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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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