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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.



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



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.



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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