Page 1062 - Basic _ Clinical Pharmacology ( PDFDrive )

1048 SECTION X Special Topics

those with molecular weights of 500–1000 cross the placenta with of equilibration do not depend on the free drug concentrations
more difficulty; and those with molecular weights >1000 cross becoming equal on both sides. If a drug is poorly lipid-soluble
very poorly. An important clinical application of this property and is ionized, its transfer is slow and will probably be impeded by
is the choice of heparin as an anticoagulant in pregnant women. its binding to maternal plasma proteins. Differential protein bind-
Because it is a very large (and polar) molecule, heparin is unable ing is also important since some drugs exhibit greater protein
to cross the placenta. Unlike warfarin, which is teratogenic and binding in maternal plasma than in fetal plasma because of a lower
should be avoided during the first trimester and even beyond binding affinity of fetal proteins. This has been shown for sulfon-
(as the brain continues to develop), heparin may be safely given amides, barbiturates, phenytoin, and local anesthetic agents.
to pregnant women who need anticoagulation. Yet the placenta
contains drug transporters, which can carry larger molecules to E. Placental and Fetal Drug Metabolism
the fetus. For example, a variety of maternal antibodies cross the Two mechanisms help protect the fetus from drugs in the mater-
placenta and may cause fetal morbidity, as in Rh incompatibility. nal circulation: (1) The placenta itself plays a role both as a
Starting in the second trimester of pregnancy, the placenta devel- semipermeable barrier and as a site of metabolism of some drugs
ops transporters that allow immunoglobulins to cross from the passing through it. Several different types of aromatic oxidation
mother to the fetus despite their large molecular size. This has reactions (eg, hydroxylation, N-dealkylation, demethylation) have
important clinical implications, because an increasing number been shown to occur in placental tissue. Pentobarbital is oxidized
of biological drugs (eg, anti-tumor necrosis factor therapy) have in this way. Conversely, it is possible that the metabolic capacity of
been shown to cross the placenta. In addition to the detection the placenta may lead to creation of toxic metabolites, and the pla-
of biologicals in cord blood, cases of severe neonatal neutropenia centa may therefore augment toxicity (eg, ethanol, benzpyrenes).
and fetal dissemination of bacillus Calmette-Guérin (BCG) have (2) Because of the ability of the placenta to convert prednisolone
been reported. With an increasing number of infants exposed to to the inactive prednisone, prednisolone can be used in pregnant
immunoglobulin biologicals in utero, there is a need to address the patients requiring corticosteroid treatment without the risk of
challenges in vaccinating these infants. fetal exposure to an active corticosteroid. Drugs that have crossed
Because maternal blood has a pH of 7.4, whereas the fetal the placenta enter the fetal circulation via the umbilical vein.
blood is 7.3, basic drugs with a pK above 7.4 will be more ionized About 40–60% of umbilical venous blood flow enters the fetal
a
in the fetal compartment, leading to ion trapping and, hence, to liver; the remainder bypasses the liver and enters the general fetal
higher fetal levels (see Chapter 1, Ionization of Weak Acids and circulation. A drug that enters the liver may be partially metabo-
Weak Bases). lized there before it enters the fetal circulation. In addition, a large
proportion of drug present in the umbilical artery (returning to
C. Placental Transporters the placenta) may be shunted through the placenta back to the
During the last decade, many drug transporters have been identi- umbilical vein and into the liver again. It should be noted that
fied in the placenta, with increasing recognition of their effects metabolites of some drugs may be more active than the parent
on drug transfer to the fetus. For example, the P-glycoprotein compound and may affect the fetus adversely.
transporter encoded by the MDR1 gene pumps back into the
maternal circulation a variety of drugs, including cancer drugs Pharmacodynamics
(eg, vinblastine, doxorubicin) and other agents. Similarly, viral
protease inhibitors, which are substrates to P-glycoprotein, achieve A. Maternal Drug Actions
only low fetal concentrations—an effect that may increase the The effects of drugs on the reproductive tissues (breast, uterus,
risk of vertical HIV infection from the mother to the fetus. The etc) of the pregnant woman are sometimes altered by the endo-
hypoglycemic drug glyburide has lower plasma levels in the fetus crine environment appropriate for the stage of pregnancy. Drug
as compared with the mother. Recent work has documented that effects on other maternal tissues (heart, lungs, kidneys, central
this agent is effluxed from the fetal circulation by the BCRP trans- nervous system, etc) are not changed significantly by pregnancy,
porter as well as by the MRP3 transporter located in the placental although the physiologic context (cardiac output, renal blood
brush border membrane. In addition, very high maternal protein flow, etc) may be altered, requiring the use of drugs that are
binding of glyburide (>98.8%) also contributes to lower fetal lev- not needed by the same woman when she is not pregnant. For
els as compared with maternal concentrations. example, cardiac glycosides and diuretics may be needed for heart
failure precipitated by the increased cardiac workload of preg-
D. Protein Binding nancy, or insulin may be required for control of blood glucose in
The degree to which a drug is bound to plasma proteins (particu- pregnancy-induced diabetes.
larly albumin) may also affect the rate of transfer and the amount
transferred. However, if a compound is very lipid-soluble (eg, some B. Therapeutic Drug Actions in the Fetus
anesthetic gases), it will not be affected greatly by protein binding. Fetal therapeutics is an emerging area in perinatal pharmacology.
Transfer of these more lipid-soluble drugs and their overall rates This involves drug administration, mostly to the pregnant woman,
of equilibration are more dependent on (and proportionate to) with the fetus as the target of the drug. At present, corticosteroids
placental blood flow. This is because very lipid-soluble drugs dif- are used to stimulate fetal lung maturation when preterm birth
fuse across placental membranes so rapidly that their overall rates is expected. Phenobarbital, when given to pregnant women near