ADME in pregnancy

Therapeutic window

The range of drug plasma concentrations between minimum effective concentration and toxic concentration

ADME

Absorption, Distribution, Metabolism, and Elimination of drugs

Physiological changes in pregnancy

Changes in maternal body systems that alter pharmacokinetics, including cardiovascular, renal, and gastrointestinal changes

Placental–foetal compartment

The placenta and fetus acting as an additional compartment affecting drug distribution and elimination

Volume of distribution (Vd)

The theoretical volume that would contain the total amount of drug in the body at the same concentration as in plasma

Cmax

The maximum drug concentration observed in plasma

Tmax

The time taken after dosing to reach Cmax

Reduced intestinal motility

Slower gastrointestinal movement during pregnancy due to increased progesterone

Increased gastric emptying time

A 30–50% increase in time for stomach and intestines to empty, delaying drug absorption

Effect of pregnancy on oral absorption

Increased Tmax and reduced Cmax for many orally administered drugs

Gastric pH increase

Reduced gastric acid secretion leading to higher stomach pH

Weak acid absorption

Reduced absorption in pregnancy due to increased gastric pH

pH partition hypothesis

Only un-ionised drug molecules can cross lipid membranes by passive diffusion

Inhalation absorption in pregnancy

Enhanced due to increased cardiac output, tidal volume, and pulmonary blood flow

Cardiac output increase

Physiological change that enhances tissue perfusion and drug distribution

Plasma volume expansion

Approximately 50% increase during pregnancy

Body water increase

Increase of ~8 L total, increasing Vd for hydrophilic drugs

Albumin binding decrease

Reduced plasma protein binding leading to higher free drug concentration

Free drug

The unbound fraction of drug that is pharmacologically active

Hydrophilic drugs in pregnancy

Show increased Vd and reduced plasma concentrations

Placental drug transfer

Movement of drugs from maternal to foetal circulation

Simple diffusion (placenta)

Main mechanism by which drugs cross the placenta

Lipophilic drugs

Cross the placenta more readily than hydrophilic drugs

Ion trapping

Accumulation of weak bases in foetal plasma due to lower foetal pH

Flow-limited transfer

Placental transfer limited by blood flow rather than diffusion

Placental transporters

Carrier systems that transfer drugs similar to endogenous molecules

Lactational transfer

Movement of drugs from maternal plasma into breast milk

Milk-to-plasma ratio (M/P)

Ratio describing drug concentration in milk relative to plasma

Absolute infant dose (AID)

Amount of drug ingested daily by the infant via breast milk

Hepatic metabolism in pregnancy

Altered enzyme activity due to increased oestrogen and progesterone

CYP3A4 activity

Increased during pregnancy

CYP2D6 activity

Increased during pregnancy

CYP1A2 activity

Decreased during pregnancy

Renal plasma flow increase

25–50% increase during pregnancy

Glomerular filtration rate (GFR)

Increases by ~50%, enhancing renal drug elimination

Foetal drug elimination

Occurs mainly by diffusion back to maternal circulation