1. Texas Children’s Hospital—The Center
Pharmacokinetics, Pregnancy-induced Physiologic Alterations and Predicaments in Practice Ruston S. Taylor, Pharm.D., BCPS, BCNSP Clinical Pharmacy Specialist
Texas Children’s Hospital—The Center

2. Objectives
Discuss clinical implications during pregnancy caused by limitations of currently available pharmacokinetic data
Identify physiologic changes along the continuum of pregnancy in specific organ systems
Relate alterations in various organ systems to influence on pharmacokinetic principles

3. ??Pharmacokinetics??
First, what do we know about pharmacokinetics in the pregnant patient??

4. Pharmacokinetics: Limitations to current knowledge
Specific data for Vd and Cls in pregnancy for individual drugs is limited due to ethical and practical considerations
Pharmacokinetic clinical trials exclude pregnant women, due to FDA moratorium
Pharmacokinetic data that does exist in pregnancy comes from small sample size studies and incorporates different gestation ages
Comparator groups are often composed of non-pregnant women, adult males, and same subject 6-8 weeks post- partum as controls
Cls is systemic clearance.

5. Pharmacokinetics: Limitations to current knowledge
Limited pharmacokinetic data available for the following:
Anticonvulsants
Antihypertensives
Antibacterials
Analgesics
All pharmacologic classes listed have lack of consistency between studies and individuals
Lack of consistency is likely due to confounding factors such as gestational age, sample size and different drug assays.

6. Pharmacokinetics: Limited data for anticonvulsants
Anti-epileptic drugs (AED) are the most studied therapeutic category of agents in pregnancy
Plasma concentrations across studied AEDs, especially in the later stages of gestation
Decrease in plasma concentrations due to clearance and lower concentrations of binding proteins affect the following:
Carbamazepine
Phenytoin
Phenobarbital
VPA is different in that only approximately 10% is eliminated by CYP pathways; glucuronidation accounts for approximately 50% of valproic acid’s elimination.

7. Pharmacokinetics: Decreased anticonvulsant plasma concentrations
Most anticonvulsants exhibit high albumin binding
However, the unbound concentration of “free drug” is pharmacologically active
Special attention should be given when interpreting the results of plasma concentrations to guide therapeutic efficacy as most labs report total plasma concentration (bound and unbound)
A fall in plasma concentrations does not reflect a fall in free drug
Ideally, free drug concentrations should be monitored
New generation AEDs like the second-generation antiepileptic agents (ie lamotrigine, topiramate, gabapentin, levetiracetam, oxcarbazepine) are eliminated via non-CYP routes.
Lamotrigine and mono-hydroxycarbazepine, the active metabolite, are primarily metabolized by glucuronidation via UGT enzymes
Topiramate, gabapentin, and levetiracetam are primarily excreted in the urine as unchanged drug.

8. Pharmacokinetics: Limited data with antihypertensives
Beta-blockers (e.g. labetalol):
Exhibit a shorter t1/2 in pregnant women, suggesting the need for more frequent doses
Calcium channel blockers (e.g. nifedipine):
Exhibit faster elimination
However, administration frequencies will continue to be ultimately based on patient response

9. Pharmacokinetics: Limited data with antibacterials
Plasma concentrations of β-lactam antibiotics are well known to correlate with response of bacterial infections and are unaltered during pregnancy
Ampicillin exhibits increased clearance and reduction in plasma concentrations during pregnancy
Ampicillin dosing frequency may need to be decreased, but no specific study information is available currently.

10. Pharmacokinetics: Extremely limited data with analgesics
There is no consistent evidence detailing the pharmacokinetics of analgesics in pregnancy (even studies of the same drug)
No management guidance can be formed concerning dosing schedule
However, management of pain will continue to be based on pain score trends which may necessitate increases in medication administration
CLINICAL PEARL:
with combination products containing APAP, the contents of ALL acetaminophen should be closely monitored and considered.
Exposure of the patient to narcotics should also be considered.
Practitioners may choose drugs with increased potency as alternatives.

11. Pharmacokinetic DISCLAIMER
Vast and complex physiologic changes during pregnancy have significant effects on drug disposition
Understanding physiologic changes during the continuum of pregnancy can help guide drug dosing in various stages
Wide interpatient and intrapatient variability necessitate monitoring serum drug levels when indicated
EMPHASIZE: when evaluating literature associated with pregnancy, do NOT “hand your hat” on one study. There are likely multiple small studies which show varying results. **TAKE AWAY POINT**: treat the patient (i.e. hypertension and infection).

12. Why is pregnancy so HARD?
??Physiologic changes??
Why is pregnancy so HARD?
Identify physiologic changes along the continuum of pregnancy in specific organ systems

13. Cardiovascular system: Pregnancy-associated changes
Changes in maternal hemodynamic variables:
Blood volume
Blood pressure (BP)
Heart rate (HR)
Stroke volume (SV)
Cardiac output (CO)
Systemic vascular resistance (SVR)

14. Cardiovascular system: Complicating variables
Factors complicating management may include:
Maternal age
Multifetal pregnancy
Gestational age
Body build
Labor (length and method of delivery)
Regional anesthesia
Blood loss

15. Cardiovascular system: Blood volume changes
Maternal plasma volume increases by 10% as early as the 7th week of pregnancy
This plasma volume plateaus at 45-50% expansion occurring around week 32 and remains stable until delivery
Red blood cell mass increases occur, but increases are less pronounced than plasma expansion and occur later in pregnancy at week 16-20 dilutional anemia despite adequate iron stores
Hemodilution may offer the possible advantages of:
Lower blood viscosity benefiting placental perfusion
Stasis prevention
Placental thrombosis prevention
McLennon CE, Thouin LG. Blood volume in pregnancy. Am J Obstet Gynecol 1948; 55:1189.

16. Cardiovascular system: Pharmacokinetic changes due to blood volume
Physiologic change
Pharmacokinetic impact
Volume expansion
Decreased Cmax of drugs
Enhanced clearance
Decreased steady-state concentration
Protein binding
Decreased drug elimination occurs as drug is inhibited from hepatic and renal elimination
Hypoalbuminemia
Decreased sites for steroids, hormones, and drugs to bind
Decreased binding capacity
Larger unbound fraction of drug (free drug)
More pharmacologic activity
volume expansion: decreases in the peak serum concentration (Cmax) of many drugs occurs
Drugs distributed mainly to water compartment have a small Vd, will show the greatest decrease in serum Cmax
Decreased steady-state concentration have been documented for different agents due to enhanced clearance
But interestingly, drug dosage increases, which would be expected, may be offset by protein binding and drug elimination (hepatic and renal)

17. Cardiovascular system: Changes in blood pressure
Blood Pressure (BP) = Cardiac output (CO) x systemic vascular resistance (SVR)
BP normally decreases by about 10% by the 7th week of pregnancy
Cardiac output (CO) = heart rate (HR) x stroke volume (SV)
Increases by 10 weeks’ gestation  30-50% increases seen by latter part of 2nd trimester
Blood pressure is a reflection of the cardiovascular system’s ability to maintain perfusion to various organs (i.e. fetoplacental unit)
Progesterone effects
A fall in SVR is due to the dilating effects of progesterone leads
to a compensatory tachycardia with activation of volume-restoring mechanisms.
Maternal heart rate (HR) increases as early as the 7th week of pregnancy as a compensatory to vasodilatory effects of progesterone to maintain cardiac output. HR increases by 20% in late pregnancy.
Systolic and diastolic BP continue to decrease until midpregnancy and then return to non-pregnant values by term
Sustained BP of > 140/90 abnormal anytime during pregnancy.
Women pregnant with twins may show cardiac output increases 20% higher than singleton pregnancies
Cardiac output remains elevated for 4-8 weeks after delivery

18. Cardiovascular system: Increased cardiac output causes
Renal blood flow
Increases by 30%
GFR increases by 30-50%
Pulmonary blood flow
Uterus
50 ml/min at 10 weeks
500 ml/min at term
Skin perfusion increases rapidly from weeks, vasodilation of dermal capillaries may serve to dissipate excess heat from fetal metabolism.

19. Genitourinary system: Changes in renal tract anatomy
As blood volume increases, the kidney increases in length
Dilation of collecting system occurs secondary to muscle relaxant effects of progesterone
Obstruction to the collecting system can occur due to enlarging uterus
Compressing the ureters causes urinary stasis
Increased risk of pyelonephritis
Kidney length increases by approximately 1 cm during pregnancy.

20. Genitourinary system: Changes in renal physiology
Elevated estrogen levels early in pregnancy result in renin production
Conversion of angiotensinogen to angiotensin I and II
Causes increase in aldosterone
Results in renal tubular sodium retention
Pregnancy best described as a state of volume overload
Pregnancy is a period of marked water retention (intravascular volume expands 1-2 L, extravascular volume expands by 4-7 L)

21. Genitourinary system: Changes in renal physiology
Glomerular filtration rate (GFR) by 50% to a peak around 180 mL/min by end of 1st trimester
Results in:
blood urea nitrogen (BUN) and serum creatinine (SCr) levels > 0.8 mg/dL are indicators of abnormal function
protein excretion considered normal
Loss of glucose in the urine (glycosuria) is normal
Predisposing factor for UTI
NOTE: protein and glucose in the urine to a limited extent is acceptable.
Limits for protein excretion are 260 mg/day
and glucose are tolerated which makes urinalysis an unreliable screening tool for gestational diabetes mellitus.

22. Genitourinary system: Pharmacokinetic change in renal drug elimination
As GFR by 50%, drugs excreted primarily unchanged in the urine are of concern:
Penicillin
Digoxin
Lithium
These drugs exhibit lower steady-state serum concentrations; however, dose alterations are generally not prescribed as data is lacking or conflicting

23. Gastrointestinal (GI) system: Changes in GI physiology
Progesterone-mediated smooth muscle relaxant effects during pregnancy may the following:
Lower esophageal sphincter tone = GERD and heartburn
Gastric and small bowel motility
Prolonged gastric emptying and extended intestinal transit times
Decreased gastric motility
Increased time in large intestine
Increased water absorption
A slower rate in gastric emptying would delay the delivery of drug to the small intestine, and could potentially delay the onset of action and reduce the rate of absorption of a drug.
A decrease in intestinal motility would increase the amount of time that a drug takes to pass through the intestine, and can potentially increase the extent of absorption, particularly for sustained-release products.
Pregnancy-related constipation occurs as less water is present in fecal matter

24. Gastrointestinal (GI) system: Pharmacokinetic changes in GI
The following factors affect the gastrointestinal absorption of drugs:
Drug formulation
Food composition
Chemical composition
pH of the intestinal secretions
Gastric emptying time
Intestinal motility
Blood flow

25. Gastrointestinal (GI) system: Changes in metabolic activity
Enzyme Pathway
Change in Activity
Drugs of interest
Comments
CYP1A2
Decreased
Theophylline, clozapine, ondansetron, propranolol, cyclobenzaprine
Caffeine half-life also prolonged
CYP2A6
Increased
Nicotine, cotinine
Cotinine is active metabolite of nicotine; may have decreased effect of nicotine gum
CYP2C9
Phenytoin, glyburide
Monitoring of phenytoin concentration indicated
CYP2D6
Many β-blockers, including metoprolol; many TCAs and SSRI, codeine
Decreased concentration of SSRI documented and may be associated with recurring symptoms of depression
Different phenotypic expressions depending on the genetic variation occur with CYP2D6 as patients are described as “poor”, “intermediate”, “extensive” and “ultrarapid metabolizers”.
SSRIs including citalopram, duloxetine, fluoxetine, paroxetine

26. Gastrointestinal (GI) system: Changes in drug metabolism in pregnancy
Enzyme Pathway
Change in Activity
Drugs of interest
Comments
CYP3A4
Increased
Most calcium channel blockers, including nifedipine; most benzodiazepines; most HIV protease inhibitors; most non-sedating antihistamines; methadone
May have withdrawal symptoms in patients on methadone maintenance
UGT1A1
Acetaminophen
Unknown significance
UGT1A4
Lamotrigine
Significant decrease in serum lamotrigine concentrations; increase in seizure activity unless monitoring and dose adjustment occurs
UGT2B7
Lorazepam
UGT represents a family of enzymes that metabolize drugs via glucuronidations

27. Gastrointestinal (GI) system: Pharmacokinetic changes in hepatic elimination
The cholestatic effects of progesterone on the gall bladder interfere with the clearance of biliary secreted drugs (e.g. rifampin)
As illustrated previously, almost all pharmacokinetic elimination mechanisms via the CYP and UGT systems increase during pregnancy
However, hepatic elimination cannot be quantified as phenotypic expressions depend on the genetic make-up which varies greatly between individuals
Progesterone inhibits cholecystkinin, inhibits function of gall bladder, inhibits clearance.

28. Endocrine system: Changes in the pancreas
β-cells undergo hyperplasia during pregnancy
This results in increased insulin secretion
Insulin hypersecretion results in hypoglycemia seen in early pregnancy
Peripheral resistance to insulin is a result of production of insulin antagonists, human placental lactogen
Placental insulin antagonists result in normal postprandial hyperglycemia

29. Placental-Fetal Compartment
Placenta acts as a permeable barrier between the maternal and fetal blood circulations
Functions to transport oxygen and nutrients from the mother to fetus, while also providing waste exchange from the fetus to the mother
Drugs cross mainly via passive diffusion
Factors that determine the ability of a compound to cross the placenta include:
pKa, lipid solubility, and molecular size
Large molecules like insulin do NOT cross the placenta
Polar and large molecules like heparin and LMWH do not cross the placenta
Drugs that are renally cleared are also cleared by the maturing fetal kidney, and these drugs are excreted into the amniotic fluid

30. Physiologic conclusions:
Physiologic adaptations occur at different times and to different degrees depending on the organ system and individual
Maternal ability to adapt may depend on pre- existing variables:
Maternal age
Multiple gestation
Ethnicity
Genetic factors

31. Physiologic conclusions:
Maternal ability to adapt may depend on pregnancy-associated factors:
Gestational age
Labor
Intrapartum blood loss
A better understanding of normal physiologic adaptations of pregnancy gives practitioners the ability to manage pregnancy-associated complications

32. References:
Belfort Michael, comp. Critical Care Obstetrics. 5th ed. Chichester: Blackwell, 2010.
Briggs GG, Nageotte, M. Diseases, Complications, and Drug Therapy in Obstetrics. Bethesda: ASHP, 2009.
Dawes M, Chowienczyk P. Pharmacokinetics in Pregnancy. Best Practice & Research Clinical Obstetrics and Gynaecology ; 15(6):
Koren G. Pharmacokinetics in Pregnancy; Clinical significance. J Popul Ther Clin Pharmacol. 2011; 18(3): e523-e527.
Little, B. Pharmacokinetics During Pregnancy: Evidence-Based Maternal Dose Formulation. Obstetrics and Gynecology May;90(5): Review.
Loebstein R, Lalkin A, and Koren G. Pharmacokinetic Changes During Pregnancy and Their Clinical Relevance. Clin Pharmacokinet ; 33(5):