DRUGMONOGRAPH

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Physostigmine
Antilirium

DrugInformationProvidedByGoldStandard

Description:Physostigmineisaparenteralandophthalmiccholinesteraseinhibitor.Physostigmine
issimilartoneostigmineexceptthatitisatertiaryaminewhileneostigmineisaquaternaryamine.
ThisdifferencemayexplaintheincreasedactivityofphysostigmineintheCNS.Physostigminemost
commonlyisusedasanophthalmicagentinthetreatmentofopenangleglaucoma.Ithasalsobeen
usedtocounteracttoxicanticholinergiceffects(bothcentralandperipheral)ofotherdrugswhich
causeanticholinergictoxicity,particularlyinoverdosesituations.Untilrecently,physostigminewas
usedtotreattricyclicantidepressant(TCA)overdose,butitisnolongerrecommendedforthis
purposeduetoitsownpotentiallyharmfuleffectsincludingseizuresandlifethreatening
bradyarrhythmiasprogressingtoasystole.2418133935Physostigminehasbeenusedtotreat
Alzheimer'sdiseaseandhereditaryataxias.Whilesomeimprovementswerenotedinsomestudies,
thedrughasnotbeenwellestablishedinthesediseases.Extractedphysostigminewasfirstused
ophthalmically,forglaucoma,in1875.Itwasfirstsynthesizedin1935,andisacceptedbytheFDAas
apre1938drug.Asustainedreleaseformofphysostigminesalicylate(Synapton)hascompleted
phaseIIIinvestigationforAlzheimer'sdiseaseasofAugust1996.
MechanismofAction:Physostigminecompeteswithacetylcholineforitsbindingsiteon
acetylcholinesterase.Byinterferingwiththeenzymaticdestructionofacetylcholine,physostigmine
potentiatestheactionofacetylcholineonboththeskeletalmuscle(nicotinicreceptor)andtheGI
tract(muscarinicreceptor).
PhysostigmineactsprimarilyatmuscariniccholinergicsynapsesandwithintheCNS,havingless
effectatthemyoneuraljunctionatlowdoses.Athigherdoses,physostigmineexertssomeeffectsnot
relatedtoacetylcholinesteraseinhibition.Physostigminemayactatthemyoneuraljunctiontocause
adepolarizingblock.Italsocanexertadirectblockingactionwithinautonomicgangliaanddirectly
potentiateCNSdepression.
Specificresponsestocholinesteraseinhibitorsparallelcholinergicstimulation:increasedskeletal
muscletone(nicotinic)increasedgastricmotilityandGItone(muscarinic)bradycardia
(muscarinic)ureteralconstriction(muscarinic)stimulationofthesweatandsalivaryglands
(muscarinic)andconstrictionofthebronchi(muscarinic).Someevidencesuggeststhereisalsoa
directactiononskeletalmuscle.

Physostigminecausesmiosisbystimulatingcholinergicresponsesintheeye.Thedrugdecreases
intraocularpressure,presumablybyinducingciliarymusclecontraction,whichwidensthetrabecular
meshwork,allowingforincreasedoutflowofaqueoushumor.
Inthepast,physostigminewasusedtomanageTCAoverdose.Althoughsomepatientsregained
consciousnessafterphysostigmineadministration,physostigminedidnotcorrectthecardiac
arrhythmias.ArrhythmiassecondarytoTCAoverdoseweredeterminedtobesecondarytothe
quinidinelikeeffectsoftheTCAandnottoanticholinergictoxicity.Becauseofthisandthefactthat
physostigminecaninduceseizures,thedrugisnolongerrecommendedfortreatmentofTCA
overdose.
Pharmacokinetics:
PhysostigmineisadministeredviaIVinjectionorappliedtopicallytotheeye.Itisdistributedwidely
throughoutthebodyandcrossesthebloodbrainbarrier.Themodeofexcretionisunknownasmall
amountisexcretedintheurine.

RouteSpecificPharmacokinetics
IntravenousRoute
Peakeffectsareseeninapproximately5minuteswhengivenIV.Cholinesterasehydrolyzes
physostigmine,makingitsdurationofactionapproximately12hourswhengivenIV.
IntramuscularRoute
Peakeffectsofphysostigmineareseeninapproximately5minuteswhengivenIM.
OtherRoute(s)
Ophthalmicroute
Peakeffectsareseeninwithin1030minuteswhenappliedtopicallytotheeye.Cholinesterase
hydrolyzesphysostigmine,makingitsdurationofactionapproximately1236hoursafter
ophthalmicuse.
Lastrevised:July2,2014

Indications&Dosage
anticholinergicsyndrome
glaucoma
Forantagonismoftoxicanticholinergiceffectswhichmanifestasthe'anticholinergic
syndrome':
IntravenousorIntramusculardosage:
Adults:0.52mgIMorslowIV(nottoexceed1mg/minIV).Mayrepeatevery1030minutesas

needed.Foroverdosagesofdrugsthatcausetoxicanticholinergiceffects,themanufacturer
recommendsadoseof2mgIMorslowIVrepeatiflifethreateningsignssuchasarrhythmia,
convulsionsorcomaoccur.Forpostanesthesiacare,themanufacturerrecommendsadoseof0.51
mgIMorslowIVmayrepeatevery1030minutesasneeded.
Children:0.02mg/kg(range0.010.03mg/kg)IMorslowIV(nottoexceed0.5mg/minIV)may
repeatat510minuteintervalsasneededuntilatotaldoseof2mgisreachedoranadverse
cholinergicreactionoccurs.Reserveuseforlifethreateningsituationsonly.
Forthetreatmentofopenangleglaucoma:
Ophthalmicdosage:
Adults,Adolescents,andChildren:Instill12dropsof0.25%or0.5%solutionintoeye(s)upto4
timesperdayorapply0.25%ointmenttolowerfornix13timesperday.
MaximumDosageLimits:
Adults
8drops/daytotalof0.5%ophthalmicsolutionforglaucomamaximumdosageforanticholinergic
syndromeisnotwelldefinedmaximumdosageisdependentuponindividualresponse.
Elderly
8drops/daytotalof0.5%ophthalmicsolutionforglaucomamaximumdosageforanticholinergic
syndromeisnotwelldefinedmaximumdosageisdependentuponindividualresponse.
Adolescents
8drops/daytotalof0.5%ophthalmicsolutionforglaucomamaximumdosageforanticholinergic
syndromeisnotwelldefinedmaximumdosageisdependentuponindividualresponse.
Children
8drops/daytotalof0.5%ophthalmicsolutionforglaucoma2mg/dayIVorIMcumulativedosage
foranticholinergicsyndrome.
PatientswithHepaticImpairmentDosing
Specificguidelinesfordosageadjustmentsinhepaticimpairmentarenotavailableitappearsthatno
dosageadjustmentsareneeded.
PatientswithRenalImpairmentDosing
Specificguidelinesfordosageadjustmentsinrenalimpairmentarenotavailableitappearsthatno
dosageadjustmentsareneeded.
nonFDAapprovedindication
Lastrevised:June8,2010

Administration

GeneralAdministrationInformation
Forstorageinformation,seethespecificproductinformationwithintheHowSuppliedsection.
RouteSpecificAdministration
InjectableAdministration
Atropineandresuscitationequipmentshouldalwaysbeavailablewhengivingphysostigmine
parenterally.
Nodilutionnecessary.Donotadministerinjectionsolutionscontainingbenzylalcoholto
neonatesorprematureinfants.
Duringadministration,frequentlymonitorpulse,respiratoryrate,bloodpressure,and
neurologicstatus.MonitorECGduringintravenousadministration.
Visuallyinspectparenteralproductsforparticulatematteranddiscolorationpriorto
administrationwheneversolutionandcontainerpermit.
IntravenousAdministration:
Intravenousinjection:
Donotadministerrapidly.Rapidadministrationmayleadtobradycardia,increasedsalivation
(whichmayleadtorespiratorydistress),orseizures.
InjectviaYsiteorthrougha3waystopcockatarateof1mgperminuteforadultsandnofaster
than0.5mgperminuteforchildren.

IntramuscularAdministration:
Intramuscularinjection:
Injectdeeplyintoalargemuscle.Aspiratepriortoinjectiontoavoidinjectionintoabloodvessel.

OphthalmicAdministration
Instructpatientonproperinstillationofeyeointmentorsolution(seePatientInformation).
Donottotouchthetipofthedropperortubetotheeye,fingertips,orothersurface.

MonitoringParameters
laboratorymonitoringnotnecessary

Contraindications
asthma
bradycardia
breastfeeding
cardiacdisease
closedangleglaucoma
diabetesmellitus
GIobstruction
hypotension
ileus
neonates
pepticulcerdisease
pregnancy
seizuredisorder
sulfitehypersensitivity
urinarytractobstruction
Physostigmineshouldnotbeusedinpatientswithclosedangleglaucomabecauseitsactiononthe
ciliarymusclescanworsenblockageofaqueoushumoroutflowandincreaseintraocularpressure.
PhysostigmineiscontraindicatedinpatientswithGIobstruction/ileusorurinarytractobstruction
becauseitcausesspasmofsmoothmuscleinthesesystems,whichcanbedamagingandevencause
perforation.
Physostigmineshouldbeusedwithcautioninpatientswithhypotensionand/orbradycardiabecause
itcanincreasevagaltoneandworsenbothoftheseconditions.Becauseofthisanditsdirect
stimulatoryeffectontheheart,physostigmineshouldnotbeusedinpatientswithcardiacdisease,
especiallyarrhythmiasorcoronaryarterydisease.
Patientswithasthmashouldnotbegivenphysostigminebecauseitcanworsenbronchoconstriction.
Physostigminecanalterinsulinrequirementssoitalsoshouldnotbeusedinpatientswithdiabetes
mellitus.

Physostigmineshouldbeusedwithcautioninpatientswithaseizuredisorderbecauseitcaninduce
seizuresbystimulatingtheCNS.
Physostigminealsocanincreasegastricsecretionsandshouldbeusedwithcautioningpatientswith
pepticulcerdisease.
Parenteralphysostigminecontainssodiumbisulphiteandshouldbeusedwithcautioninpatients
withknownsulfitehypersensitivity.Asthmaticpatientsaremorelikelytohavesulfite
hypersensitivitythannonasthmaticpatients.
Physostigmineinjectioncontainsbenzylalcoholasapreservativeandshouldbeavoidedinneonates
becausebenzylalcoholhasbeenassociatedwithafataltoxic(gasping)syndrome.
Useofphysostigmineduringpregnancyisrare.Nowellcontrolledhumanreproductivestudies
involvingphysostigminehavebeenperformed,anditisunknownwhetherornotphysostigmineis
teratogenic.Thereisapossibilitythatneonatesborntomyasthenicmotherscanhaveatransient
muscleweaknessifphysostigmineisusedduringpregnancy.Themanufacturerrecommendsuse
duringpregnancyonlyifthebenefitstothemotheroutweighthepotentialriskstothefetus.49167
Itisnotknownwhetherphysostigmineisexcretedinhumanmilk.Themanufacturerrecommends
useduringbreastfeedingonlyifthebenefitstothemotheroutweighthepotentialriskstothefetus.
49167

Considerthebenefitsofbreastfeeding,theriskofpotentialinfantdrugexposure,andtherisk
ofanuntreatedorinadequatelytreatedcondition.Ifabreastfeedinginfantexperiencesanadverse
effectrelatedtoamaternallyadministereddrug,healthcareprovidersareencouragedtoreportthe
adverseeffecttotheFDA.
Lastrevised:March9,2012

Interactions
Atropine
Digoxin
LocalAnesthetics
Mivacurium
Parasympathomimetics
Quinine
Succinylcholine

Tricyclicantidepressants
Physostigminehasadditiveeffectswithotherparasympathomimetics6380andshouldbeused
concomitantlyonlywithcarefulmonitoringofsideeffectstoavoidcholinergiccrisis.
Physostigmineinhibitsplasmacholinesterase(pseudocholinesterase)hydrolysisofdepolarizing
neuromuscularblockersandcanthereforeprolongtheneuromuscularparalysisinducedby
succinylcholine.71746950Also,sincemivacurium,anondepolarizingneuromuscularblocker,is
metabolizedbyplasmacholinesteraseinhibitors,prolongedneuromuscularparalysismayoccur
whenphysostigmineisgiventopatientsreceivingmivacurium.5121
Physostigminecounteractsmanycentralandperipheraleffectsofanticholinergicdrugssuchas
atropine600263386240anddrugswithanticholinergicsideeffects.Thismakesphysostigmineuseful
intreatingtoxicmanifestationsofthesedrugsinoverdoses.Conversely,atropinecanbeusedasan
antidotetophysostigmine.
Tricyclicantidepressants(TCAs)mayantagonizesomeoftheeffectsofparasympathomimetics(e.g.,
cholinesteraseinhibitors)duetotheiranticholinergicactivity.6002However,parasympathomimetics
6380

likebethanecholhaveoccasionallybeenusedhistoricallytooffsetsomeoftheadverseperipheral

antimuscarinic(anticholinergic)effectsofTCAs,suchasdrymouth,constipationorurinary
retention.6001Foryears,physostigminewasusedasanadjuncttothetreatmentofTCAoverdose
however,itsefficacywaslimitedtoaddressinganticholinergiceffects.Additionally,casereports
suggestthatharmfuleffectssuchasseizuresandbradyarrhythmiasprogressingtoasystole,
especiallyinpatientswithcardiacconductionabnormalitiesatbaseline,arepossible.75110788For
thesereasons,physostigmineisnolongerconsideredastandardofcareinthetreatmentofTCA
overdose.
Localanestheticscanantagonizetheeffectsofcholinesteraseinhibitorsbyinhibitingneuronal
transmissioninskeletalmuscle,especiallyiflargedosesoflocalanestheticsareused.Dosage
adjustmentofthecholinesteraseinhibitormaybenecessarytocontrolthesymptomsofmyasthenia
gravis.6156
Theactionsofquinineonskeletalmusclearepharmacologicallyoppositetothoseofcholinesterase
inhibitorssuchasedrophonium,neostigmine,physostigmine,andpyridostigmine.Therefore,
quininemayinterferewiththeactionsofcholinesteraseinhibitorsintreatingsuchconditionsas
myastheniagravis.Thisrepresentsapharmacodynamicinteractionwithcholinesteraseinhibitors
ratherthanapharmacokineticinteraction.7026
Theincreaseinvagaltoneinducedbysomecholinesteraseinhibitorsmayproducebradycardia,

hypotension,orsyncope.7719Thevagotoniceffectofthesedrugsmaytheoreticallybeincreased
whengivenwithothermedicationsknowntocausebradycardiasuchasdigoxin.Theseinteractions
arepharmacodynamicinnatureratherthanpharmacokinetic.
Lastrevised:May20,2008

AdverseReactions
abdominalpain
bradycardia
bronchospasm
confusion
diaphoresis
dyspnea
hyperhidrosis
hypersalivation
hypotension
increasedurinaryfrequency
lacrimation
miosis
muscleparalysis
myasthenia
nausea
palpitations
seizures
vomiting
Systemicphysostigminecancauseacholinergiccrisisinincidentsofoverdoseorrapidinfusionrate.
Thissituationistypicallycharacterizedbyexcessivesweating(hyperhidrosis),hypersalivation,
nausea,vomiting,miosis,sinusbradycardia,hypotension,seizures,confusion,muscleweakness,
muscleparalysis(includingrespiratoryparalysis).Deathcanensueunlesstreated.Resuscitation

equipmentandatropineshouldbeonhandwhenthedrugisgivenIVorIM.57311Atropinewill
counteractthedrug'smuscariniccholinergicactionsbutwillnotcounteractitsparalyticeffects.
Adversereactionscommonlyassociatedwithphysostigmineincludenausea,vomiting,stomach
crampsorabdominalpain,miosis,hypersalivation,diaphoresis,lacrimation,bronchospasm,
dyspnea,andincreasedurinaryfrequency.CNSstimulation,restlessness,irregularpulse,
palpitations,hallucinations,fasciculations,andmyastheniaoccurlessfrequently.Rarely,seizures,
collapse,anddeathhavebeenreported.BecauseseizureshaveoccurredwhenIVphysostigminewas
administeredtopatientswhohaveoverdosedwithtricyclicantidepressants,physostigmineisno
longerrecommendedasatreatmentforthiscondition.24181
Lastrevised:July2,2014

Classifications
AutonomicAgents
Parasympathomimetics
Cholinesteraseinhibitors
OphthalmicAgents
AntiglaucomaAgents
Miotics

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