Obstetric Pharmacology

Question 1:
Plasma volume, total body water, cardiac output and renal glomerular filtration rate all go up in pregnancy by what percentage?
A. 10%
B. 20 – 30%
C. 30 – 50%
D. 50 – 70%

Question 2:
These increases (in plasma volume, total body water, cardiac output and GFR) peak early in the second trimester and then return to normal by delivery.

True or False?

Question 3:
Penicillins and cephalosporins are renally cleared, but the increases in both renal clearance and volume of distribution in pregnancy are not sufficient to support changes in dosing recommendations.

True or False?

Question 4:
Concentrations of albumin and α-1 acid glycoprotein go down in pregnancy. This means that there is less plasma protein to bind to medications and the unbound, free fractions of drugs go up.

True or False?

Question 5:
Because of these changes in protein binding, for some critical, highly protein-bound medications, it is important to measure the free fraction, not total drug, during pregnancy.

True or False?

Question 6:
P-glycoprotein in the placenta helps to protect the fetus by metabolizing medications that try to cross the placenta.

True or False?

Question 7:
The changes in reproductive hormones during pregnancy increase the activity of some Phase II hepatic metabolizing enzymes (conjugation/biotransformation).

True or False?

Question 8:
The changes in reproductive hormones during pregnancy have no effect on Phase I hepatic metabolism (chemical modification).

True or False?

Question 9:
Methadone clearance increases in pregnancy; therefore, pregnant women on methadone often require increases in their dose.

True or False?

Question 10:
Pharmacogenetic differences in drug metabolizing enzymes and drug transporters can affect how an individual person responds to medications during pregnancy.

True or False?

Case Study 1
A 41-year-old female at 310/7 weeks of gestation with chronic hypertension previously with stable pressures on labetalol 300 mg bid (8 AM & 8 PM) calls the office with the following blood pressure report: 8 AM 165/98, 11 AM 125/82, 4 PM 134/88, 7 PM 164/102. After documenting that her preeclampsia blood and urine tests are negative, her physician increases her labetalol to 400 mg twice daily. Two days later, she calls the office, reporting that she has been now feeling mildly lightheaded and weak several hours after her morning dose.

1. Why is this happening, and what can we do to better manage her blood pressures?

Case Study 2
A 36-year-old G4P3* at 39 weeks of gestation was treated with 2 grams of cefazolin IV beginning one hour before her scheduled repeat cesarean section. Ten years earlier with her first cesarean section, she received 1 gram of cefazolin after the baby was delivered.

*Gravida (G) refers to the woman’s total number of pregnancies, including the current one.

Para (P) refers to the number of births of viable offspring.

1. Why have our prophylactic antibiotic guidelines changed?

Case Study 3
A 25-year-old female at 32 weeks of gestation reported decreased fetal movement at her routine OB visit. Fetal heart tones were regular but too rapid to count. Fetal echocardiogram showed normal anatomy and no evidence of fetal hydrops. The fetal electrocardiogram (ECG) showed a ventricular rate of 240 and supported a diagnosis of fetal supraventricular tachycardia (SVT), in particular, atrial flutter, with a 2:1 atrial to ventricular contraction rate. The patient received a loading dose of IV digoxin; however, the fetal arrhythmia continued despite maternal plasma digoxin levels in the therapeutic range.

1. Explain why the fetal arrhythmia continued although maternal plasma digoxin levels were in the therapeutic range.

Case Study 4
A 26-year-old G1P0 at 316/7 weeks of gestation with a known generalized tonic/clonic seizure disorder dating back to early childhood presents to OB Triage having had an observed seizure 1 hour before admission. She reports that this is the first seizure she has had since her medications were changed several years ago. Since that time, she has been on the same regimen of lamotrigine and levetiracetam. The last time she saw her neurologist was 3 months before she conceived and she recalls that, at that visit, her drug levels were therapeutic. She has been taking her seizure medications with good compliance.

1. Why did she have a seizure today and which of her medications are most likely to be sub-therapeutic?

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.

Question 1:
Plasma volume, total body water, cardiac output and renal glomerular filtration rate all go up in pregnancy by what percentage?
A. 10%
B. 20 – 30%
C. 30 – 50%
D. 50 – 70%

Answer: C

Question 2:
These increases (in plasma volume, total body water, cardiac output and GFR) peak early in the second trimester and then return to normal by delivery.

True or False?

Answer: False
The increases (in plasma volume, total body water, cardiac output and GFR) peak during the 3rd trimester (~32 weeks) and then decrease slightly towards term, but at delivery they are still elevated compared to the non-pregnant state.

Question 3:
Penicillins and cephalosporins are renally cleared, but the increases in both renal clearance and volume of distribution in pregnancy are not sufficient to support changes in dosing recommendations.

True or False?

Answer: False
Studies have shown that standard non-pregnant dosing regimens do not produce adequate drug concentrations in either the maternal surgical sites or in the fetus to provide the necessary prophylaxis.  Guidelines recently have increased their recommended dosing for normal weight women and even higher for obese women.

Question 4:
Concentrations of albumin and α-1 acid glycoprotein go down in pregnancy. This means that there is less plasma protein to bind to medications and the unbound, free fractions of drugs go up.

True or False?

Answer: True

Question 5:
Because of these changes in protein binding, for some critical, highly protein-bound medications, it is important to measure the free fraction, not total drug, during pregnancy.

True or False?

Answer: True

Question 6:
P-glycoprotein in the placenta helps to protect the fetus by metabolizing medications that try to cross the placenta.

True or False?

Answer: False
P-glycoprotein is an efflux transporter that sits on the maternal-facing placental surface.  It actively transports certain drugs away from the fetus, back into maternal circulation, thereby reducing fetal exposure.  It does not metabolize medications.

Question 7:
The changes in reproductive hormones during pregnancy increase the activity of some Phase II hepatic metabolizing enzymes (conjugation/biotransformation).

True or False?

Answer: True

Question 8:
The changes in reproductive hormones during pregnancy have no effect on Phase I hepatic metabolism (chemical modification).

True or False?

Answer: False
Activity of some of the Phase I hepatic metabolizing enzymes goes up in pregnancy while activity of others goes down.

Question 9:
Methadone clearance increases in pregnancy; therefore, pregnant women on methadone often require increases in their dose.

True or False?

Answer: True

Question 10:
Pharmacogenetic differences in drug metabolizing enzymes and drug transporters can affect how an individual person responds to medications during pregnancy.

True or False?

Answer: True