Upload
others
View
7
Download
0
Embed Size (px)
Citation preview
10/10/19
1
PediatricPharmacology:WhatItMeansToYourClinicalPractice
SuzanneTinsleyPhD,PT,NCSAssistantDeanforDevelopment
ParksEndowedProfessorshipinNeurologicalRehabilitationAssociateDirectorNeurorehabilitationServices– CenterforBrainHealth
DepartmentofRehabilitationSciencesDepartmentofNeurology
LouisianaStateUniversityHealth-Shreveport
MarieVazquezMorganPT,PhDAssociateProfessor
DepartmentofRehabilitationScienceLouisianaStateUniversityHealth- Shreveport
Outline
• PharmacologyinthePediatricPopulation• OverviewofImportantPharmacologyPrinciples• CommonPediatricDrugClasses• ImpactofDrugTherapyonDevelopment,AcademicsandTimingofInterventions
• ImpactofNutritiononNeurodevelopmentalDisorders
• ImpactofOpioidEpidemiconChildren• Development• NeonatalAbstinenceSyndrome
10/10/19
2
InternationalClassificationofFunctioning,DisabilityandHealth- ICF
Health Condition (disorder or disease)
Body Functions & Structures
Activity Participation
Environmental FactorsPersonal Factors
Contextual Factors
3
GeneralPrinciples
• SideEffects/AdverseDrugReactions• HalfLife• PotencyvsEfficacy• Pharmacotherapeutic DifferencesinPediatricPopulations
10/10/19
3
Definitions
• Therapeuticeffect – intendedordesiredeffectofthedruggiven.• Sideeffect/adversedrugreactions(SE/ADR)
• Effectsotherthanthedesiredeffects.• Anyunintendedorunwantedeffectofadrugthatmayoccuratacceptabledoselevels.(WHO)
• Toxiceffects – sideeffectsthatarepotentiallyharmfulorlife-threatening.• Theappearanceoftoxiceffectsusuallyrequiresthatthedosebereducedorthedrugstopped.
5
• ThreetypesofSE/ADR• Mechanismbased
• Usuallydoserelated• Samereceptororreceptortypesinthegiventissueorindifferenttissues
• Off-targetbased• Notaconsequenceofthedrug�sprimarymechanismofactionbutaconsequenceoftheparticulardrugmolecule.
• Idiosyncraticinnature• Interactionofthedrugwithuniquehostfactors
• Mechanismbased• Off-targetbased
6
10/10/19
4
• ThreetypesofSE/ADR• Mechanismbased
• Bronchoconstrictionwithanon-selectiveβ-blocker• Sedationwithananti-histamine
• Off-targetbased• Hepatotoxicityofacetaminophen
• Idiosyncraticinnature• Mechanismbased
• AngioedemaseenwithACEinhibitors• Off-targetbased
• Anaphylaxistopenicillin
7
• Reasonsaremany• Age• Inadequatehistory• Drugselectivity
8
10/10/19
5
• Elimination• Half-life
• Thetimerequiredforthebloodorplasmaconcentrationofthedrugtofalltohalfofitsoriginallevel.
• Itisdeterminedbybiotransformation/metabolismandexcretion.
• 4-5half-livesfor>90%ofthedrugtobeeliminatedfromthebody.
9
10/10/19
10
10/10/19
6
10/10/19
11
Dose– ResponseRelationship• Dose-Response-Curve – therelationshipbetweenthedosageofadrugandaspecificresponsetothedrug.
• Thresholddose• CeilingeffectorMaximalefficacy
Re
sp
on
se
Dose ( log scale )
Threshold
dose
Ceiling effect
10/10/19
BasicConceptsinPharmacology
Potency – itisameasureofthestrength,orconcentration,ofadrugrequiredtoproduceaspecificeffect.
12
Decre
ase in M
ean A
rterial P
ressure
(5)
Dose
25
50
Drug A
Drug B
10/10/19
7
13
10/10/19
BasicConceptsinPharmacology
PatientAhashypertensionaveraging150/90– Whichdrugwouldworkbestforhim?PatientBhashypertensionaveraging190/100– Whichdrugwouldworkbestforhim?
14
Decre
ase in M
ean A
rte
rial P
ressure
(5)
Dose
25
50
Drug A
Drug B
10/10/19
8
10/10/1915
• Gradeddose-responsecurvesfor3drugsdifferinginmaximalefficacyandpotency.(Emax =maximumeffect)
Re
sp
on
se
Dose (log scale)
A
B
CEmax Drug A
Emax Drug B
Relative
efficacy
Relative potency
10/10/19
• Gradeddose-responsecurvesfor2drugs,differinginmaximalefficacyandpotency,usedtotreatpain.
16
Dose mg (log scale)
\
Level of effects
of
reducin
g p
ain
A
B
Min.
Mod.
Severe
Ceiling effect
10/10/19
9
Pharmacotherapeutic DifferencesinPediatricPopulations
Pharmacologic effect
Clinical Response
Toxicity Efficacy
Drug concentration in
system circulation
Dose of drug
administered
Drug Concentration
at site of action
Drug in tissues of distribution
Drug metabolized or excreted
PK
PD
Absorption
Elimination
Distribution
10/10/19
10
• ClinicalRelevanceofTheseBasicPrinciples• IndividualVariation
• Age• Geneticmake-up• Bodyweight&composition• Physiologicalvariables
• Druginteractions• Pathologicalfactors
• Disease
• Thephysiologiccontextsinwhichthesepharmacologicalprinciplesoperatearedifferentinrapidlymaturinginfants,children,adults,andtheelderly.
• Pharmacokinetics• Pharmacodynamics
DrugTherapyinInfantsandChildren
• Drugabsorption• Bloodflow• GIfunction
• Drugdistribution• Neonate70-75%bodyweightiswater• Adult50-60%bodyweightiswater
10/10/19
11
Oraldrugabsorption(bioavailability)ofvariousdrugsintheneonatecomparedwitholderchildrenandadults
• Acetaminophen• Ampicillin• Diazepam• Digoxin• Penicillin• Phenobarbital• Phenytoin• Sulfonamides
• Decreased• Increased• Normal• Normal• Increased• Decreased• Decreased• Normal
• DrugMetabolism• Allacrosstheboard• Neonateshaveadecreaseinliverenzymesearly• Children(toddlers)haveanincreaseinliverenzymeactivityforsomedrugsandadecreaseforothers.
• Doseofdigoxinintoddlersismuchhigherthanadults.
10/10/19
12
Approximateeliminationhalf-livesofvariousdrugsinneonatesandadults.
DRUGS Neonatal Age
Neonatal half-life
(hrs)
Adult half-life
(hrs)Acetaminophen
2.25 0.9-2.2
Diazepam 25-100 40-50Phenobarbital
0-5 days5-15 days1-30 months
20010050
64-140
Phenytoin 0-2 days3-14 days14-50 days
80186
12-18
• DrugExcretion• GFRismuchlowerinnewbornsthaninolderinfants,children,oradults.• GFRreachesadultvalueby6-12months.
10/10/19
13
• PediatricDrugAdministration• Astandardmedicationdosageisnearlynonexistentinpediatrics.• Amountofmedicationsareusuallyorderedbodysurfacearea.• Weightalone shouldnotbeused.
• Childrenarenotsmalladults.
• BodySurfaceArea• Calculatedfromheightandweight• Standardnomogram
• Approximatepediatricdose=BSAXAdultdose/1.73
10/10/19
14
PolypharmacyDefinitionnToomanymedicationsoruseofunnecessarydrugsnUseofmorethanonemedicationtotreataspecificpathophysiologynWorldHealthOrganization
• FiveormoremedicationsusedempiricallyvPolypharmacy (>5)
• Excessivepolypharmacy (>10medicines)
AutismSpectrumDisorder
10/10/19
15
ASD• DiagnosticandStatisticalManualofMentalDisabilities(5th edition)–includesautism,Asperger’sdisorder,and“pervasivepersonalitydisordernototherwisespecified”
• Symptomsappearbetweentheagesof2-3yearscharacterizedbydifficultyindevelopingsocial,speechandbehavioralskills
• Behavioraltherapyisusuallythefirst-linetreatment,withdrugtherapyaddedtohelppatientsfunctions
• DrugTherapy:Approvedandoff-labelpharmacotherapiesoptionsforthevarioussymptomsofASD
ASDDrugClasses
• Anti-psychoticDrugs• risperidone,aripiprazole,clozapine,haloperidol
• CNSStimulants• methylphenidate
• Anti-Depressants• venlafaxine,fluoxetine,mirtazapine,citalopram
• EndogenousHormone• Oxytocin,secretin,melatonin
• Cholinergics (ACHesteraseAntagonists)
• rivastigmine
• Glutamatergics (NMDAAntagonists)
• memantine
10/10/19
16
Anti-psychoticDrugs
• PsychoticBehaviors- groupofdisorderswhichinclude:• breakdownofthepersonality• thoughtdisturbances• impairedperceptionofreality• inappropriatebehavior– Irritability,aggression,
• Schizophrenia• Bipolaraffectivedisorder• Severedepression
Psychosis• disorderedthinking,
emotionalwithdrawal,delusions,hallucinations
• Relativeexcessoffunctionalactivityofdopamineinthebasalganglia
SN
STRIATUM
FRONTAL CORTEX
DA
GLU
-
+
GABA-
-
10/10/19
17
AntipsychoticDrugs• �Neuroleptics�• blockdopaminergicreceptors(D2)andserotoninreceptors(5-HT2)inthelimbicsystemandstriatum• adverseeffects
• CNS• extrapyramidaleffects• sedation
• ANS• anticholinergic(e.g.,drymouth,constipation)• posturalhypotensionduringinitializationoftherapy(duetoα receptorblocking)
• Weightgain
Antipsychotics,extrapyramidaleffects
• acutedystonia--musclespasmsofface,tongue,neck,back• akathisia--motorrestlessness• Pseudo-Parkinsonism--rigidgait,tremors• TardiveDyskinesia
• occursafterlong-termtherapy• repeatedchoreiform movements--involuntarymovementsoflips,jaws,tongue,extremities
• irreversible
10/10/19
18
AntipsychoticDrugs,typical• Haloperidol(Haldol®)
• haloperidolwasmoreeffectivethanthesecond-generationantipsychoticdrugs(atypical)atreducingaggressioninchildrenwithautism(ages2- adult)(McDonaldetal2010,Clintonetal1987)
• Mosteffectivetotreatprominentsymptomsofirritability,anger,anduncooperativeness
• MOA:highlypotentandselectiveD2receptorantagonist.• AE:acutedystonicreactions,dyskinesias,andsedation,severeextrapyramidaleffects
AntipsychoticDrugs,atypical
• Risperidone(Risperdal®)• firstdrugapprovedbytheFDA(2006)totreatautism-relatedirritability.4
• It’sapprovalappliedtochildren5yearsofageandolder.–• Usefulintreeating ASDaccompaniedbyseveretantrums,aggression,orself-injuriousbehavior.
• MOA:antagonizesDA(D2)andserotonin5-HT2receptors• AE:increasedappetite,dizziness,drooling,drowsiness,andfatigue
• Veryfewextrapyramidalsideeffects
10/10/19
19
AntipsychoticDrugs,atypical
• Clozapine(Clozaril®)• usedforaggressionandtantrums(widelyusedpriortotheaproval ofnewer2nd generationdrugs
• MOA:fewextrapyramidaleffectsbecauseblocksDA(D2)primarilyinlimbicbrainregionsand5HTactivity.Thedrugalsoactsasanantagonistatadrenergic,cholinergic,histaminergic,andotherdopaminergicandserotonergicreceptors.13
• AE:weightgain,metabolicsyndrome,tachycardiaandagranulocytosis(bonemarrowsuppression).Inhighdosagesmayalsocauseseizures
• Notcurrentlyusedasafirstlinedrugfortreatmentinchildren
AntipsychoticDrugs,comboMOA
• Aripiprazole(Abilify®)• Indicatedforthetreatmentofirritabilityinchildren(ages6to17years)withASD.
• MOA:unknownbutmayinvolveacombinationofpartialagonistactivityatdopaminetype2(D2)andserotonintype1A(5-HT1A)receptorsandantagonistactivityat5-HT2A receptors.
• AE:weightincrease,extrapyramidalsystems,increasedappetite,pyrexia,fatigue,andinsomnia
10/10/19
20
AntipsychoticDrugs
• RisperidoneVersusHaloperidolforAberrantSocialBehavior• Miral etal(2008)reportedrisperidonewasmoreeffectivethanhaloperidolintreatingsocialbehavior,althoughbothdrugshadsignificanteffectsonthechangefrombaselineinchildrenages8-18.
• MeasuredbytheAberrantBehaviorChecklist• However,thehaloperidolgrouphadsignificantly(P=0.0477)morereportsofthedevelopmentorworseningofextrapyramidalsymptoms.
ASDDrugClasses
• Anti-psychoticDrugs• risperidone,aripiprazole,clozapine,haloperidol
• CNSStimulants• methylphenidate
• Anti-Depressants• venlafaxine,fluoxetine,mirtazapine,citalopram
• EndogenousHormone• Oxytocin,secretin,melatonin
• Cholinergics (ACHesteraseAntagonists)
• rivastigmine
• Glutamatergics (NMDAAntagonists)
• memantine
10/10/19
21
CNSStimulants• Methylphenidate(Ritalin ®,Novartis ®,Concerta ®,Janssen ®)
• MildCNSstimulantindicatedforattention-deficitdisordersandnarcolepsyassociatedwithASD
• Methylphenidatewassuperiortoplaceboontheteacher- ratedhyperactivitysubscaleoftheABC(2008PediatricPsychopharmacologyAutismNetworkTrial)
• MOA:blocksthereuptakeofnorepinephrineanddopamineintothepresynapticneuronandincreasesthereleaseofthesemonoaminesintotheextraneuronal space.
• AE:decreasedappetite,increasedirritability, andsocialwithdrawal,
Anti-DepressantDrugs
• PathogenesisofMajorDepression• AmineHypothesisofMood
• afunctionaldecreaseintheactivityofNEand5-HTisthoughttoresultindepression
• AfunctionalincreaseinactivityoftheseNTsresultsinmoodelevation
42
10/10/19
22
Anti-DepressantDrugs
• MedicationsusedtoTreatDepression
• MonoamineOxidaseInhibitors(MAOIs)
• AmineUptakeBlockers• Tricyclics(TCAs)– nonselective• SelectiveSerotoninReuptakeInhibitors(SSRIs)
• α2 Blockers
43
44
10/10/19
23
Anti-DepressantDrugs
• Venlafaxine(Effexor®)• Fluoxetine(Prozac®)• Citalopram(Celexa®)• Mirtazapine(Remeron®)
45
Anti-DepressantDrugs
• Venlafaxine(Effexor®)• Traditionallyforthetreatmentofmajordepressivedisorder,generalizedanxietydisorder,socialanxietydisorder,andpanicdisorder.
• Carminatietalshowedlow-dosevenlafaxine,inadditiontothepatient’scurrentantipsychoticregimen,couldimproveself-injuriousbehaviorandADHD-likesymptoms.
• MOA:serotoninandnorepinephrinereuptakeinhibitor(SNRI)• AE:
46
10/10/19
24
Anti-DepressantDrugs• Fluoxetine(Prozac®)
• Traditionallyindicatedforacuteandmaintenancetreatmentofmajordepressivedisorder,obsessivecompulsivedisorder,bulimianervosa,andpanicdisorder.
• Showntoimprovementinrepetitivebehaviorsamongadults(18-60yo)withASD(Hollanderetal2015)
• IntheStudyofFluoxetineinAutism(SOFIA-2015),alow-dose,melt-in-the-mouthformulationofthefluoxetinewasfoundtobenomoreeffectivethanplacebointreatingrepetitivebehaviorsinchildrenandadolescents(5to17yearsofage)withASD.
• MOA:selectiveserotoninreuptakeinhibitor(SSRI)• AE:mild-to-moderateinsomnia,headache,anddrymouth.
47
Anti-DepressantDrugs• Citalopram(Celexa®)
• Traditionallyindicatedforthetreatmentofdepression• OftenprescribedinchildrenwithASDforthetreatmentofrepetitivedisorder• Kingandcolleagues(2009)foundthatcitalopramwasineffectiveintreatingchildren(5to17yearsold)withASD,includingAsperger’sdisorderandunspecifieddevelopmentaldisorders.
• MOA:selectiveserotoninreuptakeinhibitor(SSRI)• AE:(SeeninchildrenwithASD)increasedenergylevel,impulsiveness,decreasedconcentration,hyperactivity,stereotypy,diarrhea,insomnia,anddryskinorpruritus.
48
10/10/19
25
Anti-DepressantDrugs
• Mirtazapine(Remeron®)• tetracyclicantidepressantthatenhancescentralnoradrenergicandserotonergicactivity
• Poeandcolleaguesshowedthatmirtazapinewaseffectiveinimprovinginsomniachildren,adolescents,andyoungadults(4to24yearsofage)withASDandotherdevelopmentaldisorders.
• Thetreatmentalsosignificantlyimprovedaggression,self-injury,andirritability
• MOA:serotoninandnorepinephrinereuptakeinhibitor(SNRI)• AE:increasedappetiteandtransientsedation.
49
WithdrawalSyndrome
• Occurswithabruptcessationofdrugtherapyfromtricyclics&SSRIs• Nausea,dizziness,anxiety,palpitations
• Ifyouaregoingtostoptakingthesemedicationsyoumustweanoffthedrugsslowly
• Thesesymptomscanoccurwithmissingasingledose
50
10/10/19
26
Anti-DepressantDrugs&Children• Ingeneral,antidepressantshavebeenassociatedwithanincreasedrisk,comparedwithplacebo, ofsuicidalthinkingandbehaviorinchildren,adolescents,andyoungadultsinshort-termstudiesofsubjectswithmajordepressivedisorderandotherpsychiatricdisorders.Therefore,thisriskmustbebalancedwiththepatient’sclinicalneedwhenanyantidepressantisusedinchildren,adolescents,oryoungadults.
• Parents&caregiversshouldbeawareofwarningsigns• Agitation,irritability,suddenchangesinbehavior
51
ASDDrugClasses
• Anti-psychoticDrugs• risperidone,aripiprazole,clozapine,haloperidol
• CNSStimulants• methylphenidate
• Anti-Depressants• venlafaxine,fluoxetine,mirtazapine,citalopram
• EndogenousHormone• oxytocin,secretin,melatonin
• Cholinergics (ACHesteraseAntagonists)
• rivastigmine
• Glutamatergics (NMDAAntagonists)
• memantine
10/10/19
27
EndogenousHormones
• Oxytocin(Pitocin)• Secretin• Melatonin
EndogenousHormones• Oxytocin(Pitocin)
• Oxytocinplaysamajorroleinrelationshipformationandsocialfunctioninginbothhumansandanimals
• Gordonetal(2015)measuredchangesinbrainactivityduringjudgmentsofsociallyandnon-sociallymeaningfulpicturesin17childrenwithASDaftertreatmentwithintranasaloxytocin.Theyfoundthatoxytocinenhancedbrainfunctioninthesesubjectsandappearedtoimprovetheirevaluationsofthesociallymeaningfulstimuli.
• ASystemtic review(2014)identified“potentiallypromising”findingsinmeasuresofemotionrecognitionandeyegaze,whichareimpairedearlyinthecourseofASDandmightdisruptthelearningofsocialskillsindevelopingchildren.Theauthorsconcludedthatlong-termoxytocinnasalsprayappearedtobeapromisingtreatmentforthesocialimpairmentsofASD.
10/10/19
28
EndogenousHormones
• Secretin• Secretinregulatesexocrinesecretionsinthestomach,pancreas,andgallbladder.Italsoactsasaneuropeptideinthecentralnervoussystem(CNS).Itishypothosized totreatsocialaberrantbehavior
• 2systematicreviewsdemonstratednosignificantlygreaterimprovementsinmeasuresoflanguage,cognition,orautisticsymptomscomparedwithplacebo.
• TheyconcludedthatsecretinshouldnotberecommendedoradministeredasanASDtreatment.
EndogenousHormones
• Melatonin• Highlyrecognizedtobeusefulininducingandmaintainingsleep• MelatoninimprovedsleeplatencyinchildrenwithASD
• Regimin suggest1-3mg30minbeforebedtime.• CortezetalandMalow etal
10/10/19
29
Cholinergics (ACHesterase Antagonists)
• Rivastigmine (Exelon,Novartis)• isindicatedforthetreatmentofmild-to-moderatedementiaoftheAlzheimer’stypeandmild- to-moderatedementiaassociatedwithParkinson’sdisease.
• Chezetal(2004)foundsignificantimprovementsfrombaselineincognitionwereseenintheCARSscoresin32children(ages3to12years)
• MOA:it’saacetylcholinesteraseinhibitor.Itisthoughttoexertitstherapeuticeffectsbyenhancingcholinergicfunction
• AE:similartothosereportedinadultstreatedwithrivastigmine (e.g.,nausea,diarrhea,irritability,andhyperactivity).
Glutamatergics (NMDAAntagonists)
• Memantine (Namenda)• Memantine isanN-methyl-D-aspartate(NMDA)receptorantagonistindicatedforthetreatmentofmoderate-to-severedementiaoftheAlzheimer’stype.PersistentactivationofNMDAintheCNSisbelievedtocontributetothesymptomsofAlzheimer’sdisease
• Owley etalshowedasignificantimprovementfrombaselinewasnotedinamemoryevaluation(P=0.021).However,therewerenosignificantdifferencesfrombaselineonmeasuresofexpressivelanguage,receptivelanguage,andnonverbalIQ.
10/10/19
30
DrugTherapyvsASDBehavioralSymptoms
• IrritabilityandAggression• risperidone,aripiprazole,clozapine,haloperidol,sertraline
• AberrantSocialBehavior• risperidone,haloperidol,oxytocin
• ADHD/HyperactivityandInattention
• Methylphenidate,Venlafaxine
• CognitiveDisorder• Memantine,rivastigmine
• RepetitiveBehaviors• fluoxetine,Citalopram,Bumetanide
• Insomnia• Mirtazapine,melatonin
ADHD/ADDMedications
10/10/19
31
• ADHD• Poorlydefinedandover-diagnosedbehavioralsyndromeconsistingofshortattentionspan,hyperkineticphysicalbehavior,andlearningproblems
SympathomimeticDrugs
• CNSEffects• Mildalerting***• Improvedattentionstoboringtasks***• Elevationofmood• Insomnia• Euphoria• Anorexia• Full-blownpsychoticbehavior
10/10/19
32
SympathomimeticDrugs
• AmphetaminevariantswithefficacyinchildrenwithADHD• Methylphenidate(Ritalin®)• Pemoline (Cylert®)• Modafinil (Provigil®)
• Methylphenidate(Ritalin®)andPemoline (Cylert®)• Amphetaminevariantswhosemajorpharmacologicaleffectsandabusepotentialaresimilartothoseofamphetamines
10/10/19
33
• Modafinil (Provigil®)• Newamphetaminesubstitute• Effectscentral⍺-1receptorsaswellasappearstoaffectGABAergic,glutaminergic andserotonergicsynapses
• Fewerdisadvantagesthatamphetamine
10/10/19
34
• ADR/SideEffects• Excessivemoodchanges• Insomnia• Weightloss• Abusepotential
ImpactofADHDMedicationonAcademics• Currieetal(2016).ExaminedwhethertheincreaseinADHDmedicationusewasassociatedwithimprovementsinemotionalfunctioningoracademicoutcomesamongchildrenwithADHD.Theyfoundlittleevidenceofimprovementineitherthemediumorthelongrun.Theysuggestthatexpandingmedicationinacommunitysettinghadlittlepositivebenefitandmayhavehadharmfuleffectsgiventheaveragewaythesedrugsareusedinthecommunity.
• NIMHsponsored theMultimodalTreatmentofADHD(MTA)study(2009).CombinationtreatmentandmedicationmanagementalonewerebothsignificantlysuperiortointensivebehavioraltreatmentaloneandtoroutinecommunitycareinreducingADHDsymptoms.
10/10/19
35
TheGutà BrainConnectionASD,ADD/ADHD
MarieVazquezMorganPTPhDAssociateProfessor
LSUHealthShreveportDepartmentofRehabilitationSciences
MitochondrialDysfunctionandDisease
• Autism• Bipolard/o• Depression• Parkinson’sDisease• Asthma• GIdisorders
10/10/19
36
TriggersforMitochondrialDysfunction
• Genemutations
• Shortagesofkeyvitaminsandmineralsindiet
• Chemicals,heavymetalsanddrugs
• Bacteriaandviruses
• Stress
AgentsforMitochondrialDysfunction
• Vitamins• C,D.E,thiamin,riboflavin
• Minerals• Magnesium,calcium,phosphate
• Lipids• Membranephospholipids,unsaturatedfattyacids
• Antioxidants• CoQ 10,alphalipoic acid
• Herbs• Curcumin
10/10/19
37
TheGut
• Microbiome• Allorganismsandgeneticmaterialinbody
• Microbiota• Populationsofmicroorganismspresentinecosystemsi.e.gut
• Humangutmicrobiota– morethan1,000speciesandover7,000subspeciesofmicroorganisms
ImportanceofGI Health
• Immune:– Physicalbarrierofdefenseagainstbacteria,viruses, etc.– Largestpartoftheimmunesystem(70%)foundinthe gut
• Neurotransmitters:– Greatestamount(90%)ofthe“brainchemical”serotoninisfoundintheGI tract– Aminoacids(absorbedfromproteindigestion)areprecursorsforneurotransmitters
• Fullbody function:– Vitamins/mineralsabsorbedinthegutarecofactorsforenzymereactions,metabolism,conversionofnutrientsand fat
�Alldiseasebeginsinthe gut�--Hippocrates,thefatherofmodernmedicine
10/10/19
38
Gut- BrainConnection
Gut- BrainConnection
10/10/19
39
LeakyGutDefined..
• Conditionof“hyperpermeableintestine”or“increasedintestinalpermeability”
• Lininghasbecomemoreporous
• Screeningoutprocessisnolongerfunctioningappropriately
Prevalence?
• IntroductionofGMFs• Currently,80%offoodsinmainstreamgrocerystoresaregeneticallymodified
• Glyphosate(RoundUp)isthemostwidelyusedherbicideintheworld.• WhenGlyphosategetsintogut,itcanbindthebeneficialmineralsthatareneededtomaintainthathealthygutfloraandmakesthesemineralsunavailable.ThiscreatestheprocessofDysbiosis
• Throughdysbiosis,thebadbacteriacreatesholesintheliningofthewallsofthesmallintestineandcreatesaleakygut
10/10/19
40
PercentageofgeneticallymodifiedcropsintheU.S.in1997and2018,bytype(aspercentoftotalacreage)
TriggersforLeakyGut
• Stress• Antibioticandanti-inflammatorydrugs(NSAIDs)• Extendeduseofantacids• Gluten/Casein
• Increaselevelsofaprotein,whichopenupthespacesbetweentheintestinalcells
10/10/19
41
Body�s Effect on BrainADHD • Autism • ADD • Allergies • Anxiety
IMMUNE
Gut Inflammation
Poor pathogen fighting
Food sensitivities
DIGESTION
Leaky gut
Dysbiosis
Less nutrient absorption
DETOXIFICATION
Decreased detoxification
Food additives
NEUROLOGY
Brain Inflammation
Microbial toxins
Neurotransmitters
Nutrient deficiencies
10/10/19
42
Autismstudies
• SauerAK1,BockmannJ2,SteinestelK3,BoeckersTM4,GrabruckerAM5,6,7AlteredIntestinalMorphologyandMicrobiotaCompositionintheAutismSpectrumDisordersAssociatedSHANK3MouseModel. IntJMolSci.2019Apr30;20(9).
• EshraghiRS1,Deth RC2,MittalR3,Aranke M3,KaySS4,Moshiree B1,EshraghiAA3.EarlyDisruptionoftheMicrobiomeLeadingtoDecreasedAntioxidantCapacityandEpigeneticChanges:ImplicationsfortheRiseinAutism. FrontCellNeurosci.2018Aug15;12:256.
• VuongHE1,HsiaoEY2.EmergingRolesfortheGutMicrobiomeinAutismSpectrumDisorder. BiolPsychiatry.2017Mar1;81(5):411-423.
ADHD/OtherStudies• SandgrenAM1,Brummer RJM2ADHD-originatinginthegut?Theemergenceofanewexplanatorymodel.MedHypotheses.2018Nov;120:135-145.
• deMagistris L1,Familiari V,Pascotto A,Sapone A,Frolli A,Iardino P,Carteni M,DeRosaM,Francavilla R,Riegler G,Militerni R,Bravaccio C.Alterationsoftheintestinalbarrierinpatientswithautismspectrumdisordersandintheirfirst-degreerelatives.JPediatrGastroenterol Nutr.2010Oct;51(4):418-24.
• Prehn-KristensenA1,ZimmermannA1,2,Tittmann L2,Lieb W3,SchreiberS2,4,BavingL1,FischerA2.ReducedmicrobiomealphadiversityinyoungpatientswithADHD. PLoSOne.2018Jul12;13(7):e0200728.
• deTheije CG1,Bavelaar BM,LopesdaSilvaS,Korte SM,OlivierB,Garssen J,KraneveldAD.Foodallergyandfood-basedtherapiesinneurodevelopmentaldisorders. PediatrAllergyImmunol.2014May;25(3):218-26.
10/10/19
43
How Diet Can PossiblyHelpSupport Digestion & Biochemistry
• LeakyGutandGut Inflammation• Removefoodsthatinflame gut• Addfoodsthatreduceinflammationandheal• Addfoodsthatsupplybeneficialbacteria
• Nutrient Deficiencies• Increasethequalityoffoodand digestibility
• YeastOvergrowth• Remove sugars• Reducerefinedflourproductsand starches• Addprobiotic--rich foods
• ToxicityandPoor Detoxification• Avoidfood additives• Avoidtoxinsinfoodsupplyandmeal preparation
Parents Report withNutritionalInterventions
• GIproblems relieved• Diarrhea&constipation lessens• Improvedlanguageskillsand learning• Greaterfocusand attention• Reducedhyperactivity• Eyecontact• Moreappropriatebehavior• Better sleeping• Skinrashesoreczemaclearup
10/10/19
44
ADD/ADHD
DietHistoryADD/ADHD
• BenjaminFeingold-1970’s• Artificialfoodadditives(colorings/flavors)• Salicylaterichfoods
• Keyofflimitfoods/ingredients:• Artificialfoodcolors/dyes/flavors• Artificialfragrancesfoods/lotions/airfresheners• Artificialsweeteners• FoodpreservativesBHA,BHT,etc• Salicylates
10/10/19
45
HighSalicylates• Fruits: Raisins,prunes,apricots,blackberries,blueberries,cherries,cranberries,grapes,pineapples,plums,oranges,tangerines,strawberriesandguava.
• Vegetables:Broccoli,cucumbers,okra,chicory,endive,radish,zucchini,watercress,alfalfasprouts,eggplant,squash,sweetpotato,spinach,artichokesandbroadbeans.
• Spices:Curry,aniseed,cayenne,dill,ginger,allspice,cinnamon,clove,mustard,cumin,oregano,pimiento,tarragon,turmeric,paprika,thymeandrosemary.
• Othersources: Tea,rum,wine,cordials,vinegar,gravies,mints,almonds,waterchestnuts,honey,licorice,jam,chewinggum,pickles,olives,foodcolorings,savory-flavoredchipsandcrackersandfruitflavorings.
FeingoldDiet
• Phase1:Childavoidsfoodsorproductsthathaveingredientsonthelist.
• Phase2:Childcanbegintotrythesesamefoodsoneatatimetoseeifsymptomscomeback.
10/10/19
46
FeingoldDietEffectiveness
Trasande L,ShafferRM,Sathyanarayana S(2018).FoodAdditivesandChildHealth.Pediatrics,2018Jul23.
“Artificialfoodcolors,commoninchildren’sfoodproducts,maybeassociatedwithworsenedattention-deficit/hyperactivitydisorder(ADHD)symptoms.StudiescitedinthereportfoundasignificantnumberofchildrenwhocutoutsyntheticfoodcoloringsfromtheirdietsshoweddecreasedADHDsymptoms.”
FeingoldDietEffectiveness
• Vojdani&Vojdani, Immunereactivitytofoodcoloring. AlternativeTherapiesinHealthandMedicine,2015;21Suppl 1:52-62.
• “consumptioncanactivatetheinflammatorycascade,canleadtocross-reactivities,autoimmunities,andevenneurobehavioraldisorders.”
• “TheCentersforDiseaseControl(CDC)recentlyfounda41%increaseindiagnosesofADHDinboysofhigh-schoolageduringthepastdecade.“
• “MoreshockingisthelegalamountofartificialcolorantsallowedbytheFDAinthefoods,drugs,andcosmeticsthatweconsumeanduseeveryday.Theconsumingpublicislargelyunawareoftheperiloustruthbehindthedeceptiveallureofartificialcolor.”
10/10/19
47
3dietaryInterventionsHistoricallyTested
1. Restrictedeliminationdiets(RED)— referredtoastheFewFoodDiet.
• WhenreductioninADHDbehaviorsresults— (generallyoccurwithin2–3weeks)ifthedietisgoingtohaveapositiveeffect— newfoodscanbeaddedbackoneatatimetoseeiftheyarewell-toleratedorleadtoanincreaseinproblembehaviors.
• Alternatively,particularfoodsthataresuspectedtoexacerbateachild’ssymptomsmayberemovedoneatatimetoseeifthechild’sbehaviorimproves.
Gluten/Casein
• Proteins– deregulatorsofpermeabilityinintestine
• Iftestpositiveforglutensensitivity/lactoseintolerance=eliminatefromdiet
10/10/19
48
Sugar
• Feeds yeast
• Depressestheimmune system
• Contributestoinflammation
• Higherreleaseofextracellulardopamine- desensitizationofreceptorsovertime
• Dopaminergicsignalingdysfunction-impactsfrontallobecontrolmechanisms– areadirectlyrelatedtoneurobiologyofADHD
Sugar
10/10/19
49
3dietaryInterventionsHistoricallyTested
2.Artificialfoodcoloringexclusion(AFCE)- removeallartificialfoodcoloringsfromchild’sdiet,i.e.,Yellow #6,Yellow#5,SodiumBenzoate,Blue#2,etc.,andobservingwhetherthisisassociatedwithareductioninADHDbehaviors.
• CarefullyconductedtrialshavedemonstratedthatAFC’s– inamountschildrencouldtypicallyconsume– canincreaseADHDsymptomsinmanychildren.
3dietaryInterventionsHistoricallyTested
3.Essentialfattyacidsupplementation— Certainfattyacids,e.g.,Omega3andOmega6,promoteneuralfunctioning.
• Thesefattyacidsarecalledessentialbecausetheyarenotsynthesizedinthebodyandmustbeingested.
• ChildrenwithADHD-lowerlevelsofessentialfattyacidsrelativetopeersandseveralstudieshavedemonstratedalinkbetweenlowlev-elsofEFAsandtheseverityofADHDsymptoms.
10/10/19
50
Evidence
• RED — Threedifferentmeta-analysesexaminingtheimpactofREDonchildrenwithADHDreport-edsignificantpositiveeffects.Themagnitudeofthiseffectvariedconsiderablyacrossthediffer-entstudies.
• restrictedeliminationdiets,ifimplementedproperly,haveasignificanteffectthatislikelytobeinthesmalltomoderaterange.Anaverageeffectinthesmalltomoderaterangereflectsthefactthatsomechildrenarelikelytoshowsubstantialbenefitswhilemanyothersmayshownobenefitsatall.
• AFCE — SmallbutsignificanteffectsofeliminatingAFC’sfromchildren’sdiethavebeenreport-ed.
• AswithRED,areasonableconclusionatthistimeisthat,onaverage,childrenwithADHDwillderivemodestbenefitswhenAFCsareremovedfromtheirdiet.SomechildrenmayshowlargereductionsinADHDsymp-tomswhileothersmayshownodiscerniblereductionsatall.
• Fattyacidsupplementation— Resultsfrommultiplemeta-analysesconvergeontheirbeingamodestbutsignificantbenefitoffattyacidsupplementationonADHDsymptoms.
• AswithREDandAFCE,somechildrenarelikelytodisplaysubstantialbenefitsfromthisapproachwhileforothers,theimpactonADHDsymptomswillbeminimalornon-existent.Eveninthesecases,however,therearegeneralhealthbenefitsthatmayaccruefromfattyacidsupplementation.
HowtobestimplementwithADD/ADHD…
• First,theeasiestofthe3dietaryinterventionstoimplementwouldbefattyacidsupplementation.
• Doesn’trequirerestrictingchildren’sfoodintakeinanyspecificway,canhavegeneralhealthbenefitsregardlessofhowitimpactsADHDbehaviors,andplacesmuchmorelimiteddemandsonchildrenandparents.
• Restrictedeliminationdietscanbedifficulttoimplement/sustain— effortstosignificantlylimitthefoodsachildeatsmayleadtoconflictsthatcreateimportantproblemsintheirownright.
• So,unlessfoodallergiesarepresent,adietrestrictingonlyAFCsmaybeabetterchoiceasthiswouldbeeasiertoimplement
• .However,giventheubiquitousnatureofartificialfoodcoloringsanddyes,thiscanalsobechallenging.
10/10/19
51
Supplementsto Consider ADHD
• IncreasedlevelsofoxidativestressinADHD• VitaminB/C/D/E• C0Q10
• Magnesium• Omega-3fattyacids-Ofthestudiesidentified,13reportedfavorablebenefitsonADHDsymptomsincludingimprovementsinhyperactivity,impulsivity,andattention
ASD
10/10/19
52
LeakyGutandDiet
• RemoveGluten,Casein
• Moreantioxidantsandanti-inflammatoryfoods
• Probioticrichfoods
• Prebioticrichfoods
Fermented FoodsRichin Probiotics
• Functionsofgood bacteria–Regulateperistalsisandbowel movements–Breakdownbacterial toxins–Helpbreakdownsugars,lactose,and oxalates– Supportimmunesystemandincreasenumberofimmune cells–Balanceintestinal pH–Protectagainstenvironmentaltoxins:mercury,pesticides,pollution
• Rawfermentedfoodscontain billionsof bacteria/serving!
10/10/19
53
ProbioticRichFoods
PrebioticRichFoods
10/10/19
54
ASD
• 2018interventiontrial(41autisticchildrenmeanage8y/o)displayedthatsupplementationofdietwithprebioticresultedinsignificantimprovementinanti-socialbehavior,GIhealthcomparedtobaseline.
Grimaldi,R.,Gibson,G.R.,Vulevic,J.etal.Aprebioticinterventionstudyinchildrenwithautismspectrumdisorders(ASDs).Microbiome(2018)6:133.
Top Diets**GFCF (Gluten--free and Casein--free) No gluten(wheat, rye, barley, spelt, kamut, and oats) or casein(dairy)
FoodSensitivityElimination/RotationEliminatingallotherfoodsensitivities:Soy,corn,eggs,citrus,peanuts,chocolate,canesugar
SCD(SpecificCarbohydrate Diet)/GAPSRestrictscarbohydratestoonlyfruits,non--starchyvegetables,andhoney.Nograins,starchyvegetables,ormucilaginousfiber
*Ketogenic– LowGlycemicMeat,fruit,vegetables,fatandnuts.Nograinsorbeans.Onenremovespotatoesanddairytoo.
LowOxalateDietRestrictshighoxalatefoods(nuts,beans,greens)
LowFODMAPS DietLowinfermentable,poorlyabsorbedcarbssuchasfructose,lactoseandFOS.
**Feingold/FAILSAFE DietsRestrictshighphenolicfoods,includingallartificialingredientsandhighsalicylatefruits(and more)
10/10/19
55
GFCF
• Allowedfoods:• Beans,seeds,nutsinunprocessedform• Fresheggs• Freshmeats• Fruits/Vegetables
AllowedGrains/Starches- GFCF
• Rice• Corn/maize• Potato• Tapioca/cassava• Arrowroot• Quinoa• Millet
• Buckwheat• Sago• Lentil/pea• Amaranth• Lupin• Teff
10/10/19
56
Avoid- GFCF
• Barley• Rye• Wheat• Triticale
GFCF
• AGF/CFdietisnoteasytofollow.• GlutenandcaseinareabigpartofUSdiet.Becausethedietdoesnotcontainmilkproducts,ormanybreadsandcereals,childmaynotgetenough:
• calcium• fiber• vitaminsA,D,andBcomplex• calories
10/10/19
57
GFCF
• BecausecalciumandvitaminDarelimitedonthisdiet,encourageothercalcium-richbeverages/foods,suchas:
• calcium-fortifiedpotatomilk
• calcium-fortifiedricemilk
GFCFEffectiveness
10/10/19
58
GFCF Effectiveness
• LangeKW1,HauserJ,Reissmann A.Gluten-freeandcasein-freedietsinthetherapyofautism. CurrOpin Clin Nutr Metab Care.2015Nov;18(6):572-5.
• 20-29%oftheparentsreportedsignificantimprovementsontheASDcoredimensions
• Thefindingsofanotherrecentinvestigationsuggestedthatageandcertainurinecompoundsmaypredicttheresponseofautismsymptomstoagluten-freeandcasein-freediet
• Agluten-freeandcasein-freedietshouldonlybeadministeredifanallergyorintolerancetonutritionalglutenorcaseinisdiagnosed
SCD(SpecificCarbohydrate Diet)• Nutrient-densedietthatisfreeofgrainsandextremelylowinsugar,includinglactose
• Dr.SidneyHaas,apediatricgastroenterologist,developeditinthe1920sasatreatmentforCeliacdisease
• Allowsalmostallfruits,vegetablesthataren’tcannedorfrozen,nuts,nut-derivedflours,meats,eggs,butter,andoils
• Exclusionsincludeallformsofgrains,sucrose,maltose,lactose,potatoes,okra,corn,fluidmilk,soy,cheesescontaininghighamountsoflactose,aswellasmostfoodadditivesandpreservatives
10/10/19
59
GFCFvsSCDHowIsItDifferentFromGFCF?
• SCDisglutenfree,butdoesnot allowstarchandsugar.SCDincludesdairythatisvirtuallylactosefreeandcontainsdenaturedcasein,butnotrequiredindiet
HowSuccessfulIsSDC?
• Anecdotalreportsindicateasuccessrateofabout80-85%• ParentsandteachersofautisticchildrenonSCDreportachangeintheirattitude,increasesinskillsandresponsiveness.Insomeofthesecasesitoccursonlyafewweeksafterbeginningthediet
Gut&PsychologySyndrome(GAPSDiet)
• Dr.NatashaCampbell-McBride2004,basedonhertheorythatmanyofthemedicalissuesaffectingthebrainarecausedbyaleakygut
• SimilartoSCD
• BigdifferencebetweenSCDandGAPSisdairyproducts.• Dairy,attherighttimeandtherightforms,playsanimportantpartintheGAPSprogram
• Also,GAPSismuchmorerestrictiveandmeantasamulti-yeardietthateventuallyallowspeopletotransitionbacktoafuller,traditionalfoodsdiet
10/10/19
60
GAPstages
Asyet,nostudieshaveexaminedtheeffectsoftheGAPSdietaryprotocolonthesymptomsandbehaviorsassociatedwithautism.
Candida/Sugarfreediet
• Limitorcompletelyexcludefoodsthatmaypromotecandidagrowth.• Non-starchyvegetables,includingallcolorsofvegetable.
• Nostarchyvegetableslikepeas,potatoes,beets,andwintersquash
• Low-glycemicfruitslikecitrusandberries• Healthyfatsincludingavocado,nutsandseeds
• Asyet,nostudieshaveexaminedtheeffectsoftheCandidafreedietonASDsymptoms
10/10/19
61
Feingold/FAILSAFE Diets
• Feingold- Removesphenolsandsalicylates• FAILSAFE- Alsoremovessalicylates,aswellasaminesandglutamates(otherrelatedfoodchemicals)
• Phenols -artificialcoloring,artificialflavoring,andartificialpreservatives• Salicylates-chemicalsthatoccurnaturallyinplants– particularlyinmanyfruitssuchasapples,grapes,andberries
• Amines- comefromproteinbreakdownorfermentation.Largeamountsarepresentincheese,chocolate,wines,beer,yeastextractsandfishproducts
• Glutamate- foundnaturallyinmostfoods• Puremonosodiumglutamate(MSG)canalsobeusedasanadditivetoincreasetheflavorofsoups,sauces,Asiancookingandsnackfoods.
Phenols, Salicylates, and Amines
Can cause:• Hyperactivity• Red cheeks/ears• Itchy skin• Upset stomach• Asthma• Headaches• Bedwepng• Fatigue• Diarrhea
• Depression• Irritability• Aggression• Defiantbehavior• Sleepissues• Cravingsforsalicylates,amines,and/orglutamates.
10/10/19
62
High Phenol/Salicylates
• Almonds• Apples• Apricots• Berries,raspberries, cherries• Chili powder• Ciderandcider vinegar• Coffee• Coladrinks• Cucumbersand pickles• Curry powder
• Grapes,raisins, currants
• Honey• Nectarinesand peaches• Orangesand oranges• Paprika• Peppers(belland chili)• Pineapple• Plumsand prunes• Radishes• Tea• Tomatoes• Wineandwine vinegar
FeingoldDiet
• Phase1:Childavoidsfoodsorproductsthathaveingredientsonthelist
• Phase2:Childcanbegintotrythesesamefoodsoneatatimetoseeifsymptomscomeback
• AutismResearchInstitute– reportsthat56%of899familieswhohadtrieddietfounditwashelpfulwiththeirchild
10/10/19
63
LowOxalateDiet• NewerdietforASD-observationfromparentsthatfoodshighinoxalateswereproblematicfortheirchildren.
• Oxalatesaresharpcrystalsandareresponsibleforcertainformsofkidneystones.
• Oxalatecrystalscanbeinflammatoryanddamagingtoachild’sdelicatebiochemistryandthelowoxalatedietreducesthesecompounds.
• ChildrenwithASDhavemuchhigherurineoxalatelevels.
HighOxalateFoods
10/10/19
64
TreatingOxalates
• Increasecalcium• LimitVitaminC• Increasefluid• Adequateprotein• Reducesodium
• KonstantynowiczJ1,Porowski T,Zoch-Zwierz W,Wasilewska J,Kadziela-Olech H,KulakW,OwensSC,Piotrowska-Jastrzebska J,KaczmarskiM.Apotentialpathogenicroleofoxalateinautism. EurJPaediatrNeurol.2012Sep;16(5):485-91.
Ketogenic
• Low-carbohydrate,moderateprotein,high-fatdiet
• TheKetogenicDiet,becauseofitsveryrestrictedcarbohydratesandlimitedproteins,forcesthebodytousefatratherthanglucoseasanenergysourceandthusproducesametabolicstatesimilartofasting
• Havebeenusedsuccessfullytotreatepilepsyinpeoplesince1921andepilepsyiscommoninwithASD
10/10/19
65
Ketogenic• LeeRWY,CorleyMJ,PangA,etal.Amodifiedketogenicgluten-freedietwithMCTimprovesbehaviorinchildrenwithautismspectrumdisorder.PhysiolBehav.2018;188:205–211.
• Forty-fivechildrenaged3-8yearsdiagnosedwithASDbasedonDSM-5criteriawereenrolledinthisstudy.
• Patientswereequallydividedinto3groups,firstgroupreceivedketogenicdietasmodifiedAtkinsdiet(MAD),secondgroupreceivedglutenfreecaseinfree(GFCF)dietandthethirdgroupreceivedbalancednutritionandservedasacontrolgroup.
• Allpatientswereassessedintermsofneurologicalexamination,anthropometricmeasures,aswellasChildhoodAutismRatingScale(CARS),AutismTreatmentEvaluationTest(ATEC)scalesbeforeand6monthsafterstartingdiet.
• BothdietgroupsshowedsignificantimprovementinATECandCARSscoresincomparisontocontrolgroup,yetketogenicscoredbetterresultsincognitionandsociabilitycomparedtoGFCFdietgroup.
• Dependingontheparametersmeasuredinourstudy,modifiedAtkinsdietandglutenfreecaseinfreedietregimensmaysafelyimproveautisticmanifestationsandcouldberecommendedforchildrenwithASD.
NutritionalDeficienciesASD
• VitaminD
• Calcium
• Potassium
• Choline
10/10/19
66
Deficienciesstem from…
• Poorqualityfoodconsumption
• Pickyandrestrictive eating
• Poordigestionorabsorption(innateor acquired)
• Intestinaldysbiosis andlackofbeneficial bacteria
• Medicationinducednutrient depletion
Choline
• Essentialforbraindevelopment
• Sourcesinclude:liver,eggs,salmon
10/10/19
67
VitaminD
• Mayplayroleingutinflammationandserotoninlevels• Maternaldeficiencymayplayarole
SupplementsASD
• Melatonin– 50-80%insomnia(dosing25-75mg)
• Probiotics
• CoQ 10– 50mgBID– improveoxidativestress
• Omega3fattyacids– (1000-1500mg)Decreasedhyperactivity?
10/10/19
68
OthernutritionalConsiderations…
Juicing
• Stored and pasteurized juices contain significantly less nutrients: zinc,iron, calcium, vitamins B1, B5, and B6
• Freshandrawvegetablejuicecontainmanytimesmorevitamins&phytonutrientsthan bottled
• Getnutrientswithoutneedingtoeat/chewvegetables
• Childrenthatlikeliquids,juicesand smoothies
10/10/19
69
Food and Nutrition Strategy
Food intolerances?
Histamines
Food
sensitivities
Feingold/
phenols
glutamates
Nourishing Diet
Child�s Diet
GFCF
SCD/GAPS
Yeast/dysbiosis/inflammation?
Juryisstillout…
• Todate,availableinterventionsforthemaintenanceandrepairofgutbarrierarehoweverfew,evenifpromising.
• Abetterunderstandingofhowthegutimpactshealthanddiseaseinchildrenwithneurodevelopmentaldisordersisneeded.
10/10/19
70
PharmacologyofToneManagementSkeletalMuscleRelaxants
NMJPharmacology
MYOFIBRILS
ACh
Motor End Plate
10/10/19
71
SkeletalMuscleRelaxantsselectively inhibit neuromuscular function
PERIPHERAL
nondepolarizers
depolarizers
Direct Muscle Relaxants
Indirect NMJ Blockers
CENTRAL Indirect Muscle Relaxants
SkeletalMuscleRelaxants
• Neuromuscularblockers• �paralytics�• peripherallyacting• interferewithtransmissionattheneuromuscularend-plate
• inhibitmusclecontraction• adjunctingeneralanesthesia• Curare&Succinylcholine
10/10/19
72
SkeletalMuscleRelaxants
• Musclerelaxants--�spasmolytics�• centrallyacting• blockconductionwithinthespinalcordtonormalizehyperexcitableskeletalmuscle
• spasticity• exaggeratedmusclestretchreflexatamotorneuron
• musclespasms• increasedmuscletensionfollowinginjuryorinflammation
10/10/19
73
SkeletalMuscleRelaxants
• CentrallyActing/Indirect/Spasmolytics• Benzodiazepines• PolysynapticInhibitors• Baclofen• Gabapentin(Neurotin)• Tizanidine(Zanaflex)
10/10/19
74
AgentsUsedtoTreatMuscleSpasms1. Diazepam(Valium)
- Centrallyacting• enhanceeffectsofGABAatGABAA-diazepam
1. PolysynapticInhibitors- carisoprodol (Soma,Vanadom),chlorphenesin carbamate(Maolate),
chlorzoxazone (Paraflex,Parafon Forte),cyclobenzaprine(Flexeril),metaxalone (Skelaxin),methocarbamol(Robaxin),&orphenadrine citrate(Antiflex,Norflex)
- Centrallyacting- Mechanismofactionnotwellunderstood
10/10/19
75
AgentsUsedtoTreatSpasticity
• Baclofen• Diazepam(Valium®)• Dantrolene (Dantirum®)• Gabapentin(Neurontin®)• Tizanidine (Zanaflex®)
AgentsUsedtoTreatSpasticity
Centrally-actingSkeletalMuscleRelaxants
depressrefleximpulseconductionwithinthespinalcordreducesthenumberofimpulsesavailabletoproducecontraction
10/10/19
76
AgentsUsedtoTreatSpasticity
• Baclofen• GABAagonistatGABAB--baclofen
GABA
K-+ 2nd messengers
GABAB
increase K
• Baclofen• HasaninhibitoryeffectonAMNactivitywithinthespinalcordatspecificsynapses
• Bothpostsynapticinhibitionandpresynapticinhibition&incombination.
Usedtotreatspasticityassociatedwithlesionsofthespinalcord&MS
AdverseEffect:Drowsiness,generalizedmuscleweakness
10/10/19
77
• IntrathecalBaclofen• Usedtotreatsevere,intractablespasticity• Deliversthedrugdirectlyintothesubarachnoidspace.• Increasesdrugeffectivenesswithmuchsmallerdoses&fewersystemicsideeffects
• Problemsoccuronlywithpumpmalfunction
• Diazepam(Valium®)• IncreasestheinhibitoryeffectsofGABA• UsedinpatientswithspasticityresultingfromSCIandCP• AE:
• sedationoccurswithdoseseffectiveinproducingmusclerelaxation
10/10/19
78
• Dantrolene (Dantirum®)• blocksreleaseofCa++ fromthesarcoplasmicreticulum
Ca++SR
muscle contraction
Ca++ Ca++
muscle relaxation
troponintroponin
• Dantrolene (Dantirum®)• blocksreleaseofCa++ fromthesarcoplasmicreticulum• usefultoRxmalignanthyperthermia• spasmolytic• usefulinmultiplesclerosis,cerebralpalsy,spinalcordinjuries
• AE• dizziness,vomiting,fatigue• hepatoxicity
10/10/19
79
• Gabapentin(Neurontin)• Originallydevelopedasananti-seizuremedication• EnhancestheinhibitoryeffectsofGABAintheSCbyeitherincreasingGABAreleaseorbystimulatingGABA-likereceptorsonspinalneurons
• DecreasesspasticitybyincreasingGABA-mediatedinhibitionoftheAMN• UsedtotreatspasticityassociatedwithSCI&MS• Veryeffectivewhenusedincombinationwithotherdrugs(baclofen)• AE:
• Sedation,fatique,dizziness&ataxia
10/10/19
80
• Tizanidine (Zanaflex)• Classifiedasanalpha-2agonist• Alpha-2receptorsareauto-receptors• Stimulationofalpha-2receptorsinhibitsfiringoftheinterneuronsthatrelayinformationtotheAMN
• UsedtotreatspasticityassociatedwithSCI,MSandCVA• AE:
• Milderside-effectsthanbaclofen&valium• Sedation,dizziness,&drymouth
XXX
10/10/19
81
SkeletalMuscleRelaxants– SE/ADR
• GeneralizedMuscleWeakness• DecreasedMuscleTone• Sedation• Dizziness,Ataxia
InterferencewithFunctionalOutcomes
• MotorControlProblems• FunctionalDecline• Alertness• Problemsattheimpairment,strategy&functionallevel.• Theydonotfixtheproblemwhenrelatedtomuscleinjuryorinflammation.
10/10/19
82
PossibleSolutions
• Scheduletherapywhensedationisless.• DiscusswithPhysicianweaknessimplicationsastheyeffectfunctionaloutcomes
• Intensetherapytofacilitatenormalphysiologicmotorcontrolforthepreviouslyusedspastictone.
• Intensetherapytoreducethestructuralorbiomechanicalproblemthatleadtotheoccurrenceofmusclespasm.
Chemodenervation UsedtoTreatSpasticity
• BotulinumToxin• ChemicalNeurolysis
• Implicationsaremany• SCI,TBI,CP,MS,PD,Stroke,Pain
10/10/19
83
• BotulinumToxin• Entersthepresynmaptic terminalattheskeletalNMJandbindsstronglytopresynatpic ACHvesicles
• Onceboundbythetoxin,thesevesicalareunabletoreleaseACHintothesynapticcleft.
• DecreasesmuscleexcitationbydisruptingsynaptictransmissionattheNMJ• Affectsmusclesundergosomedegreeofparesis&subsequentrelaxationbecausethetoxinblocksthereleaseofACH
• DOESNOTCURESPASTICITY• AE:
• Auto-immuneresponsewherebyantibodiesaresynthesizedagainstthetoxin• Temporaryeffects
PharmacologyofSeizureDisorderinChildren
10/10/19
84
• AntiepilepticDrugs• Barbiturates• Benzodiazepines• Hydantoins• Lamotrigine• Succinimides• Carbamazepine(Tegretol)• Gabapentin(Neurotin)• Topiramate (Topomax)• Levetiracetam (Keppra)• Valporic Acid(Depakene)
Anti-SeizureDrugs
Hydantoins
• blocksodiumchannel• prolonginactivationofNa+ channels• decreaseneuronalexcitability
• phenytoin(Dilantin®)• ethotoin (Peganone®)• mephenytoin (Mesantoin®)
membrane
Na+
Phenytoin
inner
outer
10/10/19
85
Lamotrigine
• blocksodiumchannel• prolonginactivationofNa+ channels• decreaseneuronalexcitability
• Maysuppressthereleaseofglutamateandaspartate,twoofthedominantexcitatoryneurotransmittersintheCNS
• Additionalactions– broaderspectrumthanothersodiumchannelblockers
• Sigmareceptoractivity
• AE:fewersideeffectsanddruginteractions
Succinimides
• Increaseseizurethresholdandlimitthespreadofelectricalactivityinthebrain
• MechanismofAction– theyreducelow-thresholdcalciumcurrents• Ethosuximide(Zarontin)
10/10/19
86
Carbamazepine
• prolongsinactivationoftheNa+ channel• similartophenytoininefficacy
• Tergretol®
Gabapentin
• StructurallyverysimilartotheGABANThoweverdoesnotinteractwiththeGABAreceptor.
• Mechanismofactionunknown• Usedextensivelytotreatneuropathicpain• Neurotin®
10/10/19
87
Topiramate
• Blocksrepetitivefiringofspinalcordneurons• Mechanismofactionistri-fold
• BlocksvoltagedependentNachannels• PortentiatestheinhibitoryeffectsofGABA• DepressesexcitatoryactionofAMPAreceptors
• Off-labeluseextensivelyforweightloss• Topomax®
Levetiracetam
• Theexactmechanismbywhichlevetiracetamactstotreatepilepsyisunknown.However,thedrugbindstoasynapticvesicleprotein,SV2A,whichisbelievedtoimpedenerveconductionacrosssynapses
• Theywork• Keppra®
10/10/19
88
Valproic Acid
• Blockshigh-frequencyfiringofneuronsviaNa+channels• MayalsoblockNMDAreceptor-mediatedexcitation.• Mayalsoincreasepotassiumconductance(hyperpolarizingtherestingmembranepotential)athighconcentrations
• Depakene®,Depakote®,Depacon®
AntiepilepticDrugs– SE/ADR• Barbiturates
• sedation,hepaticmicrosomalenzymeinduction
• Benzodiazepines• Sedation,weakness
• Hydantoins• dizziness,visualdisturbances,posturalimbalance
• Lamotrigine• Dizziness,diplopia
• Carbamazepine• dizziness,drowsiness,ataxia,blurredvision,waterretention,inductionofDMMS
• Gabapentin• Sedation,dizziness
• Topiramate• Weightloss
• Levetiracetam• Asthenia,dizziness
• Valproic Acid• GIdistress,inhibitionofdrugmetabolism
10/10/19
89
InterferencewithFunctionalOutcomes
• DecreasedArousal/Alertness• PosturalImbalance/Ataxia• Uncontrolledseizureactivity
PossibleSolutions
• ExploreoptionswithPhysiciansastotherisk/benefitsofthemedication
• UnderstandOutcomesmaybeeffected• Bodystructure&function,activity,&participationlevels
10/10/19
90
PotentiationofFunctionalOutcomesSecondarytoDrugTherapy
• Somepeoplewithseizurescanbecomeseizure-freebyusingoneormoreanti-seizuremedications
• Inothers,anti-seizuremedicationscandecreasethefrequency&intensityofseizures
• Eithersituation,theymayenablepatientstomeetrehabilitationgoals.
10/10/19
91
10/10/19
92
ImpactofOpioidEpidemiconChildren
TheProblem.• Krans etal(2016)found27.47%femalesofchild-bearingage withMedicaid ans 39.4%femalesofchild-bearingagewithprivateinsurance,filledanoutpatientprescriptionforanopioid
• Inaddition,oneoutoffiveofthosewithMedicaidinsurancewhofilledaprescriptionforanopioidwerepregnant.
• Theriseinopioidusebypregnantwomeniscorrelatedtoanincreaseinadverseneonataloutcomes. IntheUnitedStates, ababywithdrugwithdrawalisbornevery30minutes.
10/10/19
93
TheProblem
• Therewasalmosta“4-foldincrease(from7to27per1,000admissions)ininfantadmissionstotheneonatalintensivecareunitwithadiagnosisofneonatalabstinencesyndromebetween2004and2013.(Skolnick2017)
• Opioiddependenceduringpregnancyleadstovariouscomplicationsforbothmotherandbaby,includingincreasedmorbidityandmortality
OpioidEpidemicandNeonates
• ImpactofDrugsonFetalDevelopment• MedicalIssuesatBirth• NeonatalAbstinenceSyndrome• EffectsLaterinLife
10/10/19
94
• ImpactofDrugsonFetalDevelopment• Intheearlyweeksofgestationduringembryonicdevelopment,opioiddrugs
cancausesignificantabnormalitiesofphysiologicaldevelopment.
• Oncethefetalperiodhasbeenreached,theeffectsofdrugabusebecomemoresubtle,includingabnormalgrowthand/ormaturation,alterationsinvariousneurotransmittersandreceptors,andbrainorganization.
• Indirectaffectofopioidaddictiononthefetusthroughthemotherincludedecreasedbraingrowthandcelldevelopment.
• MedicalIssuesatBirth• Prenatalopiateexposureisrelatedtofetalgrowtheffects,whichisoneof
theleadingcausesoflowbirthweight.• Bada etal.(2013)reported“lowerbirthweightinopiateexposednewborninfantsborn
at33weeks’orgreatergestation,independentofuseofotherdrugs,prenatalcare,orothermedicalriskfactors”
• Low-birthweightissignificantasitincreasesthechancesofhealthproblemsasopposedtonormal-birthweightinfants.
• Possiblecomplicationsfortheinfantincludebreathingproblems,suchasrespiratorydistresssyndrome,intraventricularhemorrhaging,patentductusarteriosus,necrotizingenterocolitis,retinopathyofprematurity,jaundice,andinfectionduetoanunderdevelopedimmunesystem.
10/10/19
95
• NeonatalAbstinenceSyndrome• Describedasageneralizeddisorderwithsignsofcentralnervoussystemhyperirritability,respiratorydistress,gastrointestinaldysfunction,andvariousautonomicsymptomswhichmayincludebutarenotlimitedtothefollowing:yawning,sneezing,mottledskin,andfever.
• Theseissuesariseasaresultoftheinfant’sbodygoingthroughwithdrawalfromtheopioidstheywerepreviouslyexposedtointhewomb.
• Theonsetofthesewithdrawalsymptomscanrangefromjusthoursafterbirthtotwoweekslater,butmostsymptomswilltypicallypresentwithinthefirst72hoursafterbirth.5
10/10/19
96
• NeonatalAbstinenceSyndrome• Thisonsetcanbeinfluencedbynumerousfactors:
• thetypeofsubstancesusedbythemothers,• thetiminganddoseofthelastdrugtakenbeforedelivery,• thecharacteroflabor,• thetypeandamountofanesthesiaoranalgesiaprovidedpriortolabor,and
• thematurity,nutrition,andpresenceofintrinsicdisease”inthechild.
• Withdrawalsymptomscanrangefrommild,withthechildonlydemonstratingsymptomswhendisturbed,tosevere,withsymptomonsetoccurringspontaneously.
• Fortunately,thesymptomsofneonatalabstinencearetreatablewithouttheconcernoflingeringeffectswithproperpharmacotherapeutic management.
10/10/19
97
• NeonatalAbstinenceSyndrome• Throughoutthewithdrawalprocessinfantsshouldbeassessedwithanabstinencescoringsystemtodetermineonset,progression,andlongevityofsymptoms.2
• Additionally,theneonateshouldbecontinuallymonitoredforoverallcomfort.
• Kaltenbach etal.(2015)statesswaddling,usingapacifierforexcessivesucking,frequentdiaperchanges,softsheet,andpositioningareallimportantinmanagingtheinfant’ssymptomsthroughoutthewithdrawalprocess.
• EffectsLaterinLife• Theimpactsofopioidexposurearenotlimitedtoachild’sfirstyearsoflife.
• Whilethefulleffectsonlong-termneurodevelopmentalfunctionarestillbeingstudied,ingeneralchildrenexposedtoopioidsare“morelikelytohaveADD,disruptivebehavior,andtheneedforcomprehensivepsychiatricreferrals.”(Stoveretal2016)
• Caritis andPanigraphy (2019)statethat“animals,humanneuraltissue,adultbrains,thebrainsofchildrenandnewbornsdemonstratethatopioidsadverselyaffectthehumanbrain,primarilythedevelopingoligodendrocyteandtheprocessesofmyelinization connectivitybetweenpartsofthebrain.”
• Multiplebrainregionsareeffectedincludingthebasalganglia,thalamus,andcerebellarwhitematter.Whilethelong-termimpactsoftheseeffectshaveyettobeunderstood,researcherssuggesttheyareofsignificantconcern.
10/10/19
98
• EffectsLaterinLife• Otherknownmedicalissuesmaystemfromalowbirthweight.
• Evenintheirlateryears,childrenbornwithlowbirthweightsareatanincreasedriskfordevelopingadditionalmorbiditiescomparedtobabiesbornatanormalbirthweight:
• diabetes,heartdisease,highbloodpressure,intellectualanddevelopmentaldisabilities,metabolicsyndromes,andgeneralobesity.4
IsTheiraLinkBetweenOpioidExposureandASDand/orADHD?• Sandtory etal(2018)lookedatschool-agedchildrenprenatallyexposedtoopiatesandotherillicitsubstances(n=171)
• PrenatallyexposedchildrenhadsignificantlyhigherSNAP-IVscoresassociatedwithADHDsymptomsinbothareasofinattentionandhyperactivity/impulsivity
• HigherASSQscorerelatedtoanincreasednumberofsymptomsassociatedwithASD,comparedwiththereferencegroup
• Conclusion:prenatallyexposedchildrenhadmorementalhealthsymptomsassociatedwithADHDandASDcomparedtothecontrolgroup
10/10/19
99
IsTheiraLinkBetweenOpioidExposureandASDand/orADHD?• Nygaard,etal.(2016)conductedalongitudinalstudylookingatbehaviorandattentionproblemsineight-yearoldchildrenwithprenatalopiateandpoly-substanceexposure.
• Theycompared72childrenwhowereprenatallyexposedtoheroinanddifferentdrugswithagroupof58childrenwithoutexposure.
• Thechildren’sbehaviorandattentionwerebasedoffwhatcaregiversandteachersreportontheChildBehaviorCheckListandADHDRatingScale.
• Teachersreportedproblemsintheexposedchildrenaround4½yearsofagewherecaregiversreportedproblemsinexposedchildrenaround8½yearsofage.
• Conclusion:childrenwhowereexposedtodrugsprenatallyhaveincreasingmoreproblemsinmanyareasrelatedtobehaviorfrompreschooltoatleast8½yearsofage.
FutureStudies• BridgingResearchonAutisminNeurodevelopment(BRAiN)
• PilotDataProject:AutismSpectrumDisorders• 1)testthehypothesisthattheriskofphenotypicdiseasecategoryisassociatedwithsocioeconomicstatusandprenatalfactors.
• 2)testthehypothesisthatmarkersofoxidativestressandDNAmethylationareconsistentacrossbio-samples
• CenterforBrainHealthDevelopmentPlan• ASDInterventionProgram
10/10/19
100
• SuzanneTinsleyPhD,PT,NCS• [email protected]• 318-813-2942
• MarieVazquezMorganPhD,PT• [email protected]• 318-813-2944