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FIGURE3–4MedWatchformforreportinganadverseeventorproductproblemtotheU.S.FDA.(2/19)
“https://www.fda.gov/safety/medical-product-safety-information/medwatch-forms-fda-safety-reporting”
CASESTUDY1
A.C. is a 60-year-old Caucasian woman with newly diagnosed peptic ulcer disease, generalized
anxietydisorder,andirondeficiencyanemia.Shealsohasalonghistoryofasthmaanddepression.She
isastrongbelieverofherbalmedicine.ShetakesSt.John’swortforherdepression,ironpillsforher
anemia, andalprazolam (Xanax) as needed for her anxiety. During her asthma exacerbation, she is
instructedtotakeprednisoneforatleast5days.Shealsotakesesomeprazole(Nexium)forherpeptic
ulcerdisease.Threemonthslater,sheexperiencedseverefatigue,shortnessofbreath,dizziness,and
swelling/soreness inthetongue. Her asthma iswell controlledwiththeoccasionaluse ofalbuterol
(Proventil)inhaler.Duringherphysicalexam,herphysiciansuspectedthatshehadbacterialvaginosis
andgaveheraprescriptionfora1-weekcourseofmetronidazole(Flagyl).Shedrinksatleasttwoto
threecansofbeerperday.
Diagnosis:Drug–DrugInteractions
1. St.John’s wortis knowntoinhibitwhichofhermedicationthatisknowntobe metabolizedby
cytochromeP-450(CYP3A4)andcouldpotentiallycausehertoexperiencesignificantfatigue?
Answer:Alprazolam(Xanax)
2.Whichofhermedicationcouldinterferewiththeabsorptionofherironpills?
Answer:Ironpills
3.WhichofhermedicationcouldpotentiallycausehertodevelopvitaminB12deficiency?
Answer:Esomeprazole(Nexium)
4.Howdoesmetronidazoleinterferewithalcohol?
Answer:Metronidazoleinhibitstheenzymes,alcoholdehydrogenase,knowntometabolizealcohol
5.Ifshewasgivenaprescriptionforketoconazole,whichofhermedicationcouldinterferewithits
absorption?
Answer:Esomeprazole(Nexium)
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4
PrinciplesofPharmacotherapyinPediatrics,
Pregnancy,andLactation
PoojaShahandAnitaSiu
LearningObjective
1.Describethedifferencesinpharmacokineticsamongpregnantwomen,neonates,children,andadults.
2. Describe the unique challenges neonatal and pediatric patients pose to the medication system,
includingdrugselectionanddosages.
3.Explainthepotentialandstrategiesforthepreventionofmedicationerrorsinneonatalandpediatric
patients.
4.Identifystrategiestodeterminesafemedicationuseinpregnancybasedonavailableliterature.
5.Determinethedrug-relatedfactorsthatwouldhelpguidesafeandeffectivemedicationuseinbreast-
feedingwomen.
INTRODUCTION
Medicationuseinpediatricandpregnantpatientsposesasignificantchallengeforhealthcareproviders
duetoourlackofknowledgeoftheeffectsofmedicationonthefetusandpediatricpopulation.Accepted
termsthatdefinethe differentagecategories ofpediatric patientsare listed inTable 4.1. These terms
shouldbeusedtoensureaccuracywhendescribingyoungpatientsandespeciallywhendeterminingdrug
dosages.Additionally,90%ofwomenwilluseonemedicationduringpregnancy,andabout70%willuse
one or more prescription medications (Mitchell et al., 2011). The rate of use of over-the-counter
medicationsandillicitsubstancesalsocontinuestoposeasignificantchallengetounderstandingtherisks
andbenefitsofmedicationuseinpregnantwomenandfetuses.Asinthecaseofpediatricpatients,the
practitionerneedsasolidunderstandingofthephysiologicchangesthatoccurduringpregnancyandthe
effectsthatthesechangeshaveonmedicationefficacyandsafety.Thepractitionermustalsobalancethe
needtotreatthemotheragainstthepotentialriskofthesemedicationstothefetus(Briggsetal.,2017).
Safeandeffectivedrugtherapyinpediatricandpregnantpatientsisbasedonafirmunderstandingof
fourconcepts:
•Extentofadrug’sabsorption,distribution,metabolism,andexcretionbasedontheongoingmaturation
anddevelopment in pediatric patients or the altered physiologic changes in the mother. Interpatient
variabilitiesmaybeattributedtophysiologicchangesthroughoutchildhoodorpregnancy.
• Short- andlong-termeffects thatthe prescribed drugwill have ona pediatric patient’s growthand
development.
• The placental–fetal unit, whichaffectstheamount of drug thatcrosses theplacental membrane, the
amountofdrugmetabolizedbytheplacenta,andthedistributionandeliminationofthedrugbythefetus.
•Effectsofunderlyingcongenital,chronic,orcurrentdiseasesontheprescribeddrugandviceversa.
Thepopularconceptthatthepediatricpatientismerelya“littleorsmalladult”andthereforepediatric
pharmacokinetics, drug dosing,andeven adverse effects can be extrapolated from the results ofadult
clinicaldrugtrialsisaseriousmisconception.Althoughtheeffectsofmanydrugsaresimilarbetweenthe
adult and the pediatric populations, the assumption of similarity should not be applied to all drugs.
Severaltragicdrugmisadventuresinthe1960sand1970sillustratetheinvalidityofsuchanassumption.
Extrapolateddatafromadultresponsestochloramphenicol(Chloromycetin)ledtoitsuseinneonatesin
the1960s.Whengivenchloramphenicol,theseneonatesdevelopedgraybabysyndrome,hypotension,and
hypoxemia,leadingeventuallytoshockanddeath(Haile,1977).Thisoccurredbecauseneonates,unlike
adults,lacktheenzymeneededtometabolizechloramphenicol. Anothertragedy,inthe1970s,involved
thetopicalantimicrobialcleanserhexachlorophene.Usedroutinelyandsafelyinadults,hexachlorophene
causedvacuolarencephalopathyofthebrainsteminprematureneonatesaftertheywererepeatedlybathed
ina3%solution(Anonymous,1972).
TABLE4.1
AgeGroupsofPediatricPopulation
Group Age
Pretermorpremature <36wkgestationalage
Neonate <30dold
Infant Age1mountil1y
Child Age1until12y
Adolescent Age12until18y
Pharmaceuticalmanufacturersfaceseveralbarrierstoconductingpediatricclinicaltrials,suchasfears
of unforeseen adverse events affecting growth or development or difficulties in obtaining informed
consentorbloodsamples.Inturn,thelackofclinicaltrialsinpediatricpatientspreventstheU.S.Food
andDrugAdministration(FDA)fromapprovingdrugsforuseinthepediatricpopulation.As such,the
prescribinginformationcommonlystates, “Pediatric use: Safetyandeffectivenessinpediatric patients
hasnotbeenestablished.”
WithoutFDAapprovaloradequatedocumentedinformation,manypractitionersareuncertainaboutthe
use of drugs in pediatric patients. This leaves prescribers little choice but to use drugs in pediatric
patients in an off-label capacity, based on adult data, uncontrolled pediatric studies, or personal
experience.In1997,theFDAtooktheinitiativetoincreasethequantityandqualityofclinicaldrugtrials
inthepediatricpopulationbyproposingalternatewaystoobtainFDA approval.TheFDAwaivedthe
need for well-controlled clinical drugtrials if drug manufacturers provided other satisfactory data for
drugsalreadyapprovedforthesameuseinadults.Thesedatacouldincludetheresultsofcontrolledor
uncontrolled pedi-atric studies, pharmacodynamic studies, safety reports, and premarketing or
postmarketingstudies.Alternatively,thedrugmanufacturercouldprovideevidencedemonstratingthatthe
diseasecourseanddrugeffectsaresufficientlysimilarinadultandpediatricpatientsinordertosupport
extrapolation of data from adult clinical trials. In addition, pediatric pharmacokinetic studies are
necessarytoprovidedataforanappropriatepediatricdosagerecommendation,especiallyage-dependent
dosing. An FDA regulation issued in December 1998 required manufacturers to provide additional
informationabouttheuseoftheirdrugproductsinpediatricpatients.Thenatureofthestudiesrequiredto
supportpediatriclabelingdependsonthetype ofapplication,theconditionbeingtreated, andexisting
dataabouttheproduct’ssafetyandefficacyinpediatricpatients.Manufacturersarerequiredtostudythe
druginallrelevantpediatricagegroups(U.S.FoodandDrugAdministration,1998a).Overtheyears,the
FDAhasencouragedmorewell-controlledtrialsondrugefficacyandsafetyinpediatrics.TheFoodand
DrugAdministrationModernizationActof1997andtheBestPharmaceuticalsforChildrenActof2002
offered support for the pharmaceutical industries to conduct and submit pediatric clinical trials.
Companiesthatconductappropriateclinicaltrialsareeligibletoreceivea6-monthpatentextensionon
theirproduct.ThePediatricResearchEquityActof2003mandatedthatdrugsusedinpediatricsrequire
literature or clinical trials supporting their use, even if the original patent did not have a pediatric
indication.Asaresult,pediatricpharmacotherapywillevolvewithadditionalclinicaltrials.
PHARMACOKINETICSINPEDIATRICSANDPREGNANCY
Women undergo many physiologic changes during pregnancy, whereas pediatric patients differ from
adults,anatomicallyandphysiologically.For safeuseofdrugsinpediatricsandpregnancy, prescribers
andothercaregiversneedtorecognizethepotentialforverydifferentpharmacokineticsasopposedtothat
foradultsornonpregnantwomen.Inpediatrics,thedifferencesarebasedondevelopingbodytissuesand
organs, which affect a drug’s absorption, distribution, metabolism, and excretion. In pregnancy, the
differencesarebasedoncardiovascular,gastrointestinal(GI),kidney,andhormonalchanges(Pinheiro&
Stika,2020).
Changesinapediatricpatient’sbodyproportionsandcompositionandtherelativesizeoftheliverand
kidneyscanalterthepharmacokineticsofadrug.Duringthefirstseveralyearsoflife,achildundergoes
rapid changesingrowthanddevelopment,whichis mostrapidduringinfancy.Growthis aquantitative
changeinthesizeof thebodyor anyofits parts, anddevelopmentisaqualitativechangeinskillsor
functions.Maturation,ageneticallycontrolleddevelopmentindependentoftheenvironment,isaslower
process,lastinguntillatechildhood.Table4.2summarizespharmacokineticdifferencesinpediatricand
pregnantpopulationscomparedtoadultsandnonpregnantwomen.
Bytheendofthefirstyear oflife,aninfant’sweighttriples,whereas bodysurfacearea(BSA)and
lengthdouble.Accompanyingthesechangesingrowthanddevelopmentarechangesinbodycomposition,
intracellular andextracellular bodywater,fat, andprotein.Approximately75% to 80% ofa full-term
neonate’s body weight is total body water (Friis-Hansen, 1957). By age 3 months, total body water
constitutesapproximately 65% oftheinfant’sbody weight.Extracellular water progressively declines
andintracellularwaterincreasesfasterthantotalbodywaterdoes,exceedingextracellularwatercontent
(Friis-Hansen,1957).Thedecreaseintotalbodywaterasapercentageofbodyweightiscompensated
forbyincreasedbodyfatduringthefirst5monthsoflife.Infact,thepercentageofbodyweightfromfat
doublesinthese5months.Theproteinpercentageincreasesduringthesecondyearoflifeasfatislost,
primarilybecauseofambulation.Theliverandkidneyreachtheirmaximumsizerelativetobodyweight
by age 2, producing a “peak” in the child’s metabolism and elimination. After age 2, the ratio of the
child’sliver and kidney size tobody weightsteadily decreases until adult liver andkidneyratios are
reachedbyadolescence.
TABLE4.2
Age- and Pregnancy-Related Pharmacokinetic Differences in Children and Women Compared
withNonpregnantAdults
GI,gastrointestinal.
OralAbsorption
Theextentofadrug’sabsorptionduringpregnancymaybealteredandinpediatricpatientscandependon
a variety of factors: gastric pH, gastric and intestinal transit time, GI surface area, enzymes,
microorganismflora,oranycombinationthereof.
GastricpH
BasalandstimulatedsecretionofgastricacidcontrolsthepHofthestomach.Pregnantwomenexperience
areductioningastricacidsecretions(upto40%lessthaninnonpregnantwomen)aswellasanincrease
ingastric mucussecretion.Together,this maylead toanincrease ingastric pH anda decrease in the
absorptionofmedicationsthatneedanacidicpHforappropriateabsorption.
The stomach pH is alkaline at birth (greater than 4) because of residual amniotic fluid and the
immaturityofparietalcells.Asgastricacidisproduced,thepHfalls.Bytheendofthefirstdayoflife,
thebasalandstimulatedratesareequal,althoughlowerthantheratesinadults.AnincreasedstomachpH
(alkaline)adverselyaffectstheabsorptionofweaklyacidicdrugsandimprovestheabsorptionofweakly
basic drugs. This phenomenon results from increased ionization of the weaklyacidic drug, producing
moreionized(polar)drug,whichmovespoorlyacrossthenonpolargastricmembrane,andviceversafor
weakly basic drug. For example, the bioavailability of phenobarbital (a weak acid) is decreased in
neonates, infants, and young children because their alkaline gastric pH produces more ionized
phenobarbital,whichcrossesthegastricmembranepoorly.
Forweaklybasicdrugs,thealkalinestomachpHincreasesthenonionizedformofthedrug,whichthen
easilymovesacrossthegastricmembrane.Bythesecondyearoflife,thechild’sgastricacidoutputona
perkilogrambodyweightbasisissimilartothatobservedintheadult(Deren,1971).Asaresult,gastric
pHaffectsthedegreeofdrugionization,thuschangingtheamountofdrugabsorbed.
GastricEmptyingTimeandSurfaceArea
Pregnancy-induced maternal physiologic changes may affect GI function, and therefore, the oral
absorptionofsomedrugsmaybealtered.OfthemanyfactorsthatcanaffectGIabsorptionofdrugs,one
is the decrease in GI tract motility, especially during labor. It is believed that an increase in plasma
progesterone levels causes this decrease in motility, which may delay the absorption of orally
administered drugs. Another reason for decreased GI absorption may be the nausea and vomiting
associatedwithincreasedprogesteronelevels thatarecommonduringthefirsttrimesterofpregnancy.
Therefore,pregnantwomenmaybeadvisedtotaketheirmedicationsattimeswhennauseaisminimal.
Similarly,thegastricemptyingtimeisdelayedinbothpretermandfull-termneonatesduringthefirst24
hoursoflife.Nostudieshavebeenconductedbeyondtheimmediateneonatalperiod.Thecombinationof
delayed gastric emptying time and gastroesophageal reflux can result in the regurgitation of orally
administereddrugs,producingirregulardrugabsorption.Ingeneral,gastricemptyingismoreprolonged
inneonatesandinfantsthaninchildren.
Thecharacteristicsofadrug’smovementthroughtheintestinescandrasticallyaffecttherateandextent
ofdrug absorptionbecause mostdrugs are absorbed intheduodenum.Bothneonates andinfantshave
irregular peristalsis, whichcanlead toenhanced absorption. Inaddition, the type offeeding aninfant
receivescanaffectintestinaltransittime.Forinstance,thegastricemptyingtimeinbreast-fedinfantsis
fasterthaninformula-fedinfants(Cavell,1981).
Therelativesizeoftheabsorptivesurfaceareaintheduodenumcansignificantlyinfluencetherateand
extentofdrugabsorption.Intheyoung,thegreaterrelativesizeoftheduodenumcomparedwithadults
enhancesdrugabsorption.
GastrointestinalEnzymesandMicroorganisms
The absorption of drugs that are fat soluble or carried in fat vehicles depends on lipase. Premature
neonateshavelowlipaseconcentrationsandnoalphaamylase.Thereducedactivityofbileacids,lipase,
alpha amylase, and protease continues until approximately age 4 months. Vitamin E absorption is
decreased in neonates because of the diminished bile acid pool and biliary function; therefore,
supplementationofthisvitaminmaybenecessary.
The development of theintestinal microorganism flora depends more on dietthan onage(Yaffe &
Juchau,1974),whichmayaccountforthemorerapiddevelopmentofflorainbreast-fedinfantsthanin
formula-fedinfants.The reductionof digoxin (Lanoxin) to inactive metabolites byanaerobic intestinal
bacteriacanbeusedasa markerforthedevelopmentorchangesinintestinalflora(Lindenbaumetal.,
1981). Digoxinmetabolitesarenotdetectedinchildrenuntil 16 months,andanadult-likereductionof
digoxindoesnotoccuruntilage9(Lindayetal.,1987).
RectalAbsorption
Therectalrouteofadministrationisseldomused;itusuallyisreservedforpatientswhocannottolerate
oral drugs or who lack intravenous access. In rectal administration, the drug is absorbed by the
hemorrhoidal veins, whicharenotpartoftheportalcirculation;therefore,itavoidsfirst-pass hepatic
elimination. Unfortunately, most drugs administered by this route are erratically and incompletely
absorbed. Feces in the rectum, frequent bowel movements in neonates and infants, and lack of anal
sphinctermusclecontributetothepoorabsorptionprofileofdrugsadministeredrectally.
Although rectal administration may not be appropriate for routine dosing of drugs, the rectal
administrationofdiazepam(DiastatAcuDial),valproicacid(Depakote),ormidazolam(Versed)hasbeen
usedtocontrolseizureswhenintravenousaccesscouldnotbequicklyestablishedininfantsorchildren
withstatusepilepticus(Brigoetal.,2015;Graves&Kriel,1987).
IntramuscularandSubcutaneousAbsorption
Both the characteristics of the patient and the properties of the drug influence the absorption of
intramuscularlyor subcutaneouslyadministered drugs.Patientcharacteristics includeblood flow tothe
muscle, muscle mass, tone, and activity.Important properties of the drug are its solubility, the pH of
extracellularfluid,itseaseincrossingcapillarymembranes,andtheamountofdrugadministeredatthe
injectionsite.
In pediatric patients, all the patient characteristics are highly variable. Neonates have decreased
musclemass,andtheirlimitedmuscleactivitydecreasesbloodflowtoandfromthemuscle.Collectively,
thesefactorsproduceerraticandpoorintramusculardrugabsorption.Onthecontrary,infantspossessa
greater density of skeletal muscle capillaries than older children, allowing for more efficient drug
absorption. Some drugs, such as erythromycin, can cause pain at the injectionsite andshould not be
administered intramuscularly.However,manydrugs,suchasthepenicillins,reachconcentrationsinthe
serum with intramuscular administration that are comparable with those achieved after intravenous
administration,withminimaladverseeffects.
PercutaneousAbsorption
Anincreaseintheabsorptionofmedicationsthroughtheskinisevidentduringpregnancy.Theincreasein
peripheralvasodilationandincreaseinbloodflowtotheskin(Kraemer,1997)enhancethisincreasein
absorption.Becauseofanincreaseintotalbodywater,thereisincreasedwatercontentintheskin,which
favorsanincreasedrateandextentofabsorptioncomparedtowater-solublemedicationslikelidocaine,
whichmaybeusedasatopicalanestheticduringpregnancy(Yankowitz&Niebyl,2001).
Theabsorptionofcompoundsisinverselyrelatedtothethicknessofthestratumcorneumanddirectly
relatedtohydrationoftheskin(Morsellietal.,1980).Relativetobodymass,theBSAisgreatestinthe
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