Peer Reviewed

Title: Physostigmine as an Antidote

Journal Issue: Western Journal of Emergency Medicine, 2(4)

Author: Stilson, Matthew, University of California, Irvine Medical School Kelly, Kevin MD, University of California, Irvine Medical Center Suchard, Jeffrey MD, University of California, Irvine Medical Center

Publication Date: 2001

Publication Info: Western Journal of Emergency Medicine, Department of Emergency Medicine (UCI), UC Irvine

Permalink: http://escholarship.org/uc/item/3c0240c3

Keywords: Physostigmine

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eScholarship provides open access, scholarly publishing services to the University of California and delivers a dynamic research platform to scholars worldwide. The California Journal of Emergency Medicine II:4, October 2001 page 47

Toxicology Review uncharged. lipophilic, and easily crosses the blood-brain barrier.- This Physostigmine as an Antidote action allows physostigmine to reverse toxic CNS effects, whereas other carba~natedmgs that are charged quaternary a~nines(such as neostigmine and pyridostigmine) will only reverse peripheral signs Matthew Stilson and symptoms. Physostigmine's ability to reverse central effects led University of California; Irvine Medical School, Irvine, CA to its trade name of AntiliriurnB, since it can reverse the delirium Kevin Kelly. MD associated with anticholinergic toxicity. Jeffrey Suchard, MD University of California, Irvine Medical Center, Orange, CA Indications: Physostigmine treatment may be indicated for patients with moderate to severe anticholinergic poisoning with evidence of both Introduction: peripheral and central toxicity.Vhysostigmine is not generally con- Rapid treatment of patients with anticholinergic toxicity sidered a first-line agent, and should probably be reserved for paticnrs in the Ernergcncy Department (ED) has remained problematic for with potentially life-threatening complications of anticholinergic tox- many years. These patients are often agitated. uncooperative, and icity that are unresponsive to standard treatment regimens. Such unable to provide a clear history. Physostigmine is a specific anti- complications include severe agitation, seinires. persistent hyperten- dote for anticholinergic toxicity. yet its popularity has waned due to sion, and heinodyna~niccompromise secondary to tachycardia (i.e. controversy surrounding its potential central nervo~issystem and unstable narrow complex dysl-rhythmias). cardiac toxicities. In this brief review, we discuss physostigmine's In addition to a therapeutic role in clear-cut cases of anticho- history, method of action. indications, contraindications, dosing, linergic poisoning, physostigmine also has a potential diagnostic role. and its use in the ED. In patients with altered levels of consciousness, who bv relevant his- tory and examination may be suffe~ingfrom anticholinergic poisoning, Background: a test dose of physostigmine may help to confinn the diagnosis. If the Physostigmine is a naturally-occurring compound first patient's mental status significantly improves, more invasive and time- isolated from the extract of the West African Calabar bean (PIzysos- consuming diagnostic tests. such as lumbar puncture and cranial com- tipnza verzoszcn~)in 1864. In the same year, a crude Calabar bean puted tornogaphy, may be avoided;'.' this is particularly true if thc extract was first used as an antidote for anticholinergic toxicity among paticnt is then able to identify the substance ingested. One caution three prisoners ingesting belladonna.' Sincc that time. physostig- must bc noted: physostigrnine is an "analeptic" agent and may cause mine has been used to trcat glaucoma, post-operative ileus. and non-specific arousal whcn used in the presence of many drugs causing atropine-induced coma.' Physostigminc's popularity as an antidote depressed mental status. Therefore, minor improvelnents in a patient's grew in the late 1960s and 1970s. particularly for the treatment of level of consciousness do not prove that they wcre poisoned with an altered mental status associated with tricyclic antidepressant poi- anticholinergic agent. soning." A 1980 report of asystole complicating physostigmine use in two patients with serious tricyclic antidepressant poisoning4 Dosing and Precautions: heralded a retreat fi-om indiscriminate use of the antidote. More The initial dose of physostigmine is 1-2 mg in adults and recently. opinion has shifted again towards favoring the cautious use 0.02 mglkg in children administered slowly IV over at least 5 minutes. of physostiglnine as an antidote in selected cases of anticholinergic Many physicians are even Inore cautious, and utilize 0.5 mg aliquots. toxicity.' titrated slowly to desired effect. Rapid administration is associated with induction of seizures.' Bccause of its short half-life and rapid Clinical Pharmacology: elimination, the clinical effects of physostigmine are short in duration. Acetylcholine is a neurotransmitter that acts at muscar- Repeat dosing every 20-60 minutes may be needed to correct the inic and nicotinic receptors of the cholinergic nervous system. Un- recul-rence of life-threatening conditions initially treated with the first der notmal conditions, the action of acetylcholine is quickly tcrmi- dose."' Continuous physostigmine infiisions have been reported but nated by the enzyme acetylcholinesterase (Ach) found in the syn- are not rccommended. Although effective in reversing anticholinergic aptic cleft. Drugs and other compounds that are typically classified toxicity, treatment with physostignlinc can lead to adverse side-ef- as "anticholinergic" are actually antimuscarinic, since they block the fects and complications. Excessive doses of physostigmine may in- effect of acetylcholine at rnuscarinic receptors within the central duce cholinergic toxicity. Prior to administering physostigmine, rcac- nervous system, in peripheral ganglia, and on effector organs of the tion to potential complications should be anticipated. Urinary outlet autonomic nervous system. namely the exocrine glands (bronchial, obstl-~lctioncan be prevented by the placement of a Foley catheter and sweat. lacrimal); and cardiac and smooth muscles. Such anticholin- bedside s~lctionshould be immediately available if needed to clear crgic agents include many antihistamines, antiparkinsonian dnlgs, excess salivation, bronchial secretions. or emesis. The patient should antipsychotics, antispasmodics. tricyclic antidepressants, belladonna also be placed on continuous electrocardiographic and pulse oximetry alkaloids and co~npoundsfound in several other poisonous plants monitoring. Close physician supervision during and immediately fol- and fi~ngi.~ lowing physostigrnine administration is desirable. Atropine should Physostigmine is a carbamate that reversibly inhibits ace- also be rapidly available to counteract excessive cholinergic tone, and tylcholinesterase. Physostiglnine acts as a competitive substrate is administered IV at a dose equal to half the initial dose of physostig- for Ach, allowing acetylcholine to accumulate in the synaptic clefts mine if such complications occi~r.~Serious but relatively infrequent and overcome the blockade of muscarinic receptors by the anticho- linergic agents. Because physostigmine is a tertiary amine. it is complications, such as seizures, symptonlatic bradycardia, and bron- The California Journal of Emergency Medicine II:4, October 2001 page 48 chospasm, hake been assoc~atedw~th physostlgnnne treatment ' ' firm the diagnosis and obviate the need for additional invasive or expcnsive testing. Further review and prospective analysis concern- Contraindications: ing its use in the setting of TCA overdose or QRS interval prolonga- The contraindications to physostigrninc use form one of tion is needed to provide clear-cut contraindications. When used with the most controversial issues regal-ding the dn~g.Several conditions proper precautions. however, physostig~ninecan be a valuable tool in listed as contraindications are predictable, as enhancing cholinergic the ED armamentarium. tone may exacerbate them, including asthma. chronic obstnlctive pulmonary disease. atherosclerotic heart disease. bradycardia, pe- References: ripheral vascular disease, genitourinary and gastrointestinal obstruc- tion,'.~~~Many sources list tricyclic antidepressant (TCA) over- Aquilonius SM, Hedstrand U. The Use of Physostig~nineas an dose and prolongation of the QRS complex on the ECG 2 0.10 scc Antidote in Tricyclic Anti-depressant Intoxication. Acrn Arznest as absolute contraindications to physostigmine." Use in these Scarld 1978;22:40-5.

circumstances has been associated with severe bradyarrhythrnias Walker WE, Levy RC, Hanenson IB. Physostigmine - Its Use and asystole.' and Abuse. JACEP 1976;5:436-9. The contraindication against physostigmine use in TCA Burks JS, Walker JE, Rumack BH, Ott JE. Tricyclic Antidepres- overdose patients has reached the status of treatment dogma de- sant Poisoning: Reversal of Coma, Choreoathetosis, and Myo- spite the fact that it is based on only a few case reports. We could clonus by Physostigmine. JAIMA 1974;230:1405-7. find only 4 reported cases of asystole associated with physostig- Pentel P. Peterson CD. Asystole Complicating Physostigmine mine use if the setting of TCA overd~se.'~-~"In contrast, numerous Treatment of Tricyclic Antidepressant Overdose. Arzn Emerg case reports and series have documented successful treatment of hfed 1980;9:588-90. TCA overdose with physostigmine without scrious cardiac side Bums MJ. Linden CH, Graudins A, et al. A Comparison of effects or coniplications, only a few examples of which are refer- Physostigmine and Benzodiazepincs for the Treatment of Anti- enced here, I .'.'.(,.- Indeed, physostigrnine had been considered the cholinergic Poisoning. An11 EiilergMed 2000:35:374-8 1. treatment of choice for neurologic arid cni.diac complications of Manoguera AS, Ruiz E. Physostigmine Treatment of Anticho- TCA overdose in the early 1970s.' This disparity niost likely linergic Poisoning. J4CEP 19765:125-7. stems from several causes: I) reporting bias, where positive out- Rulnack BH. Anticholinergic Poisoning: Treatment with Phys- comes are more likely to be submitted for publication. 2) the ostigmine. Pediat1.i~~1973;52:449-5 1. cardiotoxicity of TCAs was not as well understood in decades past, Beaver KM. Gavin TJ. Treatment of Acute Anticholinergic Poi- and the reversal of altered mental status appeared to be the primary soning With Physostigmine. Ail1 .JEtllerg:bfed 1998;16:505-7. therapeutic goal: 3) TCA overdose can present with a spectnun of Shannon M. Toxicology reviews: Physostigmine. Ped Enze~ disease, where mildly toxic TCA overdose patients may benefit Care 1998; 14224-6. from reversal of CNS anticholinergic effects. while seriously poi- Tong TG. Benowitz NL. Becker CE, Forni PJ. Tricyclic Antide- sonedpatients are more prone to severe bradyarrhythmias and asys- pressant Overdose. DICP 1976:10:711-3. tole. The associated clcctrocardiograpliic contraindications to phy- Boehnert MT, Lovejoy FH. Value of the QRS Duration Versus sostigmine rely on using the QRS complex as a surrogate marker for the Senun Dnlg Level in Predicting Sein~rcsand Ventricular TCA toxicity." where a prolonged QRS is presumed to represent a Arrhythmias After an Acute Ovcrdose of Tricyclic Antidepres- patient at risk for complications with physostigminc. Bums et nl. sants. l\'Eizgl J,!4ed 1985;313:474-9. recently reported 5 patients (from a larger case series) with known amitriptyline overdose who suffered no serious complications from physostigrnine given to reverse anticholinergic effects. But even so, all these patients had ECGs documenting a QRS interval less than 0.10 seconds and were given physostigmine at least 12 hours after the initial inge~tion.~Thus, it appears that TCA overdose alone is not an absolute contraindication to physostigmine use. It may still be prudent, however, to withhold physostigniinc when there is any evidence of QRS interval prolongation.

Summary - Using Physostigmine in the ED: Since physostigmine is relatively short-acting, and be- cause luany aspects of anticholinergic toxicity can bc nianaged by standard treatment regimens (e.g. benzodiazepines for agitation or seizures). the ideal role of physostigmine in the ED has not been clearly determined. Physostigmine's prirna~yrole is probably as a back-up agent in cases where standard treatment fails for neurologic and cardiac con~plicationsof anticholinergic toxicity. Furthennore. physostigmine appears to have some benefit over bcnzodiazepines in the ~nanagcmentof anticholinergic-induced agitation.' In some cases with features suggestive of anticholinergic toxicity but where the differential diagnosis remains broad, physostigmine may con-