2013 millers review

MILLER’S
ANESTHESIA
REVIEW


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MILLER’S
ANESTHESIA
REVIEW
SECOND EDITION
Lorraine M. Sdrales,

MD

Attending Anesthesiologist
Cedars-Sinai Medical Center
Los Angeles, California

Ronald D. Miller,

MD

Professor of Anesthesia and Perioperative Care
Department of Anesthesia and Perioperative Care
University of California, San Francisco, School of Medicine
San Francisco, California

1600 John F. Kennedy Blvd.
Ste 1800
Philadelphia, PA 19103-2899

MILLER’S ANESTHESIA REVIEW

978-1-4377-2793-7

Copyright # 2013 by Saunders, an imprint of Elsevier Inc.
Copyright # 2001 by Churchill Livingstone, an imprint of Elsevier Inc.
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Notices
Knowledge and best practice in this field are constantly changing. As new research and experience
broaden our understanding, changes in research methods, professional practices, or medical treatment
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Practitioners and researchers must always rely on their own experience and knowledge in evaluating
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Library of Congress Cataloging-in-Publication Data
Sdrales, Lorraine M.
Miller’s anesthesia review / Lorraine M. Sdrales, Ronald D. Miller. – 2nd ed.
p. ; cm.
Rev. ed. of: Anesthesia review : a study guide to Anesthesia, fifth edition and Basics of anesthesia, fourth
edition / Lorraine M. Sdrales, Ronald D. Miller ; consulting editor, Robert K. Stoelting. c2001.
Includes bibliographical references and index.
ISBN 978-1-4377-2793-7 (pbk. : alk. paper)
I. Miller, Ronald D., 1939- II. Sdrales, Lorraine M. Anesthesia review. III. Title.
[DNLM: 1. Anesthesia–Examination Questions. WO 218.2]
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2012009621
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Printed in United States of America
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CONTRIBUTORS

Meredith C.B. Adams, MD
Assistant Professor, Departments of Anesthesiology,
Psychiatry, and Neurology, University of Florida;
Section Chief, Pain Medicine, North Florida/South
Georgia Veterans Health System, Gainesville,
Florida
Dean B. Andropoulos, MD, MHCM
Chief of Anesthesiology, Department of Pediatric
Anesthesiology, Texas Children’s Hospital; Professor,
Department of Anesthesiology and Pediatrics, Baylor
College of Medicine, Houston, Texas
Sheila R. Barnett, MD
Associate Professor of Anesthesiology, Harvard Medical
School, Beth Israel Deaconess Medical Center, Boston,
Massachusetts
Luca M. Bigatello, MD
Director, Surgical Critical Care, Department of

Anesthesiology and Pain Medicine, St. Elizabeth’s
Medical Center, Boston, Massachusetts
Thomas J.J. Blanck, MD, PhD
Professor and Chairman, Department of Anesthesiology,
Professor of Physiology and Neuroscience, New York
University Langone Medical Center, New York,
New York
Lundy Campbell, MD
Associate Clinical Professor, Department of Anesthesia
and Perioperative Care, University of California,
San Francisco, School of Medicine, San Francisco,
California
Lydia Cassorla, MD
Professor, Department of Anesthesia and Perioperative
Care, University of California, San Francisco, School of
Medicine, San Francisco, California
Daniel Cole, MD
Professor of Anesthesiology, College of Medicine Mayo
Clinic; Chair, Department of Anesthesiology, Mayo Clinic
Arizona, Phoenix, Arizona

Adam Collins, MD
Associate Professor, Department of Anesthesia and
Perioperative Care, University of California,
San Francisco, School of Medicine, San Francisco,
California
Anil de Silva, MD
Professor, Department of Anesthesia and Perioperative
Care, University of California, San Francisco, School
of Medicine, San Francisco, California

Ken Drasner, MD
Professor of Clinical Anesthesia, Department of
Anesthesia and Perioperative Care, University of
California, San Francisco, School of Medicine,
San Francisco, California
Helge Eilers, MD
Associate Professor, Department of Anesthesia and
Perioperative Care, University of California,
San Francisco, School of Medicine, San Francisco,
California
John Feiner, MD
Professor, Department of Anesthesia and Perioperative
Care, University of California, San Francisco, School of
Medicine, San Francisco, California
Alana Flexman, MD
Clinical Assistant Professor, Department of Anesthesia
and Perioperative Care, University of California,
San Francisco, School of Medicine, San Francisco,
California
Charles J. Fox, MD
Vice Chair for Academics, Department of Anesthesiology,
Tulane University Medical Center, New Orleans,
Louisiana
William R. Furman, MD
Professor of Anesthesiology and Surgery, Vice Chair for
Clinical Affairs, Department of Anesthesiology,
Vanderbilt University School of Medicine; Executive
Medical Director, Perioperative Services, Vanderbilt
University Hospital, Nashville, Tennessee

v


Contributors

Steven Gayer, MD, MBA
Professor, Department of Anesthesiology and
Ophthalmology, The Bascom Palmer Eye Institute,
University of Miami School of Medicine, Miami, Florida
David B. Glick, MD, MBA
Associate Professor, Department of Anesthesia and
Critical Care, University of Chicago; Medical Director,
Pre- and Post-Anesthesia Care Units, University of
Chicago, Chicago, Illinois
Erin A. Gottlieb, MD
Assistant Professor, Department of Pediatrics and
Anesthesiology, Baylor College of Medicine; Attending
Anesthesiologist, Division of Pediatric Cardiovascular
Anesthesiology, Texas Children’s Hospital, Houston, Texas

Eric Y. Lin, MD
Assistant Professor, Department of Anesthesia and
Perioperative Care, University of California,
San Francisco, School of Medicine, San Francisco,
California
Lawrence Litt, PhD, MD
Emeritus Professor, Departments of Anesthesia and
Perioperative Care, and Radiology, University of
California, San Francisco, School of Medicine,
San Francisco, California

Henry Liu, MD
Associate Professor of Anesthesiology, Director of
Cardiothoracic and Vascular Anesthesia, Tulane
University Medical Center, New Orleans, Louisiana

Tula Gourdin, MBA
Analyst, Department of Anesthesia and Perioperative
Care, University of California, San Francisco, School
of Medicine, San Francisco, California

Linda Liu, MD
Professor, Department of Anesthesia and Perioperative
Care, University of California, San Francisco, School of
Medicine, San Francisco, California

Michael A. Gropper, MD, PhD
Professor and Executive Vice Chairman, Department
of Anesthesia and Perioperative Care, University of
California, San Francisco; Director, Critical Care
Medicine, University of California, San Francisco Medical
Center, San Francisco, California

Jennifer Lucero, MD
Assistant Professor, Department of Anesthesia and
Perioperative Care, University of California, San Francisco,
School of Medicine, San Francisco, California

Jennifer E. Hofer, MD
Assistant Professor, Department of Anesthesia and
Critical Care, The University of Chicago Medical

Center, Chicago, Illinois
Robert W. Hurley, MD, PhD
Associate Professor, Departments of Anesthesiology,
Neurology, Orthopaedics and Rehabilitation, and
Psychiatry, University of Florida; Chief of Pain Medicine,
College of Medicine, University of Florida; Medical
Director, University of Florida Pain and Spine Center,
Gainesville, Florida
Steve Hyman, MD, MM
Associate Professor of Clinical Anesthesiology,
Department of Anesthesiology, Vanderbilt University
School of Medicine, Nashville, Tennessee
Alan David Kaye, MD, PhD
Professor and Chairman, Department of Anesthesiology,
Professor, Department of Pharmacology, Louisiana State
University School of Medicine-New Orleans, New
Orleans, Louisiana
Jae-Woo Lee, MD
Associate Professor in Residence, Department of
Anesthesiology and Perioperative Care, University of
California, San Francisco, School of Medicine, San
Francisco, California
vi

Anuj Malhotra, MD
Pain Management Fellow, Department of Anesthesia,
Stanford University, Palo Alto, California
Vinod Malhotra, MD
Professor, Department of Anesthesiology and Urology,
Vice Chair for Clinical Affairs, Clinical Director of the

Operating Rooms, Weill Cornell Medical College and
Medical Center, New York, New York
Rachel Eshima McKay, MD
Clinical Professor, Department of Anesthesia and
Perioperative Care, University of California,
San Francisco, School of Medicine, San Francisco,
California
Pankaj Mehta, MD
Faculty of Interventional Pain Medicine, Cleveland Clinic
Foundation, Cleveland, Ohio
Douglas G. Merrill, MD, MBA
Professor of Anesthesiology, Dartmouth Medical School;
Director, The Center for Perioperative Services; Medical
Director, Outpatient Surgery, Dartmouth-Hitchcock
Medical Center, Lebanon, New Hampshire
Ronald D. Miller, MD
Professor, Department of Anesthesia and Perioperative
Care, University of California, San Francisco, School
of Medicine, San Francisco, California


Contributors

Theodora K. Nicholau, PhD, MD
Clinical Professor, Department of Anesthesia and
Perioperative Care, University of California, San Francisco,
School of Medicine, San Francisco, California
Howard D. Palte, MBChB, FCA(SA)
Assistant Professor, Department of Anesthesiology,
University of Miami, Miami, Florida

Anup Pamnani, MD
Assistant Professor, Department of Anesthesiology, Weill
Cornell Medical College, New York, New York
Siamak Rahman, MD
Associate Clinical Professor, Department of
Anesthesiology, University of California, Los Angeles,
Los Angeles, California
James P. Rathmell, MD
Professor of Anesthesia, Harvard Medical School; Vice
Chair and Chief, Division of Pain Medicine, Department
of Anesthesia, Critical Care, and Pain Medicine,
Massachusetts General Hospital, Boston, Massachusetts
Mark Rollins, MD, PhD
Associate Professor, Department of Anesthesia and
Perioperative Care, University of California, San Francisco,
School of Medicine, San Francisco, California
Andrew D. Rosenberg, MD
Chief, Department of Anesthesiology, New York
University Hospital For Joint Diseases; Executive ViceChair, Department of Anesthesiology, New York
University School of Medicine, New York, New York
Patricia Roth, MD
Professor, Department of Anesthesia and Perioperative
Care, University of California, San Francisco, School of
Medicine, San Francisco, California
Isobel A. Russell, MD, PhD, FACC
Professor, Department of Anesthesia and Perioperative
Care, University of California, San Francisco, School of
Medicine; Chief, Cardiac Anesthesia Services, University
of California, San Francisco Medical Center,
San Francisco, California

David Shimabukuro, MDCM
Associate Professor, Department of Anesthesia and
Perioperative Care, University of California,
San Francisco, School of Medicine, San Francisco,
California
Randolph H. Steadman, MD
Professor and Vice Chair, Department of Anesthesiology,
David Geffen School of Medicine at University of
California, Los Angeles, Los Angeles, California
Greg Stratmann, MD, PhD
Associate Professor, Department of Anesthesia and
Perioperative Care, University of California,
San Francisco, School of Medicine, San Francisco,
California
Bobbie Jean Sweitzer, MD
Professor, Departments of Anesthesiology and Critical
Care and Medicine, University of Chicago; Director,
Anesthesia Perioperative Medicine Clinic, University
of Chicago Medical Center, Chicago, Illinois
Pekka Talke, MD
Professor, Chief of Neuroanesthesia, Department of
Anesthesia and Perioperative Care, University of
California, San Francisco, School of Medicine,
San Francisco, California
Arthur W. Wallace, MD, PhD
Professor in Residence and Vice Chair, Department
of Anesthesia and Perioperative Care, University
of California, San Francisco, School of Medicine; Chief of
Anesthesia, Veterans Affairs Medical Center,

San Francisco, California
Jeffrey D. Wilkinson, MD
South County Anesthesia Associates; Chairman, Quality
Committee of the Board, St. Anthony’s Medical Center,
St. Louis, Missouri
Victor W. Xia, MD
Associate Clinical Professor, Department of
Anesthesiology, David Geffen School of Medicine at
University of California, Los Angeles, Los Angeles,
California

vii


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PREFACE

As with all medical disciplines, the practice of anesthesia
requires a solid knowledge base as well as clinical
competence. There are many textbooks that provide the
student of anesthesiology with the information needed to
practice anesthesia. What was lacking was a book that
allowed students at every level to actively participate in
their learning. This study guide lets the reader evaluate
his or her own knowledge and formulate answers alone
or in groups, and it provides an alternate means of study
of the information.
The format of the book is question and answer. It is

organized in a logical progression from basic anesthesia
principles and concepts to more complex issues. These
include the delivery of anesthesia in various settings and
the administration of anesthesia to patients with organ
system dysfunction and disease states. All the answers
are current, fully formed, and self-explanatory, and
the page number references provided at the end of each
question refer the reader to the Basics of Anesthesia,
Sixth Edition, text where further information on the
given topic can be found.
There are several ways this study guide can be used.
The first-year anesthesia resident may use it to solidify

information read. Anesthesia residents at every level
may use it to prepare for specific clinical applications
that they may face on a subspecialty rotation or with
given cases. Anesthesia residents can also use this study
guide for group study in which they will be required
to verbalize answers to questions on given topics.
Similarly, faculty may use the study guide to quiz
residents orally in a coherent, progressive manner in
formal or informal settings. This question and answer
book can be used for self-study for Board examinations,
which may be particularly useful to the anesthesiologist
who is in practice and is required to register with the
ABA MOCA program for recertification every 10 years.
Finally, anesthesiologists in practice may find the study
guide useful to refresh their knowledge base and review
old and new information that they may not have been
taught during their residencies. The multiple uses of

this study guide make it an appropriate choice for
students, teachers, and clinicians of anesthesiology at
every level.
Lorraine M. Sdrales
Ronald D. Miller

ix


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CONTENTS

13

1
Scope of Anesthesia Practice
Ronald D. Miller, Tula Gourdin

1

7

16

29

40

51

64

73

84

102

117

202

Hemostasis
Greg Stratmann

209

Fluid Management
Charles J. Fox, Henry Liu, Alan David Kaye

226

Blood Therapy
Ronald D. Miller, Tula Gourdin

231

Cardiovascular Disease

Arthur W. Wallace

241

Congenital Heart Disease
Isobel A. Russell

275

24

12
Anesthesia Delivery Systems
Patricia Roth

Acid-Base Balance and Blood Gas Analysis
Linda Liu

23

11
Choice of Anesthetic Technique
Ronald D. Miller, Tula Gourdin

193

22

10
Preoperative Evaluation and Medication

Jennifer E. Hofer, Bobbie Jean Sweitzer

Anesthetic Monitoring
Anil de Silva

21

9
Neuromuscular Blocking Drugs
Ronald D. Miller, Tula Gourdin

183

20

8
Local Anesthetics
Ken Drasner

Patient Positioning and Associated Risks
Jae-Woo Lee, Lydia Cassorla

19

7
Opioids
Siamak Rahman

175

18

6
Intravenous Anesthetics
Helge Eilers

Peripheral Nerve Blocks
Adam Collins

17

5
Inhaled Anesthetics
Rachel Eshima McKay

155

16

4
Autonomic Nervous System
David B. Glick

Spinal and Epidural Anesthesia
Ken Drasner
15

3
Clinical Cardiac and Pulmonary Physiology
John Feiner

140

14

2
Basic Pharmacologic Principles
Jeffrey D. Wilkinson

Airway Management
Patricia Roth

123

Chronic Pulmonary Disease
Luca M. Bigatello

283

xi


Contents

35

25
Renal, Liver, and Biliary Tract Disease
Anup Pamnani, Vinod Malhotra

297

26
Nutritional and Gastrointestinal Disease
Steve Hyman, William R. Furman

310

324

Ophthalmology and Otolaryngology
Steven Gayer, Howard D. Palte

337

Orthopedics
Andrew D. Rosenberg, Thomas J. J. Blanck

349

363

387

407

419

Outpatient Anesthesia
Douglas G. Merrill

xii

426

492

42
501

43
Quality of Care and Patient Safety
Anuj Malhotra, Vinod Malhotra

34

480

41

Awareness Under Anesthesia
Daniel Cole

33
Organ Transplantation
Randolph H. Steadman, Victor W. Xia

40

Cardiopulmonary Resuscitation

David Shimabukuro

32
Elderly Patients
Sheila R. Barnett

39

Chronic Pain Management
Pankaj Mehta, James P. Rathmell

31
Pediatrics
Erin A. Gottlieb, Dean B. Andropoulos

458

Trauma, Bioterrorism, and Natural Disasters 469
Eric Y. Lin

30
Obstetrics
Mark Rollins, Jennifer Lucero

450

38
Critical Care Medicine
Lundy Campbell, Michael A. Gropper

29

440

37
Perioperative Pain Management
Meredith C.B. Adams, Robert W. Hurley

28

431

36
Postanesthesia Recovery
Theodora K. Nicholau

27
Central Nervous System Disease
Alana Flexman, Pekka Talke

Procedures Performed Outside the
Operating Room
Lawrence Litt

505


Chapter

1

SCOPE OF ANESTHESIA
PRACTICE
Ronald D. Miller, Tula Gourdin

INTRODUCTION

1. When did the specialty of anesthesiology become recognized?
2. Initially, how was anesthesia primarily used and how did it evolve?
3. Name the two medical organizations whose approval allowed anesthesia to be
recognized as a medical specialty.

DEFINITION OF
ANESTHESIOLOGY
AS A SPECIALTY

4. Besides monitoring and maintenance of normal physiology during the perioperative
period, what are some of the areas that define the practice of anesthesia?
5. Name some of the organizations that comprise the American system of
anesthesiology.

EVOLUTION
OF ANESTHESIA AS A
MULTIDISCIPLINARY
MEDICAL SPECIALTY

6. Name the four subspecialties of anesthesiology that require an additional
certification process from the American Board of Anesthesiology (ABA).
7. In pain management, anesthesiologists are usually part of a multidisciplinary team.
Name some of the other specialties that provide services that support pain

management.
8. Describe an open versus a closed critical care unit.
9. Which other anesthesia subspecialties are evolving toward a separate certification
process?
10. What factor dictates whether some institutions have subspecialized anesthesia
teams? Give an example of two such teams.

PERIOPERATIVE
PATIENT CARE

11. What services are included in perioperative care?
12. What was the impetus behind the creation of preoperative clinics and who generally
manages these?
13. Describe the standard perioperative pathway.
14. What is throughput?

TRAINING AND
CERTIFICATION IN
ANESTHESIOLOGY

15. What subspecialties are studied in the clinical anesthesia postgraduate training
years (years 1 to 3)?
16. Describe the fundamental steps that lead to being a “board-certified anesthesiologist.”
17. What is the emphasis of the Maintenance of Certification in Anesthesiology (MOCA)?
18. What are other anesthesia specialties that the ABA certifies?
19. Name the three new professional performance concepts developed by the
Accreditation Council for Graduate Medical Education and the American Board of
Medical Specialties.
1

MILLER’S ANESTHESIA REVIEW

OTHER ANESTHETIC
PROVIDERS

20. What are the training differences between a certified registered nurse anesthetist
and an anesthesiologist assistant?

QUALITY OF CARE
AND SAFETY IN
ANESTHESIA

21. The Joint Commission provides quality improvement guidelines in anesthesia for
health care organizations. What three fundamental areas do these guidelines
address?
22. Continuous quality improvement (CQI) programs may focus on both critical
incidents and sentinel events. Describe critical incidents versus sentinel events.
23. What are some of the key factors in preventing patient injuries related to anesthesia?
24. Provide two examples of Patient Safety Practices and the Suggested Penalties for
Failure to Adhere to the Practice as published in the New England Journal of Medicine.

ORGANIZATIONS
WITH EMPHASIS
ON ANESTHESIA
AND SAFETY

25. Anesthesia has the distinction of being the only specialty in medicine with a
foundation dedicated to issues of safety in patient care. Name the foundation.
26. Which organization provides a retrospective database of patient and safety data that

can be used to assess and improve patient care?
27. Which organization investigates legal cases as a vehicle for identifying patient and
practice areas of risk?
28. Name the foundation that provides research support in anesthesia.

PROFESSIONAL
LIABILITY

29. This chapter states that 93 claims were filed in the United Kingdom in the years 1995
to 2007. What two areas of patient care and safety did these claims emphasize?
30. What is the anesthesiologist’s best protection against medicolegal action?
31. What actions should the anesthesiologist take in the event of an accident?

RISKS OF
ANESTHESIA

32. What is the estimated mortality rate from anesthesia?
33. What are some of the factors that have contributed to the decrease in anesthesiarelated deaths?
34. What is the anesthesiologist’s greatest anesthesia patient safety issue?
35. Vigilance accounts for a large proportion of avoidance of adverse anesthesia events.
What are some of the factors in the operating room environment that diminish the
anesthesiologist’s ability to perform the task of vigilance?

HAZARDS OF
WORKING IN THE
OPERATING ROOM

36. Name some of the most prevalent hazards encountered in the operating room?

SUMMARY AND

FUTURE OUTLOOK

37. Anesthesiology is constantly evolving and changing. Describe some of the changes
the specialty has undergone and the direction it is moving toward.

ANSWERS*
INTRODUCTION

1. In the early 19th century, the concept of providing analgesia and eventually
anesthesia became increasingly possible. (11)
*Numbers in parentheses: numbers refer to pages, figures, or tables in Miller RD, Pardo MC: Basics of Anesthesia,
6th ed. Philadelphia, Elsevier Saunders, 2011.

2


Scope of Anesthesia Practice

2. The major emphasis was initially on surgical anesthesia, which evolved into airway
management including endotracheal intubation, which led to the development of
critical care medicine, regional anesthesia, and pain medicine. (11)
3. The two organizations whose approval allowed anesthesia to be recognized as a
medical specialty are the American Medical Association and the American Board
of Medical Specialties. (11)
DEFINITION OF
ANESTHESIOLOGY
AS A SPECIALTY

4. The American Board of Anesthesiology defines anesthesiology as a discipline within
the practice of medicine that deals with:

a. Assessment of, consultation for, and preparation of patients for anesthesia.
b. Relief and prevention of pain during and following surgical, obstetric,
therapeutic, and diagnostic procedures.
c. Monitoring and maintenance of normal physiology during the perioperative
period.
d. Management of critically ill patients.
e. Diagnosis and treatment of acute, chronic, and cancer-related pain.
f. Clinical management and teaching of cardiac and pulmonary resuscitation.
g. Evaluation of respiratory function and application of respiratory therapy.
h. Conduct of clinical, translational, and basic science research.
i. Supervision, teaching, and evaluation of performance of both medical and
paramedical personnel involved in perioperative care.
j. Administrative involvement in health care facilities and organizations, and
medical schools necessary to implement these responsibilities. (11-12)
5. As with other medical specialties, anesthesiology is represented by professional
societies (American Society of Anesthesiologists, International Anesthesia Research
Society), scientific journals (Anesthesiology, Anesthesia and Analgesia), a residency
review committee with delegated authority from the Accreditation Council for
Graduate Medical Education to establish and ensure compliance of anesthesia
residency training programs with published standards, and a medical specialty
board, the American Board of Anesthesiology, which establishes criteria for
becoming a certified specialist in anesthesiology. Other countries have comparable
systems of training and certifying mechanisms. (12)

EVOLUTION OF
ANESTHESIA AS A
MULTIDISCIPLINARY
MEDICAL SPECIALTY

6. In addition to board certification in anesthesiology, the American Board of

Anesthesiology has an additional certification process for pain management,
critical care medicine, hospice and palliative medicine, and sleep medicine. (12)
7. Many other supportive services are involved in the pain management specialty of
anesthesia, including neurology, medicine, psychiatry, and physical therapy. (12)
8. Regarding critical care units, usually a “closed” system means that full-time critical
care physicians take care of the patients. An “open” system means that the patient’s
attending physician continues to provide the care in the intensive care unit (ICU). (12)
9. The American Board of Pediatrics and the American Board of Anesthesiology have
commenced a combined integrated training program in both pediatrics and
anesthesiology that would take 5 years instead of the traditional 6. In addition,
cardiac anesthesiologists who now serve both pediatric and adult cardiac patients
may move toward a separate certification process. (12)
10. Institutional patient volume in a given specialty often dictates whether only
subspecialized anesthesia teams can administer anesthesia to these patients. Two
examples may be obstetric or neurosurgical anesthesia teams. (13)

PERIOPERATIVE
PATIENT CARE

11. Preoperative care includes preoperative evaluation, preparation in the immediate
preoperative period, intraoperative care, postanesthesia care unit (PACU), acute
postoperative pain management, and possibly the ICU. (13)
3


MILLER’S ANESTHESIA REVIEW

12. Initially preoperative clinics were formed when patients were no longer admitted to
the hospital the day before surgery. Also the increased complexity of patient
medical risks and surgical procedures prompted the creation of preoperative clinics

that allowed patients to be evaluated before the day of surgery. These clinics should
be multidisciplinary and lead by anesthesia. (13)
13. The pathway includes preoperative evaluation, the accuracy of predicting length
and complexity of surgical care, and patient flow in and out of PACUs. (13)
14. Throughput is the term used to describe the efficiency of each patient’s perioperative
experience. This can be influenced by such things as operating room availability,
length of surgery scheduling times, availability of beds in the PACU, and many
other issues. At some institutions perioperative or operating room directors are
appointed to manage this perioperative process. (13)

TRAINING AND
CERTIFICATION IN
ANESTHESIOLOGY

15. All aspects of clinical anesthesia are covered in postgraduate training for anesthesia,
including obstetric, pediatric, cardiothoracic, neuroanesthesia, anesthesia for
outpatient surgery, recovery room care, regional anesthesia and pain management,
as well as training in critical care medicine. (13)
16. To become a certified diplomate of the American Board of Anesthesiology, one must
complete an accredited postgraduate training program, pass a written and oral
examination, and meet licensure and credentialing requirements. (14)
17. MOCA emphasizes continuous self-improvement and evaluation of clinical skills
and practice performance to ensure quality and public accountability. In 2000,
board certification became a 10-year, time-limited certificate that emphasizes
participation in MOCA. (14)
18. Pain Management, Critical Care Medicine, Hospice and Palliative Medicine, and
Sleep Medicine are issued to diplomats who have completed 1 year of additional
postgraduate training in the respective subspecialty, meet licensure and
credentialing requirements, and pass a written examination. (14)
19. Evaluation of a clinician’s professional performance now includes data regarding

General Competences, Focused Professional Practice Evaluation, and Ongoing
Professional Practice Evaluation. (14)

OTHER ANESTHETIC
PROVIDERS

20. The certified registered nurse anesthetist (CRNA) must first be a registered nurse,
spend 1 year as a critical care nurse, and then complete 2 to 3 years of didactic and
clinical training in the techniques of administration of anesthetics in an approved
nursing training program. The anesthesiologist assistant completes a graduate level
27-month program leading to a master of science degree in anesthesia. (14-15)

QUALITY OF CARE
AND SAFETY IN
ANESTHESIA

21. The Joint Commission guidelines evaluate quality of care based on the measurement
and improvement of these areas:
a. Structure (personnel and facilities used to provide care)
b. Process (sequence and coordination of patient care activities such as
performance and documentation of a preanesthetic evaluation, and continuous
attendance to and monitoring of the patient during anesthesia)
c. Outcome (15)
22. Critical incidents (e.g., ventilator disconnection) are events that cause or have the
potential to cause injury if not noticed and corrected in a timely manner.
Measurement of the occurrence rate of important critical incidents may serve as a
substitute for rare outcomes in anesthesia and lead to improvement in patient safety.
Sentinel events are isolated events that may indicate a systematic problem

4

Scope of Anesthesia Practice

(e.g., syringe swap because of poor labeling, drug administration error related to
keeping unneeded medications on the anesthetic cart). (15)
23. Some key factors for the prevention of patient injury in anesthesia are vigilance,
up-to-date knowledge, and adequate monitoring. (15)
24. The following examples of patient safety practices and suggested penalties are from
Table 2-1, page 16. The Patient Safety Practice is listed first, followed by the
suggested initial penalty.
a. Practice hand hygiene.
i. Initial penalty: Education and loss of patient care privileges for 1 week
b. Following an institution’s guidelines regarding provider-to-provider sign out at
the end of a shift
ii. Initial penalty: Education and loss of patient care privileges for 1 week
c. Performing a “time-out” before surgery
iii. Initial penalty: Education and loss of operating room privileges for 2 weeks
d. Marking the surgical site to prevent wrong-site surgery.
iv. Initial penalty: Education and loss of operating room privileges for 2 weeks
e. Using the checklist when inserting central venous catheters
v. Initial penalty: Counseling and review of evidence; loss of catheter
insertion privileges for 2 weeks (16)
ORGANIZATIONS
WITH EMPHASIS
ON ANESTHESIA
AND SAFETY

25. The Anesthesia Patient Safety Foundation (APSF) is dedicated to patient safety
issues and has a quarterly newsletter that provides discussion on this topic. (15)

26. The Anesthesia Quality Institute (AQI) is the primary source of information for
quality improvement in the practice of anesthesiology. AQI provides the National
Anesthesia Clinical Outcomes Registry (NACOR) on its website. (16)
27. The American Society of Anesthesiology Closed Claims Project is a retrospective
analysis of legal cases with adverse outcomes. Its investigations have helped
identify patient and practice risk areas that tend to have difficulties and require
added attention with regard to quality and safety. (16)
28. The Foundation for Anesthesia Education and Research (FAER) encourages
research, education, and scientific innovation in anesthesiology, perioperative
medicine, and pain management. (16)

PROFESSIONAL
LIABILITY

29. The majority of the 93 claims in the United Kingdom from 1995-2007 involved drug
administration errors with muscle relaxants being the most common issue.
The second area involved being awake and paralyzed. (16)
30. Besides continuing medical education, the anesthesiologist should be thoroughly
knowledgeable of the patient’s condition and care. This includes preoperative and
postoperative visits, as well as detailed records of the course of anesthesia. (17)
31. The anesthesiologist should promptly document the facts on the patient’s medical
record and immediately notify the appropriate agencies, particularly one’s own
medical center administration and legal office. In addition, the anesthesiologist
should provide the hospital and the company that writes the physician’s
professional liability insurance with a complete account of the incident. (17)

RISKS OF
ANESTHESIA

32. Currently, it is estimated that the mortality rate from anesthesia is approximately

1 in 250,000 patients. (17)
33. The increased safety of anesthesia is presumed to reflect the introduction
of improved anesthesia drugs and monitoring, as well as the training of
anesthesiologists. In addition, motivating patients to stop smoking, lose weight,
avoid excess intake of alcohol, and achieve optimal medical control of essential
5


MILLER’S ANESTHESIA REVIEW

hypertension, diabetes mellitus, and asthma before undergoing elective surgery has
led to a decrease in anesthesia-related deaths. (17)
34. Difficult airway management is perceived to be the greatest anesthesia patient
safety issue. Other examples of possible adverse outcomes besides death include
peripheral nerve damage, brain damage, airway trauma, intraoperative awareness,
eye injury, fetal/newborn injury, and aspiration of gastric contents. (17)
35. Prominent among the factors are sleep loss and fatigue with known detrimental
effects on work efficiency and cognitive tasks (monitoring, clinical decision
making). (17)
HAZARDS OF
WORKING IN THE
OPERATING ROOM

36. Anesthesiologists are exposed to vapors from chemicals, ionizing radiation, and
infectious agents. There is psychological stress from demands of the constant
vigilance required for patients under anesthesia. In addition, interactions with
members of the operating team may introduce varying levels of interpersonal stress.
Other hazards include latex sensitivity from exposure to latex gloves, substance
abuse, mental illness and suicide, and infection control. (18)

SUMMARY AND
FUTURE OUTLOOK

37. Responsibilities of the anesthesiologist have grown in magnitude, scope, and depth.
Anesthesia has become a leading specialty with regard to inpatient medicine,
especially in the perioperative period including critical care and pain medicine.
The specialty will become more valuable to medicine overall by attempting to
anticipate future societal needs and continuing to dedicate its members to the
pursuit of excellence. (18)

6


Chapter

2

BASIC PHARMACOLOGIC
PRINCIPLES
Jeffrey D. Wilkinson

1. What is pharmacokinetics?
2. What is pharmacodynamics?
PHARMACOKINETICS

3. What factors govern drug absorption?
4. How is absorption via buccal mucosa significantly different from drug absorption
via the stomach?
5. What aspects of absorption make transdermal drug delivery distinct from other
modes of drug delivery? Name some examples of drugs for which a transdermal

application is clinically important.
6. What is the mechanism for the offset of local anesthetic effects following nerve
block?
7. What is “first order” transfer? How does doubling the dose of a drug affect the shape
of a plot of drug absorbed versus time?
8. How does absorption rate from its delivery site affect peak plasma concentration of
a drug? What does absorption rate mean regarding the relative safety of intercostal
nerve blocks?
9. Define distribution. Define volume of distribution.
10. Distinguish central volume of distribution from peripheral volume of distribution.
11. What factors increase a peripheral volume of distribution for a drug?
12. What are two empiric models of peripheral volumes of distribution that are
clinically useful?
13. Generally speaking, what is clearance of a drug? What is the difference between
systemic clearance and “intercompartmental” clearance?
14. How are most anesthetic drugs removed from the body?
15. What processes are used in the liver to metabolize drugs?
16. What drugs are metabolized by cytochrome CYP 3A4?
17. What drugs or substances induce CYP 3A4? What drugs or substances inhibit
CYP 3A4?
18. What function important to anesthesia does CYP 2D6 have? What drugs inhibit CYP
2D6, and what clinical implication does this have?
19. Why do remifentanil, succinylcholine, and esmolol generally vanish from the
plasma so quickly after intravenous administration?
20. Why is the pharmacokinetics of succinylcholine less predictable than other drugs
cleared by ester hydrolysis?
21. Define “linear” pharmacokinetics.
22. Describe the formula for rate of drug metabolism in terms of liver blood flow.
23. What is an extraction ratio? What is the formula for clearance in terms of hepatic
blood flow? What are the units for clearance?

7


MILLER’S ANESTHESIA REVIEW

24. In the case of a drug exhibiting “linear” pharmacokinetics, what is significant about
the constant relationship between metabolic rate and drug concentration?
25. What does it mean to say that a drug’s metabolism is “flow limited”? Name a drug
whose metabolism is “flow limited.”
26. What does it mean to say that a drug’s metabolism is “capacity limited”? What effect
does an alteration of blood flow to the liver have on drugs whose metabolism is
“capacity limited”?
27. How is the maximum metabolic rate (Vm) of the liver defined? What is Km?
28. What factors may alter the maximum metabolic rate for a drug in the liver? How do
changes in maximum metabolic rate for a drug alter the clearance of “flow limited”
and “capacity limited” drugs?
29. What does it mean for a drug to have saturable pharmacokinetics?
30. What class of drugs significant to anesthesia practice are eliminated by the kidneys?
31. Why is a normal serum creatinine value in an elderly person not a reliable indicator
of the individual’s ability to clear drugs in the kidney?
32. Describe the clearance of propofol from the bloodstream following intravenous
injection.
33. What is distribution clearance? What is the clinical significance of this
phenomenon?
34. What is the capacity for plasma proteins to bind most anesthetic drugs? How does
the number of protein binding sites for a drug in plasma influence the amount
of a drug in the plasma bound to proteins?
35. What effect does a change in plasma protein concentrations have on the apparent
potency of a drug?
36. Sketch a graph plotting time versus the amount of drug for a first order

pharmacokinetic process. What does it mean to say that a first order
pharmacokinetic process demonstrates exponential decay?
37. What do the rate constants between pharmacokinetic compartments relate?
38. For anesthetic drugs, which compartment model best reflects their pharmacokinetic
behavior? What about anesthetic drug pharmacokinetics makes this model
appropriate? What do the “compartments” correspond to?
39. Why is it impossible to achieve a steady-state drug concentration with a bolus of
drug followed by a simple infusion when a drug is best described by a multiple
compartment model?
40. What is the time course of drug effect? Why does this exist for anesthesia drugs, and
what pharmacokinetic properties does this process exhibit?
41. Define context-sensitive half-time. What are its limitations? Why is contextsensitive half-time a more meaningful concept with regard to the offset of
anesthetic drug effects than drug half-life?
42. Why is morphine not an appropriate choice for continuous infusion during
anesthesia? Define context-sensitive effect site decrement time.

PHARMACODYNAMICS

8

43. When a drug’s concentration is equal to its dissociation constant for the binding of a
certain receptor, what may be said regarding occupation of those receptors? If a
dissociation constant is relatively high, what does this mean regarding the nature
of the binding between a receptor and a drug?
44. Define receptor full agonist. What is a partial agonist?
45. Define receptor antagonist. What is an inverse agonist?
46. Distinguish efficacy from affinity.
47. What is the difference between competitive and noncompetitive antagonism?
48. How does binding of a receptor by a drug result in drug effect?
49. What three types of receptors are of most significance to anesthesia? For each type

of receptor, name several drugs important in anesthesia whose effects are mediated
by that receptor type.


Basic Pharmacologic Principles

50. Sketch a graph plotting the dose of a drug (or measure of exposure) versus its
response (drug effect). If a dose-response curve is “shifted to the left,” what does this
mean regarding drug (or exposure) potency?
51. Define ED50, LD50, and therapeutic index. Why is a drug with a higher therapeutic
index safer?
52. Describe the interaction of hypnotics and opioids, specifically with regard to
fentanyl and isoflurane MAC.
53. What is a response surface?
54. Define additive drug interactions, supraadditive interactions, and infraadditive
interactions.

ANSWERS*
1. Pharmacokinetics is the process by which the body “disposes” of drugs via
absorption, distribution, metabolism, and elimination. It can be thought of as “what
the body does to the drug.” (35)
2. Pharmacodynamics is the process by which drugs interact with specific receptors in
the body to produce pharmacologic effects. It can be thought of as “what the drug
does to the body.” (35)
PHARMACOKINETICS

3. Drug absorption is governed by route of delivery, bioavailability of the drug, and
possibly first-pass metabolism. (36)
4. Drug absorption via buccal mucosa differs from absorption from lower in the
gastrointestinal tract because presence of food does not hinder delivery of drug to

the mucosa. Also, venous outflow from the buccal mucosa returns directly to
the systemic circulation, thereby avoiding the potential for the first-pass hepatic
effect that is present for drugs absorbed in the stomach, which first enter the
portal venous system. (36)
5. Transdermal drug delivery is distinct in that skin is designed to be a significant
barrier to absorption. This means that drugs delivered transdermally will have a
markedly delayed onset of action following administration. Also, the skin serves as
a depot of the drug, resulting in prolonged drug effect following removal of the skin
application. Examples of drugs delivered transdermally include clonidine,
scopolamine, nitroglycerin, and fentanyl. (36)
6. Local anesthetics applied in nerve blocks have their pharmacologic effects
ended by movement of the drug away from the site of action. The process by
which the body absorbs this locally applied bolus of drug, thus ending its local
effects, is the same by which the body absorbs drugs injected into tissues for
the purpose of eliciting systemic drug effects that follow absorption. (36)
7. “First order” transfer is when the rate of drug absorption is proportional to the
concentration gradient. Doubling the dose of a drug does not affect the shape of the
curve (absorption over time) when a “first order” transfer is occurring.
Concentrations will be exactly twice as high at all times, but peak absorption will
occur at the same time and the shape of the curve will be identical. (36)
8. The absorption rate from drug delivery sites significantly affects peak plasma
concentrations. The higher the absorption rate, the higher the peak plasma
concentration that will result. Nerve blocks at sites with rapid absorption result
*Numbers in parentheses: numbers refer to pages, figures, or tables in Miller RD, Pardo MC: Basics of Anesthesia,
6th ed. Philadelphia, Elsevier Saunders, 2011.

9


MILLER’S ANESTHESIA REVIEW

in higher peak plasma concentrations of the local anesthetic injected, providing a
risk of toxicity relatively greater than nerve blocks at sites with slower absorption.
Intercostal blocks are performed in areas of relatively high absorption. (36)
9. Distribution is the process by which an injected drug mixes with blood and body
tissues after its administration. Measuring plasma concentration of a drug
allows calculation of a mixing volume, or volume of distribution. Volume of
distribution is thus a calculated number (dose of drug administered intravenously
divided by plasma concentration) that reflects the apparent volume of body
tissues that the drug is distributed across, assuming all the tissues it is distributed
across are in equilibrium with plasma concentration. Higher levels of drug
remaining in the plasma after drug administration lead to a smaller
calculated volume of distribution. (36)
10. Central volume of distribution is the apparent volume immediately (within a
minute) following intravenous drug injection. It anatomically consists of the heart,
the great vessels, and the lungs. Peripheral volumes of distribution are those
volumes of distribution that are calculated after the injected drug has had time to
distribute to tissues to which distribution of drug is slower. These peripheral
tissues include muscle, fat, and bone. While there is an anatomic correlation to
central and peripheral volumes of distribution, volume of distribution is a
calculated number that does not necessarily equate to an actual physical
volume. (36)
11. The solubility of the drug in the tissue relative to the solubility in the blood
or plasma determines the peripheral volume of distribution. If the drug is
highly soluble in the tissue, then less of it will stay in the plasma. Sampling the
plasma concentration of the drug will result in calculation of a higher volume
of distribution than if plasma levels remained higher. Drug properties that lower free
plasma levels include low levels of binding to plasma proteins, a lower degree of
ionization, and higher lipid solubility. (36)
12. One clinically useful model to describe peripheral volumes of distribution divides

the body into tissue beds: “vessel rich group” (brain, most organs), muscle group,
fat group, and “vessel poor group” (skin, cartilage, ligaments). Another is
to identify the number of compartments in the body needed to explain the
pharmacokinetics of the drug in question. The pharmacokinetics of most anesthetic
drugs can be explained by a three compartment model (one central volume of
distribution, and two peripheral volumes of distribution). In spite of names given
to different compartments in different models, such compartments are empiric,
and do not necessarily correlate directly to underlying anatomic structures
or physiologic processes. (36-37)
13. Clearance is the removal of drug from tissue. Systemic clearance is when the drug
is permanently removed from the body. “Intercompartmental” clearance is when
the drug leaves the body tissue in question but moves into a different body
tissue. (37)
14. Most anesthetic drugs are removed from the body by hepatic metabolism. (37)
15. In the liver, drugs are metabolized through the processes of oxidation, reduction,
conjugation, and hydrolysis. Oxidation and reduction occurs via the cytochrome
P-450 system. (37)
16. Drugs important to anesthesia that are metabolized by CYP 3A4 include
acetaminophen, alfentanil, dexamethasone, fentanyl, lidocaine, methadone,
midazolam, and sufentanil. Also, propofol is partly oxidized by CYP 3A4. (37)
17. Rifampin, rifabutin, tamoxifen, glucocorticoids, carbamazepine, barbiturates, and
St. John’s wort induce CYP 3A4, increasing the metabolism of substrates of CYP 3A4
(hastening clearance). Inhibitors of CYP 3A4 include midazolam, propofol,
grapefruit juice, antifungal drugs, protease inhibitors, “mycin” antibiotics, and
10


Basic Pharmacologic Principles

selective serotonin reuptake inhibitors (SSRIs). In the case of midazolam, this has

been shown to prolong the effects of other drugs metabolized by CYP 3A4, such as
alfentanil and fentanyl. (37)
18. CYP 2D6 is the cytochrome in the liver responsible for the conversion of codeine
to morphine (the active metabolite of codeine). CYP 2D6 is inhibited by
quinidine and SSRIs. The clinical implication of this is that codeine, oxycodone, and
hydrocodone, which all rely on activity of CYP 2D6 for production of the active
metabolite from which their clinically relevant pharmacologic effects are derived,
are poor analgesic choices for patients receiving SSRIs. (37)
19. Remifentanil, succinylcholine, and esmolol are cleared in the plasma and tissue by
ester hydrolysis. This occurs very quickly because these esterases are so abundant. (37)
20. The pharmacokinetics of succinylcholine are less reliable than that of other drugs
cleared by plasma and tissue esterases because it is metabolized specifically by
butylcholinesterase (formerly known as “pseudocholinesterase”). Defects in the
gene for butylcholinesterase lead to a potentially significant slowing in the
metabolism of succinylcholine. (37)
21. “Linear” pharmacokinetics are said to exist for a drug when the rate of the drug’s
metabolism is directly proportional to its concentration. This is a general
characteristic of anesthetic drugs. (37)
22. Rate of metabolism equals liver blood flow times the difference in drug
concentration between blood flowing into the liver and blood flowing out. (38)
23. The extraction ratio of a drug is the fraction of the drug that is removed from
the plasma during passage through the liver. Clearance by the liver is equal to
hepatic blood flow multiplied by the extraction ratio. (Therefore, units of clearance
are liters per minute.) Hepatic extraction ratios are unchanging properties of
specific drugs. More of a drug is metabolized by the liver when the drug is being
delivered to the liver in increasing concentrations. This must be true for the
extraction ratio to remain constant. (37-38)
24. For most anesthetic drugs, metabolic rate is proportional to drug concentration
(“linear” pharmacokinetics). The proportionality constant that relates the drug
concentration to the metabolic rate is another definition of clearance.

Rate of metabolism ðgrams=minuteÞ ¼
proportionality constant ðliters=minuteÞ Â
inflow concentration ðgrams=literÞ:
Extraction ratio and proportionality constant (clearance) are only constant
if drugs exhibit “linear” pharmacokinetics, but this is generally true of anesthetic
drugs. (38)
25. The clearance of a “flow limited” drug is limited only by the rate of blood flowing to
the liver. Changes in hepatic blood flow result in a proportional change in drug
clearance. Such drugs have extraction ratios near or equal to 1. The liver has a
seemingly boundless ability to metabolize such drugs. One drug exhibiting
“flow limited” clearance is propofol. (38)
26. The clearance of a “capacity limited” drug is limited by the liver’s ability to
metabolize the drug. Such drugs have low extraction ratios (much less than 1).
Alterations of liver blood flow have no effect on clearance of “capacity limited”
drugs because liver blood flow has no effect on clearance of such drugs. One drug
exhibiting “capacity limited” clearance is alfentanil. (38)
27. The maximum metabolic rate of the liver for a given drug (Vm) is the theoretical
rate of drug metabolism if every possible enzyme in the liver were being used
for that function. Km is the concentration of drug in the plasma associated
with half of the maximum metabolic rate. (38)
11


MILLER’S ANESTHESIA REVIEW

28. Factors altering the maximum metabolic rate for a drug in the liver include enzyme
inhibition, enzyme induction, and liver disease. Clearance of “flow limited”
drugs is relatively insensitive to changes in maximum metabolic rate because
there is such a reserve of metabolic capacity for these drugs. For clearance of such
drugs to be affected by an alteration in metabolic rate requires such alteration

to be massive. Clearance of “capacity limited” drugs is very sensitive to changes in
the maximum metabolic rate, because the ability of the liver to metabolize the
drug is so small. (38)
29. For a drug to have saturable pharmacokinetics means that the concentration of
the drug in the plasma exceeds the concentration at which the metabolic rate of the
drug is half its maximum (Km). Clearance of such drugs is a function of drug
concentration (at clinical plasma concentrations). On the other hand, drugs that
do not have saturable pharmacokinetics (i.e., their concentration is well below
Km) are metabolized at a rate proportional to their concentration (most
anesthetic drugs). Clearance of these drugs is a constant. (40)
30. Steroidal muscle relaxants, including pancuronium, vecuronium, and
rocuronium are at least partially eliminated by the kidneys; 85% of pancuronium
is eliminated by the kidneys, while 20% to 30% of vecuronium and 10% to
20% of rocuronium are eliminated. (40)
31. Clearance of drugs by the kidney is achieved by filtration of drug from the plasma
at the glomerulus and direct transport to the tubules. Creatinine clearance is generally
a good indicator of renal ability to clear drugs because it is a good measure of
glomerular filtration. Increasing age is an independent factor in the establishment of a
patient’s creatinine clearance. Leaving serum creatinine unchanged and increasing
a patient’s age results in shrinking of the numerator in the formula for creatinine
clearance. In this, it can be seen that creatinine clearance decreases with age even
if serum creatinine never changes. Therefore, creatinine clearance may be decreased
despite “normal” serum creatinine levels. In fact, this is inevitably true the older a
person gets. Serum creatinine must eventually fall to below “normal” values for
creatinine clearance to remain “normal” as very advanced age is reached. (40)
32. Propofol is primarily cleared by metabolism in the liver. Every bit of propofol that
flows to the liver is cleared there, at all clinically significant doses and even in the
presence of all but the most massive insults to the cellular processes responsible for
its metabolism. Propofol’s clearance is actually greater than hepatic blood flow. This
is only possible if, in addition to the robust ability of the liver to metabolize this

drug, there are extrahepatic sites of drug metabolism. About a quarter of
administered propofol is eliminated by the kidneys. Propofol is eliminated virtually
completely by metabolism (metabolism occurring in both liver and kidney), with
only a minute fraction (less than 1%) excreted in the urine unchanged. Renal
elimination of propofol is not a function of filtration, but is a function of renal blood
flow since the kidneys remove every molecule of the drug that enters them. (37-38, 40)
33. Distribution clearance is the transfer of a drug out of the plasma into peripheral
tissues. The drug remains in active form and may be sequestered in tissues for an
extended period, serving as a reservoir for recurrent or prolonged pharmacologic
effects of drug administration. (40)
34. The capacity of plasma proteins to bind most anesthetic drugs is very large. That is,
the number of sites on proteins available to bind drug is far greater than the number
of molecules of an anesthetic drug administered at clinical levels. This does not
necessarily mean that a lot of the drug will become bound to plasma proteins upon
arrival in the bloodstream. Such binding is dependent on the rate constants for
binding and dissociation of each specific drug has for plasma proteins. The effect of
an excess of protein binding sites is that the amount of drug bound to plasma
proteins is purely a function of the concentration of the plasma protein. Whether
this function allocates a large or small amount of drug to a protein-bound form is
governed by the rate constants for binding and dissociation. (40)
12