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Ebook Goodman Gilmans The Pharmacological Basis of Therapeutics PDF Full Chapter PDF
Ebook Goodman Gilmans The Pharmacological Basis of Therapeutics PDF Full Chapter PDF
Editor-in-chief
Laurence L. Brunton, PhD
Professor of Pharmacology and Medicine
School of Medicine, University of California, San Diego
La Jolla, California
Editors
Randa Hilal-Dandan, PhD
Lecturer in Pharmacology
School of Medicine, University of California, San Diego
La Jolla, California
Björn C. Knollmann, MD, PhD
William Stokes Professor of Medicine and Pharmacology
Director, Vanderbilt Center for Arrhythmia Research and Therapeutics
Division of Clinical Pharmacology
Vanderbilt University School of Medicine
Nashville, Tennessee
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In Memoriam
Contributors
Seattle, Washington Indiana University
Bloomington, Indiana
Edwin K. Jackson, PhD
Professor of Pharmacology and Chemical Biology Jody Mayfield, PhD
University of Pittsburgh School of Medicine Science Writer and Editor
Pittsburgh, Pennsylvania Waggoner Center for Alcohol and Addiction Research
University of Texas
Kenneth Kaushansky, MD Austin, Texas
Dean, School of Medicine and Senior Vice President of Health Sciences
SUNY Stony Brook James McCarthy, MD
New York, New York Senior Scientist QIMR Berghofer Intitute of Medical Research
Department of Infectious Diseases, Royal Brisbane
Jennifer Keiser, PhD and Womens Hospital
Professor of Neglected Tropical Diseases Brisbane, Queensland, Australia
Swiss Tropical and Public Health Institute
Basel, Switzerland James O. McNamara, MD
Professor and Chair of Neurobiology
Thomas J. Kipps, MD, PhD Director of Center for Translational Neuroscience
Professor of Medicine, Moores Cancer Center Duke University Medical Center
University of California Durham, North Carolina
San Diego, California
Cameron S. Metcalf, PhD
Jennifer J. Kiser, PharmD Research Assistant Professor
Associate Professor, Pharmaceutical Sciences Associate Director, Anticonvulsant Drug Development Program
University of Colorado Department of Pharmacology & Toxicology
Denver, Colorado College of Pharmacy
University of Utah
Ronald J. Koenig, MD, PhD
Salt Lake City, Utah
Professor of Metabolism, Endocrinology and Diabetes
Department of Internal Medicine Jonathan M. Meyer, MD
University of Michigan Health System Psychopharmacology Consultant
Ann Arbor, Michigan California Department of State Hospitals
Assistant Clinical Professor of Psychiatry
George F. Koob, PhD
University of California
Director, National Institute on Alcohol Abuse and Alcoholism
San Diego, California
National Institutes of Health
Rockville, Maryland S. John Mihic, PhD
Professor of Neuroscience
Alan M. Krensky, MD
Waggoner Center for Alcohol & Addiction Research
Vice Dean
University of Texas
Professor of Pediatrics and Microbiology & Immunology
Austin, Texas
Feinberg School of Medicine
Northwestern University Mark E. Molitch, MD
Chicago, Illinois Martha Leland Sherwin Professor of Endocrinology
Northwestern University
Ellis R. Levin, MD
Chicago, Illinois
Professor of Medicine; Chief of Endocrinology
Diabetes and Metabolism Dean S. Morrell, MD
University of California, Irvine, and Long Beach Professor of Dermatology
VA Medical Center University of North Carolina
Long Beach, California Chapel Hill, North Carolina
Heather Macarthur, PhD Thomas D. Nolin, PharmD, PhD
Associate Professor of Pharmacology and Physiology Associate Professor of Pharmacy and Therapeutics, and of Medicine
Saint Louis University School of Medicine University of Pittsburgh School of Pharmacy and School of Medicine
St. Louis, Missouri Pittsburgh, Pennsylvania
Conan MacDougall, PharmD, MAS Charles P. O’Brien, MD, PhD
Professor of Clinical Pharmacy Professor of Psychiatry, School of Medicine
School of Pharmacy University of Pennsylvania
University of California Philadelphia, Pennsylvania
San Francisco, California
Contributors
Emer M. Smyth, PhD Professor of Oncology and Pharmacology
Director, Cancer Research Alliances Georgetown University, School of Medicine
Assistant Dean for Cancer Research Washington DC
Assistant Professor, Pathology and Cell Biology
Herbert Irving Comprehensive Cancer Center Jürgen Wess, PhD
Columbia University Medical Center Chief, Molecular Signaling Section
New York, New York Lab. of Bioorganic Chemistry
National Institute of Diabetes and Digestive and Kidney Diseases
Peter J. Snyder, MD Bethesda, Maryland
Professor of Medicine
University of Pennsylvania David P. Westfall, PhD
Philadelphia, Pennsylvania Professor (Emeritus) of Pharmacology
University of Nevada School of Medicine
Yuichi Sugiyama, PhD Reno, Nevada
Head of Sugiyama Laboratory
RIKEN Innovation Center Thomas C. Westfall, PhD
RIKEN Yokohama Professor and Chair Emeritus, Department of Pharmacology
Yokohama, Japan and Physiology
Saint Louis University School of Medicine
Palmer Taylor, PhD St. Louis, Missouri
Sandra & Monroe Trout Professor of Pharmacology,
School of Medicine Dawn M. Wetzel, MD, PhD
Dean Emeritus, Skaggs School of Pharmacy and Assistant Professor of Pediatrics (Division of Infectious Diseases)
Pharmaceutical Sciences and Pharmacology
University of California University of Texas Southwestern Medical Center
San Diego, California Dallas, Texas
The first edition of this book appeared in 1941, the product of a Hilal-Dandan and I prepared a shortened version of each chapter and then
collaboration between two friends and professors at Yale, Louis Goodman invited contributors to add back old material that was essential and to add
and Alfred Gilman. Their purpose, stated in the preface to that edition, was new material. We also elected to discard the use of extract (very small) type
to correlate pharmacology with related medical sciences, to reinterpret the and to use more figures to explain signaling pathways and mechanisms of
actions and uses of drugs in light of advances in medicine and the basic drug action. Not wanting to favor one company’s preparation of an agent
biomedical sciences, to emphasize the applications of pharmacodynamics over that of another, we have ceased to use trade names except as needed
to therapeutics, and to create a book that would be useful to students of to refer to drug combinations or to distinguish multiple formulations of
pharmacology and to physicians. We continue to follow these principles the same agent with distinctive pharmacokinetic or pharmacodynamic
in the 13th edition. properties. Counter-balancing this shortening are five new chapters that
The 1st edition was quite successful despite its high price, $12.50, reflect advances in the therapeutic manipulation of the immune system,
and soon became known as the “blue bible of pharmacology.” The book the treatment of viral hepatitis, and the pharmacotherapy of cardiovascular
was evidence of the deep friendship between its authors, and when the disease and pulmonary artery hypertension.
Gilmans’ son was born in 1941, he was named Alfred Goodman Gilman. Editing such a book brings into view a number of overarching issues:
World War II and the relocation of both authors—Goodman to Utah, Over-prescribing of antibiotics and their excessive use in agricultural
Gilman to Columbia—postponed a second edition until 1955. The animal husbandry continues to promote the development of antimicrobial
experience of writing the second edition during a period of accelerating resistance; the application of CRISPR/cas9 will likely provide new
basic research and drug development persuaded the authors to become therapeutic avenues; global warming and the sheer size of the human
editors, relying on experts whose scholarship they trusted to contribute population require medical scientists and practitioners to promote
individual chapters, a pattern that has been followed ever since. remedial and preventive action based on data, not ideology.
Alfred G. Gilman, the son, served as an associate editor for the 5th A number of people have made invaluable contributions to the
edition (1975), became the principal editor for the 6th (1980), 7th (1985), preparation of this edition. My thanks to Randa Hilal-Dandan and Bjorn
and 8th (1990) editions, and consulting editor for the 9th and 10th editions Knollmann for their editorial work; to Harriet Lebowitz of McGraw-Hill,
that were edited by Lee Limbird and Joel Hardman. After an absence in the who guided our work, prescribed the updated style, and kept the project
11th edition, Al Gilman agreed to co-author the introductory chapter in moving to completion; to Vastavikta Sharma of Cenveo Publishers Services,
the 12th edition. His final contribution to G&G, a revision of that chapter, who oversaw the copy editing, typesetting, and preparation of the artwork;
is the first chapter in this edition, which we dedicate to his memory. to Nelda Murri, our consulting pharmacist, whose familiarity with clinical
A multi-authored text of this sort grows by accretion, posing challenges pharmacy is evident throughout the book; to James Shanahan, publisher
to editors but also offering 75 years of wisdom, memorable pearls, and at McGraw-Hill, for supporting the project; and to the many readers who
flashes of wit. Portions of prior editions persist in the current edition, have written to critique the book and offer suggestions.
and we have given credit to recent former contributors at the end of
Laurence L. Brunton
each chapter. Such a text also tends to grow in length with each edition,
San Diego, CA
as contributors add to existing text and as pharmacotherapy advances.
1 September 2017
To keep the length manageable and in a single volume, Dr. Randa
CLINICAL TRIALS
■■ Role of the FDA
■■ The Conduct of Clinical Trials
SOURCES OF DRUGS ■■ Determining “Safe” and “Effective”
■■ Small Molecules Are the Tradition
■■ From Hits to Leads
PERSONALIZED MEDICINE
■■ Large Molecules Are Increasingly Important
PUBLIC POLICY CONSIDERATIONS AND CRITICISMS OF THE
TARGETS OF DRUG ACTION PHARMACEUTICAL INDUSTRY
■■ Is the Target Drugable? ■■ Who Pays?
■■ Has the Target Been Validated? ■■ Intellectual Property and Patents
■■ Is This Drug Invention Effort Economically Viable? ■■ Drug Promotion
■■ Concerns about Global Injustice
ADDITIONAL PRECLINICAL RESEARCH ■■ Product Liability
■■ “Me Too” Versus True Innovation: The Pace of New Drug Development
The first edition of Goodman & Gilman, published in 1941, helped to of goats that gamboled and frisked through the night after eating the
organize the field of pharmacology, giving it intellectual validity and an berries of the coffee plant; the use of mushrooms and the deadly night-
academic identity. That edition began: “The subject of pharmacology is a shade plant by professional poisoners; of belladonna (“beautiful lady”) to
broad one and embraces the knowledge of the source, physical and chem- dilate pupils; of the Chinese herb ma huang (containing ephedrine) as a
ical properties, compounding, physiological actions, absorption, fate, and circulatory stimulant; of curare by South American Indians to paralyze
excretion, and therapeutic uses of drugs. A drug may be broadly defined and kill animals hunted for food; and of poppy juice (opium) containing
as any chemical agent that affects living protoplasm, and few substances morphine (from the Greek Morpheus, the God of dreams) for pain relief
would escape inclusion by this definition.” This General Principles sec- and control of dysentery. Morphine, of course, has well-known addicting
tion provides the underpinnings for these definitions by exploring the properties, mimicked in some ways by other problematic (“recreational”)
processes of drug invention, development, and regulation, followed by natural products—nicotine, cocaine, and ethanol.
the basic properties of the interactions between the drug and biological Although terrestrial and marine organisms remain valuable sources
systems: pharmacodynamics, pharmacokinetics (including drug transport of compounds with pharmacological activities, drug invention became
and metabolism), and pharmacogenomics, with a brief foray into drug more allied with synthetic organic chemistry as that discipline flour-
toxicity and poisoning. Subsequent sections deal with the use of drugs as ished over the past 150 years, beginning in the dye industry. Dyes are
therapeutic agents in human subjects. colored compounds with selective affinity for biological tissues. Study of
Use of the term invention to describe the process by which a new drug these interactions stimulated Paul Ehrlich to postulate the existence of
is identified and brought to medical practice, rather than the more con- chemical receptors in tissues that interacted with and “fixed” the dyes.
ventional term discovery, is intentional. Today, useful drugs are rarely Similarly, Ehrlich thought that unique receptors on microorganisms or
discovered hiding somewhere waiting to be found. The term invention parasites might react specifically with certain dyes and that such selectivity
emphasizes the process by which drugs are sculpted and brought into could spare normal tissue. Ehrlich’s work culminated in the invention of
being based on experimentation and optimization of many independent arsphenamine in 1907, which was patented as “salvarsan,” suggestive of
properties; there is little serendipity. the hope that the chemical would be the salvation of humankind. This and
other organic arsenicals were used for the chemotherapy of syphilis until
the discovery of penicillin. The work of Gerhard Domagk demonstrated
From Early Experiences With Plants to that another dye, prontosil (the first clinically useful sulfonamide), was
Modern Chemistry dramatically effective in treating streptococcal infections, launching the
era of antimicrobial chemotherapy.
The human fascination—and sometimes infatuation—with chemicals that The collaboration of pharmacology with chemistry on the one hand and
alter biological function is ancient and results from long experience with with clinical medicine on the other has been a major contributor to the effec-
and dependence on plants. Because most plants are root bound, many of tive treatment of disease, especially since the middle of the 20th century.
them produce harmful compounds for defense that animals have learned
to avoid and humans to exploit (or abuse).
Earlier editions of this text described examples: the appreciation of cof- Sources of Drugs
fee (caffeine) by the prior of an Arabian convent, who noted the behavior
Small Molecules Are the Tradition
*
Deceased, December 23, 2015. AGG served on the Board of Directors of Regeneron With the exception of a few naturally occurring hormones (e.g., insulin),
Pharmaceuticals, Inc., a potential conflict of interest. most drugs were small organic molecules (typically <500 Da) until
BLA: Biologics License Application the structure provides the chemist with information about substitutions
CDC: Centers for Disease Control and Prevention likely to improve the “fit” of the drug with the target and thus enhance
CDER: Center for Drug Evaluation and Research the affinity of the drug for its target. Nuclear magnetic resonance (NMR)
DHHS: U.S. Department of Health and Human Services studies of the drug-receptor complex also can provide useful information
(albeit usually at lower resolution), with the advantage that the complex
FDA: U.S. Food and Drug Administration
need not be crystallized.
HCV: hepatitis C virus
The holy grail of this approach to drug invention is to achieve success
HMG CoA: 3-hydroxy-3-methylglutaryl coenzyme A
entirely through computation. Imagine a database containing detailed
IND: Investigational New Drug
chemical information about millions of chemicals and a second database
LDL: low-density lipoprotein
containing detailed structural information about all human proteins. The
NDA: New Drug Application
computational approach is to “roll” all the chemicals over the protein of
NIH: National Institutes of Health interest to find those with high-affinity interactions. The dream becomes
NMEs: New Molecular Entities bolder if we acquire the ability to roll the chemicals that bind to the target
NMR: nuclear magnetic resonance of interest over all other human proteins to discard compounds that have
PCSK9: proprotein convertase subtilisin/kexin type 9 unwanted interactions. Finally, we also will want to predict the structural
PDUFA: Prescription Drug User Fee Act and functional consequences of a drug binding to its target (a huge chal-
PhRMA: Pharmaceutical Research and Manufacturers of lenge), as well as all relevant pharmacokinetic properties of the molecules
America of interest. Indeed, computational approaches have suggested new uses
R&D: research and development for old drugs and offered explanations for recent failures of drugs in the
SCHIP: State Children’s Health Insurance Program later stages of clinical development (e.g., torcetrapib; see Box 1-2)
siRNAs: small interfering RNAs (Xie et al., 2007, 2009).
to the Food, Drug, and Cosmetic Act in 1962. These amendments estab- resources. The PDUFA also broadened the FDA’s drug safety program and
lished the requirement for proof of efficacy as well as documentation of increased resources for review of television drug advertising. Under the
relative safety in terms of the risk-to-benefit ratio for the disease entity to PDUFA, once an NDA is submitted to the FDA, review typically takes
be treated (the more serious the disease, the greater the acceptable risk). 6–10 months. During this time, numerous review functions are usu-
Today, the FDA faces an enormous challenge, especially in view of the ally performed, including advisory committee meetings, amendments,
widely held belief that its mission cannot possibly be accomplished with manufacturing facility inspections, and proprietary name reviews (FDA,
the resources allocated by Congress. Moreover, harm from drugs that 2013a). Before a drug is approved for marketing, the company and the
cause unanticipated adverse effects is not the only risk of an imperfect FDA must agree on the content of the “label” (package insert)—the official
system; harm also occurs when the approval process delays the approval prescribing information. This label describes the approved indications for
of a new drug with important beneficial effects. use of the drug and clinical pharmacological information, including dos-
age, adverse reactions, and special warnings and precautions (sometimes
The Conduct of Clinical Trials posted in a “black box”).
Clinical trials of drugs are designed to acquire information about the Promotional materials used by pharmaceutical companies cannot devi-
pharmacokinetic and pharmacodynamic properties of a candidate drug ate from information contained in the package insert. Importantly, the
in humans. Efficacy must be proven and an adequate margin of safety physician is not bound by the package insert; a physician in the U.S. may
established for a drug to be approved for sale in the U.S. legally prescribe a drug for any purpose that he or she deems reasonable.
The U.S. NIH identifies seven ethical principles that must be satisfied However, third-party payers (insurance companies, Medicare, and so
before a clinical trial can begin: on) generally will not reimburse a patient for the cost of a drug used for
an “off-label” indication unless the new use is supported by a statutorily
1. Social and clinical value named compendium (e.g., the AHFS-DI). Furthermore, a physician may
2. Scientific validity be vulnerable to litigation if untoward effects result from an unapproved
3. Fair selection of subjects use of a drug.
4. Informed consent
5. Favorable risk-benefit ratio Determining “Safe” and “Effective”
6. Independent review
7. Respect for potential and enrolled subjects (NIH, 2011). Demonstrating efficacy to the FDA requires performing “adequate and
well-controlled investigations,” generally interpreted to mean two repli-
The FDA-regulated clinical trials typically are conducted in four phases. cate clinical trials that are usually, but not always, randomized, double
Phases I-III are designed to establish safety and efficacy, while phase IV blind, and placebo (or otherwise) controlled.
postmarketing trials delineate additional information regarding new indi- Is a placebo the proper control? The World Medical Association’s Dec-
cations, risks, and optimal doses and schedules. Table 1–1 and Figure 1–1 laration of Helsinki (World Medical Association 2013) discourages use of
summarize the important features of each phase of clinical trials; note the placebo controls when an alternative treatment is available for compari-
attrition at each successive stage over a relatively long and costly process. son because of the concern that study participants randomized to placebo
When initial phase III trials are complete, the sponsor (usually a pharma- in such a circumstance would, in effect, be denied treatment during the
ceutical company) applies to the FDA for approval to market the drug; conduct of the trial.
this application is called either an NDA or a BLA. These applications con- What must be measured in the trials? In a straightforward trial, a read-
tain comprehensive information, including individual case report forms ily quantifiable parameter (a secondary or surrogate end point), thought to
from the hundreds or thousands of individuals who have received the be predictive of relevant clinical outcomes, is measured in matched drug-
drug during its phase III testing. Applications are reviewed by teams of and placebo-treated groups. Examples of surrogate end points include
TABLE 1–1 ■ TYPICAL CHARACTERISTICS OF THE VARIOUS PHASES OF THE CLINICAL TRIALS REQUIRED FOR
MARKETING OF NEW DRUGS
PHASE I PHASE II PHASE III PHASE IV
FIRST IN HUMAN FIRST IN PATIENT MULTISITE TRIAL POSTMARKETING SURVEILLANCE
10–100 participants 50–500 participants A few hundred to a few thousand Many thousands of participants
participants
Usually healthy volunteers; Patient-subjects receiving Patient-subjects receiving Patients in treatment with
occasionally patients with experimental drug experimental drug approved drug
advanced or rare disease
Open label Randomized and controlled Randomized and controlled Open label
(can be placebo controlled); (can be placebo controlled) or
may be blinded uncontrolled; may be blinded
Safety and tolerability Efficacy and dose ranging Confirm efficacy in larger Adverse events, compliance,
population drug-drug interactions
1–2 years 2–3 years 3–5 years No fixed duration
U.S. $10 million U.S. $20 million U.S. $50–100 million —
Success rate: 50% Success rate: 30% Success rate: 25%–50% —
7 Phase II
2–5
Years 6 5–10 Phase I
5 Preclinical tests
(animal)
4
10–20
3
Basic research Synthesis,
2 examination,
screening
1
10,000–25,000
0
Number of chemical entities
Figure 1–1 The phases, time lines, and attrition that characterize the invention of new drugs. See also Table 1–1.
LDL cholesterol as a predictor of myocardial infarction, bone mineral incidence of untoward effects become known only after a drug is released
density as a predictor of fractures, or hemoglobin A1c as a predictor of the to the broader market and used by a large number of people (phase IV,
complications of diabetes mellitus. More stringent trials would require postmarketing surveillance). Drug development costs and drug prices
demonstration of reduction of the incidence of myocardial infarction in could be reduced substantially if the public were willing to accept more
patients taking a candidate drug in comparison with those taking an HMG risk. This would require changing the way we think about a pharmaceu-
CoA reductase inhibitor (statin) or other LDL cholesterol-lowering agent tical company’s liability for damages from an unwanted effect of a drug
or reduction in the incidence of fractures in comparison with those taking that was not detected in clinical trials deemed adequate by the FDA. While
a bisphosphonate. Use of surrogate end points significantly reduces cost the concept is obvious, many lose sight of the fact that extremely severe
and time required to complete trials, but there are many mitigating factors, unwanted effects of a drug, including death, may be deemed acceptable if
including the significance of the surrogate end point to the disease that the its therapeutic effect is sufficiently unique and valuable. Such dilemmas
candidate drug is intended to treat. are not simple and can become issues for great debate.
Some of the difficulties are well illustrated by experiences with eze- Several strategies exist to detect adverse reactions after marketing of a
timibe, a drug that inhibits absorption of cholesterol from the gastrointes- drug. Formal approaches for estimation of the magnitude of an adverse
tinal tract and lowers LDL cholesterol concentrations in blood, especially drug response include the follow-up or “cohort” study of patients who
when used in combination with a statin. Lowering of LDL cholesterol was are receiving a particular drug; the “case-control” study, in which the fre-
assumed to be an appropriate surrogate end point for the effectiveness quency of drug use in cases of adverse responses is compared to controls;
of ezetimibe to reduce myocardial infarction and stroke, and the drug and meta-analysis of pre- and postmarketing studies. Voluntary reporting
was approved based on such data. Surprisingly, a subsequent clinical of adverse events has proven to be an effective way to generate an early sig-
trial (ENHANCE) demonstrated that the combination of ezetimibe and nal that a drug may be causing an adverse reaction (Aagard and Hansen,
a statin did not reduce intima media thickness of carotid arteries (a more 2009). The primary sources for the reports are responsible, alert physi-
direct measure of subendothelial cholesterol accumulation) compared cians; third-party payers (pharmacy benefit managers, insurance com-
with the statin alone, despite the fact that the drug combination lowered panies) and consumers also play important roles. Other useful sources
LDL cholesterol concentrations substantially more than did either drug are nurses, pharmacists, and students in these disciplines. In addition,
alone (Kastelein et al., 2008). hospital-based pharmacy and therapeutics committees and quality assur-
Critics of ENHANCE argued that the patients in the study had famil- ance committees frequently are charged with monitoring adverse drug
ial hypercholesterolemia, had been treated with statins for years, and did reactions in hospitalized patients. In 2013, the reporting system in the
not have carotid artery thickening at the initiation of the study. Should U.S., called MedWatch, celebrated its 20th anniversary and announced
ezetimibe have been approved? Must we return to measurement of true improvements designed to encourage reporting by consumers (FDA,
clinical end points (e.g., myocardial infarction) before approval of drugs 2013b). The simple forms for reporting may be obtained 24 hours a day,
that lower cholesterol by novel mechanisms? The costs involved in such 7 days a week, by calling 800-FDA-1088; alternatively, adverse reactions
extensive and expensive trials must be borne somehow (see below). A
follow-up 7-year study involving over 18,000 patients (IMPROVE-IT)
vindicated the decision to approve ezetimibe (Jarcho and Keaney, 2015). BOX 1–2 ■ A Late Surprise in the Development of a Blockbuster
Taken in conjunction with a statin, the drug significantly reduced the inci- Torcetrapib elevates high-density lipoprotein (HDL) cholesterol
dence of myocardial infarction and stroke in high-risk patients (Box 1–2). (the “good cholesterol”), and higher levels of HDL cholesterol
No drug is totally safe; all drugs produce unwanted effects in at least are statistically associated with (are a surrogate end point for) a
some people at some dose. Many unwanted and serious effects of drugs lower incidence of myocardial infarction. Surprisingly, clinical
occur so infrequently, perhaps only once in several thousand patients, that administration of torcetrapib caused a significant increase in mortality
they go undetected in the relatively small populations (a few thousand) from cardiovascular events, ending a development path of 15 years
in the standard phase III clinical trial (see Table 1–1). To detect and verify and $800 million. In this case, approval of the drug based on this
that such events are, in fact, drug-related would require administration of secondary end point would have been a mistake (Cutler, 2007). A
the drug to tens or hundreds of thousands of people during clinical trials, computational systems analysis suggested a mechanistic explanation
adding enormous expense and time to drug development and delaying of this failure (Xie et al., 2009).
access to potentially beneficial therapies. In general, the true spectrum and
Personalized (Individualized, Precision) costs by choosing not to cover certain “brand-name” products (discussed
Medicine later). Further, a few drugs (especially for treatment of cancer) have been
introduced to the market in recent years at prices that greatly exceeded
Drug inventors strive to “fit” the drug to the individual patient. To realize the costs of development, manufacture, and marketing of the product.
the full potential of this approach, however, requires intimate knowledge Many of these products were discovered in government laboratories or in
of the considerable heterogeneity of both the patient population and the university laboratories supported by federal grants.
targeted disease process. Why does one antidepressant appear to amelio- The U.S. is the only large country that places no controls on drug prices
rate depression in a given patient, while another with the same or very and where price plays no role in the drug approval process. Many U.S.
similar presumed mechanism of action does not? Is this a difference in drugs cost much more in the U.S. than overseas; thus, U.S. consumers
the patient’s response to the drug; in patient susceptibility to the drug’s subsidize drug costs for the rest of the world, and they are irritated by that
unwanted effects; in the drug’s ADME; or in the etiology of the depres- fact. The example of new agents for the treatment of hepatitis C infection
sion? By contrast, how much of this variability is attributable to environ- brings many conflicting priorities into perspective (Box 1–3).
mental factors and possibly their interactions with patient-specific genetic The drug development process is long, expensive, and risky (see Figure
variability? Recent advances, especially in genetics and genomics, provide 1–1 and Table 1–1). Consequently, drugs must be priced to recover the
powerful tools for understanding this heterogeneity. The single most pow- substantial costs of invention and development and to fund the market-
erful tool for unraveling these myriad mysteries is the ability to sequence ing efforts needed to introduce new products to physicians and patients.
DNA rapidly and economically. The cost of sequencing a human genome Nevertheless, as U.S. healthcare spending continues to rise at an alarming
has fallen by six orders of magnitude since the turn of the 21st century, pace, prescription drugs account for only about 10% of total U.S. health-
and the speed of the process has increased correspondingly. The current care expenditures (CDC, 2013), and a significant fraction of this drug
focus is on the extraordinarily complex analysis of the enormous amounts cost is for low-priced, nonproprietary medicines. Although the increase
of data now being obtained from many thousands of individuals, ideally in prices is significant in certain classes of drugs (e.g., anticancer agents),
in conjunction with deep knowledge of their phenotypic characteristics, the total price of prescription drugs is growing at a slower rate than
especially including their medical history. other healthcare costs. Even drastic reductions in drug prices that would
Readily measured biomarkers of disease are powerful adjuncts to DNA
sequence information. Simple blood or other tests can be developed to
monitor real-time progress or failure of treatment, and many such exam-
ples already exist. Similarly, chemical, radiological, or genetic tests may be BOX 1–3 ■ The Cost of Treating Hepatitis C
useful not only to monitor therapy but also to predict success or failure, Infection with hepatitis C virus (HCV) is a chronic disease afflicting
anticipate unwanted effects of treatment, or appreciate pharmacokinetic millions of people. Some suffer little from this condition; many others
variables that may require adjustments of dosage or choice of drugs. Such eventually develop cirrhosis or hepatocellular carcinoma. Who should
tests already play a significant role in the choice of drugs for cancer che- be treated? The answer is unknown. Until recently, the treatment
motherapy, and the list of drugs specifically designed to “hit” a mutated of choice for people with genotype 1 HCV involved year-long
target in a specific cancer is growing. Such information is also becom- administration of an interferon (by injection) in combination with
ing increasing useful in the choice of patients for clinical trials of specific ribavirin and a protease inhibitor. Unwanted effects of this regimen
agents—thereby reducing the time required for such trials and their cost, are frequent and severe (some say worse than the disease); cure rates
to say nothing of better defining the patient population who may benefit range from 50% to 75%. A newer treatment involves an oral tablet
from the drug. These important subjects are discussed in detail in Chapter 7, containing a combination of sofosbuvir and ledipasvir (see Chapter 63).
Pharmacogenetics. Treatment usually requires daily ingestion of one tablet, for
8–12 weeks; cure rates exceed 95%, and side effects are minimal.
Controversy surrounds the price of the treatment, about $1000/d.
Public Policy Considerations and Criticisms of Some insurers refused to reimburse this high cost, relegating many
the Pharmaceutical Industry patients to less-effective, more toxic, but less-expensive treatment.
However, these third-party payers have negotiated substantial
Drugs can save lives, prolong lives, and improve the quality of people’s discounts of the price, based on the availability of a competing
lives. However, in a free-market economy, access to drugs is not equitable. product. Is the cost exorbitant? Should insurers, rather than patients
Not surprisingly, there is tension between those who treat drugs as enti- and their physicians, be making such important decisions?
tlements and those who view drugs as high-tech products of a capitalistic Continued and excessive escalation of drug and other healthcare
society. Supporters of the entitlement position argue that a constitutional costs will bankrupt the healthcare system. The question of appropriate
right to life should guarantee access to drugs and other healthcare, and cost involves complex pharmacoeconomic considerations. What are
they are critical of pharmaceutical companies and others who profit from the relative costs of the two treatment regimens? What are the savings
the business of making and selling drugs. Free-marketers point out that, from elimination of the serious sequelae of chronic HCV infection?
without a profit motive, it would be difficult to generate the resources and How does one place value to the patient on the less-toxic and more
innovation required for new drug development. Given the public interest effective and convenient regimen? What are the profit margins of
in the pharmaceutical industry, drug development is both a scientific pro- the company involved? Who should make decisions about costs
cess and a political one in which attitudes can change quickly. Two decades and choices of patients to receive various treatments? How should
ago, Merck was named as America’s most admired company by Fortune we consider cases (unlike that for HCV) for which the benefits are
magazine 7 years in a row—a record that still stands. In the 2015 survey quite modest, such as when a very expensive cancer drug extends
of the most admired companies in the U.S., no pharmaceutical company life only briefly? One astute observer (and an industry critic of many
ranked in the top 10. drug prices) summarized the situation as follows: “great, important
Critics of the pharmaceutical industry frequently begin from the posi- problem; wrong example.”
tion that people (and animals) need to be protected from greedy and
information is presented by non-sales representatives are widespread. arm following inadvertent arterial administration of the antinausea drug
Large numbers of physicians are paid as “consultants” to make presen- promethazine. She subsequently lost her hand. The healthcare provider
tations in such settings. The acceptance of any gift, no matter how small, had intended to administer the drug by so-called intravenous push. The
from a drug company by a physician is now forbidden at many academic FDA-approved label for the drug warned against, but did not prohibit,
medical centers and by law in several states. In 2009, the board of directors administration by intravenous push. The state court and then the U.S.
of PhRMA adopted an enhanced Code on Interactions With Healthcare Supreme Court held both the healthcare provider and the company liable
Professionals that prohibits the distribution of noneducational items, pro- for damages. Specifically, the Vermont court found that Wyeth had inad-
hibits company sales representatives from providing restaurant meals to equately labeled the drug. This means that FDA approval of the label does
healthcare professionals (although exceptions are granted when a third- not protect a company from liability or prevent individual states from
party speaker makes the presentation), and requires companies to ensure imposing regulations more stringent than those required by the federal
that their representatives are trained about laws and regulations that gov- government.
ern interactions with healthcare professionals.
“Me Too” Versus True Innovation: The Pace of
Concerns About Global Injustice New Drug Development
Because development of new drugs is so expensive, private-sector invest- Me-too drug is a term used to describe a pharmaceutical that is usually
ment in pharmaceutical innovation has focused on products that will structurally similar to a drug already on the market. Other names used
have lucrative markets in wealthy countries such as the U.S., which com- are derivative medications, molecular modifications, and follow-up drugs.
bines patent protection with a free-market economy. Accordingly, there is In some cases, a me-too drug is a different molecule developed deliber-
concern about the degree to which U.S. and European patent protection ately by a competitor company to take market share from the company
laws have restricted access to potentially lifesaving drugs in developing with existing drugs on the market. When the market for a class of drugs
countries. is especially large, several companies can share the market and make a
To lower costs, pharmaceutical companies increasingly test their exper- profit. Other me-too drugs result coincidentally from numerous compa-
imental drugs outside the U.S. and the E.U., in developing countries where nies developing products simultaneously without knowing which drugs
there is less regulation and easier access to large numbers of patients. will be approved for sale (Box 1–4).
According to the U.S. DHHS, there has been a 2000% increase in foreign There are valid criticisms of me-too drugs. First, an excessive emphasis
trials of U.S. drugs over the past 25 years. When these drugs are success- on profit may stifle true innovation. Of the 487 drugs approved by the FDA
ful in obtaining marketing approval, consumers in the countries where between 1998 and 2003, only 67 (14%) were considered by the FDA to be
the trials were conducted often cannot afford them. Some ethicists have NMEs. Between 1998 and 2011, on average only 24 NMEs were approved
argued that this practice violates the justice principle articulated in the by the FDA’s CDER. Second, some me-too drugs are more expensive than
Belmont Report (DHHS, 1979, p10), which states that “research should the older versions they seek to replace, increasing the costs of healthcare
not unduly involve persons from groups unlikely to be among the bene- without corresponding benefit to patients. Nevertheless, for some patients,
ficiaries of subsequent applications of the research.” A counterargument me-too drugs may have better efficacy or fewer side effects or promote com-
is that the conduct of trials in developing nations also frequently brings pliance with the treatment regimen. For example, the me-too that can be
needed medical attention to underserved populations. This is another taken once a day rather than more frequently is convenient and promotes
controversial issue. compliance. Some me-too drugs add great value from a business and med-
ical point of view. Atorvastatin was the seventh statin to be introduced to
Product Liability market; it subsequently became the best-selling drug in the world.
Critics argue that pharmaceutical companies are not innovative and
Product liability laws are intended to protect consumers from defective
do not take risks, and, further, that medical progress is actually slowed by
products. Pharmaceutical companies can be sued for faulty design or
their excessive concentration on me-too products. Figure 1–2 summarizes
manufacturing, deceptive promotional practices, violation of regulatory
a few of the facts behind this and other arguments. Clearly, only a modest
requirements, or failure to warn consumers of known risks. So-called
number of NMEs, about two dozen a year, achieved FDA approval in the
failure-to-warn claims can be made against drug makers even when
years 1980 to 2011, with the exception of the several-year spike in
the product is approved by the FDA. With greater frequency, courts are
approvals following the introduction of PDUFA. Yet, from 1980 to 2010,
finding companies that market prescription drugs directly to consumers
the industry’s annual investment in research and development grew from
responsible when these advertisements fail to provide an adequate warn-
ing of potential adverse effects.
Although injured patients are entitled to pursue legal remedies, the neg-
ative effects of product liability lawsuits against pharmaceutical companies BOX 1–4 ■ A Not-So-New Drug
may be considerable. First, fear of liability may cause pharmaceutical com- Some me-too drugs are only slightly altered formulations of
panies to be overly cautious about testing, thereby delaying access to the a company’s own drug, packaged and promoted as if really
drug. Second, the cost of drugs increases for consumers when pharmaceu- offering something new. An example is the heartburn medication
tical companies increase the length and number of trials they perform to esomeprazole, marketed by the same company that makes
identify even the smallest risks and when regulatory agencies increase the omeprazole. Omeprazole is a mixture of two stereoisomers;
number or intensity of regulatory reviews. Third, excessive liability costs esomeprazole contains only one of the isomers and is eliminated less
create disincentives for development of so-called orphan drugs, pharma- rapidly. Development of esomeprazole created a new period of market
ceuticals that benefit a small number of patients. Should pharmaceutical exclusivity, although generic versions of omeprazole are marketed, as
companies be liable for failure to warn when all of the rules were followed are branded congeners of omeprazole/esomeprazole. Both omeprazole
and the product was approved by the FDA but the unwanted effect was and esomeprazole are now available over the counter—narrowing the
not detected because of its rarity or another confounding factor? The only previous price difference.
way to find “all” of the unwanted effects that a drug may have is to market
)
)
) or BLAs (
PhRMA R&D expenditures (in billions) (
No. of approved NMEs ( 40 40
30 30
20 20
10 10
0 0
1980 1990 2000 2010 2015
Year
Figure 1–2 The cost of drug invention is rising. Is productivity? Each horizontal black line shows the average annual number of NMEs or BLAs for the time period
bracketed by the line’s length.
$2 billion to $50 billion. This disconnect between research and devel- ForIndustry/UserFees/PrescriptionDrugUserFee/UCM350567.pdf.
opment investment and new drugs approved occurred at a time when Accessed June 19, 2015.
combinatorial chemistry was blooming, the human genome was being FDA. MedWatch: Improving on 20 Years of Excellence. FDA Voice.
sequenced, highly automated techniques of screening were being devel- 2013b. Available at: http://blogs.fda.gov/fdavoice/index.php/2013/06/
oped, and new techniques of molecular biology and genetics were offering medwatch-improving-on-20-years-of-excellence/. Accessed May 11, 2017.
novel insights into the pathophysiology of human disease. FDA. What we do. 2014. Available at: http://www.fda.gov/AboutFDA/
In recent years, there has been a modest increase in approval of NMEs WhatWeDo/. Accessed June 19, 2015.
(inhibitors of a number of protein kinases) and new biologics (numerous Horton JD, et al. PCSK9: a convertase that coordinates LDL catabolism.
therapeutic antibodies) (see Figure 1–2). A continued increase in pro- Lipid Res, 2009, 50:S172–S177.
ductivity will be needed to sustain today’s pharmaceutical companies as Jarcho JA, Keaney JF Jr. Proof that lower is better—LDL cholesterol and
they face waves of patent expirations. There are strong arguments that IMPROVE-IT. N Engl J Med, 2015, 372:2448–2450.
development of much more targeted, individualized drugs, based on a Kaiser J. Private money, public disclosure. Science, 2009, 325:28–30.
new generation of molecular diagnostic techniques and improved under- Kassirer JP. On the Take. How Medicine’s Complicity With Big Business
standing of disease in individual patients, will improve both medical care Can Endanger Your Health. Oxford University Press, New York, 2005.
Kastelein JJ, et al. Simvastatin with or without ezetimibe in familial
and the survival of pharmaceutical companies.
hypercholesterolemia. N Engl J Med, 2008, 358:1421–1443.
Finally, many of the advances in genetics and molecular biology are
Lincoln A. Second speech on discoveries and inventions. 1859. Available
still new, particularly when measured in the time frame required for drug
at: http://quod.lib.umich.edu/l/lincoln/lincoln3/1:87?rgn=div1;view=
development. One can hope that modern molecular medicine will sustain fulltext. Accessed May 8, 2017.
the development of more efficacious and more specific pharmacological NIH. Ethics in clinical research. 2011. Available at: http://clinicalcenter.
treatments for an ever-wider spectrum of human diseases. nih.gov/recruit/ethics.html. Accessed July 8, 2015.
Poirier S, Mayer G. The biology of PCSK9 from the endoplasmic
reticulum to lysosomes: new and emerging therapeutics to control
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2009–2013. 2013a. Available at: http://www.fda.gov/downloads/
EXCRETION OF DRUGS
■■ Renal Excretion
■■ Biliary and Fecal Excretion
■■ Excretion by Other Routes
DRUG ABSORPTION, BIOAVAILABILITY, AND ROUTES OF
ADMINISTRATION CLINICAL PHARMACOKINETICS
■■ Absorption and Bioavailability ■■ Clearance
■■ Routes of Administration ■■ Distribution
■■ Novel Methods of Drug Delivery ■■ Steady-State Concentration
■■ Half-Life
BIOEQUIVALENCE ■■ Extent and Rate of Absorption
■■ Nonlinear Pharmacokinetics
DISTRIBUTION OF DRUGS ■■ Design and Optimization of Dosage Regimens
■■ Not All Tissues Are Equal
■■ Binding to Plasma Proteins THERAPEUTIC DRUG MONITORING
■■ Tissue Binding
METABOLISM OF DRUGS
■■ A Few Principles of Metabolism and Elimination
■■ Prodrugs; Pharmacogenomics
The human body restricts access to foreign molecules; therefore, to reach oriented outward. Individual lipid molecules in the bilayer vary accord-
its target within the body and have a therapeutic effect, a drug molecule ing to the particular membrane and can move laterally and organize
must cross a number of restrictive barriers en route to its target site. Fol- themselves into microdomains (e.g., regions with sphingolipids and cho-
lowing administration, the drug must be absorbed and then distributed, lesterol, forming lipid rafts), endowing the membrane with fluidity, flexi-
usually via vessels of the circulatory and lymphatic systems; in addition bility, organization, high electrical resistance, and relative impermeability
to crossing membrane barriers, the drug must survive metabolism (pri- to highly polar molecules. Membrane proteins embedded in the bilayer
marily hepatic) and elimination (by the kidney and liver and in the feces). serve as structural anchors, receptors, ion channels, or transporters to
ADME, the absorption, distribution, metabolism, and elimination of transduce electrical or chemical signaling pathways and provide selec-
drugs, are the processes of pharmacokinetics (Figure 2–1). Understand- tive targets for drug actions. Far from being a sea of lipids with proteins
ing these processes and their interplay and employing pharmacokinetic floating randomly about, membranes are ordered and compartmented
principles increase the probability of therapeutic success and reduce the (Suetsugu et al., 2014), with structural scaffolding elements linking to
occurrence of adverse drug events. the cell interior. Membrane proteins may be associated with caveolin and
The absorption, distribution, metabolism, and excretion of a drug sequestered within caveolae, be excluded from caveolae, or be organized
involve its passage across numerous cell membranes. Mechanisms by in signaling domains rich in cholesterol and sphingolipid not containing
which drugs cross membranes and the physicochemical properties of mol- caveolin or other scaffolding proteins.
ecules and membranes that influence this transfer are critical to under-
standing the disposition of drugs in the human body. The characteristics Modes of Permeation and Transport
of a drug that predict its movement and availability at sites of action are its
Passive diffusion dominates transmembrane movement of most drugs.
molecular size and structural features, degree of ionization, relative lipid
However, carrier-mediated mechanisms (active transport and facilitated
solubility of its ionized and nonionized forms, and its binding to serum
diffusion) play important roles (Figure 2–2; Figure 5–4).
and tissue proteins. Although physical barriers to drug movement may be
a single layer of cells (e.g., intestinal epithelium) or several layers of cells Passive Diffusion
and associated extracellular protein (e.g., skin), the plasma membrane is In passive transport, the drug molecule usually penetrates by diffusion
the basic barrier. along a concentration gradient by virtue of its solubility in the lipid bilayer.
Such transfer is directly proportional to the magnitude of the concentra-
tion gradient across the membrane, to the lipid:water partition coefficient
Passage of Drugs Across Membrane Barriers of the drug, and to the membrane surface area exposed to the drug. At
steady state, the concentration of the unbound drug is the same on both
The Plasma Membrane Is Selectively Permeable sides of the membrane if the drug is a nonelectrolyte. For ionic com-
The plasma membrane consists of a bilayer of amphipathic lipids with pounds, the steady-state concentrations depend on the electrochemical
their hydrocarbon chains oriented inward to the center of the bilayer gradient for the ion and on differences in pH across the membrane, which
to form a continuous hydrophobic phase, with their hydrophilic heads will influence the state of ionization of the molecule disparately on either
[protonated form]
ABC: ATP-binding cassette log = p K a − pH (Equation 2–1)
[unprotonated form]
ACE: angiotensin-converting enzyme
Equation 2–1 relates the pH of the medium around the drug and the
CHAPTER 2
TISSUE RESERVOIRS
bound free
THERAPEUTIC
UNWANTED SITE
SITE OF ACTION
OF ACTION
“Receptors”
CENTRAL bound free
bound free
COMPARTMENT
ABSORPTION CLEARANCE
DRUG [FREE DRUG]
DOSE
LIBERATION EXCRETION
BIOTRANSFORMATION
Figure 2–1 The interrelationship of the absorption, distribution, binding, metabolism, and excretion of a drug and its concentration at its sites of action. Possible
distribution and binding of metabolites in relation to their potential actions at receptors are not depicted.
SECTION I
[K+] ~ 4 mm
+++ out
anti sym
––– in
ATP
[Na+] ~ 10 mm
[K+] ~ 150 mm
ADP Na+ X Na+ Y
GENERAL PRINCIPLES
+ K+
Pi
Figure 2–2 Drugs move across membrane and cellular barriers in a variety of ways. See details in Figures 5–1 through 5–5.
is broadly characterized as facilitated diffusion or active transport (see limits the absorption of some orally administered drugs by exporting
Figure 2–2; Figure 5–4). Membrane transporters and their roles in drug compounds into the lumen of the GI tract subsequent to their absorp-
response are presented in detail in Chapter 5. tion. ABC transporters perform a similar function in the cells of the BBB,
Facilitated Diffusion. Facilitated diffusion is a carrier-mediated trans- effectively reducing net accumulation of some compounds in the brain. By
port process in which the driving force is simply the electrochemical gra- the same mechanism, P-glycoprotein also can confer resistance to some
dient of the transported solute; thus, these carriers can facilitate solute cancer chemotherapeutic agents (see Chapters 65–68).
movement either in or out of cells, depending on the direction of the elec- Members of the SLC superfamily can mediate secondary active trans-
trochemical gradient. The carrier protein may be highly selective for a spe- port using the electrochemical energy stored in a gradient (usually Na+)
cific conformational structure of an endogenous solute or a drug whose to translocate both biological solutes and drugs across membranes. For
rate of transport by passive diffusion through the membrane would oth- instance, the Na+–Ca2+ exchange protein (SLC8) uses the energy stored in
erwise be quite slow. For instance, the organic cation transporter OCT1 the Na+ gradient established by Na+,K+-ATPase to export cytosolic Ca2+
(SLC22A1) facilitates the movement of a physiologic solute, thiamine, and and maintain it at a low basal level, about 100 nM in most cells. SLC8 is
also of drugs, including metformin, which is used in treating type 2 dia- thus an antiporter, using the inward flow of Na+ to drive an outward flow of
betes. Chapter 5 describes OCT1 and other members of the human SLC Ca++; SLC8 also helps to mediate the positive inotropic effects of digoxin
superfamily of transporters. and other cardiac glycosides that inhibit the activity of Na+,K+-ATPase
and thereby reduce the driving force for the extrusion of Ca++ from the
Active Transport. Active transport is characterized by a direct require- ventricular cardiac myocyte. Other SLC cotransporters are symporters, in
ment for energy, capacity to move solute against an electrochemical
which driving force ion and solute move in the same direction. The CNT1
gradient, saturability, selectivity, and competitive inhibition by cotrans-
(SLC28A1), driven by the Na+ gradient, moves pyrimidine nucleosides
ported compounds. Na+,K+-ATPase is an important example of an active
and the cancer chemotherapeutic agents gemcitabine and cytarabine into
transport mechanism that is also a therapeutic target of digoxin in the
cells. DAT, NET, and SERT, transporters for the neurotransmitters dopa-
treatment of heart failure (Chapter 29). A group of primary active trans-
mine, norepinephrine, and serotonin, respectively, are secondary active
porters, the ABC family, hydrolyze ATP to export substrates across mem-
transporters that also rely on the energy stored in the transmembrane Na+
branes. For example, the P-glycoprotein, also called ABCB1 and MDR1,
gradient, symporters that coordinate movement of Na+ and neurotrans-
exports bulky neutral or cationic compounds from cells; its physiologic
mitter in the same direction (into the neuron); they are also the targets
substrates include steroid hormones such as testosterone and progester-
of CNS-active agents used in therapy of depression. Members of the SLC
one. MDR1 exports many drugs as well, including digoxin, and a great
superfamily are active in drug transport in the GI tract, liver, and kidney,
variety of other agents (see Table 5–4). P-glycoprotein in the enterocyte
among other sites.
Paracellular Transport
[1] [1000] 1001 = [HA] + [A–]
pKa = 4.4 In the vascular compartment, paracellular passage of solutes and fluid
HA A–+ H+ through intercellular gaps is sufficiently large that passive transfer across
the endothelium of capillaries and postcapillary venules is generally lim-
Plasma pH = 7.4
ited by blood flow. Capillaries of the CNS and a variety of epithelial tissues
Lipid Mucosal Barrier have tight junctions that limit paracellular movement of drugs (Spector
et al., 2015).
Gastric juice pH = 1.4
transport across the intestinal epithelium and into the portal circulation. liver before they gain access to the general circulation.
The absorbed drug then passes through the liver, where metabolism and Absorption from the GI tract is governed by factors such as surface
biliary excretion may occur before the drug enters the systemic circula- area for absorption; blood flow to the site of absorption; the physical state
tion. Accordingly, less than all of the administered dose may reach the of the drug (solution, suspension, or solid dosage form); its aqueous sol-
systemic circulation and be distributed to the drug’s sites of action. If the ubility; and the drug’s concentration at the site of absorption. For drugs
metabolic or excretory capacity of the liver and the intestine for the drug given in solid form, the rate of dissolution may limit their absorption.
PHARMACOKINETICS: THE DYNAMICS OF DRUG ABSORPTION, DISTRIBUTION, METABOLISM, AND ELIMINATION
is large, bioavailability will be reduced substantially (first-pass effect). This Because most drug absorption from the GI tract occurs by passive dif-
decrease in availability is a function of the anatomical site from which fusion, absorption is favored when the drug is in the nonionized, more
absorption takes place; for instance, intravenous administration generally lipophilic form. Based on the pH-partition concept (see Figure 2–3), one
permits all of the drug to enter the systemic circulation. Other anatom- would predict that drugs that are weak acids would be better absorbed
ical, physiological, and pathological factors can influence bioavailability from the stomach (pH 1–2) than from the upper intestine (pH 3–6), and
(described further in this chapter), and the choice of the route of drug vice versa for weak bases. However, the surface area of the stomach is rel-
administration must be based on an understanding of these conditions. atively small, and a mucus layer covers the gastric epithelium. By contrast,
We can define bioavailability F as: the villi of the upper intestine provide an extremely large surface area
(~200 m2). Accordingly, the rate of absorption of a drug from the intestine
Quantity of drug reaching systemic circulation will be greater than that from the stomach even if the drug is predomi-
F= (Equation 2–2)
Quantity of drug administered nantly ionized in the intestine and largely nonionized in the stomach.
Thus, any factor that accelerates gastric emptying (recumbent position
where 0 < F ≤ 1. right side) will generally increase the rate of drug absorption, whereas any
Factors modifying bioavailability apply as well to prodrugs that are acti- factor that delays gastric emptying will have the opposite effect. The gastric
vated by the liver, in which case availability results from metabolism that emptying rate is influenced by numerous factors, including the caloric
produces the form of the active drug. content of food; volume, osmolality, temperature, and pH of ingested fluid;
diurnal and interindividual variation; metabolic state (rest or exercise);
and the ambient temperature. Gastric emptying is influenced in women
Routes of Administration by the effects of estrogen (i.e., compared to men, emptying is slower for
Some characteristics of the major routes employed for systemic drug effect premenopausal women and those taking estrogen replacement therapy).
are compared in Table 2–1. Drugs that are destroyed by gastric secretions and low pH or that cause
gastric irritation sometimes are administered in dosage forms with an
Oral Administration enteric coating that prevents dissolution in the acidic gastric contents.
Oral ingestion is the most common method of drug administration. It Enteric coatings are useful for drugs that can cause gastric irritation and
also is the safest, most convenient, and most economical. Its disadvan- for presenting a drug such as mesalamine to sites of action in the ileum
tages include limited absorption of some drugs because of their physical and colon (see Figure 51–4).
SECTION I
absorption of the drug for 8 h or longer. Potential advantages of such
preparations are reduction in the frequency of administration compared Subcutaneous. Injection into a subcutaneous site can be done only with
with conventional dosage forms (often with improved compliance by the drugs that are not irritating to tissue; otherwise, severe pain, necrosis,
patient), maintenance of a therapeutic effect overnight, and decreased and tissue sloughing may occur. The rate of absorption following sub-
incidence and intensity of undesired effects (by dampening of the peaks cutaneous injection of a drug often is sufficiently constant and slow to
in drug concentration) and nontherapeutic blood levels of the drug (by provide a sustained effect. Moreover, altering the period over which a drug
elimination of troughs in concentration) that often occur after admin- is absorbed may be varied intentionally, as is accomplished with insulin
GENERAL PRINCIPLES
istration of immediate-release dosage forms. Controlled-release dosage for injection using particle size, protein complexation, and pH. The incor-
forms are most appropriate for drugs with short half-lives (t1/2 < 4 h) or poration of a vasoconstrictor agent in a solution of a drug to be injected
in select patient groups, such as those receiving antiepileptic or antipsy- subcutaneously also retards absorption. Absorption of drugs implanted
chotic agents (Bera, 2014). under the skin in a solid pellet form occurs slowly over a period of weeks
Sublingual Administration. Absorption from the oral mucosa has spe- or months; some hormones (e.g., contraceptives) are administered effec-
cial significance for certain drugs despite the fact that the surface area tively in this manner.
available is small. Venous drainage from the mouth is to the superior vena Intramuscular. Absorption of drugs in aqueous solution after intramus-
cava, thus bypassing the portal circulation. As a consequence, a drug held cular injection depends on the rate of blood flow to the injection site and
sublingually and absorbed from that site is protected from rapid intestinal can be relatively rapid. Absorption may be modulated to some extent by
and hepatic first-pass metabolism. For example, sublingual nitroglycerin local heating, massage, or exercise. Generally, the rate of absorption fol-
(see Chapter 27) is rapidly effective because it is nonionic, has high lipid lowing injection of an aqueous preparation into the deltoid or vastus lat-
solubility, and is not subject to the first-pass effect prior to reaching the eralis is faster than when the injection is made into the gluteus maximus.
heart and arterial system. The rate is particularly slower for females after injection into the gluteus
maximus, a feature attributed to the different distribution of subcutane-
Parenteral Injection ous fat in males and females and because fat is relatively poorly perfused.
Parenteral (i.e., not via the GI tract) injection of drugs has distinct advan- Slow, constant absorption from the intramuscular site results if the drug is
tages over oral administration. In some instances, parenteral administra- injected in solution in oil or suspended in various other repository (depot)
tion is essential for delivery of a drug in its active form, as in the case of vehicles.
monoclonal antibodies. Availability usually is more rapid, extensive, and
Intra-arterial. Occasionally, a drug is injected directly into an artery to
predictable when a drug is given by injection; the effective dose can be
localize its effect in a particular tissue or organ, such as in the treatment
delivered more accurately to a precise dose; this route is suitable for the
of liver tumors and head and neck cancers. Diagnostic agents sometimes
loading dose of medications prior to initiation of oral maintenance dosing
are administered by this route (e.g., technetium-labeled human serum
(e.g., digoxin). In emergency therapy and when a patient is unconscious,
albumin). Inadvertent intra-arterial administration can cause serious
uncooperative, or unable to retain anything given by mouth, parenteral
complications and requires careful management (Sen et al., 2005).
therapy may be necessary. Parenteral administration also has disadvan-
tages: Asepsis must be maintained, especially when drugs are given over Intrathecal. The BBB and the blood-CSF barrier often preclude or slow
time (e.g., intravenous or intrathecal administration); pain may accom- the entrance of drugs into the CNS, reflecting the activity of P-glycoprotein
pany the injection; and it is sometimes difficult for patients to perform the (MDR1) and other transporters to export xenobiotics from the CNS.
injections themselves if self-medication is necessary. Therefore, when local and rapid effects of drugs on the meninges or cere-
The major routes of parenteral administration are intravenous, subcu- brospinal axis are desired, as in spinal anesthesia, drugs sometimes are
taneous, and intramuscular. Absorption from subcutaneous and intra- injected directly into the spinal subarachnoid space. Brain tumors (Calias
muscular sites occurs by simple diffusion along the gradient from drug et al., 2014) or serious CNS infections (Imberti et al., 2014) also may
depot to plasma. The rate is limited by the area of the absorbing capillary be treated by direct intraventricular drug administration, increasingly
membranes and by the solubility of the substance in the interstitial fluid. through the use of specialized long-term indwelling reservoir devices.
Relatively large aqueous channels in the endothelial layer account for the Injections into the CSF and epidural space are covered in chapters on
indiscriminate diffusion of molecules regardless of their lipid solubility. analgesia and local anesthesia (Chapters 20 and 22, respectively).
Larger molecules, such as proteins, slowly gain access to the circulation by
way of lymphatic channels. Drugs administered into the systemic circula-
Pulmonary Absorption
Gaseous and volatile drugs may be inhaled and absorbed through the
tion by any route, excluding the intra-arterial route, are subject to possible
pulmonary epithelium and mucous membranes of the respiratory tract.
first-pass elimination in the lung prior to distribution to the rest of the
Access to the circulation is rapid by this route because the lung’s surface
body. The lungs also serve as a filter for particulate matter that may be given
area is large. In addition, solutions of drugs can be atomized and the fine
intravenously and provide a route of elimination for volatile substances.
droplets in air (aerosol) inhaled. Advantages are the almost instantaneous
Intravenous. Factors limiting absorption are circumvented by intrave- absorption of a drug into the blood, avoidance of hepatic first-pass loss,
nous injection of drugs in aqueous solution because bioavailability is com- and in the case of pulmonary disease, local application of the drug at the
plete (F = 1.0) and distribution is rapid. Also, drug delivery is controlled desired site of action (see Chapters 21 and 40), as in the use of inhaled
and achieved with an accuracy and immediacy not possible by any other nitric oxide for pulmonary hypertension in term and near-term infants
procedures. Certain irritating solutions can be given only in this manner and adults (see Chapter 31).
because the drug, when injected slowly, is greatly diluted by the blood.
There are advantages and disadvantages to intravenous administra- Topical Application
tion. Unfavorable reactions can occur because high concentrations of Mucous Membranes. Drugs are applied to the mucous membranes of
drug may be attained rapidly in plasma and tissues. There are therapeutic the conjunctiva, nasopharynx, oropharynx, vagina, colon, urethra, and
circumstances for which it is advisable to administer a drug by bolus injec- urinary bladder primarily for their local effects. Absorption from these
tion (e.g., tissue plasminogen activator) and other circumstances where sites is generally excellent and may provide advantages for immunother-
slower or prolonged administration of drug is advisable (e.g., antibiotics). apy because vaccination of mucosal surfaces using mucosal vaccines
delivery.
the concentration of drug in tissue is in equilibrium with that in blood.
Skin: Transdermal Absorption. Absorption of drugs able to pene- The second phase also involves a far larger fraction of body mass (e.g.,
trate the intact skin is dependent on the surface area over which they are
muscle) than does the initial phase and generally accounts for most of the
applied and their lipid solubility (see Chapter 70). Systemic absorption of
extravascular distribution. With exceptions such as the brain, diffusion of
drugs occurs much more readily through abraded, burned, or denuded
drug into the interstitial fluid occurs rapidly because of the highly perme-
skin. Toxic effects result from absorption through the skin of highly lip-
able nature of the capillary endothelium. Thus, tissue distribution is deter-
PHARMACOKINETICS: THE DYNAMICS OF DRUG ABSORPTION, DISTRIBUTION, METABOLISM, AND ELIMINATION
60
SECTION I
Thiopental concentration, arbitrary units
20 min 90 min
blood
20 adipose
GENERAL PRINCIPLES
skeletal
muscle drug
liver eliminated
10
0
0 5 10 15 20 30 60 90 120
Time, minutes
IV dose
Figure 2–4 Redistribution. Curves depict the distribution of the barbiturate anesthetic thiopental into different body compartments following a single rapid
intravenous dose. Note breaks and changes of scale on both axes. The drug level at thiopental’s site of action in the brain closely mirrors the plasma level of the
drug. The rate of accumulation in the various body compartments depends on regional blood flow; the extent of accumulation reflects the differing capacities of
the compartments and the steady but slow effect of elimination to reduce the amount of drug available. Emergence from the anesthetic influence of this single dose
of thiopental relies on redistribution, not on metabolism. The drug will partition out of tissue depots as metabolism and elimination take their course. Depletion
of compartments will follow the same order as accumulation, as a function of their perfusion.
Tissue Binding can become a reservoir for the slow release of toxic agents such as lead or
radium; their effects thus can persist long after exposure has ceased. Local
Many drugs accumulate in tissues at higher concentrations than those in
destruction of the bone medulla also may result in reduced blood flow and
the extracellular fluids and blood. Tissue binding of drugs usually occurs
prolongation of the reservoir effect as the toxic agent becomes sealed off
with cellular constituents such as proteins, phospholipids, or nuclear pro-
from the circulation; this may further enhance the direct local damage to
teins and generally is reversible. A large fraction of drug in the body may
the bone. A vicious cycle results, whereby the greater the exposure to the
be bound in this fashion and serve as a reservoir that prolongs drug action
toxic agent, the slower is its rate of elimination. The adsorption of drug
in that same tissue or at a distant site reached through the circulation. Such
onto the bone crystal surface and incorporation into the crystal lattice
tissue binding and accumulation also can produce local toxicity (e.g., renal
have therapeutic advantages for the treatment of osteoporosis.
and ototoxicity associated with aminoglycoside antibiotics).
Fat as a Reservoir
CNS, the BBB, and CSF Many lipid-soluble drugs are stored by physical solution in the neutral fat.
The brain capillary endothelial cells have continuous tight junctions; In obese persons, the fat content of the body may be as high as 50%, and
therefore, drug penetration into the brain depends on transcellular rather even in lean individuals, fat constitutes 10% of body weight; hence, fat may
than paracellular transport. The unique characteristics of brain capillary serve as a reservoir for lipid-soluble drugs. Fat is a rather stable reservoir
endothelial cells and pericapillary glial cells constitute the BBB. At the because it has a relatively low blood flow.
choroid plexus, a similar blood-CSF barrier is present, formed by epi-
thelial cells that are joined by tight junctions. The lipid solubility of the Redistribution
nonionized and unbound species of a drug is therefore an important Termination of drug effect after withdrawal of a drug usually is by metab-
determinant of its uptake by the brain; the more lipophilic a drug, the olism and excretion but also may result from redistribution of the drug
more likely it is to cross the BBB. In general, the BBB’s function is well from its site of action into other tissues or sites. Redistribution is a fac-
maintained; however, meningeal and encephalic inflammation increase tor in terminating drug effect primarily when a highly lipid-soluble drug
local permeability. Drugs may also be imported to and exported from the that acts on the brain or cardiovascular system is administered rapidly
CNS by specific transporters (see Chapter 5). by intravenous injection or inhalation. Such is the case of the intrave-
nous anesthetic thiopental, a lipid-soluble drug. Because blood flow to the
Bone brain is high and thiopental readily crosses the BBB, thiopental reaches
The tetracycline antibiotics (and other divalent metal-ion chelating agents) its maximal concentration in brain rapidly after its intravenous injection.
and heavy metals may accumulate in bone by adsorption onto the bone Subsequently, the plasma and brain concentrations decrease as thiopental
crystal surface and eventual incorporation into the crystal lattice. Bone redistributes to other tissues, such as muscle and, finally, adipose tissue.
Lipid solubility, extent of plasma binding, and degree of ionization of weak their drug response or drug metabolism, allows for improved treatment
acids and bases are important general determinants in drug transfer across of individuals or groups (Ramamoorthy et al., 2015; Zhang et al., 2015;
the placenta. The placenta functions as a selective barrier to protect the see Chapter 7).
fetus against the harmful effects of drugs. Members of the ABC family of
transporters limit the entry of drugs and other xenobiotics into the fetal
circulation via vectorial efflux from the placenta to the maternal circu- Excretion of Drugs
lation (see Figure 2–2 and Chapter 5). The fetal plasma is slightly more Drugs are eliminated from the body either unchanged or as metabolites.
acidic than that of the mother (pH 7.0–7.2 vs. 7.4), so that ion trapping Excretory organs, the lung excluded, eliminate polar compounds more
of basic drugs occurs. The view that the placenta is an absolute barrier to efficiently than substances with high lipid solubility. Thus, lipid-soluble
drugs is inaccurate, in part because a number of influx transporters are drugs are not readily eliminated until they are metabolized to more polar
also present. The fetus is to some extent exposed to all drugs taken by the compounds. The kidney is the most important organ for excreting drugs
mother. The Food and Drug Administration categorizes the relative safety and their metabolites. Renal excretion of unchanged drug is a major route
of drugs that may be used in pregnant women (see Appendix I). of elimination for 25%–30% of drugs administered to humans. Substances
excreted in the feces are principally unabsorbed orally ingested drugs or
drug metabolites either excreted in the bile or secreted directly into the
Metabolism of Drugs intestinal tract and not reabsorbed. Excretion of drugs in breast milk is
important not because of the amounts eliminated (which are small) but
A Few Principles of Metabolism and Elimination because the excreted drugs may affect the nursing infant (also small, and
The many therapeutic agents that are lipophilic do not pass readily into with poorly developed capacity to metabolize xenobiotics). Excretion
the aqueous environment of the urine. The metabolism of drugs and other from the lung is important mainly for the elimination of anesthetic gases
xenobiotics into more hydrophilic metabolites is essential for their renal (see Chapter 21).
elimination from the body, as well as for termination of their biological
and pharmacological activity. Renal Excretion
From the point of view of pharmacokinetics, the following are the three Excretion of drugs and metabolites in the urine involves three distinct
essential aspects of drug metabolism: processes: glomerular filtration, active tubular secretion, and passive tubu-
lar reabsorption (Figure 2–5). The amount of drug entering the tubular
• First-order kinetics. For most drugs in their therapeutic concentration
lumen by filtration depends on the glomerular filtration rate and the
ranges, the amount of drug metabolized per unit time is proportional
extent of plasma binding of the drug; only unbound drug is filtered. In
to the plasma concentration of the drug (Cp) and the fraction of drug
the proximal renal tubule, active, carrier-mediated tubular secretion also
removed by metabolism is constant (i.e., first-order kinetics).
may add drug to the tubular fluid (see Chapters 5 and 25). Drug from
• Zero-order kinetics. For some drugs, such as ethanol and phenytoin, met-
the tubular lumen may be reabsorbed back into the systemic circulation.
abolic capacity is saturated at the concentrations usually employed, and
In the renal tubules, especially on the distal side, the nonionized forms
drug metabolism becomes zero order; that is, a constant amount of drug is
of weak acids and bases undergo net passive reabsorption. Because the
metabolized per unit time. Zero-order kinetics can also occur at high (toxic)
tubular cells are less permeable to the ionized forms of weak electrolytes,
concentrations as drug-metabolizing capacity becomes saturated.
passive reabsorption of these substances depends on the pH. When the
• Inducible biotransforming enzymes. The major drug-metabolizing
tubular urine is made more alkaline, weak acids are largely ionized and
systems are inducible, broad-spectrum enzymes with some predictable
are excreted more rapidly and to a greater extent; conversely, acidification
genetic variations. Drugs that are substrates in common for a metab-
of the urine will reduce fractional ionization and excretion of weak acids.
olizing enzyme may interfere with each other’s metabolism, or a drug
Effects of changing urine pH are opposite for weak bases. In the treat-
may induce or enhance metabolism of itself or other drugs.
ment of drug poisoning, the excretion of some drugs can be hastened by
In general, drug-metabolizing reactions generate more polar, inac- appropriate alkalinization or acidification of the urine (see Figure 2–3
tive metabolites that are readily excreted from the body. However, in some and Chapter 4).
cases, metabolites with potent biological activity or toxic properties are In neonates, renal function is low compared with body mass but
generated. Many of the enzyme systems that transform drugs to inactive matures rapidly within the first few months after birth. During adult-
metabolites also generate biologically active metabolites of endogenous hood, there is a slow decline in renal function, about 1% per year, so that
compounds, as in steroid biosynthesis. The biotransformation of drugs in elderly patients a substantial degree of functional impairment may be
occurs primarily in the liver and involves phase 1 reactions (oxidation, present, and medication adjustments are often needed.
reduction, or hydrolytic reactions and the activities of CYPs) and phase
2 reactions (conjugations of the phase 1 product with a second molecule) Biliary and Fecal Excretion
and a few other reactions. Other organs with significant drug-metabolizing Transporters present in the canalicular membrane of the hepatocyte (see
capacity include the GI tract, kidneys, and lungs. Drug-metabolizing Figure 5–6) actively secrete drugs and metabolites into bile. Ultimately,
enzymes, especially CYPs, are inducible by some drugs and inhibited by drugs and metabolites present in bile are released into the GI tract dur-
drugs and competing substrates. Chapter 6 covers drug metabolism at ing the digestive process. Subsequently, the drugs and metabolites can be
length. Knowing which CYP metabolizes a given drug and which other reabsorbed into the body from the intestine, which, in the case of conju-
drugs may affect that metabolism is crucial to good drug therapy. gated metabolites such as glucuronides, may require enzymatic hydrolysis
SECTION I
dosing for the benefit of the patient.
The importance of pharmacokinetics in patient care is based on the
improvement in therapeutic efficacy and the avoidance of unwanted
effects that can be attained by application of its principles when dosage
Glomerulus
regimens are chosen and modified.
The following are the four most important parameters governing drug
GENERAL PRINCIPLES
active disposition:
drug
Proximal Peritubular 1. Bioavailability, the fraction of drug absorbed as such into the systemic
secretion capillary circulation.
tubule
network 2. Volume of distribution, a measure of the apparent space in the body
available to contain the drug based on how much is given versus what
Loop of Henle is found in the systemic circulation.
3. Clearance, a measure of the body’s efficiency in eliminating drug from
the systemic circulation.
4. Elimination t1/2, a measure of the rate of removal of drug from the sys-
Distal drug temic circulation.
tubule reabsorption
Clearance
Clearance is the most important concept to consider when designing a
Urine rational regimen for long-term drug administration. The clinician usually
wants to maintain steady-state concentrations of a drug within a therapeu-
Figure 2–5 Renal drug handling. Drugs may be filtered from the blood in tic window or range associated with therapeutic efficacy and a minimum
the renal glomerulus, secreted into the proximal tubule, reabsorbed from the of toxicity for a given agent. Assuming complete bioavailability, the steady-
distal tubular fluid back into the systemic circulation, and collected in the state concentration of drug in the body will be achieved when the rate of
urine. Membrane transporters (OAT, OCT, MDR1, and MRP2, among others) drug elimination equals the rate of drug administration. Thus,
mediate secretion into the proximal tubule (see Figures 5–12 and 5–13 for
details). Reabsorption of compounds from the distal tubular fluid (generally Dosing rate = CL · C ss (Equation 2–3)
acidic) is pH sensitive: Ionizable drugs are subject to ion trapping, and altering
urinary pH to favor ionization can enhance excretion of charged species (see
where CL is clearance of drug from the systemic circulation, and Css is the
Figure 2–2).
steady-state concentration of drug. When the desired steady-state concen-
tration of drug in plasma or blood is known, the rate of clearance of drug
will dictate the rate at which the drug should be administered.
by the intestinal microflora. Such enterohepatic recycling, if extensive, may
Knowing the clearance of a drug is useful because its value for a partic-
prolong significantly the presence of a drug (or toxin) and its effects within
ular drug usually is constant over the range of concentrations encountered
the body prior to elimination by other pathways. To interrupt enterohe-
clinically. This is true because metabolizing enzymes and transporters
patic cycling, substances may be given orally to bind metabolites excreted
usually are not saturated; thus, the absolute rate of elimination of the drug
in the bile (for instance, see bile acid sequestrants and ezetimibe, Chapter 33).
is essentially a linear function of its concentration in plasma (first-order
Biliary excretions and unabsorbed drug are excreted in the feces.
kinetics), where a constant fraction of drug in the body is eliminated per
unit of time. If mechanisms for elimination of a given drug become sat-
Excretion by Other Routes urated, the kinetics approach zero order (the case for ethanol and high
Excretion of drugs into sweat, saliva, and tears is quantitatively unimpor- doses of phenytoin), in which case a constant amount of drug is eliminated
tant. Because milk is more acidic than plasma, basic compounds may be per unit of time.
slightly concentrated in this fluid; conversely, the concentration of acidic With first-order kinetics, clearance CL will vary with the concentration
compounds in the milk is lower than in plasma. Nonelectrolytes (e.g., of drug (C), often according to Equation 2–4:
ethanol and urea) readily enter breast milk and reach the same concentra-
tion as in plasma, independent of the pH of the milk (Rowe et al., 2015). νm
(Equation 2–4)
CL =
Breast milk can also contain heavy metals from environmental exposures. (K m + C )
The administration of drugs to breastfeeding women carries the general
caution that the suckling infant will be exposed to some extent to the where Km represents the concentration at which half the maximal rate of
medication or its metabolites. Although excretion into hair and skin is elimination is reached (in units of mass/volume), and νm is equal to the
quantitatively unimportant, sensitive methods of detection of drugs in maximal rate of elimination (in units of mass/time). Thus, clearance is
these tissues have forensic significance. derived in units of volume cleared of drug/time. This equation is analo-
gous to the Michaelis-Menten equation for enzyme kinetics.
Clearance of a drug is its rate of elimination by all routes normalized to
Clinical Pharmacokinetics the concentration of drug C in some biological fluid where measurement
can be made:
Clinical pharmacokinetics relate the pharmacological effects of a drug and
concentration of the drug in an accessible body compartment (e.g., in CL = Rate of elimination/C (Equation 2–5)
blood or plasma) as these change in time. In most cases, the concentration
of drug at its sites of action will be related to the concentration of drug Thus, when clearance is constant, the rate of drug elimination is directly
in the systemic circulation (see Figure 2–1). The pharmacological effect proportional to drug concentration. Clearance indicates the volume of
the systemic circulation may occur as a result of processes that occur in of pathological and physiological variables on drug elimination, particu-
the kidney, liver, and other organs. Division of the rate of elimination by larly with respect to an individual organ. The rate of presentation of drug
each organ by a concentration of drug (e.g., plasma concentration) will to the organ is the product of blood flow Q and the arterial drug concen-
yield the respective clearance by that organ. Added together, these sepa- tration CA, and the rate of exit of drug from the organ is the product of
rate clearances will equal systemic clearance: blood flow and the venous drug concentration CV. The difference between
these rates at steady state is the rate of drug elimination by that organ:
PHARMACOKINETICS: THE DYNAMICS OF DRUG ABSORPTION, DISTRIBUTION, METABOLISM, AND ELIMINATION
SECTION I
dling in elderly patients. where k is the rate constant for elimination that reflects the fraction of
drug removed from the compartment per unit of time. This rate constant
Distribution is inversely related to the t1/2 of the drug [kt1/2 = ln 2 = 0.693]. The ideal-
Volume of Distribution ized one-compartment model does not describe the entire time course of
The volume of distribution V relates the amount of drug in the body to the plasma concentration. Certain tissue reservoirs can be distinguished
the concentration of drug C in the blood or plasma, depending on the from the central compartment, and the drug concentration appears to
GENERAL PRINCIPLES
fluid measured. This volume does not necessarily refer to an identifiable decay in a manner that can be described by multiple exponential terms
physiological volume but rather to the fluid volume that would be required (Figure 2–6B).
to contain all of the drug in the body at the same concentration measured
in the blood or plasma: Rates of Distribution
In many cases, groups of tissues with similar perfusion-to-partition ratios
Amount of drug in body/V = C all equilibrate at essentially the same rate such that only one apparent
phase of distribution is seen (rapid initial decrease in concentration of
or intravenously injected drug, as in Figure 2–6B). It is as though the drug
starts in a “central” volume (see Figure 2–1), which consists of plasma and
V = Amount of drug in body/C (Equation 2–11) tissue reservoirs that are in rapid equilibrium, and distributes to a “final”
volume, at which point concentrations in plasma decrease in a log-linear
View V as an imaginary volume because for many drugs V exceeds the fashion with a rate constant of k (see Figure 2–6B). The multicompartment
known volume of any and all body compartments (Box 2–1). For example, model of drug disposition can be viewed as though the blood and highly
the value of V for the highly lipophilic antimalarial chloroquine is some perfused lean organs such as heart, brain, liver, lung, and kidneys cluster
15,000 L, whereas the volume of total-body water is about 42 L in a 70-kg as a single central compartment, whereas more slowly perfused tissues
male. such as muscle, skin, fat, and bone behave as the final compartment (the
For drugs that are bound extensively to plasma proteins but are not tissue compartment).
bound to tissue components, the volume of distribution will approach that If blood flow to certain tissues changes within an individual, rates of
of the plasma volume because drug bound to plasma protein is measurable drug distribution to these tissues also will change. Changes in blood flow
in the assay of most drugs. In contrast, certain drugs have high volumes of may cause some tissues that were originally in the “central” volume to
distribution even though most of the drug in the circulation is bound to equilibrate sufficiently more slowly so they appear only in the “final” vol-
albumin because these drugs are also sequestered elsewhere. ume. This means that central volumes will appear to vary with disease
The volume of distribution defined in Equation 2–11 considers the states that cause altered regional blood flow (such as would be seen in cir-
body as a single homogeneous compartment. In this one-compartment rhosis of the liver). After an intravenous bolus dose, drug concentrations
model, all drug administration occurs directly into the central compart- in plasma may be higher in individuals with poor perfusion (e.g., shock)
ment, and distribution of drug is instantaneous throughout the volume V. than they would be if perfusion were better. These higher systemic con-
Clearance of drug from this compartment occurs in a first-order fashion, centrations may in turn cause higher concentrations (and greater effects)
as defined in Equation 2–5; that is, the amount of drug eliminated per in tissues such as brain and heart, whose usually high perfusion has not
unit of time depends on the amount (concentration) of drug in the body been reduced. Thus, the effect of a drug at various sites of action can vary
compartment at that time. Figure 2–6A and Equation 2–9 describe the depending on perfusion of these sites.
Multicompartment Volumes
In multicompartment kinetics, a volume of distribution term is useful
BOX 2–1 ■ V Values May Exceed Any Physiological Volume especially when the effect of disease states on pharmacokinetics is to be
For many drugs, Equation 2–11 will give V values that exceed any determined. The volume of distribution at steady state Vss represents the
physiological volume. For example, if 500 μg of the cardiac glycoside volume in which a drug would appear to be distributed during steady state
digoxin were added into the body of a 70-kg subject, a plasma if the drug existed throughout that volume at the same concentration as
concentration of about 0.75 ng/mL would be observed. Dividing the that in the measured fluid (plasma or blood). Vss also may be appreciated
amount of drug in the body by the plasma concentration yields a as shown in Equation 2–13, where VC is the volume of distribution of
volume of distribution for digoxin of about 667 L, or a value about drug in the central compartment and VT is the volume term for drug in
15 times greater than the total-body volume of a 70-kg man. In fact, the tissue compartment:
digoxin distributes preferentially to muscle and adipose tissue and
binds to its specific receptors, the Na+,K+-ATPase, leaving a very small Vss = VC + VT (Equation 2–13)
amount of drug in the plasma to be measured. A drug’s volume of
distribution therefore can reflect the extent to which it is present in
extravascular tissues and not in the plasma.
Steady-State Concentration
Thus, V may vary widely depending on the relative degrees of Equation 2–3 (Dosing rate = CL ⋅ Css) indicates that a steady-state con-
binding to high-affinity receptor sites, plasma and tissue proteins, the centration eventually will be achieved when a drug is administered at a
partition coefficient of the drug in fat, and accumulation in poorly constant rate. At this point, drug elimination (the product of clearance
perfused tissues. The volume of distribution for a given drug can and concentration; Equation 2–5) will equal the rate of drug availability.
differ according to a patient’s age, gender, body composition, and This concept also extends to regular intermittent dosage (e.g., 250 mg
presence of disease. Total-body water of infants younger than 1 year of drug every 8 h). During each interdose interval, the concentration of
of age, for example, is 75%–80% of body weight, whereas that of adult drug rises with absorption and falls by elimination. At steady state, the
males is 60% and that of females is 55%. entire cycle is repeated identically in each interval (Figure 2–7). Equation
2–3 still applies for intermittent dosing, but it now describes the average
C0p C0p = 31
8 8
(µg/mL)
(µg/mL)
4 4
PHARMACOKINETICS: THE DYNAMICS OF DRUG ABSORPTION, DISTRIBUTION, METABOLISM, AND ELIMINATION
2 2
t1/ t1/2
2
1 1
0 2 4 6 8 10 12 0 2 4 6 8 10 12
TIME (hours) TIME (hours)
Figure 2–6 Plasma concentration-time curves following intravenous administration of a drug (500 mg) to a 70-kg patient. A. Drug concentrations are measured in
plasma at 2-hour intervals following drug administration. The semilogarithmic plot of plasma concentration Cp versus time suggests that the drug is eliminated
from a single compartment by a first-order process (see Equation 2–12) with a t1/2 of 4 h (k = 0.693/t1/2 = 0.173 h1). The volume of distribution V may be deter-
mined from the value of Cp obtained by extrapolation to zero-time. Volume of distribution (see Equation 2–11) for the one-compartment model is 31.3 L,
or 0.45 L/kg (V = dose/C0p). The clearance for this drug is 90 mL/min; for a one-compartment model, CL = kV.
B. Sampling before 2 h indicates that the drug follows multiexponential kinetics. The terminal disposition t1/2 is 4 h, clearance is 84 mL/min (see Equation 2–7),
and Vss is 26.8 L (see Equation 2–13). The initial or “central” distribution volume for the drug (V = dose/C0p) is 16.1 L. The example indicates that multicompart-
ment kinetics may be overlooked when sampling at early times is neglected. In this particular case, there is only a 10% error in the estimate of clearance when
the multicompartment characteristics are ignored. For many drugs, multicompartment kinetics may be observed for significant periods of time, and failure to
consider the distribution phase can lead to significant errors in estimates of clearance and in predictions of appropriate dosage.
steady-state drug concentration during an interdose interval. Note the to the steady-state value of 2.4 h). Intravenous anesthetics provide a good
-
extension of this idea to derive C ss during continuous intravenous drug example; many have context-sensitive half-times; these agents, with short
infusion, as explained in the legend to Figure 2–7. half-times after single intravenous doses, exhibit longer half-times in pro-
portion to the duration of exposure when used in maintenance anesthesia
Half-Life (see Figure 21–2).
The t1/2 is the time it takes for the plasma concentration to be reduced by Clearance is the measure of the body’s capacity to eliminate a drug; thus,
50%. For the one-compartment model of Figure 2–6A, t1/2 may be deter- as clearance decreases, owing to a disease process, for example, t1/2 will
mined readily by inspection of the data and used to make decisions about increase as long as the volume of distribution remains unchanged; alter-
drug dosage. However, as indicated in Figure 2–6B, drug concentrations nately, the volume of distribution may change but CL remains constant
in plasma often follow a multicomponent pattern of decline. or a combination of the two changes. For example, the t1/2 of diazepam
increases with increasing age; however, this does not reflect a change in
Half-Life, Volume of Distribution, and Clearance clearance but rather a change in the volume of distribution. Similarly,
When using pharmacokinetics to calculate drug dosing in disease, note changes in protein binding of a drug (e.g., hypoalbuminemia) may affect
that t1/2 changes as a function of both clearance and volume of distribution: its clearance as well as its volume of distribution, leading to unpredictable
changes in t1/2 as a function of disease. The t1/2 defined in Equation 2–14
t1/2 ≅ 0.693 ¥ Vss/CL (Equation 2–14) provides an approximation of the time required to reach steady state after
a dosage regimen is initiated or changed (e.g., four half-lives to reach
This t1/2 reflects the decline of systemic drug concentrations during a dos-
~ 94% of a new steady state).
ing interval at steady state as depicted in Figure 2–7.
Terminal Half-Life Extent and Rate of Absorption
With prolonged dosing (or with high drug concentrations), a drug may
penetrate beyond the central compartment into “deep” or secondary body
Bioavailability
It is important to distinguish between the amount of drug that is adminis-
compartments that equilibrate only slowly with the plasma. When the
tered and the quantity of drug that ultimately reaches the systemic circu-
infusion or dosing stops, the drug will be initially cleared from plasma as
lation. Dissolution and absorption of drug may be incomplete; some drug
expected but will eventually drop to a point at which net diffusion from
may be destroyed prior to entering the systemic circulation, especially by
the secondary compartments begins, and this slow equilibration will pro-
hepatic first-pass metabolism. The first-pass effect is extensive for many
duce a prolongation of the half-life of the drug, referred to as the terminal
oral medications that enter the portal vein and pass directly to the liver.
half-life.
The fraction of a dose F that is absorbed and escapes first-pass elimination
Steady-State t1/2 and Terminal t1/2 Compared measures the drug’s bioavailability; thus, 0 < F ≤ 1 (see Equation 2–2).
Examples of drugs with marked differences in terminal t 1/2 ver- For some drugs, extensive first-pass metabolism greatly reduces their
sus steady-state t1/2 are gentamicin and indomethacin. Gentamicin effectiveness or precludes their use as oral agents (e.g., lidocaine, propra-
has a t1/2 of 2–3 h following a single administration, but a terminal t1/2 of nolol, naloxone, and glyceryl trinitrate). For other agents, the extent of
53 h because drug accumulates in spaces such as kidney parenchyma absorption may be very low, thereby reducing bioavailability. When drugs
(where this accumulation can result in toxicity). Biliary cycling probably are administered by a route that is subject to significant first-pass loss or
is responsible for the 120-h terminal value for indomethacin (compared incomplete absorption, the equations presented previously that contain
SECTION I
and has a small “central” volume, the concentration of drug initially will
1 be high. It will then fall as the drug is distributed to its “final” (larger) vol-
ume (see Figure 2–6B). If the same drug is absorbed more slowly (e.g., by
Steady-State Concentrations slow infusion), a significant amount of the drug will be distributed while
•Proportional to dose/dosage interval it is being administered, and peak concentrations will be lower and will
•Proportional to F/CL
occur later. Controlled-release oral preparations are designed to provide
GENERAL PRINCIPLES
Fluctuations a slow and sustained rate of absorption to produce smaller fluctuations in
•Proportional to dose interval/half-time
the plasma concentration-time profile during the dosage interval com-
•Blunted by slow absorption
0 pared with more immediate-release formulations. Because the beneficial,
0 1 2 3 4 5 6 nontoxic effects of drugs are based on knowledge of an ideal or desired
TIME (multiples of elimination half-time) plasma concentration range, maintaining that range while avoiding large
swings between peak and trough concentrations can improve therapeutic
Figure 2–7 Fundamental pharmacokinetic relationships for repeated admin- outcome.
istration of drugs. The red line is the pattern of drug accumulation during
repeated administration of a drug at intervals equal to its elimination half- Nonlinear Pharmacokinetics
time. With instantaneous absorption, each dose would add 1 concentration
unit to Cp at the time of administration, and then half of that would be elimi- Nonlinearity in pharmacokinetics (i.e., changes in such parameters as
nated prior to administration of the next dose, resulting in the oscillation of Cp clearance, volume of distribution, and t1/2 as a function of dose or concen-
between 1 and 2 after four or five elimination half-times. However, this more tration of drug) is usually caused by saturation of protein binding, hepatic
realistic simulation uses a rate of drug absorption that is not instantaneous but metabolism, or active renal transport of the drug.
is 10 times as rapid as elimination; drug is eliminated throughout the absorp-
tion process, blunting the maximal blood level achieved after each dose. With
Saturable Protein Binding
As the molar concentration of small drug molecules increases, the
repeated administration, Cp achieves steady state, oscillating around the blue
line at 1.5 units. The blue line depicts the pattern during administration of
unbound fraction eventually also must increase (as all binding sites
equivalent dosage by continuous intravenous infusion. Curves are based on the become saturated when drug concentrations in plasma are in the range of
– tens to hundreds of micrograms per milliliter). For a drug that is metab-
one-compartment model. Average drug concentration at steady state C ss is:
olized by the liver with a low intrinsic clearance-extraction ratio, satura-
F ⋅ dose F ⋅ dosing rate tion of plasma-protein binding will cause both V and CL to increase as
C ss = = drug concentrations increase; t1/2 thus may remain constant (see Equation
CL ⋅ T CL
2–14). For such a drug, Css will not increase linearly as the rate of drug
where the dosing rate is the dose per time interval and is dose/T, F is the frac- administration is increased. For drugs that are cleared with high intrinsic
tional bioavailability, and CL is clearance. Note that substitution of infusion clearance-extraction ratios, Css can remain linearly proportional to the rate
rate for [F ⋅ dose/T] provides the concentration maintained at steady state dur- of drug administration. In this case, hepatic clearance will not change, and
ing continuous intravenous infusion (F = 1 with intravenous administration). the increase in V will increase the half-time of disappearance by reducing
the fraction of the total drug in the body that is delivered to the liver per
unit of time. Most drugs fall between these two extremes.
the terms dose or dosing rate (see Equations 2–3, 2–7, and 2–12) also must Saturable Elimination
include the bioavailability term F such that the available dose or dosing In the case of saturable elimination, the Michaelis-Menten equation (see
rate is used (Box 2–2). For example, Equation 2–2 is modified to Equation 2–4) usually describes the nonlinearity. All active processes are
undoubtedly saturable, but they will appear to be linear if values of drug
F ⋅ Dosing rate = CL ¥ Css (Equation 2–15)
concentrations encountered in practice are much less than Km for that pro-
where the value of F is between 0 and 1. cess (Box 2–3). When drug concentrations exceeds Km, nonlinear kinetics
are observed. Saturable metabolism causes oral first-pass metabolism to be
Rate of Absorption less than expected (higher fractional bioavailability), resulting in a greater
The rate of absorption can be important with a drug given as a single dose,
fractional increase in Css than the corresponding fractional increase in the
such as a sleep-inducing medication that must act in a reasonable time
rate of drug administration; basically, the rate of drug entry into the sys-
temic circulation exceeds the maximum possible rate of drug metabolism,
BOX 2–2 ■ Poor Absorption Notwithstanding, Some Agents and elimination becomes zero order. The major consequences of satura-
With Low Bioavailability Are Effective Orally tion of metabolism or transport are the opposite of those for saturation of
The value of F varies widely for drugs administered by mouth, and protein binding. Saturation of protein binding will lead to increased CL
successful therapy can still be achieved for some drugs with F values because CL increases as drug concentration increases, whereas saturation
as low as 0.03 (e.g., etidronate and aliskiren). Aliskiren is the first of metabolism or transport may decrease CL.
orally applicable direct renin inhibitor approved for treatment of Css can be computed by substituting Equation 2–4 (with C = Css) into
hypertension; its bioavailability is 2.6%. Etidronate, a bisphosphonate Equation 2–3 and solving for the steady-state concentration:
used to stabilize bone matrix in the treatment of Paget’s disease and
Dosing rate ⋅ K m
osteoporosis, has a similarly low bioavailability of 0.03, meaning C ss = (Equation 2–16)
that only 3% of the drug appears in the bloodstream following oral νm − dosing rate
dosing. In these cases, therapy using oral administration is still useful,
although the administered dose of the drug per kilogram is larger As the dosing rate approaches the maximal elimination rate νm, the
than would be given by injection. denominator of Equation 2–16 approaches zero, and Css increases dispro-
portionately. Because saturation of metabolism should have no effect on
1 mg/L, and the maximal elimination rate, νm, (from Appendix II) is
Design and Optimization of Dosage Regimens
5.9 mg/kg/day, or 413 mg/day/70kg. Substituting into Equation 2–16: The Therapeutic Window
The intensity of a drug’s effect is related to its concentration (usually Cp)
15mg/L = (dosing rate)(1mg/L)/(413mg/day – dosing rate) above a minimum effective concentration, whereas the duration of the
dosing rate = 387 mg/day drug’s effect reflects the length of time the drug level is above this value
In this case, the dosing rate is just below the elimination capacity. (Figure 2–9). These considerations, in general, apply to both desired and
If the dosing rate were to vary upward by 10% (to 387 + 38.7 or ~426 undesired (adverse) drug effects; as a result, a therapeutic window exists
mg/day), the dosing rate would exceed the elimination capacity by that reflects a concentration range that provides efficacy without unac-
13 mg/day and the Cp of phenytoin would begin a slow climb to toxic ceptable toxicity. Following administration of a single dose, a lag period
levels. Conversely, if the dosing rate were to vary downward by 10% precedes the onset of the drug effect, after which the magnitude of the
(to 387-38.7 or ~348 mg/day), the Css achieved would be 5.4 mg/L, a effect increases to a maximum and then declines; if a subsequent dose
drastic reduction to a level below the therapeutic range. is not administered, the effect eventually disappears as the drug is elim-
Consider a more common Km, 8 mg/L, such that the desired Css of inated. This time course reflects changes in the drug’s concentration as
15mg/L is farther from saturating the elimination capacity. In a 70 kg determined by the pharmacokinetics of its absorption, distribution, and
subject (νm = 413 mg/day), these data require a dosing rate of only 269 elimination.
mg/day. An increase in this rate by 10% (to 296 mg/day) would not Similar considerations apply after multiple dosing associated with
saturate the elimination capacity but would lead to a Css = 20.2 mg/L. long-term therapy, and they determine the amount and frequency of
A 10% downward variance in the dosing rate (to 242 mg/day) will drug administration to achieve an optimal therapeutic effect. In general,
produce a Css = 11.3 mg/L, a much less drastic decrease than above the lower limit of a drug’s therapeutic range is approximately equal to the
and still in the therapeutic range. drug concentration that produces about half the greatest possible therapeutic
Factoring in all the variables, predicting and controlling dosage effect, and the upper limit of the therapeutic range is such that no more than
so precisely (<10% error) can be difficult. Therefore, for patients in 5%–10% of patients will experience a toxic effect. For some drugs, this may
whom the target concentration for phenytoin is ≥10 times the Km, mean that the upper limit of the range is no more than twice the lower
alternating between inefficacious therapy and toxicity is common, limit. Of course, these figures can be highly variable, and some patients
careful monitoring is essential, and a pharmacokinetic consult to may benefit greatly from drug concentrations that exceed the therapeutic
establish or revise dosing may be appropriate. range, whereas others may suffer significant toxicity at much lower values
Other agents exhibiting saturated metabolism at or near the (e.g., with digoxin).
commonly employed concentrations include aspirin, fluoxetine, For a limited number of drugs, some effect of the drug is easily mea-
verapamil, and ethanol. sured (e.g., blood pressure, blood glucose) and can be used to optimize
dosage using a trial-and-error approach. Even in an ideal case, certain
Css CLs
100
Dose Dose
Response
0
log Dose
log Cp t1/2
Time Dose
Figure 2–8 Comparative pharmacokinetic parameters with first-order and zero-order elimination. Black lines represent the relationships under first-order kinetics
of elimination. Dashed red lines indicate the effects of transitioning to a region of saturated elimination (zero-order kinetics).
"He does not look like a hard man, exactly," said May Cloudesley.
"Ah, but if you knew his story, ma'am, which I can tell it to you, for I know
it well. I've known him all my life."
May by no means wished to listen to gossip of this kind; but she found
she must listen to Mrs. Short, or abruptly say good-bye, and this she did
not like to do. She was not one of those who have one manner for the
rich and another for the poor; so it was as impossible for her to interrupt
Mrs. Short rudely, as if she had been my Lady Short, and the vulgar little
crowded parlour a spacious reception room; so she heard her perforce.
"Ralph and me were married in the same year, and his shop—it was a
shop then, afterwards an establishment, if you please—was in our
street. My Matthew was a baker,—I ain't ashamed of it,—Ralph Trulock
was a master tailor, what they call a milingtery tailor, uniforms and the
like, and officers always going in and out, going to India and sich. He got
on wonderful—often I said to my poor Matthew that's dead and buried,
that pride will have fall, and a 'aughty sperrit goes before bankruptcy,
which is as true a word as any other Solomon ever said. And yet it
lasted a long time, too. Mrs. Trulock had her carriage, and Fred his
pony, and afterwards his horse, and they lived in a viller like the gentry,
and Ralph looked down on Matthew and me, as if we were no more than
a couple of our own penny rolls. The boy grew up—and a fine young
man to look at—but got into fine company through knowing the officers
that came to the shop, and it was he could spend faster than Ralph
could save. And his father was terrible hard on him—Ah! A hard man
Trulock was, even then, and—"
Here the welcome sound of a knock at the door reached May's ears.
She sprang from her chair, saying, "That is Mr. Cloudesley; he promised
to come for me."
"I'll let him in, ma'am—what, you must go? Well, I must finish my story.
Fred spent everything, and then ran away because the father was so
hard on him, and left Trulock in debt awful—he's never got before the
world since, and had to pay half a crown in the pound, and the wife died
—"
"I beg your pardon, Mrs. Short, but Mr. Cloudesley must find it very
cold."
"Yes, ma'am, I must let the dear gentleman in. And Ralph, ma'am—I
have my own suspicions about the way things went at the last; but that's
neither here nor there, and certain it is his behaviour killed his wife; and
when Fred ventured back, he cursed him frightful, and has always sent
back his letters, just tore up, and—"
"I really must not keep Mr. Cloudesley waiting any longer; that is the
third time he has knocked," cried May in desperation; and going quickly
to the door, she opened it herself.
Mrs. Short followed her as fast as she could, and began at once:
"Well, sir, you must not think me unmannerly for letting your good lady
open the door for you, for we were so interested in what we were
saying, that we quite forgot that you had knocked, and then when you
knocked again she ran like a hare, and I hadn't a chance with her. Must
you go at once, sir? Well, ma'am, call again soon, and I'll tell you plenty
more about him; but you may take my word for it, he brought that boy up
very badly, and then turned on him, broke his wife's heart, and owes a
mint o' money, leastways did, but went through the courts, you know,
and got himself whitewashed; and what he's starving himself for now I
don't know, and I'd give my ears to find out, though not curious by
nater."
"Good evening, Mrs. Short," said May gravely, as she took her
husband's arm and turned away.
"Oh, Gilbert, I do not like Mrs. Short; and if what she has been telling me
is true, we shall not like Mr. Trulock either."
"What has she told you? You look half dead, May."
"Nothing tries me like having to listen to talk like that; but she told me—"
and May repeated the substance of Mrs. Short's story.
"Well, I know nothing of the man myself, but this is certain," said Mr.
Cloudesley in reply. "Mrs. Short may abandon her suspicion that he
behaved dishonourably in any way; for if he had, he would not have
been admitted here. I fancy he is very unhappy, poor old fellow; you
must make friends with him, May."
"But, Gilbert, if he really turned his son out of doors and cursed him?"
"You are right. Yes, Gilbert, I'll go and see him again."
May Cloudesley went several times to visit Mr. Trulock before she found
him at home; and her ineffectual knock at his door never failed to bring
Mrs. Short to hers, urging her to come in and "have a chat." Sometimes
May escaped, but more often she was obliged to go in and listen
unwillingly to much gossip, principally about poor old Ralph, but many of
the other neighbours were also discussed. Still Ralph was plainly a
mystery to her, and (of course in the most good-natured spirit) Mrs.
Short talked incessantly about him. At last Mrs. Cloudesley determined
to go quite early some day, and try if she could catch Trulock; before he
was off on his wanderings. It was not quite ten o'clock when she raised
her hand to knock at his door, and before she had reached the knocker
the door opened, and Ralph, in a worn great-coat and shabby muffler,
stood before her. He looked even more depressed than when she had
seen him last.
"Good morning, Mr. Trulock. I am a very early visitor, but later in the day
you are never at home, and I wanted so much to see you."
"You are very good, madam. I don't know why any one should trouble
themselves about such as I am now. Will you walk in, madam?—though
I fear you will find it cold."
"I sit in the kitchen, madam, in order to keep but one fire," said Ralph,
leading the way to that very melancholy apartment, where he placed her
in a chair near the grate; she perceived that the fire was raked out, and
the dismal chill of the room was most depressing.
May looked round, and then up into the face of the old man, and
wondered if she could venture to beg him to allow himself the comforts
he so sadly needed. He was watching her with a strange, sad smile.
"I know what you are thinking, madam," he said. "My neighbour, Mrs.
Short, has been telling me that she informed you that I am starving
myself to death; and I have no doubt she told you more than that. She
would not spare me. I was a fool to come here—but truly I had little
choice. She has given me a bad name with every one."
"I wish you would make yourself a little more comfortable, Mr. Trulock. I
cannot bear to think of the life you seem to lead. This place, you know,
was meant to make those who live here comfortable."
He sat down as he spoke, for hitherto he had been standing, and said:
"Madam, you are very kind to me, and I should not wish you to think
worse of me than I deserve. I don't know what you may have heard from
Mrs. Short, nor even what you may conclude from my own words and
conduct. May I briefly tell you the truth concerning myself, madam, and
then at least I shall know that you are not misled about me."
"Indeed, I will listen with great interest," said May. "I fear you have had
many trials."
"No," he replied, with his slow, grave smile; "that is true; but it hinders
sympathy, I find. You know, perhaps, that I began life as an apprentice in
a great military outfitting shop in London? I was hard-working and
careful, and got on well. I set up for myself when I married, as my wife
had a little money, and I had saved. I prospered greatly. My business
grew and grew; I was soon a rich man. I had the best wife, madam, that
ever man was blessed with, and a fine boy—only the one child. I said I
would make a gentleman of him. I gave him every advantage—I never
said No to him—I—"
"Madam, I find that I cannot speak much of him, even now. I do not
believe he ever knew what he was to me. I ruined him by over-
indulgence—letting him have too much money; and then, when I began
to fear he was going astray, I pulled him up too short. Then—I see it now
—I went as much too far the other way—would give him no money, and
wanted to part him from all his acquaintance, because I thought they
helped to make him idle. He was idle—that I know—but he was good
and affectionate until—Well, he rebelled; got into debt; borrowed money
right and left. My business went down, for I was forced to make my
customers pay up their bills, and that makes discomfort. People
naturally go where they get credit. All went wrong with me; and my poor
Annie took the boy's misdoing so much to heart that she lost her health."
"The boy went from bad to worse. At last—I never told this to mortal
before except my poor Annie, and she guessed it. I had a large sum of
money coming to me, and I depended on it, as I had a great payment to
make. He knew it; he went the day before I was to receive it, and got it,
saying I had a sudden need for it, and had sent him. And then he
disappeared. I concealed his—theft—from every one except my wife—
she guessed it, and it finished what his wild doings had begun. She
never held her head up again, madam. She pined away, longing for her
boy, that she might try to bring him to a sense of his faults; but he never
came. I put advertisements in the paper, begging him to come home,
and that all should be forgiven; but he never saw them. He was abroad,
I believe. At last—she died; and the night before her funeral, Fred,
knowing nothing of this, came home. He came in on me suddenly, and I
had no heart to speak. He said he had seen the advertisement at last,
and had come home to confess that he was married,—and he told me
who the girl was. A good girl, I believe; but she belonged to bad people
—low, dishonest folk, in a small way of trade—and my heart rose up
against the thought of her bearing my Annie's name, and she lying in
her coffin. I got up—" Ralph straightened himself and spoke louder, "I
opened the door; I said, 'Your mother lies dead upstairs, murdered by
you. You have brought her to the grave, and me to ruin. Go to the wife
you have chosen—never let me see your face again.'"
"Oh, Mr. Trulock! Surely he did not take you at your word? Surely he
saw that you were speaking wildly?"
"He had his faults, madam, but want of affection was never one of them.
He tried again and again—he both wrote and came to the house; but I
would neither see him nor read his letters. I was mad, I think; mad with
sorrow and anger. At last he got a friend to trick me into reading one
letter, the last he ever wrote to me. He said he saw that I could not
forgive him, although he hoped I would believe that he had not meant to
leave his mother to die without seeing him; that he was going to
emigrate, and that he would repay the money he had taken from me as
soon as he could. I have never heard of him since—not a word."
"He will come yet," said May; but Trulock shook his head.
"I think he must be dead," he said in a low voice. "Then I began to try to
pay my creditors, and retrieve my business. I struggled on alone,
madam, for twelve weary years, during which I never spent an
unnecessary penny—only to fail at last. I paid seventeen and sixpence
in the pound, and—I must pay the other half-crown before I die. That is
what I am saving for, Mrs. Cloudesley. I can allow myself no comforts
until that is done."
"God bless you, madam, for those tears!" said Trulock, earnestly. "You're
sorry for Annie;—yes, and you would have learned to love her—you
would have loved Annie."
"I'm crying for you, not for her," May said, looking up. "I'm so sorry; yours
has been a sad, sad life. Annie is at rest."
"Ah!" said May, smiling. "How that takes the sting out of the sorrow! But
will you let me tell my husband what you have told me? And I will try to
see you soon again, and tell you if he thinks that you are doing right
now. Gilbert is so upright—he would know."
"You may tell him, but no one else, madam, if you please. I do not care
to defend myself; let people believe Mrs. Short if they like. I care nothing
for their opinion."
"I don't care for company; I feel as if every one was a stranger, and must
always be so—and I think I don't wish it otherwise."
"They won't grow except in their own soil. Good-bye,—when shall I have
a chance of seeing you again?"
"I cannot have you troubled to come out so early on my account," Ralph
answered. "If you will leave word at the gate, appointing your own time, I
will be here. You have been very kind, madam, and I feel it deeply; but
do not mistake me, I do not promise to be ruled by what you and Mr.
Cloudesley may advise."
"Yet we may talk it over with you. Good-bye then, Mr. Trulock. I will leave
a message for you."
As May hurried away, she heard Mrs. Short calling her. She stopped,
and that worthy dame actually followed her, cold as it was.
"You've sat a long time with Trulock," said she. "I hope, ma'am, that he
was civil?"
"Civil!" said May, laughing. "Oh dear, yes, Mrs. Short. I like Mr. Trulock
very much indeed. Good morning, for I have sat so long with him that I
must hurry home now."
"After all I've told her, not to tell me one word of what passed between
'em! I could see that she cried,—but the winders is so small! It's very ill-
natured of her; and if I did right I'd never tell her another thing!"
CHAPTER III.
MAY CLOUDESLEY SPEAKS HER MIND.
"Well, Mr. Trulock, did you think I had forgotten you? You don't know
how busy we have been."
"I had no fear that you would forget me," Trulock answered, quietly.
"Well, I think Mr. Cloudesley is right," said Trulock with a smile. "I don't
know that I could talk to any one else as I did that day to you. I
wondered at myself when you were gone, for I had not meant to trouble
you with so long a story."
"But you did not trouble me, except that I was sorry for you. Well, it
seems that my husband saw a letter, written by a Mr. Arnott, and signed
by all your other creditors, which was sent to Mr. Barton when you were
named for this place; in which they say that your conduct had been so
honourable as to command their admiration; that they had had dealings
with you for many years, and felt that in spite of your failure they had lost
nothing by the connection."
"And they said that they were all most anxious to secure your election;
that they could quite afford to lose the very trifling sums you had not
paid, and that they had written to you to that effect."
"So they did. But, young lady, I could not rest in my grave knowing that I
owed any one a penny."
"Suppose you had not been elected to the Rest, I think they meant to
have made a subscription for you, Mr. Trulock."
"Madam!" said the old man almost fiercely, "I would have gone to the
poorhouse before I accepted their charity!"
"What?" cried Ralph, with a start. "That I ought to have done that—gone
to the poorhouse?"
"No, no,—but that you must look well to it that in this matter you are not
governed by pride rather than by any better feeling."
"I have always been a proud man," Ralph answered, drawing himself
up. "Mrs. Cloudesley, in living on the barest necessaries of life—and that
I do, for bread and water are my usual food, and I roam the country to
keep myself warm, to save firing,—I am doing the only thing that can
reconcile me to life. People talk of me now as a beaten man, glad to
hide my head in an almshouse, because ill-health, sorrow, and age
made it impossible for me to begin life again. But before I die, I will
prove to these proud, successful men, that I was not so utterly beaten;
that, in spite of age, and failing health, and sorrow to boot, I fought the
battle and kept my honourable name. When I have paid the money, I
may be able to feel grateful to Arnott and the rest for what they said and
did—as it is, I can only just keep from hating them."
"The money may make no difference to them," said Ralph; "but it makes
all the difference in the world to me."
"But only because you are proud. Why should you not allow men who
think well of you to show you a kindness? Why not submit to the failure
of your business, and try to find peace here, where there are so many
who would be friendly if you would allow them? And Lady Mabel didn't
mean her bequest to be used except for the benefit of those to whom
she left it."
"I asked Mr. Barton if there was any rule obliging me to spend the
money, and he said certainly I might do as I liked," Ralph replied.
"Madam, I warned you that I could not promise to be guided by you. You
were kind to me, and I thought I should like you to know the plain truth
from my own lips; and then you listened so kindly that I was led on to
say more than I intended. But I could not change my nature at this time
of day, madam. A proud man and a hard man I have always been;
giving nothing for nothing, accepting no favours. I've lived so, and I
could live no other way. What good would the money do me? I don't
want to sink into a mere eating machine, like Mrs. Short. I don't care to
seek the company of my neighbours. All I ask is, to be left in peace to go
my own way."
"Happy! How could I be happy? I have lost all I ever loved,—I loved but
two, and they are gone. I don't look for happiness, madam,—not in this
world."
"Nor in the next," said May Cloudesley, in her soft, sorrowful voice; "for
you are not going the way that leads to it."
"You have never doubted it," said May; "but you have never lived it.
'Love is the fulfilling of the law,'—'If any man have not the Spirit of
Christ, he is none of His.' I have only your own word to go upon, but you
say yourself that you have been a proud man and a hard man, keeping
far from you all the charities of life. Oh, don't fancy for a moment that
your belief is Faith. Faith means Obedience,—Obedience is Love in
action. I am not able to make my meaning plain, but my husband will if
you will talk to him. Dear Mr. Trulock, do think over what you have told
me, and then compare your own life with that of our one perfect
Example, who lived on charity, and spent His life in doing good, without
return. I have angered you, but indeed I did not mean to do so."
Trulock looked very much disturbed. He rose quickly and brought some
water, and watched anxiously until she was quite composed. Then he
said:
"I should prefer not to speak to Mr. Cloudesley, madam; but I will think of
what you have said. I am not vexed that you should speak plainly; I like
plain speaking. I don't see that you are right, though; and if I did, I doubt
that I could change now."
He shook his head; but she went on: "Help some one, be kind to some
one who needs kindness; use some of your money to relieve those who
need relief; say kind words to some one in sorrow. That's the soil in
which you must grow your Christmas roses," she concluded with a
smile.
"Madam," said he; "you will say I am no judge, but I have heard so many
sermons against that kind of thing. It seems to me that you imply that I
can be saved by works."
"There is no question here of being saved," said May, quickly. "You must
be saved by the Lord Jesus Christ, or not at all. But you say you have
faith, and I say with St. James—'Show me thy faith by thy works'; for I
think that a faith which leaves us just what nature made us, must be a
dead faith, don't you? We all have our besetting sin to conquer, and it
seems to me that pride is yours; but if you had love in your heart it would
turn out pride. And I think that though we cannot make ourselves feel
love all at once, yet we can do kind things, and then our hearts will grow
soft and warm. And I am sure that if you were doing kind things for
others, you would not dislike so much to accept kindness from others; at
least, I think so. But I am very young and ignorant, and, I'm afraid, very
presumptuous too, to talk to you like this. You'll forgive me, though,
won't you, Mr. Trulock?"
May went home and told her husband all that had passed.
"Well," said he, "you told him some plain truths, May; but you were quite
right. Now we must let him alone a bit. I fancy he will not stand too much
good advice; we'll wait and see how things go."
In May's opinion, things did not go well. Mr. Trulock changed none of his
habits, and was always out when she called. Mrs. Short assured her that
he was living like a slave or a wild Indian, just bread and water on week
days, and a morsel of meat on Sundays only, and a cup of tea once in a
way—not regular at all. Miss Jones said she had invited him to dine with
her, and that he had refused, not very courteously. And May had no
choice but to follow her husband's advice and "let him alone," for the
simple but sufficient reason that she could by no means get at him.
CHAPTER IV.
A SMALL SEAMSTRESS.
RALPH TRULOCK had never been a very happy man. Even when his
worldly affairs prospered, and his wife, whom he tenderly loved, and
who deserved his love, was with him; even before his son's behaviour
gave him cause for anxiety,—he had not been a happy man. He had
had all that the world could give him, and if you had asked him what
more he wanted, he would probably have said, "Nothing;" and yet he did
want something, and want it so badly that his heart was never at rest for
the lack of it.
The truth is, he was trying to satisfy an immortal spirit with mortal things,
and no one ever yet succeeded in doing that, excepting those who are
too dull to look beyond mere eating and drinking, warmth and comfort.
Of this class, Mrs. Short was a tolerable specimen; but Ralph cared little
for these things. His idol was of a higher order: it was his own opinion of
himself. He did not greatly care for other people's admiration, but he
must satisfy himself. His notion was, that a man should be perfectly just,
utterly truthful and upright, fulfil all his engagements honourably, and
never ask or accept a favour. He did not add, consciously, "and never
give any one anything except what they earn," but he acted on that
principle, though he never interfered with his wife's charities. He
believed that if he lived thus, perfectly righteous in all his dealings, he
should certainly go to heaven, even if he never felt any of those warmer
religious feelings of which his wife sometimes spoke. She had quite a
different kind of religion; but that was all right: she was a woman, and
humility and dependence become a woman, but men should be made of
sterner stuff.
Mrs. Trulock was a timid, gentle creature, far too humble even to think
that Ralph could need to be taught anything. She taught her boy
carefully, and when he went astray her loving heart broke, and she died,
expressing with her last breath a belief that "Fred would remember what
she had taught him, yet." I don't suppose she had ever heard the story
of the mother of St. Augustine, but she might have said with her, "He
must be saved, for he is the child of many tears and many prayers."
But if Ralph Trulock had never been a thoroughly happy man, he was
certainly a very miserable man now. He had never been idle in his life;
and here he was with nothing to do but to see on how little he could
keep body and soul together, that he might rid himself of the hated
obligation he now lay under, to men whose equal he had once been.
May Cloudesley's sweet face and sympathetic manner had thrown him
off his guard, and he had spoken to her more freely than he had ever
spoken before, even to himself, for he hardly knew that he had it in him
to feel and speak thus until he found himself doing it. And then that little
traitor, May, having stolen softly within his guard of proud silence, had
used her opportunity to stick a little dagger into his very heart!
Twenty times a day he told himself that she was only a silly young
woman, and that he knew better than she did; twenty times a day he
resolved to think no more of her words. But they kept coming back to
him, and would not be forgotten. He had always read a small portion of
the Bible on Sundays, and he found himself now, sorely against his will,
remembering that the spirit of the words he read agreed with what May
had said, more than with his own opinions. He could not keep his mind
from trying to make out a case for himself, and he could not help
knowing that he failed; that no text bore him out in his opinions. Still he
was haunted by one text which he could not remember exactly, but in
which the words, "What doth the Lord require of thee, but to do justly?"
certainly occurred; and he imagined that if he could only find that verse,
he could return to his old way of thinking comfortably, and forget May's
little dagger.
After much searching, he found the text at last; but it did not turn out a
comfort to him. "He hath showed thee, O man, what is good; and what
doth the Lord require of thee, but to do justly—" oh that it had stopped
there! But it went on—"and to love mercy, and to walk humbly with thy
God?" So not even this solitary text, on which he had built so much,
would bear the meaning he wished to find in it. Nay, might not May have
used it against him?
"To love mercy!" How could he set about that? He need not relax his
stern self-denial much,—not at all, in fact; but he might give a small
portion of what he saved, and it would only delay his hoped-for payment
a little.
One afternoon in June—it was June now, for it took him a long time to
arrive at this point in his mental struggle—he went into Fairford to buy
himself some new shirts; his old ones had gone beyond even his not
unskilful repairs. There was a good shop in High Fairford. Price's, and to
that shop he betook himself. The young man at the shirt counter told him
that he had not a shirt of the particular size he asked for in the house,
but that there were a number actually in hand, and if he would sit down
and wait a few minutes, one of the workwomen had promised him four
that very day, "and she is always punctual," concluded the young man.
Not caring to return next day, Ralph took a seat and waited. Presently a
girl—a child rather, though there was a staid, responsible air about her
that was wondrous womanly—came quickly up the shop, and laying a
parcel on the counter, said to the young shopman,—
"I told you she was punctual, Mr. Trulock!" said the shopman.
"Why, you don't mean to say that this child is one of your workers!" said
Ralph.
"And a very handy worker too! No need to look over these shirts—
there's never any scamped stitches in Miss Garland's work," added the
young man pleasantly, as he opened the parcel and took out the four
shirts. They were wonderfully well-made—you must remember that
Ralph's trade had made him a good judge of needlework—every part
was as well done as the girl could do it, the button-holes were well
worked, and the buttons conscientiously sewed on. It was all so clean,
too. Ralph conceived a good opinion of the girl at once. He bought the
shirts, and paid for them: he saw the girl cast a quick glance upon the
sixteen shillings he laid down, and give her head a little shake. She was
paid for her work at once—three shillings. Ralph lingered near the door:
something in the girl's face pleased and yet puzzled him, and he wanted
to see more of her. She came out in a moment, but was passing him
without notice, when he said to her,—
"Do you get only ninepence a piece for making these shirts?"
"That is all," she answered with a sigh; "but, sir, it is better than nothing."
"One whole day and most of another. Now I have got petticoats to make
—with braid on them; like doing that, I get on quicker."
"Your mother should not let you sew so much," said Ralph. "It is bad for
a growing girl."
"That is the same name, but Ollie's mother was French, and we have
lived in France, where they say it as I do."
"You and Ollie lived in France?" Mr. Trulock said. He felt strangely
interested in the child. She was a rather pretty little girl, with a pale
round face and very soft dark eyes: she wore her short dark hair tucked
away behind her little ears, and she was dressed in a plain and scanty
black cotton frock, her straw hat being trimmed with a morsel of fresh
black crape. Something in her look, her voice, and above all her smile,
interested him: they reminded him of some one, he could not think of
whom—the slight foreign accent puzzled him, perhaps.
Two great tears slowly welled up and then ran down her cheeks: she put
up her small right hand to rub them away, and he saw how the forefinger
was seamed with needle marks.
"And now there are only me and Ollie," she added quietly.
"No, sir; we have no friends here. Father was on his way here when his
illness came on—he bid me come here. I expected to find his people
here, but no one even knows the name. I suppose they lived here long
ago, and are all gone away now."
"Do you mean to tell me, child," said old Ralph half angrily, "that you and
this boy are alone in the world?"
"Indeed we are—quite, quite alone," the girl answered, with that quiet
sadness which was so like some one, if he could only remember who it
was.
"Oh yes, I have a little money. When my father died; he had some
money,—I do not know exactly how much—they took some to pay the
doctor, and the bill at the hotel, and—for his funeral. Oh, I don't want to
speak about it, sir!" and again the big tears rolled down, and the poor
little hard-working hand went up to her face. But after a moment she
went on again: "I am keeping all I have left very carefully. I work as hard
as I can, and so does Ollie, though he can only run with messages, of
course. I want to keep the little I have until winter."
"See what I have here! A monsieur gave me this for picking up his
whip!"
"Take it, Ruthie; I may lose it," the boy said gravely, and then returned to
his marbles.
"We live here, sir," said Ruth, stopping at the door of a small bakery.
"Good-bye, and I hope you will like your shirts."
Mr. Trulock shook hands with her—a mode of saying good-bye which
seemed to puzzle her not a little. He lingered until she had passed
through the shop. She paused and bought a fourpenny loaf, and he
heard her ask for:
"A stale one, if you please, ma'am;" then she vanished through a door
behind the counter, and Ralph entered the shop.
"Plain or fancy, sir?" said the old woman who stood behind the counter.
"I don't want any bread, thank you," Ralph answered; "I want to ask a
question about the child who has just passed through your shop."
"Do you know anything about her, sir?" asked the woman eagerly.
"It would be some other Fairford, perhaps—there are places of the same
name in other counties," suggested Ralph, much interested.
"No, sir; Fairford, —shire was written on the box the children brought
with them, in the poor man's own writing."
"But have they no means of living, ma'am, except by what they can
earn?"
"None; there's a box with good, comfortable clothes for both of them,
and the same belonging to the poor father; and Ruth has a little money
laid by, but only a few pounds. And that's all. I advised Ruth to save it up
and work hard, and she's a wise little creature, used to manage things
and to be busy. She pays me nothing for the little room they sleep in,
and I am glad to help them so far; but I'm too poor to do more. My
business is not what it used to be, nor what it ought to be," she added
with a sigh, and a look round the dingy little shop, into which indeed no
one had come since Ralph's own arrival. "I got her work from Price's;
she's a handy worker."
"Will you give the child this, ma'am, and tell her it is from the old man to
whom she was talking?" said Ralph, giving her half a crown.
"Indeed I will, sir, gladly, and very kind it is of you sir. Good evening."