The physiologic changes associated with pregnancy are multifold and often vary with advancing gestation. Maternal physiology evolves during the course of pregnancy to adjust for the development and growth of the placenta and fetus [1, 2].

Cardiovascular physiology is significantly altered during pregnancy. Cardiac output starts increasing early in pregnancy then plateaus at 28 weeks around 7 l min⁻¹, remaining at this level until delivery where it increases further [3]. A parallel increase is also noted for stroke volume [3]. A gradual increase is also seen with maternal heart rate reaching 90 beats per min at rest in the third trimester [3]. Furthermore, plasma volume increases approximately 40% throughout pregnancy reaching 3.5 l at 38 weeks of gestation [3]. An increase in red blood mass is also noted, yet at a slower pace, resulting in the common finding of “physiologic” anemia in a large proportion of pregnant women. Progesterone and relaxin are thought to contribute to the observed systemic vasodilation in early pregnancy [1, 4]. Dilation of the renal vasculature, increase in glomerular filtration rate (GFR) and renal plasma flow (RPF) are also observed [5]. GFR is 1.6‐fold higher in pregnancy compared to preconceptional and postpartum values [1]. Differences have been noted in the clearance of renally eliminated drugs that could be explained by the previously described changes in blood flow and filtration. The effects of renal changes on drug disposition during pregnancy are discussed later in the chapter.

Pulmonary function in pregnancy is affected by physiologic and anatomic changes. Functional residual capacity is decreased whereas minute ventilation and tidal volume are increased by approximately a third compared to non‐pregnant individuals [6]. These changes underline the finding of mild hyperventilation in two thirds of normal pregnancies.

Total hepatic perfusion is also notably increased during pregnancy. Nakai et al. used Doppler ultrasonography to assess hepatic blood flow during the third trimester of pregnancy and nonpregnant subjects [7]. In their study, hepatic artery blood flow was not significantly increased. The authors concluded that increased hepatic perfusion is likely due to higher portal venous return [7]. In theory, an increase in hepatic perfusion could lead to higher extraction of drugs by the liver and in consequence decreased systemic bioavailability. Nonetheless, studies of drugs with high rates of hepatic extraction show variable effects on their systemic availability. This suggests the presence of additional mechanisms affecting the pharmacokinetic properties of these drugs.

Pregnancy is also associated with delayed gastric emptying [8], decreased intestinal motility [9] and decreased gastric acid secretion [10]. In early pregnancy, a well‐known early gastrointestinal change is pregnancy is nausea and vomiting. Almost two thirds of pregnant women report nausea and vomiting during the first trimester [11–13]. For some women, the symptoms may persist beyond that time mark. Treatment of nausea and vomiting of pregnancy (NVP) has been limited by fears of teratogenicity, despite a lack of suggestive data, and the minimal efficacy of most anti‐emetics. A potential consequence of NVP is decreased intake of medications in cases with pre‐pregnancy conditions requiring chronic treatment. This may be the underlying mechanism of worsening disease status during the first trimester in cases such as seizure disorders.

1. 2. How do the physiologic changes of pregnancy affect drug disposition? (Table 23.1)

1. a. Drug Absorption

Theoretically, the slower intestinal motility and decreased gastric acid secretion in pregnancy could alter drug absorption and oral bioavailability. However, no confirmatory evidence validates these assumptions. In fact, in studies on ß‐lactam antibiotics used for asymptomatic bacteriuria, no difference was noted in bioavailability of the drugs (given orally and intravenously) between late pregnancy and postpartum [30, 31]. Little information is available on changes in drug absorption for inhaled agents. A small observational study found that the minimum alveolar concentration of inhaled isoflurane was reduced by 28% in pregnant women at 8–12 weeks of gestation compared to nonpregnant controls [32]. The mechanisms underlying this change are not well defined but could be related to pulmonary function changes occurring during early pregnancy.

1. b. Drug Distribution

Decreased plasma protein levels during pregnancy lead to an increase in the free fraction of most medications. The decreased concentrations of albumin and alpha 1‐acid glycoprotein (AAG) may result from the dilutional effect of increased plasma volume or the increased urinary protein excretion noted during pregnancy [33–35]. The increased free drug fraction may lead to higher drug clearance secondary to higher hepatic extraction or renal elimination. Another reason behind changes in free drug fraction is related to the different concentrations of both albumin and AAG between the maternal and fetal circulations. AAG is two‐thirds lower and albumin higher in fetal plasma [36]. This difference presents a gradient between maternal and fetal circulations and may alter drug distribution. Indinavir and saquinavir are examples of differential distribution, due to lower fetal AAG concentration, with higher drug concentrations in umbilical cord samples compared to maternal samples [37].

1. c. Drug Metabolism

Drug metabolism can be divided into phase I and phase II, which differ by the specialized enzymes involved in drug disposition. Phase I reactions usually involve oxidation whereas phase II reactions are mainly conjugative. Changes in drug metabolism can have implications for drug dosage in pregnancy. In drugs with a narrow therapeutic window, an increased clearance during pregnancy can lead to subtherapeutic concentrations and worsening disease control. Conversely, to avoid increased toxicity, drug doses may need to be adjusted in the postpartum period, when pregnancy‐related metabolic enzyme activity changes resolve.

1. A. Phase I metabolism

Oxidative phase I reactions are predominantly carried out by the cytochrome P450 (CYP) system. It includes a number of enzymes that differ in their substrates. CYP3A is the major P450 enzyme; it is located in the gut and liver and carries out 30% of the P450 complex’s activity. In fact, it is involved in the metabolism of more than 50% of the currently known drugs [38, 39]. CYP3A activity is increased during pregnancy. The clearance of Midazolam, one of CYP3A’s selective substrates is doubled during pregnancy compared to postpartum [28]. Similarly, metabolism of other CYP3A substrates increases during pregnancy. For example, the clearance of dextromethorphan, a cough suppressant, increases by almost 40% [39], and that of nelfinavir, an anti‐retroviral, by almost a third [40, 41]. CPY3A activity is altered by pregnancy but the enzyme’s activity is also impacted by the maternal genotype. A recent study on the pharmacokinetics of nifedipine used for tocolysis revealed a genetic variability in the CYP3A5 enzyme [42]. The authors were able to determine a specific allele that influenced oral clearance of the drug and concluded that high expressors of the specific allele had an oral clearance rate almost four times as high as expressors of other allele variants [42].

The second most common enzyme in the CYP complex is CYP2D6. Two phenotypes of the enzyme’s activity have been described. A poor metabolizer (PM) phenotype, which is associated with low enzyme activity, and an ultrarapid metabolism phenotype, associated with high enzyme activity [39]. The PM phenotype is an autosomal recessive trait with variable representation in different ethnic groups [43]. With standard doses of medications, individuals with the PM phenotype are expected to have higher concentrations of a specific drug whereas ultrametabolizers would have lower drug levels. In parallel with individual variation in phenotype, CYPD26 activity appears to undergo a gradual increase during pregnancy and resolves following delivery [43]. Changes in enzyme activity leading to lower drug levels have been associated with worsened control of disease such as recurring symptoms of depression in patients receiving fluoxetine during pregnancy [39].

In contrast to previously mentioned enzymes, some of the components of the CYP complex demonstrate decreased activity during pregnancy. Using caffeine as a substrate, CYP1A2 undergoes a gradual decrease in enzymatic activity during pregnancy [38]. Other substrates of the drug include ondansetron and theophylline. The latter has a narrow therapeutic index and a decrease in its clearance during the third trimester could lead to higher rates of toxicity [44–46]. Given the available evidence, it may necessary to use lower doses of medications metabolized by CYP1A2 during pregnancy. However, further studies are needed to fully describe the changes affecting CYP1A2 substrates before recommending specific dosing adjustments.

1. B. Phase II metabolism

An example of phase II metabolism is Uridine 5′‐Diphosphate Glucuronosyltransferase (UGT). Numerous isoforms of the enzyme have been described. One of the substrates of UGT1A4 is the anti‐seizure medication lamotrigine. The drug is almost exclusively metabolized by N‐glucuronidation by UGT1A4 in the liver [47]. In one study, lamotrigine clearance was 360% higher in the third trimester compared to pre‐pregnancy [48]. Along those findings, another study compared serum drug concentration to dose during pregnancy and postpartum in women receiving lamotrigine as monotherapy for seizure control [48]. The ratio was one fourth and two‐thirds, respectively, in the first and third trimester, compared to postpartum [48]. In this study, five women required increased doses of the drug to achieve seizure control during pregnancy. Dose adjustments were reversed in the postpartum period to avoid drug toxicity [48].

1. d. Drug Elimination

Renal drug excretion depends on GFR, tubular secretion, and reabsorption. GFR is 50% higher by the first trimester and continues to increase until the last week of pregnancy, whereby it decreases to postpartum levels [48]. If a drug were solely excreted by glomerular filtration, its renal clearance is expected to parallel changes in GFR during pregnancy. For example, pregnancy effects on the gastrointestinal track reduce oral availability of ampicillin, while increased renal elimination due to the increase in GFR further reduces its serum concentration, [49–51]. Similar changes have been described for cefazolin and clindamycin, commonly used in pregnancy [30, 52]. However, even in cases where drugs exhibit low protein binding and are not metabolized before excretion, such as antibiotics, changes in renal clearance during pregnancy varies widely [53, 54]. More specifically, the clearance of lithium is doubled during the third trimester compared to preconception [55]. By comparison, the clearance of digoxin, which is 80% cleared, is merely 20–30% higher during the third trimester compared to postpartum [56, 57]. Furthermore, the clearance of atenolol is only 12% higher across pregnancy [28, 58]. With evidence of large variation in renal clearance between different drugs, it is not possible to make assumptions about the effect of pregnancy on the clearance of renally eliminated drugs. Further studies are needed to elaborate the various metabolic and physiologic processes underlying these findings and assess the role of tubular secretion and reabsorption.

1. 3. How does the placenta affect drug therapy during pregnancy?

Fetal development is dependent upon the transport of nutrients by the placenta toward the fetal side and that of products of fetal metabolism for elimination by the mother [25]. In addition, the placenta produces and secretes hormones, which affect the maternal physiology and endocrine state [56, 59]. The transport role is mediated by the syncytiotrophoblasts, the functional cell of the placenta. These cells have a polarized plasma membrane consisting of a brush border at the maternal side and a border membrane on the fetal side. Compounds transported between mother and fetus are carried by the maternal circulation within the uterine vasculature directly through the intervillous spaces and then the syncytiotrophoblasts. Thereafter, blood flows from the fetal side of the placental villi through the fetal capillary endothelium to reach the fetal circulation (Figure 23.1). Most xenobiotics cross the placental barrier by simple diffusion. Protein binding, degree of ionization, lipid solubility, and molecular weight all affect transport. In fact, small, lipid soluble, unionized, and poorly protein bound molecules cross the placenta easily. For other substrates, the placenta facilitates maternal to fetal transport through the polarized expression of various transporters [60]. Transporters enable transport of specific endogenous substrates (such as cytokines, nucleoside analogs, and steroid hormones); however, exogenous compounds with similar structures may also interact with these transporters.

A number of placental drug transporters have been identified including the family of multi‐drug resistance proteins (MRPs). However, phosphoglycoprotein (P‐gp) and breast cancer resistance protein (BCRP

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