Pharmacokinetics, Pregnancy-induced

Physiologic Alterations and Predicaments in

Practice

Ruston S. Taylor, Pharm.D., BCPS, BCNSPClinical Pharmacy Specialist

Texas Children’s Hospital—The Center

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

??Pharmacokinetics??

First, what do we know

about pharmacokinetics in the pregnant patient??

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

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

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

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

Pharmacokinetics: Limiteddata 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

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

Pharmacokinetics: Extremelylimited 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

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

??Physiologic changes??

Why is pregnancy so HARD?• Identify physiologic changes

along the continuum of pregnancy in specific organ systems

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)

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

Cardiovascular system:Blood volume changes

McLennon CE, Thouin LG. Blood volume in pregnancy. Am J Obstet Gynecol 1948; 55:1189.

Cardiovascular system:Pharmacokinetic changes due to blood volumePhysiologic 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

Cardiovascular system:Changes in blood pressure

Pro

gest

eron

e ef

fect

s

Cardiovascular system:Increased cardiac output causes

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

Genitourinary system:Changes in renal physiology

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

Genitourinary system: Pharmacokineticchange 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

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

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

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 Increased Phenytoin, glyburide

Monitoring of phenytoin concentration indicated

CYP2D6 Increased Many β-blockers, including metoprolol; many TCAs and SSRI, codeine

Decreased concentration of SSRI documented and may be associated with recurring symptoms of depression

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 Increased

Acetaminophen Unknown significance

UGT1A4 Increased

Lamotrigine Significant decrease in serum lamotrigine concentrations; increase in seizure activity unless monitoring and dose adjustment occurs

UGT2B7 Increased

Lorazepam Unknown significance

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

Endocrine system:Changes in the pancreas

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

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

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

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. 2001; 15(6): 819-826.

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. 1999 May;90(5): 858-868. Review.

Loebstein R, Lalkin A, and Koren G. Pharmacokinetic Changes During Pregnancy and Their Clinical Relevance. Clin Pharmacokinet. 1997; 33(5): 328-343.