PK in Pregnancy
How pregnancy-related physiological changes alter drug pharmacokinetics and challenge dosing decisions for mother and fetus.
## Pregnancy Alters Every PK Parameter
Pregnancy produces dramatic cardiovascular, renal, hepatic, and body composition changes that evolve across trimesters. These changes can increase or decrease drug exposure, creating challenges for maintaining therapeutic levels while minimizing fetal risk.
## Absorption Changes
- **Nausea and vomiting** in the first trimester reduce oral drug retention
- **Delayed gastric emptying** (progesterone effect) slows absorption rate but may not reduce total absorption
- **Decreased gastric acid secretion** may reduce absorption of drugs requiring acid dissolution
- **Increased intestinal transit time** allows more complete absorption of slowly dissolving formulations
## Distribution Changes
Pregnancy expands the distribution space for most drugs:
- **Plasma volume** increases 40-50% by the third trimester
- **Total body water** increases by 6-8 liters
- **Body fat** increases by 3-4 kg on average
- **Albumin concentration** falls 20-30% due to hemodilution, increasing the free fraction of protein-bound drugs
These changes increase Vd for both hydrophilic and lipophilic drugs. Higher loading doses may be needed for drugs like phenytoin and digoxin.
## Metabolism Changes
Pregnancy induces specific CYP enzymes while suppressing others:
| Enzyme | Change in Pregnancy | Affected Drugs |
|--------|-------------------|---------------|
| CYP3A4 | Increased | Nifedipine, midazolam (faster clearance) |
| CYP2D6 | Increased | Metoprolol, fluoxetine (faster clearance) |
| CYP2C9 | Increased | Phenytoin (faster clearance) |
| UGT1A4 | Increased | Lamotrigine (clearance doubles) |
| CYP1A2 | Decreased | Caffeine, theophylline (slower clearance) |
| CYP2C19 | Decreased | Omeprazole (slower clearance) |
Lamotrigine is a critical example: UGT1A4 induction increases clearance by 50-100% during pregnancy, risking seizure breakthrough if doses are not increased. After delivery, clearance rapidly normalizes, and pre-pregnancy doses must be restored to avoid toxicity.
## Excretion Changes
- **GFR increases** by 50% during pregnancy due to increased renal blood flow and cardiac output
- **Renal clearance** of drugs like lithium, ampicillin, and digoxin increases proportionally
- Lithium doses often need to be increased during pregnancy and rapidly reduced postpartum to avoid toxicity
## Placental Transfer
Most drugs cross the placenta by passive diffusion. Factors favoring transfer:
- Low molecular weight (< 500 Da)
- High lipophilicity
- Low protein binding (free drug crosses)
- Un-ionized at physiological pH
The fetus has limited metabolic capacity, particularly in early pregnancy, making it vulnerable to drugs that cross freely.
## Key Takeaways
- Pregnancy increases Vd, GFR, and activity of several CYP and UGT enzymes
- Lamotrigine and lithium are classic examples requiring dose adjustment in pregnancy
- Plasma volume expansion reduces concentrations of many drugs
- Most drugs cross the placenta; fetal metabolic capacity is limited
- Postpartum dose reduction is as important as gestational dose increases