Effects of alcohol onmedia.voog.com/0000/0037/7454/files/PDCO Tallinn 2017.pdf · • Alcohol mixed...
Transcript of Effects of alcohol onmedia.voog.com/0000/0037/7454/files/PDCO Tallinn 2017.pdf · • Alcohol mixed...
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3X2012001775434
Effects of alcohol on children Jaanus Harro, MD, PhD
University of Tartu Psychiatry Clinic, North Estonia Medical Centre
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Ethanol:evolu-on,medicine,culture• Astraight-chainalcohol,colorlessandvola;le• Producedbyyeastandintoxicatesthosewhotrytoeatitsfood
• Consump;onembeddedinhumanculturethatitselfbearstracesofintoxica;on
• somewouldsaythisofallourciviliza;on
• Ethanolisapharmacologicallyac;vesubstance• Earlymedicalapplica;onbroadbutnowlimitedinterestinitspharmacodynamicac;on
• Solvent(secondmostcommonaJerwater)orpreserva;ve• Usedasanexcipientinmorethan700liquidprepara;onsthatmaybeadministeredtoneonates,infantsandchildren
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Childrenmeetalcohol
• Prenatal,consump;onbymother• Prenatal,epigene;ceffectsoffather’sconsump;on(Finegershetal.,Alcohol2015;49,461-479)
• DuringbreasUeeding• Accidentalconsump;on• Medicalprocedures• Excipients• Experimenta;onandeventualregularconsump;on• Inaddi;ontodirectpharmacologicaleffectstheeffectsmediatedbychangesinlifestyle
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Pharmaco-dynamics:introduc-on• excita;on(some;mesofneuronalinhibi;on)
• inhibi;on(some;mesofneuronalexcita;on)
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GABA:thevarietyofac-onsofethanol
Försteraetal.,Fron/ersinCellularNeuroscience2016;10,114
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Sitesofac-onforallostericmodula-onofGABAAreceptors
• A:upperview;puta;vesubunitstoichiometryandglobalarchitectureoftheαβγ/δGABAAR,showingthebindingsitesforGABAandbenzodiazepines
• B:lateralview;suggestedbindingsitesforethanol(red)andpicrotoxin(blue)
Försteraetal.,Fron/ersinCellularNeuroscience2016;10,114
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Fetalalcoholspectrumdisorders
• Earlymortality;abnormalappearance;percep;onimpaired
• WiderangeofCNSabnormali;es• Neuraltube,corpuscallosum,cerebellum• Reduc;onofnumberofstemcells• Increasedneuronalprolifera;onandmigra;on• Delayinneuronaldifferen;a;on
• Neurodevelopmentalimpairments• InalmostanydomainofCNSfunc;on
9 Burdetal.,JournalofPerinatology2012;32,652-659;Waltman&Iniquez,
ObstetricsandGynecology1972;40,180-185
Ethanolinthemotherandchild
• IntheUSA12.5%ofpregnantwomenreportedsomealcoholuse,and1.6%frequentuse(2001)
• FASDprevalencees;matesrangefrom0.2to50per1000livebirths
• U.S.es;matedFASannualincidence8,000-28,000
• Alcoholdetectableinfetus1minaJermaternalinges;onbutconcentra;onraisesmoreslowly
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FASDVariabili-es
• Metabolicelimina;oninpregnantwomenvarieseighUold(from0.0025to0.02 g dl−1 h−1)
• Atbirthphysiologicalchangesaltertheneonate'smetaboliccapacityanditrapidlyrisestoameanvalueof83.5%ofthemother'scapacity
• FASDsarehighlyrecurrentandyoungersiblingshaveincreasedrisk
• MothersofchildrenwithFAShavebeenfoundtodrinkfaster,getdrunkquickerandtohavehigherBACs
• Amodestincreaseintheprevalenceofapolymorphismofalcoholdehydrogenase,whichincreasessuscep;bilitytoadverseoutcomesfromPAEhasbeenreported
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Ethanolinmaternalbloodandinamnio-cfluid
Burdetal.,JournalofPerinatology2012;32,652-659
• Pathwaysofamnio;cfluidrecircula;on.27Produc;onandreuptakeareusuallynearequilibriumandthereforealcoholelimina;onthroughthesepathwaysishighlyineffec;ve.
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Pharmacokine-cs
• Absorbedrapidlyinthestomachandintes;nes,largelyinduodenum
• gastricemptyingrateimportant
• Distribu;onfreelyinwater• watercontentimportant(largerinmalesandyoungerpeople)
• Metabolized(morethan90%)toacetaldehydemostlybyalcoholdehydrogenase(mainlyClassI),subsequentlyoxidizedtoacetatebyacetaldehydedehydrogenase
• Inchildren(<5)alcoholdehydrogenaseisimmaturebutother,microsomalenzymesoperate;oxida;onbycatalaseispossiblyunimportantinvivo
Zuccoo&Fabiano,ExpertOpiniononDrugSafety2011;10,499-502;Marek&KraJ,CurrentTherapeu/cResearch:ClinicalandExperimental
2014;76,90-97
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Ethanolpharmacokine-csandneonatalfactors
• Redboxesshowwhereinfantsdifferfromadults
Marek&KraJ,CurrentTherapeu/cResearch:ClinicalandExperimental2014;76,90-97
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Acuteeffectofethanolonglutamatereceptors
Möykkynen&Korpi,Basic&ClinicalPharmacology&Toxicology2012;111,4-13
• Ethanolcannon-compe;;velyinhibitglutamatereceptorsatclinicallyrelevantconcentra;ons
• NMDAreceptorsaremoresensi;ve(25mM;about1.1‰BAC)
• KainateandAMPAreceptorsinsomecondi;onssensi;ve
• Inhibi;onmostlyinhippocampus,amygdalaandstriatum
• Maybepartoffoetalalcoholsyndrome
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TR Insel Nature 468, 187-193 (2010) doi:10.1038/nature09552
Thedevelopingbrain
• prolifera;onandmigra;onofneuronsalmostcompleteatbirth
• arboriza;onnearcomplete,myeliniza;onproceedsun;l5
• prefrontalexcitatorysystemindynamicdevelopmentun;l18,inhibitory–un;l30
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Wedoprobablyknow…notenough
• Usedasanexcipientinmorethan700liquidprepara;onsthatmaybeadministeredtoneonates,infantsandchildren(Zuccoo&Fabiano,ExpertOpiniononDrugSafety2011;10,499-502)
• “Ethanolispresentinmorethan700pharmaceu;calprepara;ons,ostensiblyasan“inert”solventordiluent”(AmericanAcademyofPediatricsCommiIeeonDrugs,Pediatrics1984;73,405-407,ci;ngPetroni&Cardoni,DrugTherapy1978;8,72-93)
• Safetystandards(FDA,AAPCD,EMA)nowinplacebutscien;ficevidencemeagre(Marek&KraJ,CurrentTherapeu/cResearch:ClinicalandExperimental2014;76,90-97)
• Importantchangestakingplace(e.g.,removalofethanolfromoralmorphinesolu;ons)
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Excipient databases, including alcohol
Salunkeetal.,Interna;onalJournalofPharmaceu/cs2013;457,310-322;Salunke&Tuleu,Interna;onalJournalofPharmaceu/cs2015;492,316-331
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Alcoholintoxica-onininfants
• Rarelyreported• Butmorecommonthanacknowledged• Alcoholmixedintobabyformula,givenasspongebath,umbilicalcorddressing
• Bloodlevelsmeasured<100to>400mg/dL• Elimina;onratemostlyasinadults• Acutealcoholwelltolerated:recoveryfastandnolong-termconsequencesreported
• Case:9-weekoldmale,9.5kg;receivedbabyformulawithappr.90mlofvodka,HR=160,respira;on22,temperature97.7F;BAC330mg/dL;dazedatadmissionbuthappyin1h
Minera&Robinson,JournalofEmergencyMedicine2014;47,524-526
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Case Report: Alcohol elimina3on over 3me
• BACdatalimitedto2+1points
• extrapolated21.6mg/dL/h
• thiswouldbeclosetoolderchildrenandadults
• veryhighratehasbeenreportedbutalsodatalimita;ons
Minera&Robinson,JournalofEmergencyMedicine2014;47,524-526
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Afewmorecases
• IT:whitewinemixedinto1-monthold’sformula;BAC75mg/dL,decreaseinconsciousness,tremor,fever;normalat1year(Palanoetal.,MinervaPediatr2007;59,275-279)
• US:vodkain7-monthold’sformula;BAC183,tachycardia,mildhypotension(Chikwavaetal.,PediatrDevPathol2004;7,400-402)
• GB:18-montholdgirldrank200mlofparacetamolelixir(10%ethanol);es;matedBAC187,GlasgowComaScale3,hypotensive,recoveredin24h(Toveyetal.,JAccidEmergMed1998;15,69-70)
• Threecasesofintoxica;onbyabsorp;on,withlargelysimilaroutcomes
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Alcoholintoxica-onininfants
• CDCrecords:oneinfantdeathduetoalcoholintoxica;onbetween1995and2007
• Butin2012alone1,349ethanolexposuresofchildren<5yearsreportedtotheAmericanAssocia;onofPoisonControlCentres
• Sevencaseswerechildrenyoungerthan18months,oneoftheseiatrogenic
• recoveryusuallygood,noabnormalityatfollow-ups
• Conclusively,intoxica;onsarenotrarebutmostlyoccurathomeandarenotfatal
Minera&Robinson,JournalofEmergencyMedicine2014;47,524-526
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Mostlynewbornshavelowercapacitytoeliminatealcohol
Burdetal.,JournalofPerinatology2012;32,652-659
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Inges-nghouseholdproducts
• Manyproductsmaycontainsignificantamountofalcohol,especiallymouthwashes,handsani;zers,cosme;cs
• Poisoningswiththeseproductsareinyoungchildrenseveralfoldmorefrequentthanwithalcoholicbeverages
• Thetrendisontheincrease• Hypoglycemiaisthemostcommonadverseeffect• Seizuresanddeathhaveoccurred• Lethaldoseisthoughttobeabove6ml/kgof100%alcoholingestedinonehour(Mofensonetal.,EmergMedClinNorthAm1984;2,159-174)orsomewhatless(3g/kg;Vogeletal.,JToxicolClinToxicol1995;33,25-33)sonotverylikelywithamedicalproductbutnotunthinkablewithsomesani;zers
Rayar&Ratnapalan,ClinicalPediatrics2012;52,203-209
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Druginterac-ons
• absorp;on,metabolism• enhancedpsychomotorinhibi;onwithseda;ves• enzymeinduc;on(P450;relevanttophenobarbital,phenytoin,meprobamate,warfarin)
• disulfiramreac;ons(flushing,tachycardia,nausea,vomi;ng;cardiacarrhythmias,cardiovascularcollapse,respiratorydepression,convulsions)possiblewithsimultaneousmoxalactam,metronidazole,sulfonamides,chloramphenicol,cefamandole
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Dopamine release after administration of ethyl alcohol in humans in dorsal and ventral striatum �(PET, [11C]-raclopride)
Urban et al., Biol. Psychiatry 2010, 68: 689-696)
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Whathappenswithadolescentdrinking
• Inhumans(12-18years)• infuturedrinkers:lowercogni;veinhibi;onandfrontalresponse
• reduc;onina|en;onandvisuospa;alfunc;oning• increasesinfrontalresponses• reduc;onoffrontolimbicwhitema|erintegrity
• Animalstudies(rat28-42days)• lessmotorimpairmentascomparedtoadults• lessreduc;oninPurkinjeneuronresponse• reduc;oninhippocampalvolume
Squegliaetal.,Alcoholism:ClinicalandExperimentalResearch2014;38,2509-2516
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ChroniceffectsofethanolonGABA-andglutamatergicneurotransmission
Roberto&Varodayan,Neuropharmacology2017;35,85-99
• Excitatoryglutamatergicneurotransmissionisincreased
• ComplexchangesinGABA-ergicneurotransmission
• releasealtera;onregion-dependent(GABAB)
• postsynap;cGABAAreceptorcomposi;onchange
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Theburdenofalcoholuseinchildren
• Thestudyofalcoholusebychildren<12yearsisverylimited
• Burdenislowinchildhoodbutearlyusemayhavelong-termconsequences
Donovan,AlcoholResearch2014;35,186-192
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exposure is changing with the involvement of gene × environment interactions
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EstonianChildrenPersonalityBehaviourandHealthStudy(ECPBHS)
Popula;onrepresenta;ve(specificsonEYHSsubsample):Schoolasasamplingunit(54of56eligibleschoolsagreed)Probabilitypropor;onaltoschoolsize,25schoolsselectedAllchildrenofgrades3and9invited,79.1%par;cipatedDuringthemostrecentfollow-ups,about80%oftheoriginalsamplerecruited
(Mul;)birthcohort
Longitudinal(seebelow)Mul;disciplinary
Familyaggrega;on
Es;ma;onofeffectsizeforpopula;on
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ECPBHS-melinesEYHSsample(79.1%)
1998/99
9-y(583)
15-y(593)
IDEFICSsample(54.5%)
2007/08 (n=1719)
3-y
7-y
15-y(483)
18-y(417+62)
25-y(541)
18-y(457)
5-y 9-y
9-y 18-y
2009/10(1334+431) 2013/14(1048+287)2018/19
33-y(n=501)
2011/13(1414)
Parents
200120042007200820142016 2022
EstonianChildrenPersonalityBehaviourandHealthStudywww.ecpbhs.ee
13-y
25-y(440)
Parents?
33-y
14-y
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Varia-onoftheSerotoninTransporterGene:ATool
toDissectIndividualDifferences
5-HTTLPR
Leschetal.,Science1996
CourtesyofKlaus-PeterLesch
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Alcoholuseissubjecttobirthcohorteffects–andthisis5-HTTLPRdependent
Vahtetal.,Psychopharmacology2014,231:2587-2594;Harro&Vaht,inTheNeuroscienceofAlcohol.Elsevier2018
•
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Conclusively,pharmacologyeverywhere
• Thereisapharmacologicalagentthat• isbroadlyavailable• inalargevarietyedibleandnon-edibleformats• canbeconsumedinvoluntarily,accidentallyordeliberately• isincreasinglyreportedtocausepoisoningsinchildren• hasthepoten;altobelethal• canbeinvolvediniatrogeniccases• leadstoseriousaltera;onsindevelopmentofthebrain• isgeongintotheorganismsofeveryoungerhumanbeings
• …andremainspartofadulteverydaylife,some;mesevenreferredtoasaquavitae
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