Clinical Pharmacology During Pregnancy

Clinical Pharmacology During Pregnancy, Second Edition is written for clinicians, physicians, midwives, nurses, pharmacists and other medical professionals involved in the care of women during pregnancy. The book focuses on the impact of pregnancy on drug disposition and includes coverage of treatments for diseases of specific body systems as well as essential content on dosing and efficacy. This update includes substantially expanded sections on the ethics of pharmacological research in pregnancy and physiologic changes, along with new sections on patient reported outcomes in pregnancy, delivery and postnatal care, and the use of pharmacokinetic and pharmacodynamic approaches to estimate maternal, placental and fetal dosing.

The broad range of this book encompasses analgesics, antiasthmatics, antidepressants, heart and circulatory drugs, vitamins and herbal supplements, and more. Topics in chemotherapy and substance abuse are also covered, as are research issues, including clinical trial design and ethical considerations.

• Uses an evidence-based approach for therapeutics during pregnancy
• Presents a summary of specific medications by indication, including up-to-date information on dosing and efficacy in pregnancy for the given indication
• Includes significant new sections on physiologic changes and the ethics of pharmacological research in pregnancy

• Language: English
• Publisher: Academic Press
• Release date: Sep 24, 2021
• ISBN: 9780128189030

Book preview

Clinical Pharmacology During Pregnancy

Second Edition

Editors

Donald Mattison

University of South Carolina, Arnold School of Public Health, Columbia, SC, United States

Risk Sciences International, Ottawa, ON, Canada

School of Epidemiology and Public Health, University of Ottawa, Ottawa, ON, Canada

Lee-Ann Halbert

Associate Professor of Nursing, University of South Carolina, Beaufort, Bluffton, SC, United States

Table of Contents

Cover image

Title page

Copyright

Dedication

Contributors

Acknowledgment

Chapter 1. Introduction

Chapter 2. Physiologic changes during pregnancy

2.1. Physiologic changes during pregnancy

2.2. Cardiovascular system

2.3. Respiratory system

2.4. Renal system

2.5. Gastrointestinal system

2.6. Hematologic and coagulation systems

2.7. Endocrine system

2.8. Summary

Chapter 3. Impact of pregnancy on maternal pharmacokinetics of medications

3.1. Introduction

3.2. Effects of pregnancy on pharmacokinetic parameters

3.3. Summary

Chapter 4. Medications and the breastfeeding mother

4.1. Medication use by the breastfeeding mother

4.2. Clinical pharmacology of drug transfer into breast milk

4.3. During delivery

4.4. General anesthesia

4.5. Epidural anesthesia

4.6. Galactogogues including dietary supplements (including herbs)

4.7. Immediate postpartum period

4.8. Pain

4.9. Methadone

4.10. Resumption of prepregnancy medications

4.11. Psycho- and neurotropic drugs

4.12. Drugs not to give to the nursing mother postpartum

4.13. Oral contraceptives

4.14. Summary

4.15. Where to find information

Chapter 5. Fetal drug therapy

5.1. Introduction

5.2. Indications for fetal therapy

5.3. Strategies to achieve fetal drug therapy

5.4. Special considerations

5.5. Ethical considerations

Chapter 6. Treating the placenta: an evolving therapeutic concept

6.1. Introduction

6.2. The placenta as the therapeutic target: the past

6.3. The placenta: therapeutic targets

6.4. The placenta as a therapeutic target today

6.5. The placenta as a therapeutic target in the future

6.6. Conclusions

Chapter 7. Conducting randomized controlled pharmaceutical trials in the pregnant population: challenges and solutions

7.1. Introduction

7.2. Ethical considerations

7.3. Including pregnant women in pharmaceutical trials for nonobstetrical conditions

7.4. Improving the success of drug trials for obstetrical conditions

7.5. Summary

Chapter 8. Pharmacogenomics in pregnancy

8.1. Pharmacogenomics

8.2. Genetics and polymorphisms

8.3. Genes that influence pharmacokinetic variability

8.4. The current state of pharmacogenetic testing

8.5. Potential therapeutic areas for pharmacogenomics in pregnancy

8.6. Study designs and approaches to pharmacogenetics trials

Chapter 9. Anesthetic drugs

9.1. Introduction

9.2. General anesthesia

9.3. Inhalational anesthetics

9.4. Intravenous anesthetics

9.5. Neuromuscular blocking agents

9.6. Regional anesthesia

9.7. Summary

Chapter 10. The management of asthma during pregnancy

10.1. Introduction

10.2. Effect of pregnancy on the course of asthma

10.3. Effect of asthma on pregnancy

10.4. Asthma management

10.5. Pharmacologic therapy

10.6. Conclusion

Chapter 11. Nausea and vomiting of pregnancy

11.1. Nausea and vomiting of pregnancy

11.2. Prevalence

11.3. Etiologies and pathogenesis

11.4. Burden of the disease

11.5. Cultural implications

11.6. Risk factors

11.7. Quantification

11.8. Effects on fetus

11.9. Late complications related to NVP

11.10. Approaches to treatment

11.11. Lifestyle alterations

11.12. Complementary and alternative medicine

11.13. Pharmacologic therapies

11.14. Differential diagnoses

11.15. Conclusion

Chapter 12. Clinical pharmacology of anti-infectives during pregnancy

12.1. Antibacterial therapy

12.2. Antifungal therapy

12.3. Malaria

12.4. Tuberculosis

12.5. HIV

12.6. Antivirals

12.7. Parasitic infections

Chapter 13. Chemotherapy in pregnancy

13.1. Introduction

13.2. Overview of chemotherapeutic agents

13.3. Treatment of specific cancers

13.4. Pharmacokinetics in pregnancy

Chapter 14. Substance abuse in pregnancy

14.1. Introduction

14.2. Substance use disorders defined

14.3. Addiction defined as a disease of the brain

14.4. The good news: the brain can recover

14.5. Addiction in women and pregnancy

14.6. Psychiatric comorbidity

14.7. Substances used in pregnancy

14.8. Screening and detection

14.9. The role of urine and meconium testing

14.10. Brief office screening strategies

14.11. Brief office interventions

14.12. Long-term care and maintenance

14.13. Conclusion

Chapter 15. Diabetes in pregnancy

15.1. Introduction

15.2. Epidemiology

15.3. Classification

15.4. Gestational diabetes

15.5. Diabetes management in pregnancy

15.6. Conclusion

Chapter 16. Cardiovascular medications in pregnancy

16.1. Introduction

16.2. Resources for guidance

16.3. Cardiovascular changes in pregnancy

16.4. Cardiovascular disease in pregnancy

16.5. Mechanism of action for hypertensive medications

16.6. Coronary artery disease and Spontaneous Coronary Artery Dissection

16.7. Coronary Microvascular Disease and angina

16.8. Medications for cardiomyopathy

16.9. Electrophysiological

Chapter 17. Antidepressants in pregnancy

17.1. Introduction

17.2. Effects of untreated perinatal depression on women and children

17.3. Approach to treatment

17.4. Potential risks of selective serotonin reuptake inhibitor use during pregnancy

17.5. Potential risks of non-SSRI antidepressant use during pregnancy

17.6. Potential risks of older antidepressant use during pregnancy

17.7. Anxiety

17.8. Summary

Chapter 18. Uterotonics and tocolytics

18.1. Introduction

18.2. Uterotonics

18.3. Tocolytics

Chapter 19. Antenatal thyroid disease and pharmacotherapy in pregnancy

19.1. Thyroid function and physiology in pregnancy

19.2. Hyperthyroidism in pregnancy

19.3. Pharmacotherapy with thionamides in pregnancy

19.4. Hypothyroidism in pregnancy

19.5. Pharmacotherapy with levothyroxine in pregnancy

19.6. Summary

Chapter 20. Management of dermatological conditions in pregnancy

20.1. Introduction

20.2. Acne

20.3. Psoriasis

20.4. Oral agents

20.5. Dermatoses

20.6. Bacterial infections

20.7. Viral infections

20.8. Fungal infections

20.9. Parasitic infections

20.10. Dermatological wounds

Chapter 21. Herbs and alternative remedies

21.1. Herbal teas frequently used during pregnancy

21.2. Essential oils used as aromatherapy during pregnancy

21.3. Herbs used as capsules or dried extracts

21.4. Herbal topical preparations used in pregnancy

21.5. Nonherbal supplements used in pregnancy

21.6. Herbs used to induce labor

21.7. Acupuncture and acupressure therapy in pregnancy

21.8. Meditation and hypnosis in pregnancy

Chapter 22. Envenomations and antivenom during pregnancy

22.1. General principles about envenomation

22.2. Snake bites

22.3. Spider bites

22.4. Jellyfish

22.5. Antivenom use during pregnancy

22.6. Conclusions

Chapter 23. Gastrointestinal disorders

23.1. Gastroesophageal reflux disease

23.2. Peptic ulcer disease

23.3. Constipation

23.4. Diarrhea

23.5. Abdominal pain

23.6. Gastrointestinal infections

23.7. Inflammatory bowel disease

Liver diseases in pregnancy

Chapter 24. Challenges in predicting the pharmacokinetics of drugs in premature and mature newborns: example with piperacillin and tazobactam

24.1. Introduction

24.2. What is a PBPK model?

24.3. Neonates are not just little adults

24.4. PIP and TAZ PBPK model for preterm and term neonates [49–51]

24.5. Ability of the neonate PBPK model to predict plasma levels of PIP and TAZ

24.6. Conclusions

Index

Copyright

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Dedication

This book is dedicated to all the individuals who have added to and benefit from the collective knowledge and wisdom presented within this book. The chapter authors share their insights with the express goal of helping health care practitioners and their clients make the best clinical decisions when it comes to the use of medications in pregnancy.

Contributors

Mahmoud Abdelwahab,     Ohio State University, Columbus, OH, United States

Mahmoud S. Ahmed,     Department of Obstetrics & Gynecology, University of Texas Medical Branch, Galveston, TX, United States

Sarah Armstrong,     Frimley Park Hospital, Surrey, United Kingdom

Cheston M. Berlin Jr. ,     Department of Pediatrics/Division of Academic General Pediatrics, Penn State College of Medicine, Penn Statae Children's Hospital, Hershey, PA, United States

Brookie M. Best,     University of California, Skaggs School of Pharmacy and Pharmaceutical Sciences, San Diego, CA, United States

Carolyn Bottone-Post,     University of Northern Colorado, Greeley, CO, United States

Shannon M. Clark,     Department of ObGyn, Division of Maternal-Fetal Medicine, University of Texas Medical Branch-Galveston, Galveston, TX, United States

Maged M. Costantine,     Ohio State University, Columbus, OH, United States

Kala R. Crobarger,     Tanner Health System School of Nursing, University of West Georgia, Carrollton, GA, United States

Cara D. Dolin,     Department of Obstetrics and Gynecology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, United States

Jeffrey W. Fisher

Division of Biochemical Toxicology, National Center for Toxicological Research, Food and Drug Administration, Jefferson, AR, United States

ScitoVation, LLC, Durham, NC, United States

David A. Flockhart,     Indiana University School of Medicine, Indianapolis, IN, United States

Jeffrey S. Fouche-Camargo,     School of Health Sciences, Georgia Gwinnett College, Lawrenceville, GA, United States

William D. Fraser,     Department of Obstetrics and Gynecology, Université de Sherbrooke, Sherbrooke, QC, Canada

Jennifer L. Grasch,     Indiana University School of Medicine, Indianapolis, IN, United States

David M. Haas,     Indiana University School of Medicine, Indianapolis, IN, United States

Lee-Ann Halbert,     University of South Carolina Beaufort, Bluffton, SC, United States

Isabelle Hardy,     Department of Obstetrics and Gynecology, Université de Sherbrooke, Sherbrooke, QC, Canada

Carmen V. Harrison,     School of Nursing, Simmons University, Boston, MA, United States

Mary F. Hebert,     Departments of Pharmacy and Obstetrics & Gynecology, University of Washington, Seattle, WA, United States

Henry M. Hess,     Emeritus Professor of Obstetrics and Gynecology, University of Rochester School of Medicine, Rochester, NY

Janelle Komorowski,     Department of Nurse-midwifery, Frontier Nursing University, Versailles, KY, United States

Miao Li,     Division of Biochemical Toxicology, National Center for Toxicological Research, Food and Drug Administration, Jefferson, AR, United States

Megan Lutz,     University of Wisconsin School of Medicine and Public Health, Department of Medicine, Madison, WI, United States

Donald R. Mattison

University of South Carolina, Arnold School of Public Health, Columbia, SC, United States

Risk Sciences International, Ottawa, ON, Canada

School of Epidemiology and Public Health, University of Ottawa, Ottawa, ON, Canada

Darshan Mehta,     Division of Biochemical Toxicology, National Center for Toxicological Research, Food and Drug Administration, Jefferson, AR, United States

Jeremiah D. Momper,     University of California, Skaggs School of Pharmacy and Pharmaceutical Sciences, San Diego, CA, United States

Luis A. Monsivais,     Department of ObGyn, Division of Maternal-Fetal Medicine, University of Texas Medical Branch-Galveston, Galveston, TX, United States

Jennifer A. Namazy,     Scripps Clinic, San Diego, CA, United States

Luis Pacheco,     University of Texas Medical Branch, Galveston, TX, United States

Maria P. Ramirez-Cruz,     Department of Obstetrics and Gynecology, University of New Mexico School of Medicine, Albuquerque, NM, United States

William F. Rayburn,     Obstetrics and Gynecology, University of New Mexico School of Medicine, Albuquerque, NM, United States

Michael D. Reed,     Professor Emeritus of Pediatrics, Department of Pediatrics, School of Medicine, Case Western Reserve University, Cleveland, United States

Sharon E. Robertson,     Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN, United States

Erik Rytting,     Department of Obstetrics & Gynecology, University of Texas Medical Branch, Galveston, TX, United States

Rachel Ryu,     Department of Pharmacy, University of Washington, Seattle, WA, United States

Sumona Saha,     University of Wisconsin School of Medicine and Public Health, Department of Medicine, Madison, WI, United States

Michael Schatz,     Kaiser Permanente, San Diego, CA, United States

Jeanne M. Schilder,     Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN, United States

Steven A. Seifert

Department of Emergency Medicine, University of New Mexico School of Medicine, Albuquerque, NM, United States

Medical, New Mexico Poison and Drug Information Center, Clinical Toxicology, Albuquerque, NM, United States

Harry Soljak,     Frimley Park Hospital, Surrey, United Kingdom

Kimberly K. Trout,     Department of Family and Community Health, University of Pennsylvania, School of Nursing, Philadelphia, PA, United States

Jennifer Waltz,     School of Medicine, University of Texas Medical Branch, Galveston, TX, United States

Xiaoxia Yang,     Division of Infectious Disease Pharmacology, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United States

Andrew Youmans,     University of Michigan School of Nursing, MI, United States

Acknowledgment

Although each chapter author is acknowledged by having his/her/their name associated with the chapters, the timing of this book necessitates an additional thank you to each author. Research and writing for this book started before anyone was aware that a pandemic would change the world and raise concerns about therapeutic interventions during pregnancy.

As the authors became involved with the challenges of working in healthcare, a world turned upside down—long hours in uncertain times, isolation, trying to understand and predict the impact of coronavirus on pregnancy, shortages of equipment and staff, and countless other trials of the times—the authors continued their research and writing for these chapters.

Under normal times, completing a book chapter takes dedication and commitment, and during pandemic, it goes beyond measure. For this, we are appreciative.

Chapter 1: Introduction

Donald R. Mattison ¹ , ² , ³ , and Lee-Ann Halbert ⁴       ¹ University of South Carolina, Arnold School of Public Health, Columbia, SC, United States      ² Risk Sciences International, Ottawa, ON, Canada      ³ School of Epidemiology and Public Health, University of Ottawa, Ottawa, ON, Canada      ⁴ University of South Carolina Beaufort, Bluffton, SC, United States

Abstract

Over the past decade, attention to clinical therapeutics during pregnancy has grown substantially. Despite these advances, there is increasing concern that discovery and development of new drugs for these important populations is lagging. This edition addresses the growth in knowledge of medications during pregnancy.

Keywords

Pharmacology; Therapeutics

Over the past decade, attention to clinical therapeutics during pregnancy has grown substantially [1–3]. Examples of these advances are summarized in many different chapters in this edition Despite these advances, there is increasing concern that discovery and development of new drugs for these important populations is lagging [4–9]. For example, while there are many advances in treating depression and mood disorders, we are still struggling with questions concerning whether these diseases should be treated during pregnancy [Chapter 14]. Clearly, select populations are excluded from drug development, especially women and children [5,10–12]. One consequence of this failure to develop drugs for maternal and child health is to dissociate therapeutic opportunities for women and children from the drugs and treatments currently available. This distancing of women and children from drug development and therapeutic knowledge produces a host of clinical challenges for the concerned practitioner. In the absence of sufficient therapeutic knowledge, appropriate dosing is not known [[13–17], see Chapter 26]. Without the understanding of appropriate dosing, the clinician does not know if the dose recommended on the product label will produce the desired drug concentration at the site of action, or if the concentration produced will be above or below the needed concentration, producing toxicity or inadequate response, respectively. Similarly, without thoughtful therapeutic development in women and children, it is not known if differences in pharmacodynamics will produce different treatment goals and needs for monitoring effectiveness and safety [14,18–21].

A consequence of the failure to develop drugs for use in pregnancy is that most drugs are not tested for use during pregnancy [4,22]; consequently, labeling, which may include extensive information about fetal safety [10,23], includes nothing about dosing, appropriate treatment, efficacy, or maternal safety [3–5,10,11,22,23]. Yet, these are concerns of health care providers considering treatment during pregnancy. Therefore, the practitioner treats the pregnant woman with the same dose recommended for use in adults (typically men) or may decide not to treat the disease at all. However, is the choice of not treating a woman during pregnancy better than dealing with the challenges which accompany treatment? Clearly, treatment of depression poses risks for both mother and fetus, as does stopping treatment [24–26]. This is also the case with respect to influenza during pregnancy [13,27,28]. All combined, the state of therapeutics during pregnancy underscores the continued tension that exists between maternal–placental–fetal health and maternal quality of life during pregnancy and the lack of critical study of gestational therapeutics. This book hopes to address many of these imbalances.

A second and equally important aspect of this edition is the focus on collaborative practice. Physicians and their students, nurses (advanced practice and generalist) and their students, and physician assistants (and their students) are all involved in the care of the pregnant woman. The American College of Nurse-Midwives and the American College of Obstetricians and Gynecologists formalized support of the collaborative practice between midwives and physicians in statements dating back to 2011 [29]. The American College of Obstetricians and Gynecologists 2016 Executive Summary on collaborative practice extends interdisciplinary practice support to include not only physicians and nurses but also pharmacists and physician assistants [30]. This edition reflects this goal of collaborative practice, with an editorial team comprised of a physician and certified nurse-midwife.

Medical and health care providers caring for women during pregnancy have many excellent resources describing the safety of medications for the fetus [10,23]. However, none of these references provide information on appropriate dosing as well as the efficacy of the various medications used during pregnancy for maternal/placental therapeutics. We are all familiar with the potential/actual costs, financial and psychosocial, of having treatments which produce developmental toxicity; however, how many of us ever think critically about the costs of having inadequate therapeutic options to treat the major diseases of pregnancy, growth restriction, pregnancy loss, and preeclampsia/eclampsia? Where we have effective treatments for maternal diseases, infection, depression, diabetes, and hypertension, we are recognizing that continuation of treatment during pregnancy carries benefit for mother, placenta, and baby. In the end what is important for the mother, baby, and family is the appropriate balancing of benefit and risk—as indeed is the important balancing for all clinical therapeutics [11,12]. This book provides medical and health professionals involved in the care of pregnant women with contemporary information on clinical pharmacology for pregnancy. It covers an overview of the impact of pregnancy on drug disposition, summarizing current research about the changes of pharmacokinetics and pharmacodynamics during pregnancy. This is followed by specific sections on the treatment, dosing, and clinical effectiveness of medications during pregnancy, providing health care providers with an essential reference on how to appropriately treat women with medications during pregnancy. At one level, the question is simple: how to treat, how to monitor for benefit and risk, or how to know if treatment is successful? This book was developed to explore that question for women during pregnancy. The book is meant to be a guide to clinicians who care for women during pregnancy. We hope the busy clinician and student of obstetrics will find this a useful guide.

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Chapter 2: Physiologic changes during pregnancy

Mahmoud Abdelwahab ¹ , Maged M. Costantine ¹ , and Luis Pacheco ²       ¹ Ohio State University, Columbus, OH, United States      ² University of Texas Medical Branch, Galveston, TX, United States

Abstract

Human pregnancy is characterized by profound anatomic and physiologic changes that affect virtually all systems and organs in the body. Many of these changes begin in early gestation. Understanding of the various physiologic adaptations in pregnancy is vital to the clinician and the pharmacologist as many of these alterations will have a significant impact on pharmacokinetics and pharmacodynamics of different therapeutic agents. A typical example involves the increase in glomerular filtration rate during pregnancy leading to increased clearance of heparins, thus requiring the use of higher doses during pregnancy. This chapter discusses the most relevant physiologic changes that occur during human gestation.

Keywords

Physiologic changes during pregnancy; Summary of cardiovascular changes during pregnancy; Summary of hematologic changes in pregnancy; Summary of renal changes in pregnancy; Summary of respiratory changes in pregnancy

2.1. Physiologic changes during pregnancy

Human pregnancy is characterized by profound anatomic and physiologic changes that affect virtually all systems and organs in the body. Many of these changes begin in early gestation. Understanding of the various physiologic adaptations in pregnancy is vital to the clinician and the pharmacologist as many of these alterations will have a significant impact on pharmacokinetics and pharmacodynamics of different therapeutic agents. A typical example involves the increase in glomerular filtration rate (GFR) during pregnancy leading to increased clearance of heparins, thus requiring the use of higher doses during pregnancy. This chapter discusses the most relevant physiologic changes that occur during human gestation.

2.2. Cardiovascular system

Profound changes in the cardiovascular system characterize human pregnancy and are likely to affect the pharmacokinetics of different pharmaceutical agents. Table 2.1 summarizes the main cardiovascular changes during pregnancy.

Cardiac output (CO) increases by 30%–50% during pregnancy, secondary to an increase in both heart rate and stroke volume; the increase in CO in early pregnancy is thought to be mainly mediated by an increase in stroke volume, whereas later in gestation the increase is attributed to elevated heart rate [29]. Most of the increase in CO occurs early in pregnancy such that by the end of the first trimester 75% of the increase has already occurred. In addition, CO is expected to be 15% more in a twin pregnancy compared to a singleton [30]. CO plateau at 28–32 weeks and afterward remains relatively stable until delivery. At 32 weeks, CO increased to about 7.21 l/min vs 4.88 l/min prior to conception [43].

As CO increases, pregnant women experience a significant decrease in both systemic and pulmonary vascular resistances [1]. Systemic vascular resistance decreases in early pregnancy, reaching a nadir (5–10   mm below baseline) at 14–24 weeks. Subsequently, vascular resistance starts rising, progressively approaching the prepregnancy value at term [1]. Blood pressure tends to fall toward the end of the first trimester and then rises again in the third trimester to prepregnancy levels [2]. Physiologic hypotension may be present between weeks 14 and 24, likely due to the decrease in the systemic vascular resistance observed during pregnancy.

Table 2.1

Maternal blood volume increases in pregnancy by 40%–50%, reaching maximum values at 32 weeks [3]. Despite the increase in blood volume, central filling pressures like the central venous and pulmonary occlusion pressures remain unchanged secondary to an increase in compliance of the right and left ventricles [4]. The precise etiology of the increase in blood volume is not clearly understood. However, increased mineralocorticoid activity with water and sodium retention does occur [5]. Production of arginine vasopressin (resulting in increased water absorption in the distal nephron) is also increased during pregnancy and thought to further contribute to hypervolemia. Secondary hemodilutional anemia and a decrease in serum colloid osmotic pressure (due to a drop in albumin levels) are observed.

Finally, left ventricular wall thickness and left ventricular mass increase by 28% and 52% above pregnancy values [31]. Despite the multiple changes in cardiovascular parameters, left ventricular ejection fraction does not appear to change during pregnancy [32].

The latter physiological changes could have theoretical implications on the pharmacokinetics of drugs in pregnancy. The increase in blood volume, increased capillary hydrostatic pressure, and decrease in albumin concentrations would be expected to increase significantly the volume of distribution of hydrophilic substances. In addition, highly protein-bound compounds may display higher free levels due to decreased protein binding availability.

2.3. Respiratory system

The respiratory system undergoes both mechanical and functional changes during pregnancy. Table 2.2 summarizes these changes.

The sharp increase in estrogen concentrations during pregnancy leads to hypervascularity and edema of the upper respiratory mucosa [6]. These changes result in an increased prevalence of rhinitis and epistaxis in pregnant individuals. Theoretically, inhaled medications such as steroids used in the treatment of asthma could be more readily absorbed in the pregnant patient. Despite this theoretical concern, however, there is no evidence of increased toxicity with the use of these agents during pregnancy.

Progesterone acts centrally to increase the sensitivity of respiratory center to carbon dioxide [33]. This drives an increase in minute ventilation by 30%–50% secondary to an increase in tidal volume. As a result of in the increase in ventilation, there in an increase in the arterial partial pressure of oxygen to 101–105   mmHg and a diminished arterial partial pressure of carbon dioxide (PaCO2), with normal values of PaCO2 of the range 28–31   mmHg during pregnancy. This decrement allows for a gradient to exist between the PaCO2 of the fetus and the mother so that carbon dioxide can diffuse freely from the fetus into the mother through the placenta and then be eliminated through the maternal lungs. Of note, maternal respiratory rate remains unchanged during pregnancy [7].

The normal maternal arterial blood pH in pregnancy is between 7.4 and 7.45, consistent with a mild respiratory alkalosis. The latter is partially corrected by an increased renal excretion of bicarbonate to allow for a normal serum bicarbonate between 18 and 21 meq/L during gestation [8]. As pregnancy progresses, the increased intraabdominal pressure (likely secondary to uterine enlargement, bowel dilation, and third-spacing of fluids into the peritoneal cavity secondary to decreased colloid osmotic pressure) displaces the diaphragm upward by 4–5   cm leading to alveolar collapse in the bases of the lungs. Bibasilar atelectasis results in a 10%–20% decrease in the functional residual capacity and increased right to left vascular shunt [9,10]. The decrease in expiratory reserve volume is coupled with an increase in inspiratory reserve volume. As a result, no change is seen in the vital capacity [9].

Table 2.2

An increase in the transverse diameter of the rib cage occurs to accommodate the upward shit of the diaphragm due to the enlarging gravid uterus and upward displacement of intraabdominal contents, in order to allow space for the lung and preserve total lung capacity. The average subcostal angle of the ribs at the xiphoidal level increases from 68.5 degrees at the beginning of pregnancy to 103.5 degrees at term [34].

Changes in respiratory physiology may impact the pharmacokinetics of certain drugs. Topical drugs administered into the nasopharynx and upper airway could be more readily available to the circulation as local vascularity and permeability of the mucosa are increased. As discussed earlier, the latter assumption is theoretical, and no evidence of increased toxicity from inhaled or topical agents during pregnancy has been demonstrated.

2.4. Renal system

Numerous physiologic changes occur in the renal system during pregnancy. These changes are summarized in Table 2.3.

The relaxing effect of progesterone on smooth muscle and mechanical effects of the enlarging uterus leads to dilation of the urinary tract with subsequent urinary stasis. It is estimated that the dilated collecting system seen in pregnancy can hold 200–300   mL of urine [42]. Hydronephrosis affects 43%–100% of pregnant women and is more prevalent with advancing gestation. However, studies have shown that exogenous administration of progesterone in nonpregnant women fails to cause hydronephrosis. The changes observed in the urinary tract predispose pregnant women to infectious complications, most notably urinary tract infections [35].

The 50% increase in renal blood flow during early pregnancy leads to a parallel increase in the GFR of approximately 50%. This massive elevation in GFR is present as early as 14 weeks of pregnancy [11]. As a direct consequence of increased GFR, creatinine clearance increases and serum values of creatinine and blood urea nitrogen decrease. In fact, a serum creatinine above 0.8   mg/dL may be indicative of underlying renal dysfunction during pregnancy.

Besides detoxification, one of the most important functions of the kidney is to regulate sodium and water metabolism. Progesterone favors natriuresis, while estrogen favors sodium retention [12]. Although the increase in GFR leads to more sodium wasting, it is counterbalanced by an elevated level of aldosterone which reabsorbs sodium in the distal nephron [12]. Relaxin may also play a role in water retention since it stimulates ADH production in animal studies and is normally elevated in pregnancy [36]. The net effect during pregnancy is a state of avid water and sodium retention leading to a significant increase in total body water with up to 6   L of fluid gained in the extracellular space and 2   L in the intracellular space. This dilutional effect leads to a mild decrease in both serum sodium (concentration of 135–138 meq/L) and serum osmolarity (normal value in pregnancy ∼280 mOsm/L) [13]. In comparison, in the nonpregnant state, normal serum osmolarity is 286–289 mOsm/L with a concomitant normal serum sodium concentration of 135–145 meq/L.

Table 2.3

Changes in renal physiology have profound repercussions on drug pharmacokinetics. Agents cleared renally are expected to have shorter half-lives, and fluid retention is expected to increase the volume of distribution of hydrophilic agents. A typical example involves lithium. Lithium is mainly cleared by the kidney, and during the third trimester of pregnancy, clearance is doubled compared to the nonpregnant state [14]. However, not all renally cleared medications undergo such dramatic increases in excretion rates. For example, digoxin clearance is only increased by 30% during the third trimester of pregnancy.

2.5. Gastrointestinal system

The gastrointestinal tract is significantly affected during pregnancy secondary to progesterone-mediated inhibition of smooth muscle motility [15]. Table 2.4 summarizes these changes.

Gastric emptying and small bowel transit time are considerably prolonged during pregnancy. The increase in intragastric pressure (secondary to delayed emptying and external compression from the gravid uterus) together with a decrease in resting muscle tone of the lower esophageal sphincter favors gastroesophageal regurgitation. Of note, studies have shown that gastric acid secretion is not affected during pregnancy [16]. However, overall gastric acidity might be increased due to increased serum levels of gastrin [37]. Finally, constipation commonly affects pregnant women and is multifactorial in nature. The combination of increased bowel transit time, mechanical obstruction by gravid uterus, decreased maternal activity, decreased motilin, increased colonic water and sodium absorption, and routine iron supplementation all contribute to constipation in pregnancy [38].

Conflicting data exist regarding liver blood flow during pregnancy. Recently, with the use of Doppler ultrasonography, investigators found that blood flow in the hepatic artery does not change during pregnancy, but portal venous return to the liver was increased [17].

Most of the liver function tests are not altered. Specifically, serum transaminases, bilirubin, lactate dehydrogenase, and gamma-glutamyl transferase are all unaffected by pregnancy. Serum alkaline phosphatase is elevated secondary to production from the placenta and levels two to four times higher than that of nonpregnant individuals may be seen [18]. Other liver products that are normally elevated include serum cholesterol, fibrinogen, and most of the clotting factors, ceruloplasmin, thyroid-binding globulin, and cortisol-binding globulin (CBG). The observed increase in all of these proteins is likely estrogen mediated [18]. Progesterone, on the other hand, decreases gallbladder motility rendering the pregnant woman at increased risk for cholelithiasis.

Table 2.4

These observed physiologic changes can clearly affect pharmacokinetics of orally administered agents, with delayed absorption and onset of action resulting. For example, the pharmacokinetics of antimalarial agents undergo significant changes at the gastrointestinal level during pregnancy that could decrease their therapeutic efficacy [19].

2.6. Hematologic and coagulation systems

Pregnancy is associated with an increased white cell count, mainly consisting of an increase in neutrophils. On the contrary, lymphocyte count decreases during the first and second trimesters with return to baseline in the third trimester. The rise in white cell count is thought to be related to increased bone marrow granulopoiesis and may make a diagnosis of infection difficult at times. However, it is usually not associated with significant elevations in immature forms like bands. There is also an absolute monocytosis and increase in the monocyte-to-lymphocyte ratio, which is thought to aid in preventing fetal allograft rejection by infiltrating decidual tissue at 7–20 weeks of gestation [39].

An increase in red cell mass by 30% during pregnancy is likely secondary to an increase in renal erythropoietin production. Placental lactogen may also enhance the effect of erythropoietin on erythropoiesis [39]. This occurs simultaneously with a much higher (around 45%) increase in plasma volume leading to what is referred to as physiologic anemia of pregnancy which peaks early in the third trimester (30–32 weeks) [20,21]. This hemodilution is thought to confer maternal and fetal survival advantage as the patient will lose more dilute blood during delivery. In addition, the decreased blood viscosity improves uterine perfusion, while the increase in red cell mass serves to optimize oxygen transport to the fetus. As an example, patients with preeclampsia, despite having fluid retention, suffer from reduced intravascular volume (secondary to diffuse endothelial injury and resultant third-spacing), which makes them less tolerant to peripartum blood loss [22,23].

Pregnancy is also associated with changes in the coagulation and fibrinolytic pathways that favor a hypercoagulable state. Plasma levels of fibrinogen, clotting factors (VII, VIII, IX, X, and XII), and von Willebrand factor increase during pregnancy leading to a hypercoagulable state. Factor XI decreases and levels of prothrombin and factor V remain the same. Protein C is usually unchanged, but protein S is decreased in pregnancy. There is no change in the levels of antithrombin III. The fibrinolytic system is suppressed during pregnancy as a result of increased levels of plasminogen activator inhibitor (PAI-1) and reduced plasminogen activator levels. Platelet function remains normal in pregnancy. Routine coagulation screen panel will show values around normal.

Table 2.5

Table 2.6

This hypercoagulable state predisposes the pregnant patient to a higher risk of thromboembolism. However, it is also thought to offer survival advantage in minimizing blood loss after delivery [24]. Tables 2.5 and 2.6 summarize some of the most relevant changes discussed previously.

2.7. Endocrine system

Pregnancy is defined as a diabetogenic state. Increased insulin resistance is due to elevated levels of human placental lactogen, progesterone, estrogen, and cortisol. Carbohydrate intolerance that occurs only during pregnancy is known as gestational diabetes. Most gestational diabetes patients are managed solely with a modified diet. Approximately 10% of patients will require pharmacological treatment, mainly in the form of insulin, glyburide, or even metformin. Available literature suggests that glyburide and metformin may be as effective as insulin for the treatment of gestational diabetes.

Pregnancy is also associated with higher glucose levels following a carbohydrate load. In contrast, maternal fasting is characterized by accelerated starvation, increased lipolysis, and faster depletion of liver glycogen storage [25]. This is thought to be related to the increased insulin resistance state of pregnancy induced by placental hormones such as human placental lactogen. Pancreatic β-cells undergo hyperplasia during pregnancy resulting in increased insulin production leading to fasting hypoglycemia and postprandial hyperglycemia. All of these changes facilitate placental glucose transfer, as the fetus is primarily dependent on maternal glucose for its fuel requirements [26].

Leptin is a hormone primarily secreted by adipose tissues. Maternal serum levels of leptin increase during pregnancy and peak during the second trimester. Leptin in pregnancy is also produced by the placenta.

When considering changes in certain endocrine glands during pregnancy, the thyroid gland faces a particular challenge. Due to the hyperestrogenic milieu, thyroid-binding globulin (the major thyroid hormone (TH)–binding protein in serum) increases by almost 150% from a prepregnancy concentration of 15–16   mg/L to 30–40   mg/L in mid-gestation. This forces the thyroid gland to increase its production of THs to keep their free fraction in the serum constant [27,28]. The increase in THs production occurs mostly in the first half of gestation and plateaus around 20 weeks until term.

Other factors that influence THs in pregnancy include a minor thyrotropic action of human chorionic gonadotropin hormone (hCG), higher maternal metabolic rate as pregnancy progresses, in addition to increase in transplacental transport of TH to the fetus early in pregnancy, inactivity of placental type III monodeiodinase (which converts T4 to reverse T3), and in maternal renal iodine excretion.

Although the free fraction of T4 and T3 concentrations declines somewhat during pregnancy (but remains within normal values), these patients remain clinically euthyroid [27,28]. Thyroid-stimulating hormone (TSH) decreases during the first half of pregnancy secondary to a negative feedback from peripheral THs secondary to thyroid gland stimulation by hCG. During the first half of pregnancy, the upper limit of normal value of TSH is 2.5 mIU/L (as compared to 5 mIU/L in the nonpregnant state).

Serum cortisol levels are increased during pregnancy. Most of this elevation is secondary to increased synthesis of CBG by the liver. Free cortisol levels are also increased by 30% during gestation.

Serum parathyroid hormone and 1, 25 dihydroxy vitamin D increase to favor an environment of calcium accumulation in the fetus. The placenta forms a calcium pump in which a gradient of calcium and phosphorus is established which favors the fetus. The total level of calcium decreases, but ionized calcium remains the same [41].

Table 2.7

Finally, the anterior pituitary enlarges 2–3-fold in pregnancy primarily due to hyperplasia and hypertrophy of lactotrophs, which causes increase in serum prolactin as pregnancy progress. The increase in pituitary size is thought to cause hypophyseal artery compression and predisposes the pituitary to infarction in cases of hypotension secondary to postpartum (i.e., Sheehan syndrome) [40]. The endocrine changes during pregnancy are summarized in Table 2.7.

2.8. Summary

Pregnancy is associated with profound changes in human physiology. Virtually every organ in the body is affected and the clinical consequences of these changes are significant. Unfortunately, our knowledge of how these changes affect the pharmacokinetics and pharmacodynamics of therapeutic agents is still very limited. Future research involving pharmacokinetics of specific agents during pregnancy is desperately needed.

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Chapter 3: Impact of pregnancy on maternal pharmacokinetics of medications

Rachel Ryu ¹ , and Mary F. Hebert ²       ¹ Department of Pharmacy, University of Washington, Seattle, WA, United States      ² Departments of Pharmacy and Obstetrics & Gynecology, University of Washington, Seattle, WA, United States

Abstract

The efficacy and safety of medications during pregnancy is highly variable and often different than in the nonpregnant population. In part, this variability can be explained by changes in pharmacokinetics. This chapter discusses many of the physiologic changes that occur during pregnancy and their impact on medication pharmacokinetics. Changes in volume of distribution, protein binding, blood flow, renal filtration, drug metabolizing enzymes (e.g., CYP3A, CYP2D6, CYP2C9, uridine diphosphate glucuronyltransferase, CYP1A2, and CYP2C19) and transporters (e.g., p-glycoprotein) are discussed. Taking into account and adjusting for the pharmacokinetic changes that occur during pregnancy will help to minimize the variability in patient response. This approach is particularly important for medications with narrow therapeutic ranges. Although critically important, pharmacokinetic changes should be taken as only one component in determining optimum medication selection and dosage.

Keywords

AUC; Bioavailability; Blood flow; Clearance; Enzymes; Half-life; Metabolism; Pharmacokinetics; Pregnancy; Protein binding; Transporters; Volume

3.1. Introduction

Variability in drug efficacy and safety is multifactorial. Both the pharmacokinetics (how the body handles the drug) and the pharmacodynamics (how the body responds to the drug) play significant roles in drug efficacy and safety. This chapter will discuss the effects of pregnancy on medication pharmacokinetics.

The physiologic changes that occur during pregnancy result in marked changes in the pharmacokinetics for some medications. Whether or not the physiologic changes will result in clinically significant pharmacokinetic changes for an individual medication depends on many factors. The discussion of these factors will be the focus of this chapter. Generally speaking, pharmacokinetic changes are most important clinically for medications with narrow therapeutic ranges. The therapeutic range includes all the concentrations above the minimum effective concentration, but less than the maximum tolerated concentration (Fig. 3.1A and B). Medications such as cyclosporine, tacrolimus, lithium, warfarin, carbamazepine, valproic acid, phenytoin, digoxin, vancomycin, and the aminoglycosides are examples of narrow therapeutic range drugs. These are medications for which the concentrations needed for therapeutic benefit are very close to those that result in toxicity. For these agents, small changes in drug concentrations can lead to inefficacy if the concentrations decrease or intolerable toxicity if the concentrations increase. Typically, when drug interactions, disease states or conditions alter the concentration-time profile for a medication, if no changes have occurred in the pharmacodynamics, the patient's dosage is adjusted to keep the concentrations similar to those prior to the altered state or similar to those for the population in which the drug has been approved. This dosage adjustment is done to maintain concentrations within the therapeutic range. For narrow therapeutic range medications, even a 25% change in drug concentration can be considered clinically significant. In contrast, for most medications, which have wide therapeutic ranges, small changes in pharmacokinetics have little to no clinical effect. However, given the magnitude of some of the pharmacokinetic changes that occur during pregnancy in which there can be 2–6-fold changes in drug exposure (Fig. 3.2A), even medications that have wide therapeutic ranges can be clinically affected.

Figure 3.1 (A) is a stereotypic oral concentration-time curve. The upper horizontal solid line represents the maximum tolerated concentration, and the lower horizontal solid line represents the minimum effective concentration. The therapeutic range for this drug, represented by the vertical double-sided arrow, includes all the concentrations between the minimum effective concentration and the maximum tolerated concentration. (B) illustrates a stereotypic oral concentration-time curve with the shaded area depicting the area under the concentration-time curve, which is a measure of total drug exposure.

3.2. Effects of pregnancy on pharmacokinetic parameters

A change in pharmacokinetics for a medication can result in the need to change dosage. As described above, altered concentrations during pregnancy can result in the need for higher (Fig. 3.2A) or lower (Fig. 3.2B) drug dosage to maintain concentrations within the therapeutic range. The changes in medication pharmacokinetics during pregnancy in some cases are so great that altered medication selection should be considered. For example, oral metoprolol concentrations are 2–4-fold lower during pregnancy than in the nonpregnant state [1,2]. Given the magnitude and variability in metoprolol concentrations during pregnancy, for those patients that require a beta blocker (e.g., cardiac rate control), selecting another agent such as atenolol, which is renally eliminated, should be considered. Even with the changes in renal function that are expected during pregnancy, atenolol will give much more consistent and