Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5200_Библиотеки_им_академика_М_И_Перельмана
.pdf
infantandyoungchildcomparedwitholderchildrenandadults.Thedecreasedthicknessoftheskinwith
increased skin surface hydration relative to body weight produces much greater percutaneous drug
absorptioninneonates than inadults. Thepercutaneous administrationof drugs inneonates does pose
somerisksoftoxiceffects.Neonatalskinisstructurallyimmature,resultinginlesssubcutaneousfatanda
thinner stratum corneum and epidermis (Rutter, 1987). Adverse effects resulting from the inadvertent
systemicabsorptionofpercutaneouslyadministered hexachloropheneemulsion,salicylicacidointment,
andhydrocortisonecreamsinneonateshavelimitedtheuseofthisrouteofdrugadministration.Butsince
agreaterskinsurfacearea–bodyweightratioisobservedduringtheneonatalperiod,percutaneousdrug
absorption is also superior. Both the advantages and the subsequent disadvantages of enhanced
percutaneousabsorptiondisappearafterinfancy,however.
MucosalAbsorption
Mucosaladministrationofmedications,whethervia thenasalorthebuccalroute,hasbecomeaviable
method for use in children. Some medications, such as nasal corticosteroids, are intended for a local
effectandhavealmostnosystemicabsorptionoreffects.However,somemedications,suchasmidazolam
(VersedandNayzilam)andketamine(Ketalar),havebeenadministeredbynasalaerosolizationwithgood
absorptionandsystemiceffect(HosseiniJahromietal.,2012;Kleinetal.,2011).Administrationbythese
routesavoidsthetraumaofplacinganintravenouslineandtheassociatedcosts.Also,inurgentsituations,
where there may be considerable difficulty placing an intravenous line(i.e., status epilepticus), nasal
administrationcanbeutilizedwithgreateffectiveness(Thakker&Shanbag,2013).
PulmonaryAbsorption
Aerosolized drug delivery to the lungs continues to be a preferred technique in many respiratory
disorders, such as asthma. Factors affecting drug deposition in the lungs include particle size, lipid
solubility,proteinbinding,drugmetabolisminthelungs,andmucociliarytransport(AmericanAcademy
ofPediatrics,1997).Aerosolparticlesizeandlipidsolubilityarefactorsindeterminingwhetherthedrug
isdepositedintheupperorlowerairways;drugswithsmallerparticlesizeandlipid-solubledrugsare
more likely to be absorbed and deposited in the lower airways (Bond, 1993). Besides drug
considerations, physiologic changes in pregnancy favor the absorption of medications administered
through the inhalation route. Both cardiac and tidal volumes are increased by approximately 50% in
pregnancy, resulting in hyperventilationand increased pulmonary blood flow (Loebsteinet al., 1997).
These alterations aid in the transfer of medications through the alveoli into the maternal bloodstream
(Loebstein et al., 1997). Because of this increased transfer into the bloodstream, it is important to
considerdosereductionsofcertaininhaledmedicationssuchasvolatileanesthetics.
Pediatric characteristics also affect aerosol drug delivery. Infants and children have lower tidal
volumesandincreasedrespiratoryrates(especiallywhilecrying),reducingdrugdeliveryandabsorption
inthelungs.Studieshaveshownthatlessthan2%ofaerosolizeddrugsaredepositedinyounginfantsand
toddlers(Foketal.,1996;Salmonetal.,1990).Therefore,adultdosingmaybenecessarytocounteract
theseeffects.
Distribution
Maternalbloodvolumeincreasessignificantlyduringpregnancyduetotheincreaseinestrogenactivation
ofthereninangiotensin–aldosteronesystem.The30%to50%increaseinbloodvolume(Guyton&Hall,
1996;Loebsteinetal.,1997)ischaracteristicallydistributedtovariousorgansystemsservingtheneeds
ofthegrowingfetus.Thefullincreaseintotalbodywaterduringpregnancyis8L,with60%distributed
totheplacenta,fetus,andamnioticfluidand40%goingtomaternaltissues(Loebsteinetal.,1997).These
increasescausethevolumeofdistributionofmedicationstoincrease,resultinginadecrease(dilutional
effect) in drug concentrations. Studies show thatpeak andtotal concentrationsofwater-soluble drugs
decreasebecauseoftheincreasedvolumeofdistribution(Philipson,1977).Conversely,drugdistribution
is affected byanincrease inmaternalfatdeposits. Medications thatare highly lipophilicdistributeto
maternalfatdeposits,alsoresultingindecreasedserumdruglevels.Bodyfatincreasesduringpregnancy
by3to4kgandmayactasareservoirformedicationsthatfavorafat-solubleenvironment(Yankowitz&
Niebyl,2001).Anotherfactorthatmayaffectmedicationdistributionistheconcentrationofalbuminin
thematernalblood.Theconcentrationofplasmaalbumindecreasesduringpregnancy. Thisdecreaseis
believed to be caused by a reduction in the rate of albumin synthesis or an increase in its rate of
catabolism(Fredericksen,2001).Furthermore,thereisanincreaseinarterialpH,whichmayaffectdrug–
proteinbinding.Medicationsthatarehighlyboundtoplasmaalbumin(e.g.,anticonvulsants)mayhavean
increasedfreedrugconcentrationduetodecreasedalbuminbinding.
Sixfactorsaffectdrugdistributioninthepediatricpopulation:vascularperfusion,bodycomposition,
tissue-bindingcharacteristics,physicochemicalpropertiesofthedrug,plasmaproteinbinding,androute
of administration (Stewart & Hampton, 1987). During the neonatal period, most of these factors are
significantlydifferentfromthoseintheadultpopulation,whilechildrenandadolescentsareverysimilar
toorthesameasadults.
VascularPerfusion
Changes invascular perfusion are common in neonates. For example, in neonatal respiratory distress
syndromeandpostasphyxia,aright-to-leftvascularshuntmayoccuranddivertbloodfromthelungstothe
tissuesandorgans,potentiallychangingtheVdofsomedrugs.
BodyComposition
Neonates have increased total body water (75% to 80%) with decreased fat compared with adults,
resulting in a higher water–lipid ratio. After the neonatal period, fat increases and total body water
decreases steadily until puberty, especially in girls. For instance, neonates and infants have increased
total body and extracellular water, creating a larger volume of distribution and affecting the
pharmacokinetics of some drugs, such as aminoglycosides. The larger volume, in turn, requires
administeringa larger milligram-per-kilogramdose ofaminoglycosides toneonatesandinfants thanto
adults.
Tissue-BindingCharacteristics
Themassoftissueavailableforbindingcanaffectdrugdistribution.Drugsextensivelyboundtotissues
exhibitincreased“free”bloodlevelswhenthemassoftissueisreducedbydiseaseordegenerationor
immaturity,asinthepediatricpopulation.
PhysicochemicalProperties
Thephysicochemicalpropertiesofadrugincludelipidsolubility(ionizedvs.nonionized)andmolecular
configuration.Thesepropertiesaffecttheabilityofadrugtomoveacrossmembranesintotargetcellsor
tissues. Drugsthatdisplay favorable properties for absorption may pose a greater risk for toxicity in
neonates,whohaveenhancedpercutaneousdrugabsorption.
PlasmaProteinBinding
Pretermneonateshavelowercirculatingamountsofalpha1acidglycoprotein,whichbindsalkalinedrugs,
thanfull-termneonates,whohaveloweralpha1acidglycoproteinlevelsthanadults.Neonatesalsohave
areducedamountofcirculatingalbumincomparedwithadults.Albuminisresponsibleforbindingacidic
drugs,fattyacids,andbilirubin.Whiletheaffinityofdrugsforeitheroftheseplasmaproteinsisharderto
determine,theoreticallyaneonate’saffinityforproteinbindingisreduced,resultinginthelikelihoodof
displacingdrugsorbilirubinboundtoalbuminandleadingtoincreasedserumconcentrations.Allthese
factors producea larger volumeofdistributionandincreased free drugconcentrations (e.g.,phenytoin
[Dilantin])inneonatesthaninadults.
RouteofAdministration
Theroutebywhichadrugisadministeredhasaprimaryinfluenceonthedrug’sdistribution.Ifthedrugis
administeredorally,theliverbecomestheprimarydistributionsite.However,ifadrugisadministered
intravenously,theheartandlungsactastheprimarydistributionsites.Thisisimportantbecausewhena
drugpassesthroughtheliver before reachingits siteofactivity,it is subjecttothefirst-passeffectof
extensive hepatic metabolism, which typically reduces the amount of circulating active drug and thus
limitsitseffects.Therefore,toachieveanequaleffect,thedosageofadrugadministeredbytheoralroute
usuallyneedstobehigherthanthedosageofadrugadministeredintravenously.
Metabolism
Clearanceofmanydrugsismainlyreliantonhepaticmetabolism.Thetwophasesofdrugmetabolismin
theliveraretheoxidation,reduction,andhydrolysisreactions(phaseI)andconjugationreactions(phase
II). Age-relatedchanges in metabolism affect howdrugsare brokendown or transformedin pediatric
patientsandhowcertainmetabolicenzymesareactivated.(Table4.3summarizesdevelopmentalpatterns
inphaseIoxidationreactions.)PhaseIandphaseIIreactionsaredelayedinneonates,infants,andyoung
children,withconsequentialdrugtoxicities.
TABLE4.3
SummaryofAge-RelatedChangesinMetabolism
P-450
Cytochromes
ReducedActivityversus
Adults
IncreasedActivityversus
Adults
AgeatwhichAdultActivityIs
Reached
CYP1A2 Untilage4mo 1-2y Endofpuberty
CYP2C9 Firstweekoflife 3-4y Endofpuberty
CYP2D6 Untilage3-5y 3-5y
CYP2E1 Unknown Unknown Unknown
CYP3A4 Firstmonthoflife 1-4y Endofpuberty
CYP,cytochromeP-450.
Based ondatafromLeader,J.S.,&Kearns,G.L. (1997).Pharmacogeneticsinpediatrics:Implicationsforpractice. Pediatric Clinicsof
NorthAmerica,44,55-77.
The P-450 cytochrome (CYP) is the most important component of phase I drug metabolism.
CytochromesintheCYP1,CYP2,andCYP3families havebeenidentifiedas importantinhumandrug
metabolism.Additional information suggeststhere is substantial genetic variability in the quantity and
qualityofCYPinthehumanbody(Kearns,1995).Forexample,codeineismetabolizedtomorphinevia
CYP2D6 andcan resultin high levels of morphine in patients whoare ultrarapid metabolizers of the
enzyme. Similarly, tramadol utilizes the CYP2D6 enzyme and can lead to supratherapeutic levels in
patients who are ultrarapid metabolizers of this enzyme. Deaths in children who are ultrarapid
metabolizershavebeenreportedaftertheyreceivedcodeineandtramadol.ThesereportsledtotheFDA
creating a boxed warning regarding the use of codeine pain and cough medications and the use of
tramadolpainmedicationsinchildrenlessthan12yearsofagewithrestrictionsforolderchildren(U.S.
Food and Drug Administration, 2018). Additionally, breast-feeding is not recommended in mothers
receivingcodeineortramadolduetotheriskofadverseeffectsinbreast-fedinfants,suchassleepiness
andbreathingproblemsthatcouldresultindeath.
Themetabolismofcaffeineandtheophylline,theprototypicsubstrateforCYP1A2,isreducedatbirth;
the drug concentration increases linearly over the first year of life and exceeds adult levels in older
infants and children. To maintain therapeutic serum theophylline concentrations, smaller doses are
prescribedandadministeredlessfrequentlyinneonatesthaninolderinfantsandchildren.
In pediatrics, phase II reactions have been less well studied than phase I reactions. In adults,
acetaminophen(Tylenol),asubstrateforglucuronosyltransferase1A6and1A9,ismetabolizedbyaphase
IIglucuronidationreaction.Inneonatesandinfants,however,thismetabolic pathwayisdeficient.As a
result, acetaminophen metabolism is shifted to sulfate conjugation, which results in a half-life for
acetaminophenthatissimilartoitshalf-lifeinadults.
Elimination
Almostalldrugsandtheirmetabolitesareexcretedthroughthekidneys.Thekidneyeliminatesdrugsby
glomerular filtration (passive diffusion) or tubular secretion (energy-dependent channels or pumps).
Hormonalchangesthatnormallyoccurduringpregnancycanaffecttheeliminationofvariousmedications.
Thenormal increaseinprogesteronelevels canstimulate hepatic microsomalenzymesystems,thereby
increasing the elimination of some hepatically eliminated medications (e.g., phenytoin [Dilantin]).
Progesteronemayalsodecreasetheeliminationofsomemedications(e.g.,theophylline[Theo-Dur])by
inhibitingspecific microsomal enzymesystems. Therefore, dependingonthe eliminationpathwayof a
specificmedication,theeliminationratemaynotbepredictable.Theextentofthesephysiologicchanges
isdifficulttoquantify,anditisunknownwhetherchangesindosagesarerequired.
Glomerular filtrationrate (GFR) increasesinpregnancyduetoincrease incardiac outputcombined
withareductioninoncoticpressureduetodecreasedalbuminandincreasedrenalbloodflow.Withthe
increaseinrenalbloodflowby50%andincreasedGFR,drugsexcretedprimarilybythekidneyshow
increased elimination. Cefuroxime, an antibiotic, has increased clearance and decreased half-life in
pregnantwomen(Loebsteinetal.,1997).Medicationscanbeaffectedbythesechangesinplasmavolume
andincreased clearanceinearly(12 to15weeks) andlate pregnancy(30 to33 weeks),asseenwith
enoxaparin,alowmolecular weightheparin(Caseleetal.,1999). Themagnitudeoftheseincreasesin
eliminationmayvarydependingonthemedication.
TheGFRincreasesquicklyduringthefirst2weeksofpostnatallifeanddoesnotapproachadultrates
untilage2(Rubinetal.,1949);tubularsecretionandreabsorptionratesdonotreachadultvaluesuntil
age5to7months.Theproximaltubulesarecharacterizedbyaninabilitytoconcentrateurineorreabsorb
variousfiltered compoundsandareducedabilitytosecreteorganicacids.This immaturityoftherenal
system in neonates and infants results from restricted blood flow and a resultant decrease in cardiac
outputtothekidneys,combinedwithincompleteglomerularandtubulardevelopment.Asaresult,plasma
clearanceofmanydrugsviathekidneysisaltered.Forexample,duringinfancy,theresponsetothiazide
diuretics, whichrequire aGFR greater than 30 mL/minto be effective, is diminished.Often,a larger
dosageofathiazidediureticorsubstitutionbyaloopdiureticisrequiredtoproduceadequatediuresis.
BecausetheeliminationofaminoglycosidesisdirectlyrelatedtotheGFR,aminoglycosideshavealonger
half-life in neonates and infants, who thus require a longer dosing interval than adults. In addition,
decreased tubular secretion in neonates and infants can lengthen the elimination half-life of other
antibiotics,suchasthepenicillinsandsulfonamides.Selectingtheappropriatedosingregimenbasedon
age,weight,andkidneymaturationandidentifyingconcomitantagentsrenallyeliminatedare important
factorstopreventtoxicity.Ingeneral,renalexcretionofmanydrugsisdirectlyproportionaltoage.
CLINICALIMPLICATIONSINPREGNANCY
While multiple studies highlight pharmacokinetic changes in pregnancy, limited studies evaluate the
efficacychanges ofdrugsanddosesdue tothesephysiologic changes.Dose changesare generallynot
recommendedunlesstherearedataofalteredefficacyduetopharmacokineticchanges.Examplesofthese
drugsincludelamotrigineorindinavir,wheredosechangesarerecommended.Pregnantwomenareoften
excludedfromclinicaltrials.Therefore,thereisoftenlimitedinformationontheeffectofdosechanges
thatwouldberequiredinpregnancy(Pinheiro&Stika,2020).
FactorsinPlacental–FetalPhysiology
Untilthe1960s,itwaswidelybelievedthattheuterusprovidedasecureandprotectedenvironmentfor
thedevelopingfetus.Verylittlethoughtwasgiventothepotentialharmposedtothefetusfrommaternal
druguse. After the thalidomide tragedy in the 1960s, the government required testing of drugs before
humanuse.Itisnowknownthatbythefifthweekoffetaldevelopment,virtuallyeverydrughastheability
tocrosstheplacenta(Kraemer,1997).
Thetreatmentofmedicalconditionsiscomplicatedduringpregnancybyvariousfactors,whichmustbe
consideredbeforeinitiatingorcontinuingdrugtherapy.Akeyfactoris whetherthedrugwillcrossthe
placentaandpotentiallycausefetalharm.
PlacentalTransferofMedications
Thefollowingfactorsaffectadrug’sabilitytocrosstheplacenta:
• Lipid-soluble drugs can cross the placenta more freely than water-soluble drugs because the outer
layersofmostcellmembranesaremadeupoflipids.Manyantibioticsandopiatecompoundsarehighly
solubleinlipidsandcanthereforeeasilycrosstheplacentalmembrane.
• Theionization status of thedrug affects placental transfer. Drugs withhigh lipid solubilitytend to
remaininanonionizedstate;therefore,placentaltransferisincreased.Heparin,forexample,isahighly
ionizeddrug,andtherefore,itdoesnotreadilycrosstheplacentalmembrane.
•Themolecularweightofthedrugcandeterminetheeaseofplacentaltransfer.Thelowerthemolecular
weightorthesmallerthedrugmolecule,themorereadilythedrugcrossestheplacenta(Table4.4).
• Drugs that are not bound to a protein (e.g., albumin) can cross the placenta. Albumin is the most
abundant protein in the humanbody. During pregnancy, the concentration of albumin decreases, and
therefore,fewerproteinsarepresent,allowingformoreunboundor“free”drugtocrosstheplacental
membrane. Furthermore, changes in the drug–protein binding ability of albumin in pregnancy may
increasetheamountof“free”drug.
•Activeplacentaltransportersmayalsoaffecttheconcentrationsofmedicationsthatcrosstheplacenta.
Specifically,P-glycoprotein(P-gp)isthemostwellstudiedandhasbeenshowntopreventthetransfer
of many medications. Conversely, when mothers are administered medications that inhibit P-gp,
medicationsthatwould normallybe preventedfromcrossingtheplacentaareabletocrossandmay
causecongenitalabnormalities.
TABLE4.4
EffectofMolecularWeightonPlacentalTransferofDrugs
Molecular
Weight
DrugExample RateofPlacentalTransfer
<500g/mol Acetaminophen,caffeine,cocaine,labetalol,morphine,
penicillins,theophylline
Readilycrossestheplacenta
600-1,000
g/mol
Digoxin Crossestheplacentaataslowerrate
>1,000g/mol Heparin,insulins Transferacrosstheplacenta
severelyimpeded
PlacentalandFetalMetabolism
Evidence exists to support the theory that the human placenta and fetus are capable of metabolizing
medications.Researchfindingssuggestthatliverenzymesystemsarepresentinfetalliversasearlyas7
to 8 weeks’ gestation (Juchau & Choa, 1983). Although these enzyme systems are present, they are
immature,andanydrugeliminationthatoccursisaresultofdrugdiffusingbackintomaternalblood.
FetalPhysiology
Notall drugsthatcrosstheplacentalbarrier causefetalharm.Therefore,thepractitionerneeds toask
whether a specific drug will cross the placenta and cause fetal harm. Currently, it is not possible to
directlystudytheeffectsof medicationsonthefetus.Asingle drugconcentrationmeasurementat birth
fromtheumbilicalcordisallthatisavailabletounderstandthedrugexposureonthefetus.Fetalfactors
tobeconsideredinansweringthequestionincludethegestationalageatthetimeofexposuretothedrug,
whichis importantbecausesomedrugscanexerttheir effectsonthefetusthroughoutgestation.Onthe
other hand, some drugs exert their effects on the fetus at different stages of gestation. For example,
angiotensin-convertingenzymeinhibitors,suchascaptopril(Capoten),quinapril(Accupril),andenalapril
(Vasotec),varyintheirfetalriskduringpregnancy;theyposealesserriskinthesecondtrimesteranda
higherriskinthethirdtrimester.Inotherwords,theybecomelesssafeasthepregnancyadvances.
Withinthefirst14daysafterconception,theembryoisprotectedfromexogenoustoxicity(Kraemer,
1997;Rayburn, 1997). Thecells atthis time are totipotential, meaningthat if one cell is damaged or
killed,anothercellcanperformthedeadcell’sfunction,andtheembryoremainsunharmed(Dicke,1989).
Afterthispoint,thedevelopingfetusissusceptibletotheeffectsofdrugs.Thefirst3monthsofgestation
arethemostcrucialintermsofabnormalitiesandmalformations,anditisestimatedthatapproximately
70%ofpregnantwomentakemedicationsduringthefirsttrimesterduringorganogenesis(Briggsetal.,
2017; Mitchell et al., 2011). Medications that may be relatively safe during the middle trimester of
pregnancy may not be safe in the last trimester or during delivery. For example, aspirin use late in
pregnancyisassociatedwithincreasedbleedingatthetimeofdelivery.Moreover,theeffectthataspirin
hasonprostaglandinsmaydelaylabor.
Fetal total body water and fat deposition are associated with gestational age, and they affect the
absorptionanddistributionofdrugs.Asthefetusmatures,totalbodywaterdecreasesandfatdeposition
increases, and the fetus is more likely to be affected by medications that are highly lipophilic (e.g.,
opiates)thanbymedicationsthatarewatersoluble(e.g.,ampicillin[Principen]).
Fetal circulatory patterns can alter the amount of drug distributed to the fetus. In early gestation, a
disproportionatelylargepercentageofthefetalcardiacoutputispresentedtothebrain,andconsequently,
theconcentrationofdruginthefetalcirculationisincreased(Kraemer,1997).
TeratogenicityofMedications
ThewordteratogenicityisderivedfromtheGreekrootteras,meaning“monster.”Teratogenicityisthe
abilityofanexogenousagenttocausethedysgenesis offetalorgansasevidencedeitherstructurallyor
functionally(Korenetal.,1998;Kraemer,1997).
Theriskoffetalabnormalitydependsonmanyfactors,includingnotonlythegestationalageofthefetus
atthetimeofexposurebuttheagentor medicationsthefetusis exposedtoandthelengthofexposure.
Asidefromfetalmalformations,fetaldrugexposuremayaffectnewborndevelopmentandfunction.
The health care provider must therefore balance therisk of exposing the fetus to thedrugwith the
benefitoftreatmenttothemother.Ifitisdeterminedthatthedrugisnecessary,thedrugwiththesafest
profileshouldbeusedatthelowesteffectivedose.Thepractitionershouldalwayskeepinmindthatthe
motherisnottheonlyrecipientofthedrug—thefetusisaswell.Inaddition,itisimportanttoremember
thatanyillnessesorchronicmedicalconditionsthatgountreatedduringpregnancycouldpotentiallycause
harmtothemotherandfetus,eventhoughmedicationstotreattheseillnessesmayposearisktothefetus
aswell.Therefore,weighingthebenefitofdrugtherapytothemotheragainsttheriskofdrugtherapyto
thefetusneedstobeasbalancedaspossible.
In1979,theU.S.FDA categorizeddrugsaccordingtofetalriskstohelppractitionersguide therapy.
Thecategorieswerebasedonanimaldataandthepresenceorabsenceofcontrolledstudiesinpregnant
womentodeterminetheleveloffetalrisk:categoriesA,B,C,D,andXbasedonlevelofdata.Health
careproviderswerechallengedwithusingtheseoversimplifiedcategoriestoassessrisk–benefitratiosof
medicationsduringpregnancyduetothescarcity ofcontrolled trials inpregnant women.Thisclinical
dilemmapromptedthenewcurrentFDArule,entitledthePregnancyandLactationLabelingRule(PLLR),
whichwaspassedinDecember2014andtookeffectinJune2015.Thenewruleincludesthreeseparate
sections that are required in package labeling: pregnancy, lactation, and a new section—females and
malesofreproductiveage.
TheupdatedrequirementsforthesenewsectionsinthepackagelabelingaresummarizedinTable4.5.
All newmolecular entities comingtothemarketrequired manufacturers toincludethecurrentlabeling
requirementsandwerenotassignedapregnancycategory.Pregnancyriskcategorieswereremovedfrom
existing drugs by 2018. All drugs approved after June 2001 were required to submit new labeling
information by June of 2020; however, there has a been delay in conforming to this new labeling
requirement based on the initial implementation schedule. Manufacturers are also required to update
labelingwithnewavailableinformationunderthenewrule.Itisimportanttonotethatover-the-counter
products were not affected by this new legislation. Drugs approved before 2001 must have removed
pregnancycategoriesbutarenotrequiredtoconformtothenewlabelingrequirements.Themanufacturers
ofthesedrugsareencouragedtovoluntarilyusethenewlabelingsections.
TABLE4.5
PregnancyandLactationLabelingRule
LabelingSection Requirements
8.1Pregnancy(includes
laboranddelivery)
Includesrisksummary,clinicalconsiderations,anddata(tosupporttherisksummary)
Mustincludeinformationforapregnancyexposureregistryifoneisavailable
8.2Lactation Alsoincludesrisksummary,clinicalconsideration,anddata,includingtheamountof
drugappearinginbreastmilkandpotentialeffectsontheinfant
8.3Femalesandmalesof
reproductivepotential
Includesinformationaboutneedforpregnancytesting,contraception
recommendations,andinfertilityinformationwhenapplicable
DRUGTHERAPYINTHEBREASTFEEDINGMOTHER
With the number of women who choose to breast-feed their infants increasing yearly, the number of
questions presented to health care practitioners concerningthesafetyof medicationuse while breastfeeding is also increasing. Recommendations to discontinue or interrupt breast-feeding are often
inappropriateasthiscautiousapproachmaybeunnecessaryformostpatients.Healthcarepractitioners
are often reluctant to recommend medication use while the mother is breast-feeding because of the
potentialadverseeffectsontheinfant.Mostresearchonlactationhasbeenconductedinsmallgroupsor
onanimalmodels.TheAmericanAcademyofPediatricsandFDArecommendthatforthemostup-to-date
information providers use databases such as LactMed
(https://www.ncbi.nlm.nih.gov/books/NBK501922/)tohelpguidetreatmentoptionsformotherswhoare
breast-feeding(Sachs&CommitteeonDrugs,2013).LactMedisavailabletoallpractitioners,andithas
comprehensiveandup-to-dateinformationregardingtheknownconcentrationsofdrugreachingtheinfant
throughbreastmilk,possibleadversereactions,andpotentialalternatives.Thisisanexcellentresource
thatispoweredbytheNationalLibraryofMedicine.Consultingtheknownpharmacokineticparameters
ofmedicationscanalsobehelpfulinprescribingmedications.
Humanbreastmilkisacomplex,nutrient-enrichedfluid.Containingapproximately80%water,breast
milkalsohasimmunologicpropertiesandproteins,fats,carbohydrates,minerals,andvitaminsneededfor
normal development. The availabilityof the drug to be distributed into breast milk depends on many
factors. For a drug to be distributed into breast milk, it must first be absorbed into the maternal
circulation. The concentration or level of the drug in the mother’s plasma influences the amount and
degreeofdrugdistributedintobreastmilk.Oncethedrugisavailablefordistributionintobreastmilk,
severalotherfactorsneedtobeconsidered.Thesefactorsaresimilartothosedeterminingwhetheradrug
willcrosstheplacentalmembraneandincludethefollowing(Dillonetal.,1997):
•Bloodflowtothebreast—thegreaterthebloodflowtothebreast,thegreaterthedruglevelinbreast
milk.
• Plasma pH (7.45) and milk pH (7.08)—the medication will stay in the maternal plasma if the
medicationfavorsahigherpH.
• Mammary tissue composition—high adipose or fat content of the breast tissue causes lipophilic
medicationstobedistributedintothebreasttissueandthenintobreastmilk.
•Breastmilkcomposition—breastmilkcontainsproteins,fat,water,andvitamins.Anymedicationthat
hasahighaffinityforanyofthesecomponentswillhaveanincreaseddistributionintobreastmilk.
• Physicochemical properties(i.e.,lipophilicity,molecular weight,ionizationofmedicationinplasma
andbreastmilk)ofthedrug—drugcharacteristicsthatfavortransferofmedicationintobreastmilkare
lowmolecularweight,lowionizationinplasma,lowproteinbinding,andhighlipophilicity.
•Extentofdrug–proteinbindinginplasmaandbreastmilk—medicationsthatarehighlyproteinboundin
theplasmaarelesslikelytobedistributedintothebreastmilk.
• Therateofbreastmilkproduction—themorebreastmilkproduced,themoredilutedthemedication
willbeinthebreastmilk.
Whenconsideringthesefactors,itcaneasilybeappreciatedthatdifferentmedicationsdistributeinto
breastmilkatdifferentrates andtodifferentextents.Aside frommedication-specific factors,thereare
somegeneral considerationsforminimizingtheriskofmedication-relatedadverseeffectsinbreast-fed
infants. Medications withshorter half-lives are preferred to decrease drug accumulation in the breast
milk.Similarly,sustained-release productsare less preferred.Drugs withhighoralbioavailabilityare
lesspreferredastheyaremoreeasilyabsorbed.Itisrecommendedtousethelowesteffectivedoseand
choosemedicationswiththeleastseriousadverseeffectswhenpossible.Dosingschedulesalsohelpin
minimizing the amount of drug reaching the infant. Scheduling the mother to take the medication
immediatelyafterbreast-feedingminimizesthedosetotheinfantbycircumventingpeakbreastmilklevels
(Sachs&CommitteeonDrugs,2013).
Patients with chronic conditions, such as hypertension, epilepsy, or diabetes, need to consult their
healthcarepractitionersaboutcontinuingtreatmentandminimizingrisktotheinfant.Ifamedicationisfor
short-termuse,thecliniciancanalsoconsiderifthemedicationcouldbe postponeduntilthemotheris
finished breast-feeding and limiting the medication to the shortest possible duration. Without other
options, patients with short-term illnesses can temporarily interrupt breast-feeding for the duration of
treatmentandresumebreast-feedingafew daysaftertherapyiscompletediftheriskofthedrugtothe
infantisthoughtto outweighthebenefits. By this time,no residual drugshould be concentrated inthe
breast milk. During the interruption, however, the mother must pumpthe breastanddiscard the milk.
Doingsorelievesengorgementandpromotescontinuedmilkproductionandflow.
DRUGSELECTIONINPEDIATRICS
Various factors are considered when prescribing a drug for a pediatric patient. Among them are the
benefitsofthedruginrelationtotherisksofadministration,thelong-termeffects,thedosageform,and
therouteandfrequencyofadministration(Figure4.1).
FIGURE4–1Approachtoprescribingdrugtherapyforthepediatricpatient.
BSA,bodysurfacearea.
RisksandBenefits
The classic medicationwhen discussingrisksandbenefits inthepediatric populationis ciprofloxacin
(Cipro),afluoroquinolone. Ciprofloxacin wasbroughtto marketin 1987 andcarried a riskofsevere
degenerativearthropathy. Thiseffectwasseeninjuvenilestudyanimals during drugdevelopment.The
potentialforthisproblemledtothesedrugsbeingcontra-indicatedinallpediatricpopulations.Numerous
studiesoverthepast20yearsdisputingthisriskhaveledtoover500,000prescriptionsforthedrugbeing
written annuallyfor children younger than age18. TheAmericanAcademyof Pediatrics developed a
policystatementthatprovidesanoutlinefortheuseoffluoroquinolonesinchildrenwithaclinicalreport
updatein2016(AmericanAcademyofPediatrics,2011,2016).Theuseofthedrugclassinchildrenis
Соседние файлы в папке Библиотека им академика М.И. Перельмана