Physiologic changes during pregnancy and their impact on drug disposition and dosing

Pregnancy brings on physiologic changes that can alter drug disposition. Changes in the kidney, liver, and GI tract are of particular interest. Because of these changes, a compensatory change in dosage may be needed.

By the third trimester, renal blood flow is doubled, causing a large increase in glomerular filtration rate. As a result, there is accelerated clearance of drugs that are eliminated by glomerular filtration. Elimination of lithium, for example, is increased by 100%. To compensate for accelerated excretion, dosage must be increased.

For some drugs, hepatic metabolism increases during pregnancy. Three antiseizure drugs—phenytoin, carbamazepine, and valproic acid—provide examples.

Tone and motility of the bowel decrease in pregnancy, causing intestinal transit time to increase. Because of prolonged transit, there is more time for drugs to be absorbed. In theory, this could increase levels of drugs whose absorption is normally poor. Similarly, there is more time for reabsorption of drugs that undergo enterohepatic recirculation, and hence effects of these drugs could be prolonged. In both cases, a reduction in dosage might be needed.

Placental drug transfer

Essentially all drugs can cross the placenta, although some cross more readily than others. The factors that determine drug passage across the membranes of the placenta are the same factors that determine drug passage across all other membranes. Accordingly, drugs that are lipid soluble cross the placenta easily, whereas drugs that are ionized, highly polar, or protein bound cross with difficulty. Nonetheless, for practical purposes, the clinician should assume that any drug taken during pregnancy will reach the fetus.

Adverse reactions during pregnancy

Drugs taken during pregnancy can adversely affect both the mother and fetus. The effect of greatest concern is teratogenesis (production of birth defects). This issue is discussed separately below. Not only are pregnant women subject to the same adverse effects as everyone else, they may also suffer effects unique to pregnancy. For example, when heparin (an anticoagulant) is taken by pregnant women, it can cause osteoporosis, which in turn can cause compression fractures of the spine. Use of prostaglandins (eg, misoprostol), which stimulate uterine contraction, can cause abortion. Conversely, use of aspirin near term can suppress contractions in labor. In addition, aspirin increases the risk of serious bleeding.

Regular use of dependence-producing drugs (eg, heroin, barbiturates, alcohol) during pregnancy can result in the birth of a drug-dependent infant. If the infant is not supplied with a drug that can support its dependence, a withdrawal syndrome will ensue. Symptoms include shrill crying, vomiting, and extreme irritability. The neonate should be weaned from dependence by giving progressively smaller doses of the drug on which he or she is dependent.

Certain pain relievers used during delivery can depress respiration in the neonate. The infant should be closely monitored until respiration is normal.

Incidence and causes of congenital anomalies

The incidence of major structural abnormalities (eg, abnormalities that are life threatening or require surgical correction) is between 1% and 3%. Half of these are obvious and are reported at birth. The other half involve internal organs (eg, heart, liver, GI tract) and are not discovered until later in life or at autopsy. The incidence of minor structural abnormalities is unknown, as is the incidence of functional abnormalities (eg, growth retardation, mental retardation).

Congenital anomalies have multiple causes, including genetic predisposition, environmental chemicals, and drugs. Genetic factors account for about 25% of all birth defects. Of the genetically based anomalies, Down’s syndrome is the most common. Less than 1% of all birth defects are caused by drugs. For the majority of congenital anomalies, the cause is unknown.

Teratogenesis and stage of development

Fetal sensitivity to teratogens changes during development, and hence the effect of a teratogen is highly dependent upon when the drug is given. As shown in Figure 9–1, development occurs in three major stages: the preimplantation/presomite period (conception through week 2), the embryonic period (weeks 3 through 8), and the fetal period (week 9 through term). During the preimplantation/presomite period, teratogens act in an “all-or-nothing” fashion. That is, if the dose is sufficiently high, the result is death of the conceptus. Conversely, if the dose is sublethal, the conceptus is likely to recover fully.

Gross malformations are produced by exposure to teratogens during the embryonic period (roughly the first trimester). This is the time when the basic shape of internal organs and other structures is being established. Hence, it is not surprising that interference at this stage results in conspicuous anatomic distortions. Because the fetus is especially vulnerable during the embryonic period, expectant mothers must take special care to avoid teratogen exposure during this time.

Teratogen exposure during the fetal period (ie, the second and third trimesters) usually disrupts function rather than gross anatomy. Of the developmental processes that occur in the fetal period, growth and development of the brain are especially important. Disruption of brain development can result in learning deficits and behavioral abnormalities.

Identification of teratogens

For the following reasons, human teratogens are extremely difficult to identify:

As a result, only a few drugs are considered proven teratogens. Drugs whose teratogenicity has been documented (or at least is highly suspected) are listed in Table 9–1. It is important to note, however, that lack of proof of teratogenicity does not mean that a drug is safe; it only means that the available data are insufficient to make a definitive judgment. Conversely, proof of teratogenicity does not mean that every exposure will result in a birth defect. In fact, with most teratogens, the risk of malformation following exposure is only about 10%.

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