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1034TBBRITISHMEDICALJOURNALNov121887weakenedorarrestedbyaddingatoxicdoseofpotassiumchloridevertriaquiteantagonisesthepotatsiumchlorideeffectsandrestoresspontaneousandnormalcontractionsBariumand ID: 236577
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Nov:~i887,]THEBRITISHMRDICWLJOUR~dL.103IANA-^DDRESSCONCERMSINGTHEANTAGONISMOFDRUGS.1DeliveredbeforetheMidlandMedicalSocietyonNovember9th,1887.BySYDNEYRINGER,M.D.,F.R.S.,HolmeProfessorofClinicalMedicineinUniversityCollege,andPhysiciantotheHospital.RECENTinvestigationsrenderitprobablethatalkaloidsorextractivesformedfromfoodinthegastro-intestinalcanal,orfromthetissuesofthebody,causemanyofthediseaseswearecalledupontotreat.Thesealkaloidsorextractives-arisefromphysiologicalormorbidchanges,andifinunduequantity,orifnotquicklyeliminated,theymayactlikepoisonsintroducedintothesystemfromwithout.Someoftheseptomainesandleucomainesproduceeffectssimilartovegetablealkaloids,as,forinstance,atropine,muscarine,orcurare.Indeed,muscarinecanbeobtained,notonlyfromthefungusagaricus,butalsofromanimaltissues.Nowmuscarine,eveninpoisonousdoses,wecaneffectuallyantagonisebyatropine.Ishallshowyouto-nightthatsomeinorganicandorganicpoisonscanbecompletelyantagonized,normalfunctionbeingrestored.Thestudy,then,oftheantagonismsofpoisonsbecomesofmuchinterestandimportance,aswemayconfidentlyexpect,astheresultoffurtherresearch,thatweshallbeabletoobviatetheeffects,notonlyofin-organicandorganicalkaloids,etc.,introducedintothesystem,buttheeffectsofptomainesorleucomainesengenderedintheanimalbody.Probablysomeofoursuccessesintreatmentarealreadyduetoourdrugsantagonisingtheseproducts.Ashorttimeagoaninterestingcontroversyaroseregardingthereciprocal(mutual)antagonismofdrugs.Ononesideitwasmain-tainedthatdrugsmightbemutuallyantagonistic,whilstotherob-serversdeniedthisstatement.Theformermaintainedthattheeffectofadrugmightbeantagonisedbyaseconddrug,which,ifincreasedinquantity,wouldmanifestitsownindividualeffects,buttheseeffectscouldberemovedbyincreasingthequantityofthefirstdrug.Totakeanexample,atropinewillantagonisetheactionofmuscarine,andmuscarinetheactionofatropineontheheart.Totakeanotherinstance,atropinewillantagonisetheactionofjaborandionthesub-maxillarygland,andviceversd;ifafteratropinehasantagonisedtheactionofjaborandi,afurtherquantityofjaborandiisadministered,itwillovercometheactionofatropineandsalivarysecretionwillreturn.Rossbachdisputedthis,andmaintainedthatwhilstonedrugin-creasesanotherdepressesorsuspendsfunction,andthedrugwhichincreasesfunctioncanneverovercometheeffectofadrugthathasabolishedfunction.Headmittedthatwhenatropinearreststhesecretionofthesweat-glands,pilocarpinemayproduceperspiration,butheassertsthatthisoccursonlywithasmalldoseofatropinejustsufficienttoparalysethesecretorynerves,butnotthesecretorycells.ofthegland,andthatpilocarpinestimulatingthecellsmayproduceperspiration.Buthemaintainsthatalargerdoseofatropinepara-lysesboththesecretorynervesandthesecretorycells,andafterthisstagenoamountofpilocarpinewillexciteperspiration.Ishallshowyouconclusivelythatdrugscanbereciprocallyan-tagonistic.Ishalldemonstratethattheeffectofatoxicdoseofcal-ciumchlorideonthedetachedventricleofthefrog'sheartcanbequiteantagonisedbyatoxicdoseofpotassiumchloride,andviceversdthatatoxicdoseofpotassiumchloride,sufficientnotonlytoarrest,spontaneousbeats,butsufficienttopreventastronginductionshockexcitinganycontraction,canbeantagonisedentirefybyatoxicdoseofcalciumchloride,andbythecarefulapportionmentofthetwosaltstheirantagonismcanbesonicelybalanced,thattheventriclewillbeatspontaneouslyandquitenaturally.Moreover,Ishallshowthatatoxicdoseofpotassiumchloridewillantagoniseatoxicdoseofveratria,andviceverseatoxicdoseofveratriawillantagoniseatoxicdoseofpotassiumchloride,andthesetwosubstancesmaybegivenwithsuchequipoiseascompletelytoantagoniseeachother,sothattheventriclewillbeatquitenaturallyandspontaneously.Sothatinthecaseofcalciumchlorideandpotassiumchloride,andagaininthecaseofveratriaandpotassiumchloride,wemayhaveinthecirculat-ngfluidtwoofeachseriespresentintoxicdoseswithouteither1Thislecturewasillustratedbyexperimentsonthedetachedventricleofthefrog'sheartplacedinaRoy'stonometer,thecontractionsbeingrecordedonarevolvingcylinder.L]402Jpoisonexertinganyapparentinfluenceontheventricle,whichgotsonbeatingspontaneouslyandnormally,butifonesaltweread-ministeredsingly,itwouldpowerfullyaffectthefunctionsoftheveiPtricletoanextentincompatiblewithlife.'ConcerningtheantagonismstowhichIwishtodrawyourattentionto-night,Iwillreferfirsttoaaphysiological'antagonism.Iftheventricleofthefrog,oroftheeel,orofthetortoise,isfedwithsalinesolution(.66percent.),contractilitysoonceases,andcannotbeinducedbyastrongelectricshock.Ontheadditionofalimesalt,even'inveryminuteproportions,as1partoflime-saltto10,000parts'ofsalinesolution,contractilityimmediatelyreturns,butthecontractionisabnormal,'forthedilatationofthe'ventricleisgreatlyprolonged,sothatthewholecontractionlastsmuchlongerthannatural.Thead-ditionofasmallquantityofapotassiumsalt,asforinstance,potas-siumchloride,1partin15,000ofcirculatingfluid,obviatesthiseffectofthecalciumsalt,acceleratesdilatation,andinducesaperfectlynormalbeat,andwithsuchasolutiongoodcontractionsaresustainedforseveralhours.Here,then,wehaveanantagonismbetweenlimeandpotassiumsalts,affecting,however,onlyonepartofacontrec-tion-namely,therelaxationofthecontractedmuscle.Notonlyarethesaltsofthesetwosubstances-potassiumandcal-cium-antagonisticinphysiologicaldoses,buttheyarelikewisean-tagonisticintoxicquantities.Iftoasolutioncapableofsustainingtheventricularcontractionsweaddatoxicdoseofpotassiumchloride,thecontractionsspeedilycease,evenwhentheventricleisstronglystimulated.Now,onaddingatoxicdoseofcalciumsalt,thepotassiumchlorideisan-tagonised,andifthecalciumsaltisaddedinsuitablequantity,com-pletecontractilityisrestored,andtheventriclebeatsspontaneouslyandnormally;andviceversdifweaddtothecirculatingfluidatoxicdoseofcalciumchloride,wegreatlyprolongthedurationofthecontraction,andespeciallyretardrelaxation,butontheadditionofatoxicdoseofapotassiumsalt,theselimeeffectsareobviated,andnormalspontaneouscontractionsensue.Here,then,wehaveinstanceswheretwosubstancesintoxicdosessoantagoniseeachotherthatnaturalbeatsoccur;whilsteithersub-stance,addedalonetothecirculatingfluid,powerfullyaffectsthefunctionsofventricletoanextentincompatiblewithlife.Weareable,however,toanalysetheantagonismbetweenthesesaltsmoreminutelystill.Duringacontraction,fourdistinctsetsofchangesoccurinthemusculartissueoftheventriclenamely,changesoccurringduringthelatentperiod,duringtheperiodofcontraction,duringtheperiodofrelaxation,andreparativechanges,independentofthosepermittingrelaxation.Nowpotashsalts,likeveratriasalts,greatlyretardthesereparativechanges,sothatinaventriclepoisonedbypotassiumchloride,thesereparativechangesareveryslowlyper-formed,andhence,afterthecompletionofcontractionandrelaxation,ifasubsequentcontractionissooninduceditisaveryweakone,orifthestimulusistoosoonappliedtotheventriclenocontractionmayoccur,andcannotbeinducedtillashorttimehaselapsed,andthentheamountofcontractiondependsonthelengthofthediastolicpause.Thiseffectofpotassiumchlorideonthereparativechangesacalciumsaltcompletelyobviates.Wesee,then,thatapotassiumsaltacceleratesrelaxationbutretardsreparation,inboththeserespectsbeingantagonisedbyacalciumsalt,andviceversd.Anotherantagonismbetweenpotassiumandcalciumsaltsstillremainstobenoticed.Ifaventriclebeallowedtoremainwithoutcontractingfromafewsecondstoaminute,then,onexcitingitthefirstcontractionisweak,andthesubsequentcontractionsgrowgraduallystrongertillnormalcontractionsoccur.Thisstair-casecharacterofbeatsdepends,Ibelieve,ontheactionofthepotas-siumsaltinthecirculatingfluid,andthedegreeinwhichitoccursisinproportiontotherelativeamountofpotassiumchlorideinthecircu-latingfluid.Acalciumsalt,ascalciumchloride,quiteobviatesthiseffect.Ifsufficientcalciumchloridebeadded,nomatterhowlongtheventricleremainswithoutcontracting,thestaircasecharacterofthebeatsisprevented,orisveryslightindeed.Strangeasitmayappear,veratriaaffectstheventriclemuchafterthemanneroflimesalts.Thus,addedtosimplesalinesolution,itwillrestorecontractility,andfurther,likelime,itgreatlyprolongsthedurationofthecontraction,andespeciallydelaysrelaxationofthecontractedventricle,and,likelimeandpotassiumsalts,wefindveratriaandpotassiumsaltsaremutually,orreciprocally,antago-nistc.Forinstance,theadditionofveratriatothecirculatingfluidpro-duceseithergreatirregularityinthecontractions,orverygreatdelayindilatation,accordingtothetemperatureoftheroom.Thisirregularityatoxicdoseofpotassiumquiteremoves,andgoodspon-taneouscontractionsreturn.Further,iftheventricleisgreatlyNov.LR,188.17,1033-TR-RBRJTISHaTjITO 1034TBBRITISHMEDICALJOURNAL.Nov.12,1887.weakenedorarrestedbyaddingatoxicdoseofpotassiumchloride,vertriaquiteantagonisesthepotatsiumchlorideeffects,andrestoresspontaneousandnormalcontractions.Bariumandcalciumsalts,asmightbeexpectedfromtheirchemicalrelationship,havemanyactionsincommon.Itisinterestingtoobservethat,althoughlimesaltsandbariumsaltsbothbroadenthebeat,causingfusionandcontracture,bariumsaltseffectthismorepowerfullythancalciumsalts;yet,afterbariumhasproduceditseffects,ontheadditionofacalciumsalt,insteadofobtainingthesumoftheirunitedactiontheeffectscommontobothsaltsbecomeless.Inotherwords,limetakespossessionofthemusculartissue,exclud-ingtheactionofthebariumsalts.Itwouldappear,then,thattwosub-stanoesaffectingthesametissueinthesameway,whenadministeredtherapeutically,onewillnotnecessarilyintensifytheactionoftheother,butmayreplacetheother,andwegettheactionofonlyonesubstance,andthis,whilsthavingagreateraffinityforthetissue,mayinducealessphysiologicaleffect.Theseresultsareveryin-teresting,andIventuretothinkhaveconsiderableimportance,bothphysiologicallyandtherapeutically.Thuswehaveseenthatbariumandcalciumbothexertaninfluenceinthesamedirection,butthebariummoleculeisthemoreactiveinrespectofitsinfluenceontheventricularcontraction.If,however,webringbothmoleculesintoactionsimultaneously,weseethattheresultanteffect,insteadotbeinggreaterthanwitheithercomponent,isless,thelimedisplacingthebariumandinducingitslessphysiologicaldisturbance.Therela-tionofthissubjecttopracticalmedicineisveryclearandimportant,foronthequestionofthecombinationofdragswemustrememberthatthejointactionoftwodrugsfunctionallysimilarisnotneces-sarilygreaterthanthatofeitherseparately,andmaybeevenweakerthanoneofthemgivenseparately.Ihavesaidnecessarily,forinsomeinstancestwosubstanceshavingthesameactiondoincreasetheactionofeitherseparately,sothatwegetthesumoftheirjointaction.Thisisthecasewithlimeandveratria.80farwehaveseenthatsubstancesmaybeantagonisticintwoways.Thefirstwemaytermphysiological,forinstanceswheretwosubstancesinducinganoppositephysiologicaleffectonatissuemaybesoadjustedthatthepoisonousactionofbothisprevented.Intheothercasetheantagonismisprobablychemical,andonesubstancemaybyastrongerchemicalaffinitydisplaceanotherpoison,andthismayoccur,andindeedismostlikelytooccur,whenbothsub-stancesarechemicallyrelatedandhaveasimilarphysiologicaleffect.Butthereareotherwaysinwhichasubstancemayactasanantidote.Alimesaltinthecirculatingfluidwehaveseenisnecessaryforthecontractionofcardiacmuscle.Nowasolubleoxalatedestroysfunction,inpart,bycombiningwiththelimeinthecirculation,andrenderingitinsolubleandsoinoperative.Here,then,weobviatethepoisonouseflectofanoxalatebyaddinglimetothecirculation.Therearestill,however,otherwaysinwhichwecanantidoteapoison.Asolubleoxalatenotonlydestroysfunctionbywithdrawinglime,butisdirectlytosomeextentpoisonoustothecardiacmusculartissue;andthispoisonousactionweobviatebytheadministrationofalimosalt,whichcombineswiththeoxalicacid,forminganinsolubleandthereforeinoperativecompound.Totakeanotherinstance,solublebariumsaltsarepoisonoustothecardiacmuscleandarresttheven-tricleinsystole.NowIfindthattheadditiontothecirculatingfluidofasolutionofsulphateofsodawillprecipitatethewholeofthebarium,andtheventriclewillspeedilyresumeitsnormalcon-tractility,eventhoughthecontractionshadbeensuspendedforanhour.Theeffectofthesodiumsulphateisveryrapid.Bariumsalts,cnewouldthink,canprovepoisonousonlytothetissuesaftermorethanenoughhasbeenabsorbedtocombinewiththewholeofthesulphuricacidinthebloodandtissues,anditispossiblethatpartoftheactionofabariumsaltmaybeduetothewithdrawalofsulphuTicacidfromthetissues.Finally,thereisanotherwaybywhichthepoisonousactionofsomesubstancescanbegreatlylessened.Somepoisonspreventthechangeswhichtakeplaceintheexerciseofafunction,as,forinstance,thecontractionofmuscle.Theydonotdestroythestructure,theyonlysuspendfunction,andthispowertheypossessonlywhenthepoisonreachesacertainpercentageofthecirculatingfluid.Ifthefluidisdiluted,thentheperceintageamountbecominglessthepoisonousactionisgreatlyreduced.Thisisthecasewithpotawsiumandmostothersalts.Thisfactprobablyexplainstheeffectofbleeding,whichhasbeensuccessfullyemployeilsomecasesofpoisoning,andishighlysuccessfulinurnemia.Thelossofbloodinducesarapidab-sorptionoftheintercellularfluidandwaterfromthegastro-intestinalanal,andsodilutingthepoison,lessensorremovesthesymptomsIfbleedingprovesunsuccessfultheinfluenceofdilutionsuggest*transfusionofasalinesolution,alsothefreeadministrationofliquidsbythestomach-methodsIlongagosuggested.Inowbringthisdemonstrationtoaclose,andIconcludebyex-pressingthehopewithwhichIcommencedmyremarks,thattheantagonismswehavewitnessedjustifyusinconfidentlyexpectingthatfurtherinvestigationwilldiscoverremediesbywhichweshallsafelyantidotethepoisonsgeneratedinthebody,andthatthesedis-coverieswillenableustorelievemuchsufferingoreventosavelife.BRITISHMEDICALASSOCIATION.FIFTY-FIFTHANNUALMEETING.PROCEEDINGSOFSE:CTIONS.INTRODUCTIONTOADISCUSSIONONTHEPREVENTIONOFPUERPERALFEVER.ReadintheSectionofObstetricMedicineattheAnnualMleetingoftheBritishMedicalAssociationheldatDublin,August,1S87.BrW.S.PLAYFAIR,M.D.,LL.D.,F.R.C.P.,ProfessorofObstetricMedicineatKing'sCollege,andPhysicianfortheDiseasesofWomenandChildrentoKing'sCollegeHospital.THEsubjectwhichIhavethehonourtointroducetoyoufordiscus-sioncannotfail,Ithink,tobeofinteresttoallonwhomtherespon-sibilityfallsofattendingwomeninthetryingtimeoflabour.Whothathasundergonethedistressofseeingsepticoemiadevelopinoneofhispatients,andwhohashadtosuffertheterribleanxietywhicheverysuchcaseinvolves,willhesitatetoendorsethestatementthatthepreventionofthisscourgeofmidwiferypracticeisoneofthemostimportantdutiesthatcanpossiblyfalltohislot.ItwillbeoutofthequestionthatintheshortspaceofaquarterofanhourallottedtomeIcanendeavourtodomorethanlaydownsomefewbroadgeneralprinciplesthatshouldguideus.Toenterintodetailswillbeimpos-sible;myobjectwillbefullygainedifIamabletoinaugurateause.fuldiscussiononaquestionofsuchinteresttousall,andIcannotdoubtthatmuchinformationofvaluewillbeelicitedfromacom-parisonoftheopinionsandpracticeofthemanygentlemeninthisroomwhoarequalifiedtospeakonthistopicwithauthority.Iammoreparticularlyanxiousto-daytoinsistonthepreventionofpuerperaldiseaseinprivateanddomiciliarypractice.Inlying-inhos-pitals,sincethegreatrevolutionproducedbythegeneralrecognitionoftheimportanceofantisepsis,amarvellouschangehasbeeneffected.Frombeinghotbedsofdeathanddisease,inwhichnowomancouldbeconfinedwithoutrunningaseriousrisk,sometimeshardlylessgravethanthatofacapitalsurgicaloperation,inthemajorityofwellmanagedlying-inhospitalsawomanisnowactuallyassafe,ifnotsafer,thanifshewasconfinedinalargeandluxuriousprivatehouse,withnurse,physician,andallthatmoneycanprocure.Thisisnoexaggeratedstatement.ObstetricliteraturewithinthelastfewyearsteemswithfactsandstatisticsprovingtheaccuracyofwhatIhavesaid.Thegreatlying-ininstitutionofDublinisacaseinpoint.ThestatisticsofsimilarinstitutionsinLondon,Paris,St.Petersburg,andeverylargeContinentalcity,corroborateit.ThereisnothinginthehistoryofmedicinemoreremarkablethanthechangewhichhascomeovertheworkingofthesepublicinstitutionssinceLister'slife-savingprincipleshavebeenadopted.Therethebattleisgained.Idoubtifsuchathingcanbefoundnowasalying-inhospitalinwhichrigidantisepsisisnottherule,andinwhichsimilargoodresultsLavenotfolloweditsintroduction.Althoughtheprincipleisuniversallyrecognised,and,Ibelieve,everywherepractisedinpublicinstitutions,Iverymuchquestionifevenyetantisepticmidwiferyisatallingeneraluseinprivateprac-tice.Itismylot,asofotherconsultants,oftentoseecasesinwhichsepticsymptomshavedeveloped,andveryseldom,heretofore,haveIfoundthatthepractitionersinattendancefollowedanyoftheanti-septicruleswhicharenowsouniversallyandsorigidlyenforcedinourlying-inhospitals.Perhapsinthenearfuture,whentheyoungermembersoftheprofessionentermorelargelyintowork,itwillbedifferent;butwiththebulkofmennowinpracticenospecialcatristaken.Yet,iftheworkofpubliccharitiesinwhichlying-inwomenarecongregated-inwhich,asthebitterexperienceofthepastsofully