephrine ' has been shown to modulate (see ophthalmic drugs). T h e P-blockers oxpreno- the Na' K + pump, and this effect can be blocked

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SEMINAKS I N NEUKOLOGY

by propranolol." It has been suggested that pump a patient with LEMS and small cell carcinoma of activity controls endplate depolarization by ACh the lung, Krendel and HopkinsH1 reported the agonists through its electrogenic effectsqqand ACh temporal association of acute respiratory failure receptor sensitivity through regulating the phos- with the administration of oral doses of verapamil. phorylation state of the receptor.'"" In addition, P- I have observed one patient with moderately sereceptors appear to be involved in the modulation vere, generalized myasthenia (class IV)"' who deof transmitter release from mammalian motor veloped acute respiratory failure following veranerve terminals; norepinephrine and isoproter- pamil initiation. Low doses of verapamil or its en01 enhance neurally evoked transmitter output, timed-release preparation have been used successand this is blocked by propranolol and atenol01.'~~ fully for the treatment of hypertension in patients Other alternative mechanisms of action for these with MG receiving cyclosporine (Howard JF; Undrugs other than specific blocking of p-adrenergic published observations; Phillips JT: Personal comreceptors could include competitive curare-like ac- munication). tions, channel blockade, reduction of single-channel conductance, and general anesthetic effects.Io2 That P-blockers had qualitatively different effects Procainamide (Pronestyl) is reported to proon MEPP frequency which were also concentration duce acute worsening of strength in patients with dependent and that not all drugs had the same MG.'13~''4 The rapid onset of neuromuscular block qualitative effects on MEPP and EPP time courses and the rapid resolution of symptoms following suggest that at least some of'their effects are not discontinuation of the drug suggest a direct toxic related to 6-receptor blockade. Of course, specific effect on synaptic transmission rather than the in6-blocker and more general effects of these drugs duction of an autoimmune response against the could both contribute to the quantitative and qual- neuromuscular junction. The postulated mechaitative, concentration-dependent effects that have nism of action is primarily at the presynaptic membeen described. brane with impaired formation of ACh or its reBRETYLIUM

Bretylium is a quaternary amrnoniurn compound used previously for refractory ventricular arrhythmias. In high concentrations it is reported to cause weakness and to potentiate the neuromuscular blockade of competitive neuromuscular blocking agents.g7.109 CALCIUM CHANNEL BLOCKERS

The effects of calcium channel blockers on myocardial muscle have been extensively characterized, but their effects on skeletal muscle are less well understood. Studies to date have resulted in conflicting information. Some have demonstrated neuromuscular blockade with postsynaptic curarelike e f f e ~ t s , l ~presynaptic ~ - ~ ~ ~ inhibition of ACh release,Io5 and both presynaptic and postsynaptic effects."'"he oral administration of calciunl channel blockers to cardiac patients without neuromuscular disease did not produce any evidence of altered neuromuscular transmission by SFEMG.Iog There is one reported case of a patient with Duchenne muscular dystrophy who had an acute exacerbation of weakness with respiratory failure following the intravenous administration of verapamil."' Precise details are not known, but it was postulated that the patient had end-stage muscle disease, and even minimal alteration of synaptic efficacy was enough to decompensate the patient. In

lease, although it is known to have postsynaptic blocking effects as well. QUININE AND QUINIDINE

W e i ~ m a n "was ~ first to report that quinidine, the stereoisomer of quinine, can aggravate weakness in MG. There are several reports of the unmasking of previously unrecognized cases of MG following treatment with q ~ i n i d i n e . ~ ' ~ . " ~T. 'h' 'e neuromuscular block is presynaptic, impairing either the formation or release of acetylcholine, or, in large doses, also postsynaptic, with a curare-like a c t i ~ n . "The ~ literature suggests that the ingestion of small amounts of quinine, in a gin and tonic, will acutely worsen a myasthenic, although this cannot be substantiated with objective report^."^-'^^ Quinidine is also capable of potentiating the weakness of nondepolarizing and depolarizing neuromuscular blocking agents.'"."" TRZMETHAPHAN

There are isolated case reports that trimethaphan, a ganglionic blocking agent used in hypertensive emergencies, dissecting aortic aneurysms, and cerebral aneurysm surgery, and for decreasing cardiac afierload in patients with myocardial infarction, can produce neuromuscular weakness. It has been reported to cause acute respiratory paralysis, probably due to curare-like action at the neuromuscular j ~ n c t i 0 n . In l ~ addition, ~ it has'been

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F.I'FE:CTS OF DRUGS ON NEUKOMUSCULAR TRANSMISSION-HOWARD

SEMINARS I N NEUKOLOGY

MARCH 1996

HORMONES ESTROGEN AND PROGESTERONE

Estrogen therapy has been reported to worsen the strength of a patient with MG acutely,I4' alCORTICOSTEROIDS though the details of this case are subject to question. Parenteral progesterone has been reported to Exacerbations of MG can occur after begin- aggravate the weakness of myasthenic women after ning any form of steroid t h e r a p y . 1 1 2 ~ 1 2 8 ~ 1de2~om a edelay of 3 to 5 days.'"' There is an isolated case gree of worsening occurs in about one-half of pa- report of MG occurring in a woman taking birth tients, l to 21 days after beginning a high-dose control pills,'42but there are no data to suggest that daily prednisone protocol, and lasts an average of their use increases the incidence of MG or worsens 6 days.'0.'1.112 In 75% of cases this worsening can the strength of patients with MG. The mechanism be managed by changing doses of cholinesterase of acute worsening in these patients has yet to be inhibitors. In patients with severe oropharyngeal elucidated. weakness, plasma exchange may be used to prevent o r reduce the severity of steroid-induced exTHYROID HORMONE acerbations. Once improvement begins, further The relationship of the thyroid gland to MG is exacerbations are not usually seen unless the dose well r e ~ 0 g n i z e d . The l ~ ~ older literature states that of prednisone is reduced below minimal required thyroid hormone and antithyroid medications can levels. Exacerbations do tend to be less frequent aggravate the weakness of patients with myaswhen lower doses of steroids are used,lgOalthough thenia,144-14"erhaps through a reduction in the rethe beneficial effects of therapy are also reduced. lease of ACh, although with newer modes of therSome recommend that treatment with prednisone apy this has not been thought to be a problem of begin with low doses on alternate days to minimize late. exacerbations, and that the dose be increased until improvement occurs.'" Severe exacerbation may also occur with this approach, although the time of onset of the worsening is less predi~tab1e.I~~ The NEUROMUSCULAR BLOCKING DRUGS onset of improvement is also less certain and the ultimate response may be less.132Equivalent doses It is common to categorize the muscle relaxof different steroid preparations produce roughly ants into depolarizing agents or nondepolarizing similar responses when given in short intensive agents, depending on their effects on the muscle courses, except that the frequency and severity of membrane potential. T h e actions of these neuroexacerbations appear to be greater with adrenal muscular blocking agents are modified by a number corticotrophic hormone.13* of factors and include the degree of neuromuscular Direct effects of corticosteroid on synaptic blockade, associated disease states, acid-base state, transmission have been demonstrated by some in- and electrolyte imbalance.14' Competitive, nondevestigators in experimental nerve-muscle prepara- polarizing neuromuscular blocking agents can be tion~.'~ These ~ - ~findings ~~ include depolarization many times more sensitive in their effects in myasof nerve terminals, reduction in neurotransmitter thenic and presumably in Lambert-Eaton syndrome release, alterations in MEPPs, changes in choline patients than in those patients without these distransport, antagonism of neuromuscular blocking eases. Small amounts of these drugs may produce agents, and intracellular potassium depletion. a greater degree and a more prolonged period of However, none of these has been seen in clinical neuromuscular blockade. Depolarizing agents such as succinylcholine also must be used with causituations. Abramsky et all3' noted enhanced lymphocyte tion; the inhibition of hydrolysis by cholinesterase transformation in vitro in patients with predni- inhibitors will prolong their duration of action." sone-induced worsening of their weakness: It has In addition, patients with MG are less sensitive to been postulated that immunologically nonreactive this drug, lulling one into a sense of false security lymphocytes are destroyed by corticosteroids, with and thus ending up with prolonged blockade beresulting enhanced proliferation of sensitized lym- cause of the larger amount of the drug used. I and others who see large numbers of myasthenic paphocyte~.'~'-~~~ Because of the possibility of steroid-induced tients have observed the occasional unmasking of exacerbation of myasthenic weakness, patients should MG in patients given these drugs.13 In addition to be hospitalized under close observation to begin the effects of' disease, the pharmacologic effects of these neuromuscular blocking agents are potenprednisone therapy for their disease.

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reported to potentiate the neuromuscular block in patients receiving both n ~ n d e p o l a r i z i n g ' ~ and "'~~ depolarizing neuromuscular blocking agents."'

VOLUME 10, NUMBER I

EFFECTS OF DRUGS ON NEUROMUSCULAR TRANSMISSION-HOWARD

OPHTHALMIC DRUGS The P-adrenergic blocking eye drops, timolol maleateR"-R~Timoptic) have been reported to be associated with the temporal exacerbation of MG. I have seen the same association with betaxolol hydrochloride (Betopic). Their mechanism of neuromuscular blockade is as described before (see cardiovascular section). Echothiophate, a long-acting cholinesterase inhibitor used in the treatment of open angle glaucoma, is reported to have produced muscle weakness and fatigue, which resolved following the discontinuation of the drug.150 Although the mechanism of weakness was not determined, it is possible that the use of a long-acting cholinesterase inhibitor could produce additive effects, cholinergic weakness, in patients with MG receiving cholinesterase inhibitors or potentiate the weakness induced by depolarizing neuromuscular blocking agents.15'

LITHIUM

Chronic lithium carbonate administration has been reported to produce varying degrees of muscle weakness, although in the majority of instances the mechanisms for such occurrences are not known. T h e experimental literature is conflicting: some investigators have postulated a progressive accumulation of lithium inside the presynaptic nerve terminal, where it functions as a competitive cation for calcium, resulting in an inhibition of ACh synthesis and a reduction in quantal reOthers have demonstrated a reduction in the number of ACh receptors in denervated muscle preparations and suggested that lithium selectively increases the rate of degradation of receptors without altering the rate of their synthesis.15s There are several reports of prolonged neuromuscular blockade in patients receiving chronic lithium therapy and neuromuscular blocking a g e n t ~ . l ~ ~ - l ~ l Neil et a1"j2 give the best account of the development of fatigable weakness responsive to cholinesterase inhibitors and electrophysiologic abnormalities consistent with the diagnosis of MG. GranacheP3 reports the development of ptosis and weakness within 48 hours of receiving the lithium, although that patient did not respond to cholinesterase inhibitors and decremental responses were not seen with repetitive nerve stim~1ation.l~~ OTHERS

Argov and Mastaglia1 have also implicated amitriptyline, amphetamines, droperidol, haloperidol, imipramine, paraldehyde, and trichloroethan01 as being capable of interfering with synaptic transmission under experimental conditions.

PSYCHOTROPIC DRUGS RHEUMATOLOGIC DRUGS PHENOTHZAZZNES

Chlorprornazine was first reported to produce an acute exacerbation of muscle weakness in a myasthenic, schizophrenic patient,152confirming studies of nerve-muscle preparations which had shown that chlorpromazine produces a postsynaptic block with a reduction in MEPP and EPP amplitudes but without alteration in quantal content or MEPP frequency. (Others have suggested that there are presynaptic effects as well.)'"Vhenothiazines (chlorpromazine and promazine) can antagonize applied ACh and may prolong the effects of succinylcholine. Anecdotal reports exist of prolonged neuromuscular blockade in patients given depolarizing neuromuscular blocking drugs while receiving promazinel" and ~ h e n e 1 z i n e . l ~ ~

CHLOROQUZNE

Chloroquine is used primarily as an antimalarial but in higher doses is also used in the treatment of several collagen vascular disorders, including rheumatoid arthritis (RA) discoid lupus erythematosus, and porphyria cutanea. It may produce a number of neurologic side effects, among which are myopathies and disorders of neuromuscular transmission. T h e reported mechanisms of action for the latter have been both presynaptic, with a reduction in EPP amplitude resulting from a decrease in the amplitude of nerve action potentials and ACh releaseIG4;and postsynaptic, with competitive postjunctional blockade.'" In addition, it is reported that chloroquine directly suppresses the

95

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tiated by a number of different drugs, including antibiotics, general anesthetics, local anesthetics, and antiarrhythmics (see before). Although the newer neuromuscular blocking agents are of much shorter duration, the same concerns and guidelines apply when they are used in patients with MG or LEMS. Prolonged apnea and muscle weakness in patients given depolarizing neuromuscular blocking agents may also occur in situations in which plasma cholinesterase levels are reduced, either by plasma exchange14' or by genetic abn0rma1ities.l~~

excitability of muscle membrane. There is some evidence to suggest that chloroquine may alter immune regulation and produce a clinical syndrome of MG similar to that reported with DP. Two patients have been reported, one with rheumatoid arthritis and the other with systemic lupus erythematosus, who following prolonged treatment with chloroquine developed the typical clinical, physiologic, and pharmacologic picture of MG. Antibodies to the AChR were present and subsequently slowly disappeared, as did the clinical and electrophysiologic abnormalities, with discontinuation of the d r ~ g . ' ~Robberecht ~ , ~ ~ ' and colleagues1" report the transient development of a postjunctional disorder of neuromuscular transmission following 1 week of chloroquine therapy. In this case, AChR antibodies were not demonstrated and the rapid resolution of symptoms suggested that this syndrome was related to a direct toxic effect at the neuromuscular junction rather than a derangement of immune function as previously mentioned. That this drug could have both effects on neuromuscular transmission is not unheard of: the hydantoin drugs exert their effects similarly. D-PENZCZLLAMZNE

DP is used in the treatment of RA, Wilson's disease, and cystinuria. A number of autoimmune diseases occur in patients receiving DP, including polyimmune complex nephritis,l'jg pemphigu~,'~" myositis,171-173 systemic lupus erythematosus,l'%and,

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most frequently, MG."5-177 T h e myasthenia induced by DP is usually mild and may be restricted to the ocular muscles. In many patients the symptoms are not recognized and it may be difficult to demonstrate mild weakness of the limbs in the presence of severe arthritis. The diagnosis can be confirmed by the response to cholinesterase inhibitors, electromyographic abnormalities, and elevated serum AChR a n t i b o d i e ~ . ' ~ In ~ - 'our ~ ~ experience, repetitive stimulation studies are abnormal less often than is SFEMG, reflecting the relatively mild neuromuscular abnormality present in most of these patients. Intercostal muscle biopsy studies have shown reduced MEPP amplitude, as seen in acquired MG.180 In normal rats, DP given in doses equivalent to the human therapeutic dose produces no neuromuscular abnormality.'" In guinea pigs, longterm administration of doses more than ten times the therapeutic level produced a mild degree of neuromuscular block.18' These studies provide no evidence that DP produces a direct, clinically significant effect on neuromuscular transmission. Since MG begins after prolonged DP therapy in most patients, has relatively low incidence in pa-

VOLUME 10, NUMBER 1 MARCH 1990

tients receiving DP for Wilson's disease compared with those receiving it for RA,17',"8 and has been reported to produce a variety of other autoinimune disorders, it is unlikely that DP has a direct effect on neuromuscular transmissiori. It is more likely that DP induces MG by stimulating or enhancing an immunologic reaction against the neuromuscular junction. '~~ Similarly, tiopronin'" and p y r i t h i o ~ i n have been reported to induce MG after prolonged administration of the drug. In each, antibodies to the AChR were demonstrated and the time course of resolution was prolonged. This suggests that the effects of these drugs are due not to direct toxicity to the neuromuscular junction but rather to an alteration of immune function, as is the case with DP. It is not rare to see MG and RA in the same patient. When myasthenia begins while the patient is receiving UP, it remits in 70% of patients within a year after the drug is di~continued."~As the myasthenia improves, the AChR antibody titer falls~79,~so,lsj and the electromyographic abnormalities improveIx5or disappear altogether (Sanders DB, Howard JF: Unpublished observations). I have seen a few patients in whom MG persists after DP is discontinued, implying that a subclinical myasthenic state existed prior to the initiation of the DP.

MISCELLANEOUS DRUGS D,L-carnitine, but not 1,-carnitine, has been reported to worsen acutely the strength of patients with MG undergoing dialy~is.'~"he precise mechanism of neuromuscular blockade is not known but postulated to be a presynaptic block similar to that produced by hemicholiniunl or a postsynaptic block by the accun~ulationof acylcarnitine esters.''' It has been suggested that diuretics aggravate the weakness of patients with MG, probably by wasting potassium.188Myasthenic patients are uniquely sensitive to hypokalemia or even to low-normal serum levels of potassium. Emetine, originally used as an amebicide and the principal ingredient of ipecac syrup, has been reported to produce acute neuromuscular weakness in nonmyasthenic patients receiving the drug as an amebicide.lWOne of the postulated mechanisms of action in experimental preparations is to inhibit indirectly elicited action potentials, an effect that is not reversed by cholinesterase inhibitors.19' Hutchinsonlgl has reported acute crisis in patients with MG given enemas preparatorv to radiographic proced~res.'~' This has not been confirmed by others,'" but it could be postulated that the abrupt

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EFFECTS O F DRUGS O N NEUKOMUSCULAR TRANSMISSION-HOWARD

retrospective study of their patients, although they recommended caution.Ig5The mechanism of these adverse reactions in patients with MG is not known. There is one report of a single patient with LEMS who developed transient, severe respiratory insufficiency following the intravenous infusion of iodinated contrast material.'g'Vhe postulated mechanism of action is acute hypocalcemia due to direct binding by the contrast agent and resulting in further presynaptic blockade with a reduction in ACh release. The intravenous infusion of sodium lactate is reported to worsen the strength, including respiratory function, in patients with MG."' The mechanism of this is unknown but postulated to be related to transient hypocalcemia resulting in impaired neurotransmitter release from the nerve terminal. The adverse effects of magnesium on neuromuscular transmission will not be discussed here. The reader is directed to the article by Krendel in this issue of Seminars. There is a single case report of' myasthenic weakness occurring following administration of tetanus antitoxin. Aprotinin (Trasylol),a proteolytic enzyme inhibitor no longer available, is reported to potentiate the action of succinylcholine and t ~ b o c u r a r i n e . ~ ~ ~ Trihexyphenidyl (Artane) is reported to have unmasked the illness and worsened the strength of a single patient with MG. In this case report it was stated that the concentration of AChK antibody paralleled the degree of weakness when the patient was challenged with this drug.lg" Numerous drugs have been demonstrated to produce or worsen a neuromuscular block in experimental situations. To date, there are no known reports of' clinical adverse reactions with these drugs in patients with neuromuscular disorders or the precipitation of muscle weakness in otherwise normal patients. Amantadine appears to reduce the postjunctional sensitivity to iontophoretically applied ACh by interacting with the ionic channel of the AChR.'OO Ironically, azathioprine, often used as treatment for MG, has been shown to potentiate the neuromuscular block of succinylcholine in cat nerve-muscle preparations but to antagonize the neuromuscular block of curare.'" Like theophyl-

line, it has been found to inhibit the action of phosphodiesterase, the enzyme that hydrolyzes cyclic adenosine monophosphate (CAMP).T h e increased concentration of CAMP produces increased neurotransmitter release. I t has been postulated that such an effect occurs because of the inhibition of phosphodiesterase in the motor nerve terminal. In my experience there have been no untoward neuromuscular blocking effects on myasthenic patients receiving this drug as part of treatment. Diphenhydramine has been shown to potentiate the neuromuscular block of barbiturates and neuromuscular blocking agents and to reduce the amount of neurotransmitter released from the neuromuscular jun~tion.'~' Downloaded by: University of Pennsylvania Libraries. Copyrighted material.

removal of cholinesterase inhibitors from the gastrointestinal tract could precipitate acute myasthenic worsening in the brittle patient or a large magnesium load could reduce ACh release from the nerve terminal. The intravenous infusion of iodinated contrast agents has been reported to worsen acutely the strength of patients with MG or precipitate a myasthenic crisis (Arsura E: Personal communication).1'43.194 Others have not found such problems in a

CONCLUSIONS With the possible exception of DP, there are no drugs that are absolutely contraindicated in patients with MG, and probably the same is true for patients with LEMS. There are, however, numerous drugs that can and will interfere with neuromuscular transmission and will make the weakness of these patients worse or prolong the duration of neuromuscular block in patients receiving muscle relaxants. Drug-induced disturbances of synaptic transmission resemble MG, with varying degrees of ptosis and ocular, facial, bulbar, respiratory, and generalized muscle weakness. Treatment includes discontinuation of the inciting drug and, when necessary, reversing the neuromuscular block with intravenous infusions of calcium, potassium, or cholinesterase inhibitors. Although it is most desirable to avoid drugs that may adversely affect neuromuscular transmission, in certain instances they must be used for the management of other illness. In such situations a thorough knowledge by the physician of the deleterious side effects can minimize their potential danger. If at all possible, it is wise to use a drug from a class of drugs that has been shown (at least experimentally) to have the least effect on neuromuscular transmission. Unfortunately, such studies are few.

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