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PERINATAL & PEDIATRIC PHARMACOLOGY

Pharmacokinetics

- Factors affecting placental drug transfer and drug effects on the fetus include the following
o Physicochemical properties of the drug
o The rate at which the drug crosses the placenta and the amount of drug reaching the
fetus
o The duration of exposure to the drug
o Distribution characteristics in different fetal tissues
o The stage of placental and fetal development at the time of exposure to the drug
o The effects of drugs used in combination

- Lipid solubility
o Passage across placenta is dependent on lipid solubility and the degree of drug
ionization
o Salicylates which is almost completely ionized at physiologic pH crosses the placenta
rapidly because the small amount of salicylate that is not ionized is highly lipid-soluble

- Molecular size
o 250-500 MW → can easily cross placenta
o 500-1000 MW → cross more difficultly
o 1000> → cross very poorly

- Placental transporters
o Example is P-glycoprotein transporter encoded by the MDRI gene pumps back into the
maternal circulation a variety of drugs, including cancer drugs like vinblastine and
doxorubicin

- Protein-binding
o Affects rate of transfer and the amount transferred
o Very lipid-soluble drugs will not be affected greatly by protein binding
o Differential protein binding is also important since some drugs exhibit greater protein
binding in maternal plasma than in fetal plasma because of a lower binding affinity of
fetal proteins

- Placental and fetal drug metabolism

o Two mechanisms that help protect the fetus from drugs in the maternal circulation
 Placenta itself plays a role both as a semipermeable barrier and as a site of
metabolism of some drugs passing through it
 Drugs that have crossed the placenta enter the fetal circulation via the umbilical
vein about 40-60% of umbilical venous blood flow enters the fetal liver; the
remainder bypasses the liver and enters the general fetal circulation. A drug
that enters the liver may be partially metabolized there before it enters the fetal
circulation

Pharmacodynamic

- Matenal drug actions

o Drug affects on the reproductive tissues may be altered – breast, uterus, etc.
o Drug effects on other maternal tissues (heart, lungs, kidneys, CNS, etc.) are not changed
significantly by pregnancy, although the physiologic context (cardiac output, renal blood
flow, etc.) may be altered requiring drugs

Pharmacology and Therapeutics II Lecture Notes

Romeo C. Ongpoy, Jr.
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- Therapeutic drug actions in fetus

o Corticosteroids are used to stimulate fetal lung maturation when pretrerm birth is
expected
o Phenobarbital when given to pregnant women near term, can induce fetal hepatic
enzymes responsible for the glucorunidation of bilirubin, and the incidence of jaundice
is lower in newborns when mothers are given phenobarbital than when phenobarbital is
not used
o Antiarrythmic drugs have also been given to mothers for treatment of fetal cardiac
arrhythmias – digoxin, flecainamide, procainamide, verapamil, etc.)
o Maternal useof zidovudine decreases by 2/3s transmission of HIV from the mother to
the fetus and use of combinations of 3 antiretroviral agents can eliminate fetal infection
almost entirely

- Predictable toxic drug actions in the fetus

o Use of opioids by mother give dependence to fetus and newborn shown by the
neonatal withdrawal symptoms
o ACE inhibitors result in irreversible renal damage in fetus
o Diethylstilbestrol gives adenocarcinoma of vagina to the fetuses exposed after their
puberty (delayed effect)

- Teratogenic drug actions

o Thalidomide causes phocomelia
o Vitamin A analogs (isotretinoin and etretinate) are potential teratogens
o Folic acid supplementation during pregnancy reduce neural tube defects like spina bifida
o Chronic high alcohol consumption during 1 st and 2nd trimester of pregnancy lead to fetal
alcohol syndrome

- Teratogen
o Result in a characteristic set of malformations, indicating selectivity for certain target
organs
o Exert its effects at a particular stage of fetal development, e.g., during the limited time
period of organogenesis of the target organs
o Show a dose-dependent incidence

- Teratogenic drugs

Pharmacology and Therapeutics II Lecture Notes

Romeo C. Ongpoy, Jr.
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- FDA system in teratogenic potential

- Counseling pregnant women on teratogenic risk

o The baseline teratogenic risk in pregnancy (risk of a neonatal abnormality in the absence
of any known teratogenic exposure) is about 3%
o Cannot stop medication immediately – morbidity in women who discontinued selective
serotonin reuptake inhibitor therapy for depression in pregnancy

Drug Therapy in Infants and Children

- Drug absorption
o Same in adults
o Unique factors that influence drug absorption
 Blood flow at the site of administration
 Physiologic conditions that might reduce blood flow to injection afrea
(IM and SC)
o Cardiovascular shock
o Vasoconstriction due to sympathomimetic agents
o Heart failure

Pharmacology and Therapeutics II Lecture Notes

Romeo C. Ongpoy, Jr.
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 IM has diminished peripheral perfusion so absorption becomes irregular

and difficult to predict, because the drug may remain in the muscle and
be absorbed more slowly than expected
 Example is cardiac glycosides, aminoglycosides, antibiotics and
anticonvulsants
 Gastrointestinal function
 Drugs that are partially or totally inactivated by the low pH of gastric
contents should not be administered orally
 Peristalsis is slow and irregular so amount of drug absorbed is
unpredictable
 Gastrointestinal enzymes are low

- Drug distribution
o High water content in body 70-75% than adult which is 50-60%
o More diuresis
o Protein binding of drugs is reduced in neonates (diazepam, phenytoin, ampicillin and
phenobarbital) which may result in toxicity
o Greater permeability in blood brain barrier so bilirubin may enter brain and cause
kernicterus

- Drug metabolism
o Decrease ability to metabolize drugs
o Many drugs have slow clearance rates and prolonged elimination half-lives
o Phenobarbital
 Can induce early maturation of fetal hepatic enzymes when mother is taking it

- Drug excretion
o Lower filtration rate, only 30-40% of the adult value

- Drug use in lactation

o It is important to remember that formula feeding is associated with higher morbidity
and mortality in all socioeconomic group
o If there is really a need to take drugs, take medications 30-60 minutes after nursing and
3-4 hours before feeding

- Drugs used in lactation and possible effects to the infant

Pharmacology and Therapeutics II Lecture Notes

Romeo C. Ongpoy, Jr.
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Pharmacology and Therapeutics II Lecture Notes

Romeo C. Ongpoy, Jr.