在妊娠哺乳期用藥

Drugsinpregnancy&lactation

ByDrAttiaMJabrDrAmalHassanainFacultyofMedicineQassimUniversity1編輯pptTherearetwomajorconsiderationsregardingdruguseinpregnantwomen:Effectofpregnancyon:drugs(pharmacokinetics)

Effectofdrugson:pregnancy(fetus)編輯pptDrugsinpregnancy編輯pptIntroductionAbout40%ofpregnantwomentakedrugs(atleast1drug)6%takedrugsduring1sttrimester(excludefolic,iron,vitamins)Themostcommondrugsareanalgesics,antibacterial,antacids.Whataboutnewdrugs?4編輯pptI.Effectofpregnancyondrugs

(Pharmacokinetics)

Absorption:TheratemaybereducedbecauseofdelayedgastricemptyingTheextentmaynotbeabsorbedVomitingiscommon.Effect?Reducedbioavailability5編輯pptEffectofpregnancyondrugsB)Distribution:1.Maternalplasmavolume&ECF▲50%(3rdtrimester)2.Totalbodywater▲20%&totalbodyfat3.WhatistheeffectonVd&steadystateconcentration?4.Serumalbumin▼byabout20%(inpre-eclampsia35%)5.Alpha1-acidglycoprotein

▲Byabout40%(inpre-eclampsia100%)6.Thefreefractionofacidicdrugs

▲7.Thefreefractionofbasicdrugs

▼8.E.G.Diazepam,phenytoin,valproate.What?Whatistheeffectont?ofthedrug?E.g.phenytoin6編輯pptDrugmetabolism:▲HepaticmicrosomalmixedfunctionoxidaseIncreasedduringpregnancy(2nd,3rd)Explainwhyherateofclearanceofphenytoin,valproate,carbamazepineisincreasedduringpregnancyThereisnochangeinhepaticbloodflow.Effect?Drugsoffirstpasseffect.ExamplespropranololEffectofpregnancyondrugs7編輯pptB.Excretion:Effectiverenalplasmaflow▲(doubles)

GFR▲by70%Clearancerateincreasese.g.ampicillin.Solve?WhataboutdoseinUTI?

Explainwhythedosagesofdigoxinandlithium,areincreasedduringpregnancy?Doyouthinkthatpregnancycanalsoaffectdrugpharmaco-dyamics?▲B.blockersEffectofpregnancyondrugs8編輯pptII.EffectofdrugsonfetusDrugscaninfluencefetaldevelopmentat3separatestages:

Fertilization&implantationperiod:fromconceptiontoabout17daysgestationOrganogenesis:18-55days

Growth&development:56thdayonward

9編輯ppt編輯pptTerminology:

Dysmorphogenesis&teratogenicity

1-

Teratogen:

→agentthatinterfereswithnormal

growth&developmentofFoetus

→describedrugsorchemicalsthatcause

majororgrossbirthDefects

2-Congenitalmalformations:

→structuralabnormalitiesofprenatal

originthatarepresentatbirth編輯pptTeratogens

Asubstance,organism,physicalagentsordeficiencystatecapableofinducingabnormalstructureorfunctionsuchas:

GrossstructuralabnormalitiesFunctionaldeficienciesIntrauterinegrowthrestriction

BehavioralaberrationsDemise

12編輯pptTeratogenicFactors

TimingofexposureDevelopmentalstageduringexposureMaternaldoseanddurationMaternalpharmacokineticsGeneticfactors/phenotypesInteractionsbetweenagents13編輯ppt3-Congenitalanomaly:

→non-reversiblebirthdefectscausedbygeneticpredispositionordrugexposure

→maybe→obviousatbirth(hydrocephalus)

or→delayed

manyyearstobeidentified(behavioural&intellectualdisorders)withinutero,alcoholexposure)

4-Dysmorphogenesis:

→structural&functionaldefects編輯pptThalidomideIsotretinoinWarfarinValproicAcidCarbamezepineCoumarinPhenytoin編輯pptEffectofdrugsonpregnancy(fetus):

1-Placentaldrugtransfer:

Factorsaffectingtherateofdrugtransferacrossplacentaanditseffectonfetus:

1.Physico-chemicalpropertiesofthedrug:

a)

Molecularweight(size):

?DrugswithMW<600crosseasily→Mostdrugs

?DrugswithverylargeMWe.gInsulin&HeparinCannotcross

編輯pptb)Lipidsolubility

:

?Lipidsoluble(un-ionized)substancescrossrapidly

?Weaklybasicdrugsmaybecometrappedinfetalcirculation(SlightlylowerpHcomparedtomaternalplasma)e.g.thiopental.

c)Ionization:

?MoleculesthatareionizedatphysiologicalpHcrossslowly(e.g.salicylates,tubocurarine)

NB.Consideranydrugcancrosstheplacenta.E.g.atenolol.

編輯pptd)Proteinbinding

Onlyfreeunbounddrugs,crossplacenta2.Therateatwhichthedrugcrossestheplacentaandamountreachingthefetus:a.Uterine&umbilicalbl.flow

?Maternalbloodpressure?Cordcompression

?Drugtherapy→alpha-stimulantb.Maternaldiseases

?pregnancy-inducedhypertension,DM→changepermeabilityofplacenta

編輯pptc)Placentaltransporters:

e.g.PGpwithanticancerdrugs,proteaseinhibitors

d.

Placentalandfetaldrugmetabolisme.g.oxidationreactionsofplacenta,fetalliver50%3.Thedurationofexposuretothedrug4.Distributioncharacteristicsindifferentfetaltissues5.Stageofplacentalandfetaldevelopmentatthetimeofexposuretothedrug

6.Theeffectsofdrugsusedincombination19編輯ppt2-Pharmacologicaleffects:

?Drugscrossingplacentamayexert→direct

effect(corticosteroids→adrenalsuppression)

→indirect

effect

(anti-hypertensives→fetalhypoxia2rytomaternalhypotension)?Drugsmayaffect:→Organdevelopment→Organfunction

編輯ppt1.Fertilization&implantationperiodInterferencebydrugsinthisstageleadstofailureofpregnancy(deathoffetus)ataveryearlyandprobablysub-clinicalstage.21編輯pptThemostsensitiveperiodtoTeratogeniceffectsTetragon=anysubstancethatproducesdeformityDifferentinspecies(animals,humans)ThalidomidePhenytoin5%,warfarin25%ThemostcommonTeratogenicdrugsare:

2.OrganogenesisDrugEffectDanazolSexhormonesVerilizationoffemalefet.Multiple,cardiacLithiumcardiacPhenytoinCraniofacial;limbCarbamazepineCraniofacial;limbValproateNeuraltubewarfarinMultipledefects;chondrodysplasiaretinoidsCNS,craniofacial,heart22編輯pptPredictabletoxicdrugactionsinthefetusOpioids?dependenceoffetusandnewbornACEI?irreversiblerenaldamageoffetusDiethylstilbosterol?adenocarcinomaofvaginaafterpuberty23編輯pptDefinition:Developmentalabnormality&drugAnimalstudiesRateofspontaneousis1-2%Teratogenicmechanisms:Poorlyunderstoodandmulti-factorialDirecteffectonmaternaltissueswith2ryeffectonfetaltissues.▼OxygenandnutrientsthroughplacentaDirectactionsonfetaltissuese.g.differentiationofdevelopingtissues.E.g.Vit.AanaloguesDeficiencyofcriticalsubstancelikefolicacidTeratogenesis24編輯pptDangerousperiod:

2nd

to8th

weeksofpregnancy(structuralabnormalities

Lateron:dugsaffectgrowth,development,

integrityofbodystructureespeciallybrainButwhataboutthestoreddrug?Likeetritinate?2yearsTeratogenesis25編輯pptCAUSESOFBIRTHDEFECTS

INHUMANSSchardeinJL,2000.*Evidence:LevelB編輯pptCharactersoftheteratogen:

Tobedefinedasateratogen,thesubstanceortheprocessshould:ResultinacharacteristicsetofmalformationExertitseffectataparticularstageoffetaldevelopmentShowsdose-dependenceincidenceE.g.retinoids,warfarin,sexhormones

編輯pptFoodanddrugadministrationclassificationofDrugsinpregnancy

FDACategories:teratogenicriskofdrugs編輯pptDRUGLABEL

Pregnancy“Categories〞AControlledstudiesinhumans

noriske.gPenicillin????BanimalstudiesshownoriskbutnocontrolledhumanORanimalstudiesshowadverseeffects)e.g.Acetaminophen,Cephalosporins

CAnimalstudiespositive(teratogen)butnocontrol.humanHuman&animalslacking.Riskcannotruledout.gAspirin,Chloramphenicol,corticosteroid,Ciprofloxacin,Digoxin,MetronidazoleDHumandatashowrisk,benefitmayoutweighe.g.Enalapril,Captopril,Glyburide,Indapamide,Amitriptyline

XAnimalorhumandatapositive.Riskoutweighbenefit.Contraindicated.e.g.Oralcontraceptives,Triazolam,Ethanol,estrogen*編輯pptDrugswithhighriskofcausingabnormalitiesDrugEffectAlcoholFetalalcoholsyndromeAndrogensVirilization;multipledefectsAnticancerMultiplecongenitaldefectsCarbimazoleAplasiacutisCorticosteroidsCleftpalateCyproteroneFeminizationofmalefetusErgotamineIncreaseuterinetoneMisoprostolIncreaseuterinetoneFibrinolyticlikestreptokinasePlacentalseparationTetracyclines▼Bone,yellowdiscolorationValproateNeuraltubedefectsVit.AanaloguesCongenitaldefectsWarfarinMultiplecongenitaldefects30編輯pptDrugsconsideredtobeprovenhumanteratogensACEinhibitorsDanazolCumarinderivatives(warfarin)DiethylstilbestrolEthanolLithiumVitaminAandderivatives,e.g.isotretinoinPhenytoinTetracyclineValproicacidAndrogensCarbamazipineCyclophosphamideThalidomidePenicillamineDiethylstillbestrol編輯pptDrugsunderstrongsuspicionofproducingabnormalities(slightlyincreasedrisk)DrugEfectAmiodaroneGoitreChloroquineDeafness(acutemalaria)PhenytoinMultiplecongenitaldefects(Epilepsy)Otherdrugstoavoid(theoreticalriskfromanimalandotherstudies)ACEinhibitorsQuinoloneantibioticsVaccines(live)DeferoxamineRifampicinVigabatrinCCblockersSimvastatinXamoterolFibratesSpironolactoneGrisofulvinSulfonylureaIdoxuridineThiabendazoleKetoconazoleTocainideMefloquineTrimethoprimomiprazoleCotrimoxazole32編輯pptIII.Growth&developmentMajorbodystructureshavebeenformedSubsequentdevelopmentandfunctioncanbeaffected33編輯pptAdverseeffectsofdrugsonthefetusduringthelaterstagesofpregnancyDrugsRisktofetusorneonateACEinhibitorsfetalrenalfailure,PDA,RDS.Aminoglycosides8thnervedamageAntithyroiddrugsGoitre&hypothyroidism(use?dose)AspirinKernicterus,hge(fetal/maternal)BenzodiazepinesFloppyinfantsyndromeFibrinolyticHge(infant/maternal)NarcoticanalgRdepression,withdrawalifdependentNitrofurantoinhemolysisNSAIDsClosureofDA?PH,delayedprolongedlabor,hgeNovobiocinKernicterusWarfarinFetal,placentalhge,microcephalySulfonyureasHypoglcemiaSulfonamidesKernictrus(Exceptsulfasalazine)TetracyclinesYellowdiscolorationofteeth&boneThiazidediureticsthrombocytopenia34編輯pptDrugsthataresafeinpregnancyClassDrugsthataresafeinpregnancyMineralsIronVitaminsFolicacidAntiemeticMeclozine&cyclozineAnalgesicsParacetamolAntibioticsPenicillinTranquilizersHypnoticsNotcompletelysafeAntidiabeticInsulinAnticoagulantsHeparin(osteoporosisofmothers)AntihypertensivesMethyopa/nifedipine/labetalol-diureicsnot/notACEI35編輯pptTreatmentofsomecommondiseasesdrugduringpregnancyDiseasetreatmentAnemiaIron30mg+folicacid200-500mg/dayInfectionse.g.UTIAmpicilin,amoxicillin,cephalosporines/nitrofurantoin,metronidazoleINH,ethambutolnotrifampicin(TBdrugs)Whataretheantibioticdrugscontraindicatedinpregnancy?T,C,ADiabetesmilletusInsulin(short,intermediate)BronchialasthmaInhaledsalbutamol,steroids,theophylline.HyperthyroidismPropylthiouracilHypertensionPre-eclampsiaChronicHTMethyldpa,nifedipine,labetalol+Mgsulphate(convulsions)NotACEI,diuretics.ThrombosisHeparin(warfarininartifialvalves,cong.HD,AF)EpilepsyFetalanticonvulsantsyndrome2.4,4.2,6%,newdrugs?VomitingMeclozine,cyclizinePreventionofNTDFolicacid4mg/day,400microfornormalpregnancy/3monthsMalariaprophylaxisChloroquine,proguanil+5mgfolicacid(PF)Meloprim(pyrimethamine+dapsone)not1sttrimisterLateron+folicacidMefloquineiscontraindicated36編輯pptTherapeuticdrugactionsinthefetusCorticosteroidsforfetallungmaturationPhenobarbitoneforneonatalindirecthyperbilirubinemiaAntiarrhythmicdrugs

forfetalarrhythmiasZidovudineforprotectionofHIVtransmission37編輯pptBreastfeedinganddrugs編輯pptDrugexcretioninmilk:

Mechanismsoftransferfrombloodtomilk:1-Diffusionoflowmolecularweightsubstances(throughsmall,water-filledpores).2-Diffusionoflipidsolublecompounds(throughlipidsolublemembrane)

3-Carriermediated,activetransport.編輯pptFACTORSINFLUENCINGDRUGTRANSFERINTOBREASTMILKMaternalFactorsMetabolism,dose&frequency,durationoftherapy,routeofadministration,PPBInfantFactorsAge,drugabsorption,metabolism,extentofbreastfeeding(quantity,frequency,solidfoods),timingoffeedsDrugfactors(transfer)Breastbloodflow,breastmetabolismpKa(ionization),lipidsolubility,proteinbinding,MW,bioavailability,pHdifferences編輯ppt編輯pptFactorsaffectingadverseeffectsofdrugsinsucklinginfants:PassageofthedrugfromthematernalbloodintomilkConcentrationofthedruginmilkVolumeofthemilksuckedPharmacokineticsofthedrugintheinfants;particularlyitsabsorptionandclearanceInherenttoxicityofthedrugWhatisthebesttimeoftakingthedrugsforlactatingmothers?Drugtherapy&breastfeeding42編輯pptSomedrugstobeavoidedinbreastfeedingmothersHighexcretionorhypersensitivityAmiodaroneCo-trimoxazoleSulfonamidesAmphetamineCiclosporinestetracyclinesAndrogensDoxazocintrimethoprimAnticancerErythromycinVitaminAanalogueAntipsychoticsEthosuxamideVitaminD(Highdosage)AntithyroidFluoxitineXanth