Case Study 1
In this woman with chronic hypertension, the blood pressures she recorded initially show good control as the levels of labetalol rise after her morning dose, but then, at the end of the 12-hour dosing interval, her blood pressures go back up, suggesting that her labetalol concentrations are no longer adequate to control her blood pressure.
Labetalol clearance goes up in pregnancy: the increase in reproductive hormones that occurs in pregnancy causes an increase in labetalol glucuronidation (for the UGT enzyme that metabolizes labetalol, it’s the increase in progesterone that increases its activity). At the end of the dosing cycle, her labetalol concentrations fall below the therapeutic threshold and her blood pressure rises. Increasing the dose to 400 mg bid pushed her maximum labetalol concentrations up too high and she became orthostatic, as the labetalol over-corrected her blood pressure. Shortening the dosing interval and changing her regimen to 300 mg q 8 hours would provide more even control of her blood pressure.
Case Study 2
Recent pharmacokinetic studies have shown that higher doses of the renally cleared cephalosporins and penicillins are required to provide adequate tissue concentrations in both the mother and the fetus when used for surgical prophylaxis during pregnancy. Dosing recommendations for obese women have increased even further to 3 grams of intravenous cefazolin.
Case Study 3
Transport of digoxin across the placenta to the fetus is restricted because of active transport back out into maternal circulation by placental P-glycoprotein. As a result, fetal concentrations are much lower than simultaneous maternal levels for most infants. To achieve adequate fetal drug concentrations, maternal dosing needs to be increased. If the mother cannot tolerate these higher levels, options include either direct fetal injection of digoxin or use of an alternate medication.
Case Study 4
Therapeutic drug monitoring of her anti-epileptic drugs (AEDs) shortly after this seizure showed that her levetiracetam level was just below the therapeutic range and her lamotrigine concentration was almost non-detectable.
Levetiracetam is renally cleared. Renal clearance increases by 30 – 50% over the course of pregnancy. Levetiracetam levels have been shown to slowly decrease as pregnancy progresses, requiring dose escalations in some but not all women.
On the other hand, beginning early in the first trimester, glucuronidation of lamotrigine dramatically increases as pregnancy progresses (this UGT goes up because of rising estradiol levels), requiring monthly drug testing and appropriate increases in her lamotrigine dosing. After delivery, estradiol levels dramatically fall and glucuronidation rapidly normalizes. If her lamotrigine dose is not quickly tapered back to her pre-pregnancy regimen over the first 3 weeks, she may develop lamotrigine toxicity side effects.
Presented by the PhRMA Foundation Safe and Effective Prescribing Project
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