Ant icho l inerg ic Tox ic i tyAnticholinergic drugs were involved in 5,650 exposuresreported to the American Association of Poison ControlCenters (AAPCC) Toxic Exposure Surveillance System (TESS)in 2001.1 Life-threatening symptoms were present in 186cases and eight resulted in a fatal outcome. However, thisonly includes pure anticholinergic drugs (hyoscyamine,dicyclomine, scopolamine, atropine, etc). Numerousprescription and over-the-counter medications haveanticholinergic properties which are not their primarypharmacologic activity. Anticholinergic toxicity can occurwith these medications as well as the pure anticholinergicdrugs. Table 1 is a list of medications and plants that haveanticholinergic properties.Anticholinergic agents competitively inhibit acetylcholine byblocking the action of acetylcholine at muscarinic andcentral cholinergic receptors. Central cholinergic pathwaysare important for memory, wake-sleep cycle, alertness,orientation and fine motor movements. Nicotinic receptorsat the skeletal muscle and ganglion are unaffected byanticholinergic agents. Both central and peripheral anticholinergic effects may beseen following an overdose. The following mnemonic hasbeen used to describe adverse and toxic effects associatedwith anticholinergic agents: “Mad as a hatter, red as a beet,dry as a bone, blind as a bat, and hot as a hare.” Acomprehensive list of anticholinergic adverse and toxiceffects can be found in Table 2. The most commonperipheral anticholinergic effects are mydriasis, dry mucousmembranes, flushed skin, tachycardia, urinary retention andhypoactive bowel sounds. Common central effects includeconfusion, disorientation, ataxia and hallucinations.Supportive care is the primary treatment for anticholinergictoxicity. Activated charcoal may be useful to preventabsorption if the ingestion was recent. Becauseanticholinergic drugs can decrease GI motility, activatedcharcoal may be of benefit more than one-hour postingestion. Activated charcoal should not be used in patientswith an ileus. Benzodiazepines can be used to treat deliriumand agitation. Physostigmine can also be used to reverseanticholinergic toxicity.

Administrative (801) 581-7504 • http://uuhsc.utah.edu/poison Emergency (800) 222-1222

tox pdateA P U B L I C A T I O N O F T H E U T A H P O I S O N C O N T R O L C E N T E R F O R H E A L T H P R O F E S S I O N A L SUPCC

2003VOLUME 5

ISSUE 3

Physost igmine for Ant ichol inerg ic Tox ic i tyPhysostigmine (Antilirium®) Physostigmine, also known as eserine, is an alkaloid obtainedfrom the dried ripe seed of Physostigma venenosum, aperennial plant found in West Africa. It was first usedtherapeutically in 1877 to treat glaucoma. In addition tobeing used as a treatment for anticholinergic poisoning, ithas also been used as a non-specific treatment for coma andfor tricyclic antidepressant poisoning.

Pharmacology Physostigmine is a short-acting, reversible cholinesteraseinhibitor that binds to acetylcholinesterase and prevents itfrom hydrolyzing acetylcholine. It increases concentrationsof acetylcholine at both muscarinic and nicotinic receptorsites. Unlike other drugs that inhibit acetylcholinesterase,physostigmine has a tertiary ammonium structure thatallows it to pass the blood-brain barrier and exert its effectscentrally as well as peripherally. Physostigmine does notshorten the duration of action of anticholinergic agents, buttemporarily reverses the effects.

Pharmacokinetics Physostigmine is readily absorbed following intramuscularor subcutaneous injection and following ophthalmologicadministration. Its onset of action following parenteraladministration is usually within 3-8 minutes and the durationof action is 0.5-5 hours. The half-life of physostigmine is 15-40 minutes. Physostigmine is metabolized in the liver byplasma esterases. Only a small amount is excretedunchanged.

Dosing and administrationThe dose of physostigmine to treat anticholinergic toxicity is0.5 to 2 mg in an adult and 0.01-0.03 mg/kg in children. It canbe administered intramuscularly, subcutaneously orintravenously. The usual route of administration isintravenously at a rate not to exceed 1 mg/minute. The dosecan be repeated, as needed every 20 to 30 minutes. It isrecommended to start with the lowest dose possible forolder adults. Repeat administration of physostigmine maybe necessary due to its short duration of action. Signs ofrelapse may occur as soon as 30 minutes or as long as threehours following physostigmine administration. Patientsshould be monitored closely for 4 hours after the last dose ofphysostigmine. A flow chart may be helpful to monitor thedose of physostigmine administered and any changes inpulse, temperature, bowel motility and urine output. Physostigmine should be used cautiously in patients withasthma, peptic ulcer disease, colitis, chronic obstructivepulmonary disease, gangrene, cardiovascular disease, and

compare the safety and efficacy of physostigmine andbenzodiazepines for the treatment of anticholinergicagitation or delirium.4 Medical records for 52 patients treatedwith physostigmine, benzodiazepines or both foranticholinergic toxicity were reviewed for the specifics ofdrug therapy and side effects of treatment. Physostigminewas used in 86%, benzodiazepines in 50% and 4% receivedadditional sedating agents such as haloperidol to controlagitation. Physostigmine controlled agitation in 96% andreversed delirium in 87%. Relapse occurred in 78% ofpatients who initially responded with a mean relapse time of100 minutes. Multiple doses were given in 58% of patients.The mean number of doses of physostigmine was 2.5. Themean total dose of physostigmine given was 3.9 mg with arange of 0.5 to 13.5 mg. Benzodiazepines controlled agitationin 24% and did not reverse delirium in any patient. Initialtreatment with physostigmine had a significantly lowerincidence of complications and shorter time to recovery thanthose treated initially with benzodiazepines (Table 3).

SummaryPhysostigmine is a short-acting drug that requires closepatient monitoring and frequent dosing. It is an effectiveagent to reverse severe anticholinergic toxicity.Benzodiazepines may not control agitation and deliriumassociated with anticholinergic toxicity in all patients.Physostigmine, when used appropriately, may controlagitation and delirium with minimal side effects. However, itshould not be used to treat tricyclic antidepressant overdoseor non-specific coma. It should be reserved for patients thatpresent with moderate to severe anticholinergic effects withagitation and delirium. Atropine should be readily availableto reverse cholinergic toxicity associated withphysostigmine. Any treatment for anticholinergic toxicityshould be based on symptoms and not only on history ofingestion.

Sophea Koy, PharmD Student

References1. Litovitz TL, Klein-Schwartz W, Rodgers GC, et al. 2001

Annual Report of the American Association of PoisonControl Centers Toxic Exposure Surveillance System. AmJ Emerg Med 2002;20: 391-452.

2. Schneir AB, Offerman SR, Ly BT, et al. Complications ofDiagnostic Physostigmine Administration to EmergencyDepartment Patients. Ann Emerg Med. 2003;42:14-19.

3. Beaver KM and Gavin TJ. Treatment of acuteanticholinergic poisoning with physostigmine. Am J EmergMed. 1998 Sept; 16(5):505-507.

4. Burns MJ, Linden CH, Graudins A, et al. A comparison ofphysostigmine and benzodiazepines for the treatment ofanticholinergic poisoning. Ann Emerg Med. 2000 April;35(4):374-381.

diabetes mellitus. Comatose patients should be intubatedprior to receiving physostigmine to avoid possible aspirationof emesis. Patients with mechanical obstruction of theintestine or urogenital tract or any vagotonic state shouldnot receive physostigmine.

Adverse effectsAdverse effects reported following administration ofphysostigmine include bradycardia, nausea, vomiting,diarrhea, and other signs of cholinergic excess. Seizureshave also been reported and may be associated with rapidadministration or high doses. Asystole has been reportedwhen physostigmine has been used to treat tricyclicanticholinergic toxicity. In a recent study evaluatingcomplications of diagnostic physostigmine administration inan emergency department no patient had an arrhythmia orsigns of cholinergic excess.2 One patient, who had 1-2seizures prior to arrival at the emergency department,experienced another seizure approximately 12 minutes afterthe administration of physostigmine. Atropine can be used to reverse the effects of excessivephysostigmine. Atropine can cross the blood-brain barrierand add to the delirium of anticholinergic toxicity. It shouldbe reserved for patients with central cholinergic symptoms.Glycopyrrolate (Robinul®) and methscopolamine bromide(Pamine®) are the drugs of choice for reversingphysostigmine overdose because both agents are quaternaryamines and are not able to cross the blood-brain barrier.Each 1 mg of physostigmine can be counteracted with either0.4 mg of glycopyrrolate, 0.5 mg of methscopolaminebromide, or 0.5 mg of atropine sulfate.

Management of Anticholinergic Delirium Benzodiazepines are often used as sedatives to manage thecentral toxic effects of anticholinergic agents. Large dosesmay be required to treat the anticholinergic delirium leadingto oversedation, need for intensive care monitoring,respiratory support, and potentially an increased length ofstay in the hospital.Physostigmine has shown clinical success in reversinganticholinergic toxicity, but it has not been used routinely forthe treatment of severe anticholinergic delirium. Somehesitation to use physostigmine has occurred due to thereports of seizures and arrhythmias. The majority of theseproblems occurred when physostigmine was used in thetreatment of tricyclic antidepressants or non-specific coma.In 2001, physostigmine was used in the management ofpoisoning exposures reported to U. S. poison centers only302 times.1 Many treatment protocols considerphysostigmine a last resort.Several recent reports highlight the benefits ofphysostigmine in the treatment of anticholinergic agitationand delirium. In one case series, five patients who presentedto an inner-city emergency department with anticholinergicagitation and delirium were successfully treated withphysostigmine.3 All five patients had used heroin that wasmixed with scopolamine, thiamine, dextromethorphan andsmall amounts of cocaine. Physical restraints were requiredand benzodiazepines were not effective in calming thepatients. Treatment with physostigmine resulted indecreased agitation within 15 to 20 minutes. A recent retrospective study was conducted at a Universityteaching hospital with a medical toxicology service to

Page 2 U t a h P o i s o n C o n t r o l C e n t e r

The Utah Poison Control Center expressesits sincere thanks to

MCNEIL CONSUMER & SPEC IALTY PHARMACEUTICALSfor their generous contribution that allows us

to produce and distribute this newsletter.

A P r o g r a m o f t h e U n i v e r s i t y o f U t a h C o l l e g e o f P h a r m a c y Page 3

Meet the UPCC Staf fJohn JohnsonJohn started working for the UtahPoison Control Center after graduatingfrom The University of Utah with a

b a c h e l o r ’ sdegree inPharmacy in1996. He leftthe PoisonCenter for ayear and a halfto try his luckin retail andlong-term carep h a r m a c ypractice. He

has now been back with the center forover a year. His favorite part ofworking at the Poison Center is the factthat he can say that he saves lives bybeing a poison specialist. He is thefather of 3 boys and 1 girl, ages 4 to 12years old, and recently adopted a cat.His hobbies include: golfing, skiing(water and snow), biking, camping andreading.

New EmployeesThe Utah Poison Control Center ispleased to welcome Scott Marshall,PharmD as a poison informationspecialist-pharmacist and ErlynnWallace, RN as a poison informationspecialist. Scott graduated from theUniversity of Utah in 2000 and nowjoins us from within the University ofUtah Hospitals and Clinics network.Erlynn has been working for IHC in avariety of capacities for many yearsand is new to the University of Utah.

EmploymentOpportunities

The UPCC has one position available.The UPCC is looking for a Specialist inPoison Information to work days andevenings. You can find out more aboutthis position on our website athttp://uuhsc.utah.edu/poison/employment.

Drugs and Chemicals That May Produce the Central Anticholinergic Syndrome

Antidepressants Antipsychotic drugs Antihistamines PlantsAmitriptyline Chlorpromazine Brompheniramine BittersweetAmoxapine Prochlorperazine Chlorpheniramine Black henbaneClomipramine Thiothixene Cyclizine Black night shadeDesipramine Thioridazine Dimenhydrinate Deadly night shadeDoxepin Diphenhydramine Fly agaricImipramine Local Mydriatics Hydroxyzine Jerusalem cherryNortriptyline Atropine Meclizine Jimson weedProtriptyline Cyclopentolate Orphenadrine Lantana

Homatropine Promethazine Loco seed or weedAntispasmodics Tropicamide Cyproheptadine MandrakeClidinium Matrimony vineMethantheline Night bloomingPropantheline Others Antiparkinsonian Jessamine

Asthma-Dor Benztropine PantherCompozIpratropium Biperiden and lactate Potato leaves

Belladonna Alkaloids Excedrin-PM Ethopropazine Red sageAtropine Sleep-Eze Procyclidine StinkweedScopolamine Sominex Trihexyphenidyl SproutsGlycopyrrolate Doxylamine Tubers

Amantadine Wild sage

Anticholinergic Clinical Presentation

Central* Peripheral

Short-term Psychomotor agitation Dilated pupils Dry, mucous

memory loss unreactive to light membranes

Confusion Delirium Dry, flushed skin Tachycardia

Ataxia Seizures+ Hyperpyrexia Urinary retention

Visual/auditory Extrapyramidal Rhabdomyolysis Decreased bowel

hallucinations reactions sounds

Disorientation Psychosis Hypertension Hypotension (late

finding)*The degree of central toxicity depends on the drug’s ability to cross the blood-brain barrier. +may be related to other properties of drug as opposed to pure anticholinergic effect

Intergroup Comparisons After Physostigmine and Benzodiazepine TherapyCharacteristics Physostigmine Benzodiazepine P value

(n=30) (n=22)

Incidence of agitation 1/28 (4%) 16/22 (73%) P<0.001

Level of CNS stimulation 0.1 3 P<0.001

Incidence of complications 2 (6.7%) 3 (45.5%) P<0.002

Recovery time (median) 12 hours 24 hours P=0.004

Length of stay (median) 32 hours 39 hours P=0.15

Side effects 7% 14% P=0.6

Table 1

Table 2

Table 34

Utah PoisonControl Center

StaffDirectorBarbara Insley Crouch, PharmD, MSPH

Medical DirectorE. Martin Caravati, MD, MPH

Associate Medical DirectorDouglas E. Rollins, MD, PhD

Assistant DirectorHeather Bennett, MPA

Office SupportRenate Hulen

Specialists in PoisonInformationKathleen Theresa Anderson, PharmDBrian R. Beck, PharmDBradley D. Dahl, PharmD, CSPI*David Evans, PharmD, RPh, CSPI*Francine Goitz, RN, BSN, CSPI*John Johnson, BS Pharm, RPh, CSPI*Scott Marshall, PharmDEd Moltz, RN, BSNDeborah Moss, RN, BSN, CSPI*John Stromness, BS Pharm, RPh, CSPI*Erlynn R. Wallace, RN

Outreach Education ProviderHeather Hunter, MS, CHES

Intern, Community OutreachJason Gillman, BS

UTOX EditorsE. Martin Caravati, MD, MPHBarbara Insley Crouch, PharmD, MSPH

Editorial Advisor Heather Bennett, MPAHeather Hunter, MS, CHES

Please send comments andsuggestions for future articles to theeditor ofUTOX Update at:410 Chipeta Way, Suite 230Salt Lake City, Utah 84108Or send e-mail to poison@hsc.utah.edu

*CSPI denotes Certified Specialist inPoison Information.

Utah Poison Control Center410 Chipeta Way, Suite 230Salt Lake City, UT 84108

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Journal Donation Request!The UPCC would like your help in completing our resource library. Weare missing assorted issues between the years 1983 and 2000 of THEAMERICAN JOURNAL OF EMERGENCY MEDICINE. We are also in need of variousissues between the years 1982 and 2002 of the ANNALS OF EMERGENCYMEDICINE Journal. Please contact Renate at 801-581-7504 to makearrangements for pickup or delivery.

Education UpdateMrs. Alyson O’Steen appeared on Oprah on July 15th to tell the story of heryoung son’s iron ingestion. Upon discovery of an empty bottle, Mrs. O’Steen ofSalt Lake City, quickly called the Utah Poison Control Center and receivedinstructions that saved her child’s life. Both the Oprah show and Lifetime T.V.devoted a segment to the incident and highlighted the importance of theservices of poison control centers.

Mercury Thermometer Exchange ProgramThe Mercury Thermometer Exchange Program conducted between June 9thand June 21st was a great success. The project was sponsored by Smith’sPharmacies, Household Hazardous Waste Division of the Salt Lake ValleyHealth Department, Department of Environmental Quality, and Utah PoisonControl Center. The exchange program was held in every Smith’s pharmacyacross the state of Utah. Residents who took a mercury thermometer into thestore received a coupon for a digital thermometer at half price. 2,116 mercurythermometers were collected in a two week period and were sent to HouseholdHazardous Waste for disposal.