Principles of Obstetric Pharmacology

Maternal Physiologic and Hepatic Metabolism Changes

Catherine S. Stika, MD *      Department of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, 250 East Superior Street, Suite 03-2303, Chicago, IL 60611, USA
* Corresponding author. 
email address: c-stika@northwestern.edu

Since the recognition of pregnancy as a special pharmacokinetic population in the late 1990s, investigations have expanded our understanding of obstetric pharmacology. Many of the basic physiologic changes that occur during pregnancy impact on drug absorption, distribution, or clearance. Activities of hepatic metabolizing enzymes are variably altered by pregnancy, resulting in concentrations sufficiently different for some drugs that efficacy or toxicity may be affected. Understanding these unique pharmacologic changes will better inform our use of medications for our pregnant patients.

Keywords

Pregnancy; Pharmacokinetics; Renal clearance; Renal secretion; Drug metabolizing enzymes; Enzyme induction; Enzyme inhibition; Pharmacogenetics

Key points

1. Pregnancy is a pharmacologic special population, where changes in absorption, distribution, metabolism, and elimination of drugs can impact concentrations sufficiently that different dosing may be required.
2. Normal physiologic changes in pregnancy (increases in plasma volume, total body water, glomerular filtration rate, and renal secretion and decreases in plasma proteins) can impact drug concentrations and clearance.
3. Hormonal changes in pregnancy alter drug-metabolizing enzymes; activities of cytochrome P450 (CYP) 2D6, CYP2C9, CYP3A4, and uridine 5´-diphosphate glucuronosyltransferase (UGT) 1A1 and UGT1A4 increase, whereas CYP1A2 and CYP2C19 decrease.

The changes in pregnancy that affect drug absorption, distribution, metabolism, and elimination can be broken down into two categories: (1) physiologic changes in pregnancy that make intuitive sense to us as obstetricians and (2) changes that occur in hepatic metabolism, which for many of us are a confusing "black box." Although knowledge of obstetric physiology has evolved fairly commensurate with general medical knowledge, the first paper describing the failure of a standard drug dose to achieve therapeutic concentrations in pregnancy was not published until 1977. 1 Since then, and especially since the turn of the millennium with expansion of the United States Food and Drug Administration (FDA) and the National Institutes of Health (NIH) support, our understanding of pregnancy as a special pharmacologic population has significantly advanced. Although we often categorize these pharmacologic changes as pregnant versus nonpregnant, pregnancy is not uniform: pregnant people in the third trimester handle drugs differently than in the second or first trimester. Each pharmacokinetic parameter evolves across pregnancy on its own trajectory (Table 1). In addition, some of the hepatic enzymes have important pharmacogenetic differences, which further add to variability in pregnancy response. Changes in pharmacokinetics do not always require changes in dosing regimens. If maximum or minimum concentrations and total drug exposures are different but still within therapeutic range, dosing guidelines may stay the same. However, optimal obstetric care requires that when we prescribe medications to this special maternal-fetal dyad, we understand each drug's unique pharmacokinetics during pregnancy so that its administration is both safe and effective.

Impact of physiologic changes in pregnancy on pharmacology

Case #1

A pregnant woman with a URI caused by ampicillin-sensitive Haemophilus influenzae was treated with oral ampicillin 500 mg every 6 hours. She failed to respond, and an ampicillin level was reported as "undetectable." 1 Why was the ampicillin concentration so low?

Increase in blood volume and total body water

Fundamental to many of the changes that occur in pregnancy is the 40% to 45% increase in blood volume. This expansion begins by 6 to 8 weeks and progressively adds 1200 to 1300 mL of blood, peaking at 32 to 34 weeks. 2 , 3 In twin gestations, the increase is approximately 20% greater. 3 Multiple factors contribute to these dramatic changes, including increases in steroid hormone concentrations and nitric oxide. Estrogen stimulates both production of hepatic angiotensinogen and renal renin, which increases aldosterone and subsequent sodium and fluid retention. 4 Extracellular fluid and total body water also increase proportional to patient weight. 5 In a nonpregnant woman, extracellular fluid space is approximately 0.156 L/kg versus approximately 0.255 L/kg in singleton pregnancies. 6

Table 1

PK Parameter Early First T Late First T Early Second T Late Second T Early Third T Late Third T <8 wk PP >12 wk PP Renal: CrCL = Plasma volume/TBW = Albumin ? = a1-acid glycoprotein = = Hepatic arterial blood flow ? = = = = = ? = Hepatic portal blood flow ? ? = UGT1A1 ? ? = UGT1A4 = = CYP1A2 ? = CYP2B6 ? ? ? = = = ? = CYP2C9 ? ? = CYP2C19 EM/RM/UM ? ? ? ? ? = CYP2D6 EM/RM ? ? ? = CYP3A4/5 ? ? =

Abbreviations: =, no different from nonpregnant state; ?, parameter change is unknown; CrCL, creatinine, clearance; CYP, cytochrome P450; EM, extensive metabolizer; PK, pharmacokinetic; PP, postpartum; RM, rapid metabolizer; T, trimester; TBW, total body water; UGT, uridine 5'-diphosphate glucuronosyltransferase; UM, ultrarapid metabolizer.

This expansion of plasma volume and total body water increases the volumes of distribution (Vd) and reduces the concentrations of hydrophilic medications. Vd is the theoretic volume that would be necessary to contain the administered dose at the same concentration as measured in plasma: Vd = dose/concentration. An example of this effect, Casele and colleagues 7 reported that following the same dose of enoxaparin, whose Vd is essentially plasma volume, the anti-factor Xa activity at 4 hours was significant lower (P < .05) in the first and third trimester (19% and 29%, respectively) compared with 6 to 8 weeks postpartum. 7 Because body fat has an extensive capacity to absorb lipophilic drugs, the Vd for these drugs greatly exceeds the actual volume of body fat. Although pregnant people gain body fat, the impact on Vd is less significant for lipophilic medications because this change only minimally increases the already large Vd.

Decreased protein binding

Plasma protein concentrations change during pregnancy. The best known is the decrease in plasma albumin from 4.2 g/dL in nonpregnancy to 3.6 g/dL in the midtrimester of pregnancy. 8 The plasma concentration of a1-acid glycoprotein, which binds many basic drugs, is reduced by almost 50% during the third trimester of pregnancy. 9 These reductions in plasma protein concentrations increase the free fraction, Vd, and clearance of many drugs. For highly protein bound medications with a narrow therapeutic range (little difference between the minimal therapeutic and toxic concentrations), monitoring of free drug, rather than total drug, is often recommended in pregnancy, for example, digoxin and...