Drug Metabolism in Pregnancy

Introduction

• The majority of organ systems are affected by the anatomic and physiologic changes during pregnancy.¹
• Changes to the hepatic and renal systems in pregnancy significantly affect the pharmacokinetic (absorption, distribution, metabolism, and elimination) and pharmacodynamic properties of many medications.^2-5
• Expansion of plasma volume results in the dilution of plasma proteins (concentrations of albumin and α1-acid glycoprotein, for example, decrease 20-40% at term). This leads to decreased drug binding and increased concentrations of unbound drugs.^1-3

Hepatic and Renal Changes in Pregnancy

Hepatic Changes

• Many drugs undergo hepatic metabolism, so changes in hepatic physiology can result in significant changes in drug metabolism.
• Most members of the cytochrome P450 enzyme family have increased activity during pregnancy, resulting in increased metabolism of many commonly used drugs (Table 1). The mechanism for this increase has not been fully elucidated but may be related to changes in cortisol, estradiol, or progesterone.

• The activities of a smaller number of hepatic enzymes involved in drug metabolism are decreased during pregnancy (Table 2).

• Liver size, morphology, and blood flow do not change.

Renal Changes

• Renal blood flow is 75% greater than prepregnancy by 16 weeks. By 34 weeks, renal blood flow declines to 50% above baseline and remains stable until the end of pregnancy.¹
• Creatinine clearance is increased from 120 mL/min at baseline to 150 to 200 mL/min early in pregnancy, with a slight decrease near term. The mechanism behind the increase in glomerular filtration rate is likely secondary to vasodilation of afferent and efferent arterioles.¹
• The increase in renal clearance can have a significant increase (20–65%) in the elimination rates of renally cleared medications leading to shorter half-lives.^4,5
• The kidneys are also involved in water and sodium osmoregulation. Pregnancy results in a significant increase in sodium and water retention. Total body water increases 6-8 L, and the “dilutional effect” leads to mild hyponatremia. This volume expansion leads to reductions in peak serum concentrations (Cmax) of many hydrophilic drugs, particularly if the drug has a relatively small volume of distribution.^4,5

Dosing Considerations for Commonly Used Anesthetic Agents

Placental Drug Transfer and Metabolism

• The placenta is a semipermeable barrier to drug passage, much like the blood–brain barrier. Placental drug transfer is determined by a number of characteristics as outlined in Table 4.

• The placenta is capable of drug metabolism; it expresses both phase 1 enzymes (oxidation, reduction, and hydrolysis) and phase 2 enzymes (conjugation) like the liver. Phase 1 enzymes expressed by the placenta include CYP1A1, CYP2E1, CYP3A4, CYP3A5, CYP3A7, CYP4B1, and CYP19 (aromatase).²
• Prednisone and dexamethasone undergo significant placental metabolism in pregnancy.²
• The esterases that metabolize remifentanil are highly expressed in the placenta. This results in much lower fetal remifentanil concentrations when compared to the mother.