Pediatric Pharmacology: What It Means To Your Clinical ... · Pediatric Pharmacology: What It Means To Your Clinical Practice Suzanne Tinsley PhD, PT, NCS Assistant Dean for Development

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




• EndogenousHormone• Oxytocin,secretin,melatonin


• rivastigmine


• 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


• MedicationsusedtoTreatDepression

• MonoamineOxidaseInhibitors(MAOIs)

• AmineUptakeBlockers• Tricyclics(TCAs)– nonselective• SelectiveSerotoninReuptakeInhibitors(SSRIs)

• α2 Blockers

43

44

10/10/19

23


• Venlafaxine(Effexor®)• Fluoxetine(Prozac®)• Citalopram(Celexa®)• Mirtazapine(Remeron®)

45


• 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


• 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




• EndogenousHormone• oxytocin,secretin,melatonin


• rivastigmine


• 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


2.Artificialfoodcoloringexclusion(AFCE)- removeallartificialfoodcoloringsfromchild’sdiet,i.e.,Yellow #6,Yellow#5,SodiumBenzoate,Blue#2,etc.,andobservingwhetherthisisassociatedwithareductioninADHDbehaviors.

• CarefullyconductedtrialshavedemonstratedthatAFC’s– inamountschildrencouldtypicallyconsume– canincreaseADHDsymptomsinmanychildren.


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


• Musclerelaxants--�spasmolytics�• centrallyacting• blockconductionwithinthespinalcordtonormalizehyperexcitableskeletalmuscle

• spasticity• exaggeratedmusclestretchreflexatamotorneuron

• musclespasms• increasedmuscletensionfollowinginjuryorinflammation

10/10/19

73


• 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®)


Centrally-actingSkeletalMuscleRelaxants

depressrefleximpulseconductionwithinthespinalcordreducesthenumberofimpulsesavailabletoproducecontraction

10/10/19

76


• 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

Pediatric Pharmacology: What It Means To Your Clinical ... · Pediatric Pharmacology: What It Means To Your Clinical Practice Suzanne Tinsley PhD, PT, NCS Assistant Dean for Development

Documents