Page 1064 - Basic _ Clinical Pharmacology ( PDFDrive )

1050 SECTION X Special Topics

has been shown to have important differentiation-directing provide such counsel to pregnant women must ensure that their
actions in normal tissues. Several vitamin A analogs (isotretinoin, information is up-to-date and evidence-based and that the woman
etretinate) are powerful teratogens, suggesting that they alter the understands that the baseline teratogenic risk in pregnancy (ie,
normal processes of differentiation. Finally, deficiency of a critical the risk of a neonatal abnormality in the absence of any known
substance appears to play a role in some types of abnormalities. teratogenic exposure) is about 3%. It is also critical to address the
For example, folic acid supplementation during pregnancy appears maternal-fetal risks of the untreated condition if a medication is
to reduce the incidence of neural tube defects (see Box, page 599). avoided. Recent studies show serious morbidity in women who
Continued exposure to a teratogen may produce cumulative discontinued selective serotonin reuptake inhibitor therapy for
effects or may affect several organs going through varying stages of depression in pregnancy.
development. Chronic consumption of high doses of ethanol dur-
ing pregnancy, particularly during the first and second trimesters,
may result in the fetal alcohol spectrum disorder (see Chapter 23). DRUG THERAPY IN INFANTS & CHILDREN
In this syndrome, the central nervous system, growth, and facial
development may be affected. Physiologic processes that influence pharmacokinetic variables in
the infant change significantly in the first year of life, particularly
2. Defining a teratogen—To be considered teratogenic, a during the first few months. Therefore, special attention must be
candidate substance or process should (1) result in a character- paid to pharmacokinetics in this age group. Pharmacodynamic
istic set of malformations, indicating selectivity for certain target differences between pediatric and other patients have not been
organs; (2) exert its effects at a particular stage of fetal develop- explored in great detail but are probably important for those spe-
ment, eg, during the limited time period of organogenesis of cific target tissues that mature at birth or immediately thereafter
the target organs (Figure 59–1); and (3) show a dose-dependent (eg, the ductus arteriosus).
incidence. Some drugs with known teratogenic or other adverse
effects in pregnancy are listed in Table 59–1. Teratogenic effects Drug Absorption
are not limited only to major malformations, but also include Drug absorption in infants and children follows the same gen-
intrauterine growth restriction (eg, cigarette smoking), miscarriage eral principles as in adults. Unique factors that influence drug
(eg, alcohol), stillbirth (eg, cigarette smoke), and neurocognitive absorption include blood flow at the site of administration, as
delay (eg, alcohol, valproic acid). determined by the physiologic status of the infant or child; and,
In addition to teratogenic drugs, teratogenicity can be induced for orally administered drugs, gastrointestinal function, which
by a large group of infectious pathogens, including viruses such changes rapidly during the first few days after birth. Age after
as rubella, cytomegalovirus, herpes, and recently, Zika virus. birth also influences the regulation of drug absorption.
Similarly, numerous chemicals, such as heavy metals (eg, mercury,
lead) and environmental factors (eg, radiation, hyperthermia) can
damage the fetus. It is important to consider these nondrug factors A. Blood Flow at the Site of Administration
in the differential diagnosis of drug-induced adverse fetal effects. Absorption after intramuscular or subcutaneous injection depends
The widely cited US Food and Drug Administration (FDA) mainly, in neonates as in adults, on the rate of blood flow to the
system for teratogenic potential (Table 59–2) has been an attempt muscle or subcutaneous area injected. Physiologic conditions that
to quantify teratogenic risk from A (safe) to X (definite human might reduce blood flow to these areas are cardiovascular shock,
teratogenic risk). This system has been criticized as inaccurate vasoconstriction due to sympathomimetic agents, and heart failure.
and impractical. For example, several drugs have been labeled “X” However, sick preterm infants requiring intramuscular injections
despite extensive opposite human safety data (eg, oral contracep- may have very little muscle mass. This is further complicated
tives). Diazepam and other benzodiazepines are labeled as “D” by diminished peripheral perfusion to these areas. In such cases,
despite lack of positive evidence of human fetal risk. The FDA absorption becomes irregular and difficult to predict, because the
has recently changed its system from the A, B, C grading system drug may remain in the muscle and be absorbed more slowly than
to narrative statements that summarize evidence-based knowledge expected. If perfusion suddenly improves, there can be a sudden
about each drug in terms of fetal risk and safety. and unpredictable increase in the amount of drug entering the cir-
culation, resulting in high and potentially toxic concentrations of
3. Counseling women about teratogenic risk—Since the drug. Examples of drugs especially hazardous in such situations are
thalidomide disaster, medicine has been practiced as if every drug cardiac glycosides, aminoglycoside antibiotics, and anticonvulsants.
were a potential human teratogen when, in fact, fewer than 30
such drugs have been identified, with hundreds of agents proved B. Gastrointestinal Function
safe for the unborn. Owing to high levels of anxiety among Significant biochemical and physiologic changes occur in the
pregnant women—and because half of the pregnancies in North neonatal gastrointestinal tract shortly after birth. In full-term
America are unplanned—every year many thousands of women infants, gastric acid secretion begins soon after birth and increases
need counseling about fetal exposure to drugs, chemicals, and gradually over several hours. In preterm infants, the secretion of
radiation. The ability of appropriate counseling to prevent unnec- gastric acid occurs more slowly, with the highest concentrations
essary abortions has been documented. Clinicians who wish to appearing on the fourth day of life.