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Special Aspects of
Perinatal Pharmacology(Drug Therapy in Pregnancy and Lactation)Gideon Koren, MD & Martin S.Cohen, MD
Dept. of Pediatric PharmacologyFaculty of Medicine, University of Toronto, Canada(Teks dari Katzung BG, Basic & Clinical Pharmacology, 6thed, 1995)
Kuliah sebelumnyaPengantar Perinatologi
Kuliah berikutnyaCongenital Malformations
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The effects of drugs on the fetus and newborn infant are based on the general principles. However, the
physiologic context in which these pharmacologic laws operate, are DIFFERENT in pregnant women and
in rapidly maturing infants.
At present, the special pharmacokinetic factors operative in these patients are beginning to be understood,
whereas information regarding pharmacodynamic differences (eg, receptor characteristics and response) is
still quite preliminary. This chapter presents basic principles of pharmacology in the special context of perinatal and pediatric therapeutics.
DRUG THERAPY IN PREGNANCY
Pharmacokinetics
Most drugs taken by pregnant women CAN cross the placenta and expose the developing embryo and fetus
to their pharmocologic and teratogenic effects.
Critical factors affecting placental drug transfer and drug effects on the fetus include the following :1. The physiochemical properties of the drug
2. The rate at which the drug crosses the placenta and the amount sure to the drug3. The duration of exposure to the drug
4. Distribution characteristics in different fetal tissues
5. The stage of placental and fetal development at the time of exposure to the drug
6. The effects of drugs used in combination
A. Lipid Solubility
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As is true also of other biologic membranes, drug passage across the placenta is dependent on lipid
solubility and the degree of drug ionization. Lipophilic drugs tend to diffuse readily across the placenta and
enter the fetal circulation. For example, thiopental, a drug commonly used for cesarean sections, crosses the
placenta almost immediately and can produce sedation or apnea in the newborn infant. Highly ionized
drugs such as succinylcholine and tubocurarine, also used for cesarean section, cross the placenta slowlyand achieve very low concentrations in the fetus. Impermeability of the placenta to polar compounds is
relative rather than absolute. If high enough maternal-fetal concentration gradients are achieved, polar compounds cross the placenta in measurable amounts. Salicylate, which is almost completely ionized at
physiologic pH, crosses the placenta rapidly. This occurs because the small amount of salicylate that is not
ionized is highly lipid-soluble.
B. Molecular Size
The molecular weight of the drug also influences the rate of transfer and the amount of drug transferredacross the placenta. Drugs with molecular weights of 250-500 can cross the placenta easily, depending
upon their lipid solubility and degree of ionization; those with molecular weights of 500-1000 cross the
placenta with more difficulty; and those with molecular weights greater than 1000 cross very poorly. An
important clinical application of this property is the choice of heparin as an anticoagulant in pregnant
women. Because it is a very large (and polar) molecule, heparin is unable to cross the placenta. Unlike
warfarin, which is teratogenic and should be avoided during the first trimester, heparin may be safely given
to pregnant women who need anticoagulation. Apparent exceptions to the "size rule" are maternal antibody
globulins and certain polypeptides that cross the placenta by some selective mechanisms that has not yet been identified.
C. Protein Binding
The degree to which a drug is bound to plasma proteins (particularly albumin) may also affect the rate of
transfer and the amount of drugs transferred. However, if a compound is very lipid-soluble (eg, some
anesthetic gases), it will not be affected greatly by protein binding. Transfer of these more lipid-soluble
drugs and their overall rates of equilibration are more dependent on (and proportionate to) placental blood
flow. This is because very lipid-soluble drugs diffuse across placental membranes so rapidly that their
overall rates of equilibration do not depend on the free drug concentrations becoming equal on both sides.
If a drug is poorly lipid-soluble and is ionized, its transfer is slow and will probably be impeded by its binding to maternal plasma proteins. Differential protein binding is also important, since some drugs
exhibit greater protein binding in maternal plasma than in fetal plasma because of a lowered binding
affinity of fetal proteins. This has been shown for sulfonamides, barbiturates, phenytoin, and localanesthetic agents.
D. Placental and Fetal Drug Metabolism
Two mechanisms help to protect the fetus from drugs in the maternal circulation : (1) The placenta itself
plays a role both as a semipermeable barrier and as a site of metabolism of some drugs passing through it.Several different types of aromatic oxidation reactions (eg, hydroxylation, N-dealkylation, demethylation)
have been shown to occur in placental tissue. Ethanol and phenobarbital are oxidized in this way.
Conversely, it is possible that the metabolic capacity of the placenta may lead to creation of toxic
metabolites, and the placenta may therefore augment toxicity (eg, ethanol, benzypyrenes). (2) 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 remaiinder bypasses the liver and enters the general fetal
circulation. A drug that enters the liver may be partly metabolized there before it enters the fetal circulation.
In addition, a large proportion of drug present in the umbilical artery (returning to the placenta) may beshunted through the placenta back to the umbilical vein and into the liver again. It should be noted that
metabolites of some drugs may be more active than the parent compound and may affect the fetusadversely.
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Pharmacodynamics
A. Maternal Drug
Actions
The effects of drug on the
reproductive tissues
(breast, uterus, etc) of the
pregnant woman aresometimes altered by the
endocrine environment
appropriate for the stages
of pregnancy. Drug
effects on other maternal
tissues (heart, lungs,
kidneys, central nervous
system, etc), are NOTchanged significantly by
pregnancy, though the physiological context
(cardiac output, renal
blood flow, etc) may bealtered and may require
the use of drugs that are
not needed in the same
woman when she is not
pregnant. For example,cardiac glycosides and
diuretics may be needed
for congestive heart
failure precipitated by the
increased cardiac
workload of pregnancy,
or insulin may be
required for control of blood glucose in
pregnancy-induced
diabetes.
B. Therapeutic Drug
Actions in the Fetus
Fetal therapeutics is an
emerging area in perinatal pharmacology.
This involves drug administration to the pregnant woman with the fetus as the target of the drug. At present, corticosteroids are used to stimulate fetal lung maturation when premature birth is expected.
Phenobarbital, when given to pregnant women near term, can induce fetal hepatic enzymes responsible for
the glucoronidation of bilirubin, and the incidence of jaundice is lower in newborns when mothers aregiven phenobarbital than when phenobarbital is not used. Recently, administration of phenobarbital to the
mother has been shown to decrease the risk of intracranial bleeding in preterm infants. Antiarrythmic drugs
have also been given to mothers for treatment of fetal cardiac arrhytmias.
C. Predictable Toxic Drug Actions in the Fetus
Chronic use of opioids by the mother may produce dependence in the fetus and newborn. This dependence
may be manifested after delivery as a neonatal withdrawal syndrome. A less well understood fetal drug
toxicity is caused by the use of angiotensin-converting enzyme inhibitors during pregnancy. These drugs
can result in significant and irreversible renal damage in the fetus and are therefore contraindicated in
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pregnant women. Adverse effects may also be delayed, as in the case of female fetuses exposed to
diethylstilbestrol (DES), who may be at increased risk for adenocarcinoma of the vagina after puberty.
D. Teratogenic Drug Actions
A single intrauterine exposure to a drug can affect the fetal structures undergoing rapid development at thetime of exposure. Thalidomide is an example of a drug that may profoundly affect the development of the
limbs after only brief exposure. This exposure, however, must be at a critical time in the development of the limbs. The thalidomide phocomelia riskk occurs during the fourth through the seventh weeks of
gestation because it is during this time that the arms and legs develop.
The mechanisms by which different drugs produce teratogenic effects are poorly understood and are
probably multifactorial. For example, drugs may have a direct effect on maternal tissues with secondary or
indirect effects on fetal tissues. Drugs may interfere with the passage of oxygen or nutrients through the
placenta and therefore have effects on the most rapidly metabolizing tissues of the fetus. Finally, drugs mayhave important direct actions on the processes of diferentiation in developing tissues. For example, vitamin
A (retinol) has been shown to have important differentiation-directing actions in normal tissues. Several
vitamin A analogues (isotretinoin, etretinate) are powerful teratogens, suggesting that they alter the normal
processes of differentiation. Finally, deficiency of a critical substance appears to play a role in some types
of abnormalities. For example, folic acid supplementation during pregnancy appears to reduce the
incidence of neural tube defects, eg, spina bifida.
Continued exposure to a teratogen may produce cumulative effects or may affect several organs going
through varying stages of development. Chronic consumption of high doses of ethanol during pregnancy, particularly during the first and second trimesters, may result in the fetal alcohol syndrome. In this
syndrome, the central nervous system, growth, and facial development may be affected.
To be considered as teratogenic, a candidate substance or process should :
(1) result in a characteristic set of malformations, indicating a selectivity for certain target organs;
(2) exert its effects at a particular stage of fetal development, ie, during the limited time period of
organogenesis of the target organs;
(3) show a dose-dependent incidence. Some drugs with known teratogenic or other adverse effects in
pregnancy are listed in the table.
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DRUG USE DURING LACTATION
Drugs should be used conservatively during lactation, and the physician must know which drugs are
potentially dangerous to nursing infants (see table).
Most drugs administered to lactating women ARE detectable in breast milk. Fortunately, the concentration
of drugs achieved in breast milk is usually low.
Therefore, the total amount the infant would receive in a day is substantially less than what would be
considered a "therapeutic dose". If the nursing mother must take medications and the drug is a relatively
safe one, she should optimally take it 30-60 minutes after nursing and 3-4 hours before the next feeding.
This allows time for many drugs to be cleared from the mother’s blood, and the concentrations in breast
milk will be relatively low. Drugs for which no data are available on safety during lactation should be
avoided, or the breastfeeding discontinued while they are being given.
Most antibiotics taken by nursing
mothers can be detected in breast
milk. Tetracycline concentrations in breast milk are approximately 70%
of maternal serum concentrations
and present a risk of permanent
tooth staining in the infant.
Chloramphenicol concentrations in
breast milk are not sufficient to
cause the gray baby syndrome, but
there is a remote possibility of causing bone marrow suppresion,
and chloramphenicol should be
avoided during lactation. Isoniazid
reaches a rapid equilibrium between
breast milk and maternal blood. The
concentrations achieved in breast
milk are high enough so that
pyridoxine deficiency may occur inthe infant if the mother is not given
pyridoxine supplements.
Most sedatives and hypnotics
achieve concentrations in breast
milk sufficient to produce a
pharmacologic effect in some
infants. Barbiturates taken in
hypnotic doses by the mother can
produce lethargy, sedation, and poor sucking reflexes in the infant.
Chloralhydrate can produce sedation
if the infant is fed at peak milk concentration. Diazepam can have a
sedative effect on the nursing infant,
but most importantly, its long half
life can result in significant drug
accumulation.Opioids such as heroin, methadone, and morphine enter breast milk in quantities potentially sufficient to
prolong the state of neonatal narcotic dependence if the drug was taken chronically by the mother duriing
pregnancy. If conditions are well controlled and there is a good relationship between the mother and the
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