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Physiology
SEVENTH EDITION
Physiology
SEVENTH EDITION

Linda S. Costanzo, Ph.D.

Professor of Physiology and Biophysics
School of Medicine
Virginia Commonwealth University
Richmond, Virginia
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Seventh edition

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Library of Congress Cataloging-in-Publication Data

Names: Costanzo, Linda S., 1947- author.
Title: Physiology / Linda S. Costanzo.
Other titles: Board review series.
Description: Seventh edition. | Philadelphia : Wolters Kluwer, [2019] | Series: BRS | Includes index.
Identifiers: LCCN 2017054852 | ISBN 9781496367617
Subjects: | MESH: Physiological Phenomena | Examination Questions
Classification: LCC QP40 | NLM QT 18.2 | DDC 612.0076—dc23 LC record available at
https://lccn.loc.gov/2017054852

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 For Richard
And
for Dan, Rebecca, and Sheila
And
for Elise and Max
 Preface

The subject matter of physiology is the foundation of the practice of medicine,

and a firm grasp of its principles is essential for the physician. This book is
intended to aid the student preparing for the United States Medical Licensing
Examination (USMLE) Step 1. It is a concise review of key physiologic
principles and is intended to help the student recall material taught during the
first and second years of medical school. It is not intended to substitute for
comprehensive textbooks or for course syllabi, although the student may find it a
useful adjunct to physiology and pathophysiology courses.
The material is organized by organ system into seven chapters. The first
chapter reviews general principles of cellular physiology. The remaining six
chapters review the major organ systems—neurophysiology, cardiovascular,
respiratory, renal and acid–base, gastrointestinal, and endocrine physiology.
Difficult concepts are explained stepwise, concisely, and clearly, with
appropriate illustrative examples and sample problems. Numerous clinical
correlations are included so that the student can understand physiology in
relation to medicine. An integrative approach is used, when possible, to
demonstrate how the organ systems work together to maintain homeostasis.
More than 130 full-color illustrations and flow diagrams and more than 50 tables
help the student visualize the material quickly and aid in long-term retention.
Appendices contain “Key Physiology Topics for USMLE Step 1,” “Key
Physiology Equations for USMLE Step 1,” and “Normal Blood Values.”
Questions reflecting the content and format of USMLE Step 1 are included
at the end of each chapter and in a Comprehensive Examination at the end of the
book. These questions, many with clinical relevance, require problem-solving
skills rather than straight recall. Clear, concise explanations accompany the
questions and guide the student through the correct steps of reasoning. The
questions can be used as a pretest to identify areas of weakness or as a posttest to
determine mastery. Special attention should be given to the Comprehensive
Examination, because its questions integrate several areas of physiology and
related concepts of pathophysiology and pharmacology.
New to this edition:
 Addition of new full-color figures
Updated organization and text
Expanded coverage of neurophysiology, and respiratory, renal,
gastrointestinal, and endocrine physiology
Addition of new multi-step questions
Best of luck in your preparation for USMLE Step 1!
Linda S. Costanzo, Ph.D.
 Acknowledgments

It has been a pleasure to be a part of the Board Review Series and to work with
the staff at Wolters Kluwer. Crystal Taylor and Andrea Vosburgh provided expert
editorial assistance.
My sincere thanks to students in the School of Medicine at Virginia
Commonwealth University/Medical College of Virginia, who have provided so
many helpful suggestions for BRS Physiology. Thanks also to the many students
from other medical schools who have taken the time to write to me about their
experiences with this book.
Linda S. Costanzo, Ph.D.
 Contents

Preface
Acknowledgments

1. CELL PHYSIOLOGY
I. Cell Membranes
II. Transport Across Cell Membranes
III. Osmosis
IV. Diffusion Potential, Resting Membrane Potential, and Action Potential
V. Neuromuscular and Synaptic Transmission
VI. Skeletal Muscle
VII. Smooth Muscle
VIII. Comparison of Skeletal Muscle, Smooth Muscle, and Cardiac Muscle
Review Test

2. NEUROPHYSIOLOGY
I. Autonomic Nervous System (ANS)
II. Organization of the Nervous System
III. Sensory Systems
IV. Motor Systems
V. Higher Functions of the Cerebral Cortex
VI. Blood–Brain Barrier and Cerebrospinal Fluid (CSF)
VII. Temperature Regulation
Review Test

3. CARDIOVASCULAR PHYSIOLOGY
I. Circuitry of the Cardiovascular System
II. Hemodynamics
III. Cardiac Electrophysiology
IV. Cardiac Muscle and Cardiac Output
V. Cardiac Cycle
 VI. Regulation of Arterial Pressure
VII. Microcirculation and Lymph
VIII. Special Circulations
IX. Integrative Functions of the Cardiovascular System: Gravity, Exercise,
and Hemorrhage
Review Test

4. RESPIRATORY PHYSIOLOGY
I. Lung Volumes and Capacities
II. Mechanics of Breathing
III. Gas Exchange
IV. Oxygen Transport
V. CO2 Transport
VI. Pulmonary Circulation
VII. V/Q Defects
VIII. Control of Breathing
IX. Integrated Responses of the Respiratory System
Review Test

5. RENAL AND ACID–BASE PHYSIOLOGY

I. Body Fluids
II. Renal Clearance, Renal Blood Flow (RBF), and Glomerular Filtration
Rate (GFR)
III. Reabsorption and Secretion
IV. NaCl Regulation
V. K+ Regulation
VI. Renal Regulation of Urea, Phosphate, Calcium, and Magnesium
VII. Concentration and Dilution of Urine
VIII. Renal Hormones
IX. Acid–Base Balance
X. Diuretics
XI. Integrative Examples
Review Test

6. GASTROINTESTINAL PHYSIOLOGY
I. Structure and Innervation of the Gastrointestinal Tract
 II. Regulatory Substances in the Gastrointestinal Tract
III. Gastrointestinal Motility
IV. Gastrointestinal Secretion
V. Digestion and Absorption
VI. Liver Physiology
Review Test

7. ENDOCRINE PHYSIOLOGY
I. Overview of Hormones
II. Cell Mechanisms and Second Messengers
III. Pituitary Gland (Hypophysis)
IV. Thyroid Gland
V. Adrenal Cortex and Adrenal Medulla
VI. Endocrine Pancreas–Glucagon and Insulin
VII. Calcium Metabolism (Parathyroid Hormone, Vitamin D, Calcitonin)
VIII. Sexual Differentiation
IX. Male Reproduction
X. Female Reproduction
Review Test

Comprehensive Examination

APPENDIX A.KEY PHYSIOLOGY TOPICS FOR USMLE

STEP 1

APPENDIX B.KEY PHYSIOLOGY EQUATIONS FOR USMLE

STEP 1

APPENDIX C.NORMAL BLOOD VALUES

Index
 Chapter 1 Cell Physiology

For additional ancillary materials related to this chapter, please

visit thePoint.

I. CELL MEMBRANES
are composed primarily of phospholipids and proteins.

A. Lipid bilayer
1. Phospholipids have a glycerol backbone, which is the hydrophilic (water
soluble) head, and two fatty acid tails, which are hydrophobic (water
insoluble). The hydrophobic tails face each other and form a bilayer.
2. Lipid-soluble substances (e.g., O2, CO2, steroid hormones) cross cell
membranes because they can dissolve in the hydrophobic lipid bilayer.
3. Water-soluble substances (e.g., Na+, Cl−, glucose, H2O) cannot dissolve
in the lipid of the membrane, but may cross through water-filled channels,
or pores, or may be transported by carriers.

B. Proteins
1. Integral proteins
are anchored to, and imbedded in, the cell membrane through
hydrophobic interactions.
may span the cell membrane.
include ion channels, transport proteins, receptors, and guanosine 5′-
triphosphate (GTP)–binding proteins (G proteins).
2. Peripheral proteins
are not imbedded in the cell membrane.
are not covalently bound to membrane components.
are loosely attached to the cell membrane by electrostatic interactions.
C. Intercellular connections
1. Tight junctions (zonula occludens)
are the attachments between cells (often epithelial cells).
may be an intercellular pathway for solutes, depending on the size,
charge, and characteristics of the tight junction.
may be “tight” (impermeable), as in the renal distal tubule, or “leaky”
(permeable), as in the renal proximal tubule and gallbladder.
2. Gap junctions
are the attachments between cells that permit intercellular
communication.
for example, permit current flow and electrical coupling between
myocardial cells.

II. TRANSPORT ACROSS CELL

MEMBRANES (TABLE 1.1)

table 1.1 Characteristics of Different Types of Transport

*One or more solutes are transported uphill; Na+ is transported downhill.

A. Simple diffusion
1. Characteristics of simple diffusion
is the only form of transport that is not carrier mediated.
 occurs down an electrochemical gradient (“downhill”).
does not require metabolic energy and therefore is passive.
2. Diffusion can be measured using the following equation:
J = − PA(C1 − C2)
where:
J = flux (flow) (mmol/sec)
P = permeability (cm/sec)
A = area (cm2)
C1 = concentration1 (mmol/L)
C2 = concentration2 (mmol/L)
3. Sample calculation for diffusion
The urea concentration of blood is 10 mg/100 mL. The urea
concentration of proximal tubular fluid is 20 mg/100 mL. If the
permeability to urea is 1 × 10−5 cm/sec and the surface area is 100
cm2, what are the magnitude and direction of the urea flux?

Note: The minus sign preceding the diffusion equation indicates that
the direction of flux, or flow, is from high to low concentration. It can
be ignored if the higher concentration is called C1 and the lower
concentration is called C2.
Also note: 1 mL = 1 cm3.
4. Permeability
is the P in the equation for diffusion.
describes the ease with which a solute diffuses through a membrane.
depends on the characteristics of the solute and the membrane.
a. Factors that increase permeability:
↑ Oil/water partition coefficient of the solute increases solubility in
the lipid of the membrane.
 ↓ Radius (size) of the solute increases the diffusion coefficient and
speed of diffusion.
↓ Membrane thickness decreases the diffusion distance.
b. Small hydrophobic solutes (e.g., O2, CO2) have the highest
permeabilities in lipid membranes.
c. Hydrophilic solutes (e.g., Na+, K+) must cross cell membranes through
water-filled channels, or pores, or via transporters. If the solute is an
ion (is charged), then its flux will depend on both the concentration
difference and the potential difference across the membrane.

B. Carrier-mediated transport
includes facilitated diffusion and primary and secondary active
transport.
The characteristics of carrier-mediated transport are
1. Stereospecificity. For example, D-glucose (the natural isomer) is
transported by facilitated diffusion, but the L-isomer is not. Simple
diffusion, in contrast, would not distinguish between the two isomers
because it does not involve a carrier.
2. Saturation. The transport rate increases as the concentration of the solute
increases, until the carriers are saturated. The transport maximum (Tm)
is analogous to the maximum velocity (Vmax) in enzyme kinetics.
3. Competition. Structurally related solutes compete for transport sites on
carrier molecules. For example, galactose is a competitive inhibitor of
glucose transport in the small intestine.

C. Facilitated diffusion
1. Characteristics of facilitated diffusion
occurs down an electrochemical gradient (“downhill”), similar to
simple diffusion.
does not require metabolic energy and therefore is passive.
is more rapid than simple diffusion.
is carrier mediated and therefore exhibits stereospecificity, saturation,
and competition.
2. Example of facilitated diffusion
Glucose transport in muscle and adipose cells is “downhill,” is carrier
mediated, and is inhibited by sugars such as galactose; therefore, it is
 categorized as facilitated diffusion. In diabetes mellitus, glucose
uptake by muscle and adipose cells is impaired because the carriers for
facilitated diffusion of glucose require insulin.

D. Primary active transport

1. Characteristics of primary active transport
occurs against an electrochemical gradient (“uphill”).
requires direct input of metabolic energy in the form of adenosine
triphosphate (ATP) and therefore is active.
is carrier mediated and therefore exhibits stereospecificity, saturation,
and competition.
2. Examples of primary active transport
a. Na+, K+-ATPase (or Na+–K+ pump) in cell membranes transports Na+
from intracellular to extracellular fluid and K+ from extracellular to
intracellular fluid; it maintains low intracellular [Na+] and high
intracellular [K+].
Both Na+ and K+ are transported against their electrochemical
gradients.
Energy is provided from the terminal phosphate bond of ATP.
The usual stoichiometry is 3 Na+/2 K+.
Specific inhibitors of Na+, K+-ATPase are the cardiac glycoside drugs
ouabain and digitalis.
b. Ca2+-ATPase (or Ca2+ pump) in the sarcoplasmic reticulum (SR) or
cell membranes transports Ca2+ against an electrochemical gradient.
Sarcoplasmic and endoplasmic reticulum Ca2+-ATPase is called
SERCA.
c. H+, K+-ATPase (or proton pump) in gastric parietal cells and renal α-
intercalated cells transports H+ into the lumen (of the stomach or renal
tubule) against its electrochemical gradient.
It is inhibited by proton pump inhibitors, such as omeprazole.

E. Secondary active transport

1. Characteristics of secondary active transport
a. The transport of two or more solutes is coupled.
b. One of the solutes (usually Na+) is transported “downhill” and provides
 energy for the “uphill” transport of the other solute(s).
c. Metabolic energy is not provided directly but indirectly from the Na+
gradient that is maintained across cell membranes. Thus, inhibition of
Na+, K+-ATPase will decrease transport of Na+ out of the cell, decrease
the transmembrane Na+ gradient, and eventually inhibit secondary
active transport.
d. If the solutes move in the same direction across the cell membrane, it is
called cotransport or symport.
Examples are Na+-glucose cotransport in the small intestine and renal
early proximal tubule and Na+–K+–2Cl– cotransport in the renal thick
ascending limb.
e. If the solutes move in opposite directions across the cell membranes, it
is called countertransport, exchange, or antiport.
Examples are Na+-Ca2+ exchange and Na+–H+ exchange.
2. Example of Na+–glucose cotransport (Figure 1.1)
a. The carrier for Na+–glucose cotransport is located in the luminal
membrane of intestinal mucosal and renal proximal tubule cells.
b. Glucose is transported “uphill”; Na+ is transported “downhill.”
c. Energy is derived from the “downhill” movement of Na+. The inwardly
directed Na+ gradient is maintained by the Na+–K+ pump on the
basolateral (blood side) membrane. Poisoning the Na+–K+ pump
decreases the transmembrane Na+ gradient and consequently inhibits
Na+–glucose cotransport.
3. Example of Na+–Ca2+ countertransport or exchange (Figure 1.2)
a. Many cell membranes contain a Na+–Ca2+ exchanger that transports
Ca2+ “uphill” from low intracellular [Ca2+] to high extracellular [Ca2+].
Ca2+ and Na+ move in opposite directions across the cell membrane.
b. The energy is derived from the “downhill” movement of Na+. As with
cotransport, the inwardly directed Na+ gradient is maintained by the
Na+–K+ pump. Poisoning the Na+–K+ pump therefore inhibits Na+–
Ca2+ exchange.
FIGURE 1.1 Na+–glucose cotransport (symport) in intestinal or
proximal tubule epithelial cell.
FIGURE 1.2 Na+–Ca2+ countertransport (antiport).

III. OSMOSIS
A. Osmolarity
is the concentration of osmotically active particles in a solution.
is a colligative property that can be measured by freezing point
depression.
can be calculated using the following equation:
Osmolarity = g × C
where:
Osmolarity = concentration of particles (Osm/L)