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Brenner and Stevens’
PHARMACOLOGY
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Brenner and Stevens’
PHARMACOLOGY
SIXTH EDITION
Craig W. Stevens, PhD

Professor of Pharmacology
Oklahoma State University
Center for Health Sciences
Tulsa, Oklahoma
Elsevier
1600 John F. Kennedy Blvd.
Ste 1800
Philadelphia, PA 19103-2899
BRENNER AND STEVENS’ PHARMACOLOGY, SIXTH EDITION ISBN: 978-0-323-75898-7

Copyright © 2023 by Elsevier, Inc. All rights reserved.
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Preface
Medical pharmacology is primarily concerned with the the cell membrane, like morphine acting on opioid recep-
mechanisms by which drugs treat disease processes, relieve tors. Small molecule inhibitors are effective in many neo-
symptoms, and counteract the molecular manifestations of plastic (cancer) diseases and other pathological states with
pathological states. Pharmacology is also concerned with a well-defined molecular pathway. This new class of drugs
the factors that determine the time course of drug action, with intracellular targets was added to Chapter 45.
including drug absorption, distribution, metabolism, and The book has been meticulously organized to include
excretion. Students are often overwhelmed by the vast extensive cross-referencing of many drugs that have more
amount of pharmacological information available today. than one therapeutic use or multiple classifications. This
This textbook provides the essential concepts and drug will aid the reader in following a particular drug that is
information that students need to be successful in their included in different chapters. Additionally, to aid the
courses without an overwhelming amount of detail. reader in drug recognition, drug names are followed by trade
This text is primarily intended for students who are tak- (brand) names in Small Caps Font. This helps because the
ing their first course in pharmacology, but it will also be trade name of many drugs are heavily advertised and the
useful for those who are preparing to take medical boards reader may already have some knowledge of their drug uses.
or licensing examinations. Because of the large number of As all medications are indexed under both their generic
drugs available today, this text emphasizes the general prop- and brand names, this book is also a valuable reference for
erties of drug categories and prototypical drugs. The chapters a quick review of drugs encountered in the reader’s personal
begin with a drug classification box to familiarize students or professional life. However the student reader will bear in
with drug categories, subcategories, and specific drugs to be mind that for purposes of examination and boards, the un-
presented in the chapter. Additionally, all FDA-approved branded generic drug name is exclusively used.
drugs are listed along with the emphasized drugs to enhance The book now in your hands was extensively revised
the value of this textbook as a reference volume. for the 6th edition to include all new drugs on the mar-
In the four years since the publication of the previous ket since the last edition (more than 200), and to exclude
edition of Brenner and Stevens’ Pharmacology, major trends older drugs that were withdrawn from the market. Much
in the development and marketing of new medications ancillary drug information, such as chemical structures and
and new formulations were apparent. First, there was an unremarkable pharmacokinetics, was shortened or deleted.
explosion of combination drugs released onto the market The figures that were retained were updated and new figures
in recent years. This is a good thing, as there is often phar- added, with an emphasis on illustrating drug mechanisms of
macological synergy between combined agents, but also action. A modern graphic style was developed for the figures
because patient compliance is greatly improved. It is easier to improve understanding and to entice the eye.
to take one pill than two, or three, or four. The usual prod- This new edition is sadly noted by the recent passing of Dr.
uct combines two successful and effective single agents for George M. Brenner, my mentor, my friend, and co-author on
the treatment of a disorder. These newly approved combi- previous editions of this textbook. George hired me 30 years
nation drugs are included in this 6th edition of Brenner & ago as a young Assistant Professor of Pharmacology, collabo-
Stevens’ Pharmacology. rated on research projects, and encouraged my career as an
Second, the market is flush with immunopharmacology academic scientist. Dr. Brenner had an encyclopedic knowl-
drug products. Immunopharmacology products are rampant edge of medications and his expertise is greatly missed. On
and apparent to both the physician and consumer by the another sad note, this book was written during the COVID-
numerous monoclonal antibody drugs touted in TV com- 19 pandemic which took hundreds of thousands of lives
mercials. Pharmaceutical manufacturing of monoclonal due to infection with the SARS-CoV-2 virus. Although at
antibody drugs that target enzymes, receptors, or other pro- the time of this writing there are no fully-approved FDA
teins is a rapidly growing sector of biologicals. Many thera- treatments for the pandemic virus, special sections on the
peutic classes of pharmacological agents now have one or emergency use drugs and developing vaccines are included
two drugs that work via antibodies or that target immune in Chapter 43 and Chapter 46.
system factors. Because of the exponential growth of immu- I thank my numerous offspring and their mates for their
nopharmacology drugs, a new Chapter 46 was added to close constant love and attention which inspires me to undertake
the book. such massive projects like this textbook. I especially want
Third, the development and marketing of small molecule to thank my OB/GYN wife, Dr. Timmeni L. Stevens, D.O.,
inhibitors skyrocketed in the last five years. Small molecule (‘the real doctor’) for her help on Chapter 34, Drugs Affecting
inhibitors were developed to go inside of cells and inhibit Fertility and Reproduction. I also appreciate the fine people
particular kinases or other enzymes and proteins. By con- at Elsevier, who bring it all together to produce the nicely
trast, more traditional drugs target receptor or enzymes on designed textbook now in your hands. The interactions with
vi Preface
Alexandra Mortimer, Meghan Andress, and Kevin Travers Craig W. Stevens, PhD
were especially professional and pleasant. They seem to Professor of Pharmacology
really enjoy their career and know what they are doing. OSU-Center for Health Sciences
Finally, I am a pharmacologist who spent most of my Tulsa, Oklahoma
career as a preclinical researcher using animals and cell
cultures as models for understanding the human condition.
I am not a physician or medical consultant. Therefore none
of the following text should be taken as medical advice.
Contents
Section I 21 L ocal and General Anesthetics 233

22 Psychotherapeutic Drugs 243
PRINCIPLES OF PHARMACOLOGY
23 Opioid Analgesics and Antagonists 261
1 Introduction to Pharmacology and Drug
24 Drugs for Neurodegenerative Diseases 273
Names 3
25 Drugs of Abuse 285
2 Pharmacokinetics or What the Body Does to
the Drug 11
3 Pharmacodynamics or What the Drug Does to Section V
the Body 27 PHARMACOLOGY OF RESPIRATORY AND
4 Drug Development and Drug Safety 35 OTHER SYSTEMS
5 Toxicology Principles and the Treatment of
26 utacoid Drugs That Mimic Endogenous
A
Poisoning 47
Substances 301
27 Pharmacological Treatment of Respiratory
Section II Disorders 313
AUTONOMIC AND NEUROMUSCULAR 28 Pharmacological Treatment of
PHARMACOLOGY Gastrointestinal Disorders 325
29 Drugs for Headache Disorders 339
6 Parasympathetic, Neuromuscular
Pharmacology, and Cholinergic Agonists 59 30 Drugs for Pain, Inflammation, and Arthritic
Disorders 347
7 Cholinergic Receptor Antagonists 75
8 Sympathetic Neuropharmacology and
Adrenergic Agonists 83 Section VI
9 Adrenergic Receptor Antagonists 95 ENDOCRINE PHARMACOLOGY
31 ypothalamic and Pituitary Hormone
H
Section III Drugs 363
CARDIOVASCULAR, RENAL, AND 32 Drugs for the Treatment of Thyroid
HEMATOLOGIC PHARMACOLOGY Disorders 371
33 Adrenal Steroids and Related Drugs 379
10 Antihypertensive Drugs 105
34 Fertility and Reproduction Drugs 389
11 Antianginal Drugs 119
35 Drugs for the Treatment of Diabetes 407
12 Drugs for the Treatment of Heart
Failure 127 36 Drugs Affecting Calcium and Bone
Formation 421
13 Diuretic Drugs 137
14 Drugs for Cardiac Dysrhythmia 147
Section VII
15 Drugs for Hyperlipidemia 161
16 Antithrombotic and Thrombolytic Drugs 173 ANTIMICROBIAL AND CHEMOTHERAPEUTIC
17 Hematopoietic Drugs 187 AGENTS
37 rinciples of Antimicrobial
P
Chemotherapy 433
Section IV
38 Antibiotics That Inhibit Bacterial Cell Wall
CENTRAL NERVOUS SYSTEM PHARMACOLOGY Synthesis 445
18 Introduction to Central Nervous System 39 Antibiotics That Inhibit Bacterial Protein
Pharmacology 197 Synthesis 457
19 Sedative-Hypnotic and Anxiolytic Drugs 209 40 Other Antimicrobial Agents Such as
20 Antiepileptic Drugs 221 Quinolones and Antifolate Drugs 467
viii Contents
41 ntimycobacterial Drugs for Treating

A 45 Antineoplastic Agents 515
Tuberculosis and Other Diseases 475 46 Immunopharmacology, Biologicals, and Gene
42 Drugs for the Treatment of Fungal Therapy 531
Infections 483
43 Drugs for the Treatment of Viral Answers and Explanations 545
Infections 491 Index 565
44 Drugs for the Treatment of Parasites 505
I
Section
PRINCIPLES OF
PHARMACOLOGY
Introduction to Pharmacology and Drug Names 3
Pharmacokinetics or What the Body Does to the Drug 11
Pharmacodynamics or What the Drug Does to the Body 27
Drug Development and Drug Safety 35
Toxicology Principles and the Treatment of Poisoning 47
1

CHAPTER
Introduction to Pharmacology
1 and Drug Names
PHARMACOLOGY AND RELATED SCIENCES a more rational understanding of disease mechanisms pro-
Pharmacology is the study of drugs and their effects on vided a scientific basis for using drugs whose physiologic
living organisms, whether it be whole organisms, tissues, actions and effects were understood. The advent of pharma-
or cells. Pharmacology is a fundamental biomedical sci- cology was particularly dependent on the isolation of pure
ence that sprang to the forefront of modern medicine with drug compounds from natural sources and on the develop-
a demonstrated success in using drugs to treat disease and ment of experimental physiology methods to study these
save human lives. Pharmacology is also the scientific disci- compounds. The isolation of morphine from opium in 1804
pline that drives the international pharmaceutical industry was rapidly followed by the extraction of many other drugs
to multibillion-dollar sales. This chapter reviews the his- from plant sources, providing a diverse array of pure drugs
tory of pharmacology, identifies its major subdivisions, and for pharmacologic experimentation. Advances in physi-
introduces the types of drugs, formulations, and routes of ology allowed pioneers, such as François Magendie and
administration. Claude Bernard, to conduct some of the earliest pharma-
cologic investigations, including studies that localized the
History and Definition of Pharmacology site of action of curare to the neuromuscular junction. The
Since the beginning of our species, people have treated pain first medical school pharmacology laboratory was started
and disease with substances derived from plants, animals, by Rudolf Buchheim in Estonia. Buchheim and one of his
and minerals. However, the science of pharmacology is less students, Oswald Schmiedeberg, trained many other phar-
than 150 years old, ushered in by the ability to isolate pure macologists, including John Jacob Abel, who established
compounds from plants and the establishment of the scien- the first pharmacology department at the University of
tific method. Michigan in 1891 and is considered the father of American
Initially, drug use for aiding the sick consisted of crude pharmacology.
plant and animal preparations given in a ritualistic manner The goal of pharmacology is to understand the mech-
to rid the body of the evil spirits believed to cause illness. anisms by which drugs interact with biologic systems to
Their effectiveness was probably due as much to beliefs or enable the rational use of effective agents in the diagnosis
a placebo effect as it was to any medicinal property of the and treatment of disease. The success of pharmacology in
substances administered. Many cultures relied on a magic- this task has led to an explosion of new drug development,
man or shaman to perform the healing rituals. Indeed, the particularly in the past 50 years. Significant drug develop-
Greek word pharmakon, from which the term pharmacology ment includes the isolation and use of insulin for diabetes,
is derived, originally meant a magic charm for treating dis- the discovery of antimicrobial and antineoplastic drugs,
ease. Later, pharmakon came to mean a remedy or drug. and the advent of modern psychopharmacology. Recent
In the next phase of pharmacology, accrued knowledge advances in molecular biology, genetics, and computer-aided
from generations of medicinal rituals enabled people to cor- drug design suggest that new drug development and phar-
relate natural substances with treatment of particular dis- macologic innovations will provide even greater advances
eases or symptoms. The first effective drugs were probably in the treatment of medical disorders in the coming years.
simple external preparations, such as cool mud for sunburn The history of many significant events in pharmacology,
or a soothing mixture of plant leaves for an insect bite. The as highlighted by selected Nobel Prize recipients, is pre-
earliest known prescriptions, dating from 2100 bce, included sented in Table 1.1.
salves containing the spice thyme. In the ensuing centuries,
people learned the therapeutic value of natural products Pharmacology and Its Subdivisions
through trial and error. By 1500 bce, Egyptian prescriptions Pharmacology is the biomedical science concerned with
called for castor oil, opium, and other drugs still used today. the interaction of chemical substances with living cells, tis-
In China, ancient scrolls from that time listed prescriptions sues, and organisms. It is particularly concerned with the
for herbal medicines for more than 50 diseases. Dioscorides, mechanisms by which drugs counteract the manifestations
a Greek army surgeon who lived in the 1st century, described of disease and affect fertility. Pharmacology is not primarily
more than 600 medicinal plants that he collected and stud- focused on the methods of synthesis, isolation of drugs, or
ied as he traveled with the Roman army. Susruta, a Hindu with the preparation of pharmaceutical products. The disci-
healer, described the principles of Ayurvedic medicine in plines that deal with these subjects are described later.
the 5th century. During the Middle Ages, Islamic physicians Pharmacology is divided into two main subdivisions,
(most famously Avicenna) and Christian monks cultivated pharmacokinetics and pharmacodynamics. The rela-
and studied the use of herbal medicines. tionship between these subdivisions is shown in Fig. 1.1.
The current phase of pharmacology gradually evolved Pharmacokinetics is concerned with the processes that deter-
with important advances in chemistry and physiology mine the concentration of drugs in body fluids and tissues over
that gave rise to modern pharmacology. At the same time, time, including drug absorption, distribution, metabolism,
3
4 Section I Principles of Pharmacology
TABLE 1.1 The Nobel Prize and the History of and excretion (ADME). Pharmacodynamics is the study of
Pharmacology* the actions of drugs on target receptors and tissues. A short-
PERSON(S) AND YEAR SIGNIFICANT DISCOVERY IN hand way of thinking about it is that pharmacodynamics is
AWARDED PHARMACOLOGY what the drug does to the body, and pharmacokinetics is what
Ilya Metchnikoff and Paul First antimicrobial drugs (magic the body does to the drug. Modern pharmacology is focused
Ehrlich (1908) bullet) on the biochemical and molecular mechanisms by which
Frederick Banting and John Isolation and discovery of insulin
drugs produce their physiologic effects and with the dose-
Macleod (1923) and its application in the response relationship, defined as the relationship between
treatment of diabetes the concentration of a drug in a tissue and the magnitude of
Sir Henry Dale and Otto Loewi Chemical transmission of nerve the tissue’s response to that drug. Most drugs produce their
(1936) impulses effects by binding to protein receptors in target tissues, a
Sir Alexander Fleming, Ernst Discovery of penicillin and its
process that activates a cascade of events known as signal
Chain, and Sir Howard Florey curative effect in various transduction. Pharmacokinetics and pharmacodynamics are
(1945) infectious diseases discussed in greater detail in Chapters 2 and 3, respectively.
Daniel Bovet (1957) Antagonists that block
biologically active amines, Toxicology
including the first Toxicology is the study of poisons and organ toxicity. It
antihistamine focuses on the harmful effects of drugs and other chemi-
Sir Bernard Katz, Ulf von Euler, Transmitters in the nerve cals and on the mechanisms by which these agents produce
and Julius Axelrod (1970) terminals and the mechanism pathologic changes, disease, and death. As with pharmacol-
for storage, release, and ogy, toxicology is concerned with the relationship between
inactivation
the dose of an agent and the resulting tissue concentration
Sune Bergström, Bengt Discovery of prostaglandins and biologic effects that the agent produces. Most drugs
Samuelsson, and John Vane and the mechanism of
(1982) action of aspirin that inhibits
have toxic effects at high enough doses and may have
prostaglandin synthesis adverse effects related to toxicity at therapeutic doses.
Sir James Black, Gertrude Elion, Development of the first β-
and George Hitchings (1988) blocker, propranolol, and Pharmacotherapeutics
anticancer agents that block Pharmacotherapeutics is the medical science con-
nucleic acid synthesis cerned with the use of drugs in the treatment of disease.
Alfred Gilman and Martin Discovery of G proteins and the Pharmacology provides a rational basis for pharmacothera-
Rodbell (1994) role of these proteins in signal peutics by explaining the mechanisms and effects of drugs
transduction in cells on the body and the relationship between dose and drug
Robert Furchgott, Louis Ignarro, Recognition of nitric oxide as response. A cadre of research pharmacologists around the
and Ferid Murad (1998) a signaling molecule in the world does much preclinical research before drug candidates
cardiovascular system emerge. Human studies known as clinical trials are then
Arvid Carlsson, Paul Greengard, Role of dopamine in used to determine the efficacy and safety of drug therapy
and Eric Kandel (2000) schizophrenia and signal in human subjects. The purpose, design, and evaluation of
transduction in the nervous human drug studies are discussed in Chapter 4.
system leading to long-term
potentiation
Pharmacy and Related Sciences
Robert J. Lefkowitz and Brian K. The structural basis of G protein–
Kobilka (2012) coupled receptor signaling
Pharmacy is the science and profession concerned with
the preparation, storage, dispensing, and proper use
*Selected from the list of recipients of the Nobel Prize for Physiology or Medicine, of drug products. Related sciences include pharmacog-
or the Nobel Prize for Chemistry; note that many other discoveries pertinent to
pharmacology have been made by other Nobel Prize winners and that the original nosy, medicinal chemistry, and pharmaceutical chemistry.
discovery was often made many years before the Nobel Prize was awarded. Pharmacognosy is the study of drugs isolated from natural
Pharmacokinetics Pharmacodynamics
Dose of drug Drug concentration Magnitude of

administered in blood or target tissue drug effect
Absorption Receptor binding

Distribution Signal transduction
Metabolism Pharmacological effects
Excretion Dose-response
Fig. 1.1 Relationship between pharmacokinetics and pharmacodynamics.
Chapter 1 Introduction to Pharmacology and Drug Names 5
Natural drug source Opium poppy
Crude drug preparation Raw opium
Pure drug extract Morphine sulfate
Pharmaceutical formulation Morphine tablets
Fig. 1.2 Types of drug preparations. A crude drug preparation retains most or all of the active and inactive compounds contained in the natural source
from which it was derived. After a pure drug compound (e.g., morphine) is extracted from a crude drug preparation (in this case, opium), it is possible to
manufacture pharmaceutical preparations that are suitable for administration of a particular dose to the patient.
sources, including plants, microbes, animal tissues, and min- occurring drugs. Aspirin, barbiturates, and local anesthetics
erals. Medicinal chemistry is a branch of organic chemistry (e.g., procaine) were among the first drugs to be synthesized
that specializes in the design and chemical synthesis of drugs in the laboratory. Semisynthetic derivatives of naturally
used in medicine. Pharmaceutical chemistry, or pharma- occurring compounds have led to new drugs with different
ceutics, is concerned with the formulation and chemical properties, such as the morphine derivative oxycodone.
properties of pharmaceutical products, such as tablets, liquid In some cases, new drug uses were discovered by accident
solutions and suspensions, and aerosols. when drugs were used for another purpose, or by actively
screening a huge number of related molecules for a specific
DRUG SOURCES AND PREPARATIONS pharmacologic activity. Medicinal chemists now use molec-
A drug can be defined as a natural product, chemical sub- ular modeling software to discern the structure-activity
stance, or pharmaceutical preparation intended for admin- relationship, which is the relationship among the drug mol-
istration to a human or animal to diagnose or treat a disease. ecule, its target receptor, and the resulting pharmacologic
A drug can also be a biologic (e.g., a preparation of monoclo- activity. In this way a virtual model for the receptor of a par-
nal antibodies). The word drug is derived from the French ticular drug is created, and drug molecules that best fit the
drogue, which originally meant dried herbs and was applied three-dimensional conformation of the receptor are synthe-
to herbs in the marketplace used for cooking rather than for sized. This approach has been used, for example, to design
any medicinal reason. Ironically, the medical use of the drug agents that inhibit angiotensin synthesis, treat hyperten-
marijuana, a dried herb, is hotly debated in many societies sion, and inhibit the maturation of the human immunode-
nowadays. Drugs may be hormones, neurotransmitters, or ficiency virus (HIV).
peptides produced by the body; conversely, a xenobiotic is
a drug produced outside the body, either synthetic or natu- Drug Preparations
ral. A poison is a drug that can kill, whereas a toxin is a Drug preparations include crude drug preparations obtained
drug that can kill and is produced by a living organism. The from natural sources, pure drug compounds isolated from
terms medication and, used less frequently, medicament are natural sources or synthesized in the laboratory, and phar-
synonymous with the word drug. maceutical preparations of drugs intended for administra-
tion to patients. The relationship among these types of drug
Natural Sources of Drugs preparations is illustrated in Fig. 1.2.
Drugs have been obtained from plants, microbes, animal
tissues, and minerals. Among the various types of drugs Natural Sources of Drugs
derived from plants are alkaloids, which are substances that The natural source of drugs is often a plant well known for
contain nitrogen groups and produce an alkaline reaction in its medicinal use and taken as is. Nicotine and marijuana
aqueous solution. Examples of alkaloids include morphine, plants are usually administered as drugs in their raw form as
cocaine, atropine, and quinine. Antibiotics have been iso- dried leaves. Other natural sources of drugs include Amanita
lated from numerous microorganisms, including Penicillium mushrooms, which yield the plant alkaloid muscarine, and
and Streptomyces species. Hormones are the most common peyote cacti with the active ingredient of mescaline.
type of drug obtained from animals, whereas minerals have
yielded a few useful therapeutic agents, including the lith- Crude Drug Preparations
ium compounds used to treat bipolar mental illness. Some crude drug preparations are made by drying or pulver-
izing a plant or animal tissue. Others are made by extracting
Synthetic Drugs substances from a natural product with the aid of hot water
Modern chemistry in the 19th century enabled scientists or a solvent such as alcohol. Familiar examples of crude drug
to synthesize new compounds and to modify naturally preparations are coffee and tea, made from distillates of
the beans and leaves of Coffea arabica and Camellia sinensis hours. The two methods used to extend the release of a drug
plants, respectively, and opium, which is the dried juice of are controlled diffusion and controlled dissolution. With
the unripe poppy capsule of the plant Papaver somniferum. controlled diffusion, a rate-controlling membrane regulates
release of the drug from the pharmaceutical product. Inert
Pure Drug Compounds polymers gradually break down in body fluids creating a con-
It is difficult to identify and quantify the pharmacologic trolled dissolution. These polymers may be part of the tablet
effects of crude drug preparations because these products matrix, or they may be used as coatings over small pellets of
contain multiple ingredients with varying amounts from drug enclosed in a capsule. In either case, the drug is gradu-
batch to batch. Therefore the development of methods to ally released into the gastrointestinal tract as the polymers
isolate pure drug compounds from natural sources was an dissolve.
important step in the growth of pharmacology and rational Some products use osmotic pressure to provide a sus-
therapeutics. Frederick Sertürner, a German pharmacist, tained release of a drug. These products contain an osmotic
isolated the first pure drug from a natural source in 1804. He agent that attracts gastrointestinal fluid at a constant rate.
extracted and tested a potent analgesic agent from opium The attracted fluid then forces the drug out of the tablet
and named it morphine, from Morpheus, the Greek god of through a small laser-drilled hole (Fig. 1.3A).
dreams. The subsequent isolation of many other drugs from Capsules are hard or soft gelatin shells enclosing a
natural sources provided pharmacologists with a number of powdered or liquid medication. Hard capsules are used to
pure compounds for study and characterization. One of the enclose powdered drugs, whereas soft capsules enclose a
greatest medical achievements of the early 20th century was drug in solution. The gelatin shell quickly dissolves in gas-
the isolation of insulin from the pancreas. This achievement trointestinal fluids to release the drug for absorption into the
led to the development of insulin preparations for treating circulation.
diabetes mellitus. Solutions and Suspensions. Drug solutions and par-
ticle suspensions, the most common liquid pharmaceutical
Pharmaceutical Preparations preparations, can be formulated for oral, parenteral, or other
Pharmaceutical preparations or dosage forms are drug prod- routes of administration. Solutions and suspensions provide
ucts suitable for administration of a specific dose of a drug a convenient method for administering drugs to pediatric
to a patient by a particular route of administration. Most and other patients who cannot easily swallow pills or tab-
of these preparations are made from pure drug compounds, lets. However, they are less convenient than solid dosage
but a few are made from crude drug preparations and sold forms because the liquid must be measured each time a dose
as herbal remedies. By far, the most common formulation is given.
of drugs is for the oral route of administration, followed by Solutions and suspensions for oral administration are
formulations used for injections. often sweetened and flavored to increase palatability.
Tablets and Capsules. Tablets and capsules are the most Sweetened aqueous solutions are called syrups, whereas
common preparations for oral administration because they sweetened aqueous-alcoholic solutions are known as elixirs.
are suitable for mass production, are stable and convenient Alcohol is included in elixirs as a solvent for drugs that are
to use, and can be formulated to release the drug immedi- not sufficiently soluble in water alone.
ately after ingestion or to release it over a period of hours. Sterile solutions and suspensions are available for par-
In the manufacture of tablets, a machine with a punch enteral administration with a needle and syringe or with an
and die mechanism compresses a mixture of powdered drug intravenous infusion pump. Many drugs are formulated as
and inert ingredients into a hard pill. The inert ingredi- sterile powders for reconstitution with sterile liquids at the
ents include specific components that provide bulk, prevent time the drug is to be injected, because the drug is not stable
sticking to the punch and die during manufacture, maintain for long periods of time in solution. Sterile ophthalmic solu-
tablet stability in the bottle, and facilitate solubilization tions and suspensions are suitable for administration with an
of the tablet when it reaches gastrointestinal fluids. These eyedropper into the conjunctival sac.
ingredients are called fillers, lubricants, adhesives, and dis- Skin Patches. Transdermal skin patches are drug prepa-
integrants, respectively. rations in which the drug is slowly released from the patch
A tablet must disintegrate after it has been ingested, and for absorption through the skin into the circulation. Most
then the drug must dissolve in gastrointestinal fluids before skin patches use a rate-controlling membrane to regulate
it can be absorbed into the circulation. Variations in the the diffusion of the drug from the patch (see Fig. 1.3B).
rate and extent of tablet disintegration and drug dissolution Such devices are most suitable for potent drugs, which are
can give rise to differences in bioavailability of drugs from dif- therefore effective at relatively low doses and that have suf-
ferent tablet formulations (see Chapter 2). ficient lipid solubility to enable skin penetration.
Tablets may have various types of coatings. Enteric coat- Aerosols. Aerosols are a type of drug preparation admin-
ings consist of polymers that will not disintegrate in gas- istered by inhalation through the nose or mouth. They are
tric acid but will break down in the more basic pH of the particularly useful for treating respiratory disorders because
intestines. Enteric coatings are used to protect drugs that they deliver the drug directly to the site of action and may
would otherwise be destroyed by gastric acid and to slow the thereby minimize the risk of systemic side effects. Some
release and absorption of a drug when a large dose is given at aerosol devices contain the drug dispersed in a pressurized
one time, for example, in the formulation of the antidepres- gas and are designed to deliver a precise dose each time they
sant fluoxetine, called Prozac Weekly. are activated by the patient. Nasal sprays, another type of
Sustained-release products, or extended-release prod- aerosol preparation, can be used either to deliver drugs that
ucts, release the drug from the preparation over many have a localized effect on the nasal mucosa or to deliver
A B
Active drug Stored drug in
Air
drug reservoir
Backing
Rate-limiting
membrane
Stored drug
Osmotic agent Active drug
Skin
H2O molecules
Fig. 1.3 Mechanisms of sustained-release drug products. In the sustained-release tablet (A). Water is attracted by an osmotic agent in the tablet, and
this forces the drug out through a small orifice. In the transdermal skin patch (B). The drug diffuses through a rate-controlling membrane and is absorbed
through the skin into the circulation.
drugs that are absorbed through the mucosa and exert an drug metabolism in the liver. Drugs for sublingual and buccal
effect on another organ. For example, butorphanol, an opi- administration are given in a relatively low dose and must
oid analgesic, is available as a nasal spray (Stadol NS) for have good solubility in water and lipid membranes. Larger
the treatment of pain. doses might be irritating to the tissue and would likely be
Ointments, Creams, Lotions, and Suppositories. Oint washed away by saliva before the drug could be absorbed.
ments and creams are semisolid preparations intended for Two examples of drugs available for sublingual administra-
topical application of a drug to the skin or mucous mem- tion are nitroglycerin for treating ischemic heart disease
branes. These products contain an active drug incorporated and hyoscyamine for treating bowel cramps. Fentanyl, a
into a vehicle (e.g., polyethylene glycol or petrolatum), potent opioid analgesic, is available in an oral transmucosal
which enables the drug to adhere to the tissue for a suffi- formulation (Actiq) with a lozenge on a stick (“lollypop”)
cient length of time to exert its effect. Lotions are liquid for rapid absorption from the buccal mucosa in the treat-
preparations often formulated as oil-in-water emulsions and ment of breakthrough cancer pain.
are used to treat dermatologic conditions. Suppositories are In medical orders and prescriptions, oral administration
products in which the drug is incorporated into a solid base is designated as per os (PO), which means to administer
that melts or dissolves at body temperature. Suppositories “by mouth.” The medication is swallowed, and the drug is
are used for rectal, vaginal, or urethral administration and absorbed from the stomach and small intestine. The oral
may provide either localized or systemic drug therapy. route of administration is convenient, relatively safe, and
the most economical. However, it does have some disad-
ROUTES OF DRUG ADMINISTRATION vantages. Absorption of orally administered drugs can vary
Some routes of drug administration, such as the enteral widely because of the interaction of drugs with food and gas-
and common parenteral routes compared in Table 1.2, are tric acid and the varying rates of gastric emptying, intestinal
intended to elicit systemic effects and are therefore called transit, and tablet disintegration and dissolution. Moreover,
systemic routes. Other routes of administration, such as some drugs are inactivated by the liver after their absorption
the inhalational route, can elicit either localized effects or from the gut, called first-pass metabolism (see Chapter 2),
systemic effects, depending on the drug being administered. and oral administration is not suitable for use by patients
who are sedated, comatose, or experiencing nausea and
Enteral Administration vomiting.
The enteral routes of administration are those in which Rectal administration of drugs in suppository form
the drug is absorbed from the gastrointestinal tract. These can result in either a localized effect or a systemic effect.
include the sublingual, buccal, oral, and rectal routes. Suppositories are useful when patients cannot take medi-
In sublingual administration, a drug product is placed cations by mouth, as in the treatment of nausea and
under the tongue. In buccal administration, the drug is vomiting. They can also be administered for localized
placed between the cheek and the gum. Both the sublingual conditions such as hemorrhoids. Drugs absorbed from the
and the buccal routes of administration enable the rapid lower rectum undergo relatively little first-pass metabo-
absorption of certain drugs and are not affected by first-pass lism in the liver.
TABLE 1.2 Advantages and Disadvantages of Four Common Routes of Drug Administration
ROUTE ADVANTAGES DISADVANTAGES
Oral Convenient, relatively safe, and economical. Cannot be used for drugs inactivated by gastric acid,
for drugs with a large first-pass effect, or for drugs
that irritate the gut.
Intramuscular Suitable for suspensions and oily vehicles. Absorption is rapid May be painful. Can cause bleeding if the patient is
from solutions and is slow and sustained from suspensions. receiving an anticoagulant.
Subcutaneous Suitable for suspensions and pellets. Absorption is similar to Cannot be used for drugs that irritate cutaneous tissues
that in the intramuscular route but is usually somewhat or for drugs that must be given in large volumes.
slower.
Intravenous Bypasses absorption to give an immediate effect. Allows for Poses more risks for toxicity and tends to be more
rapid titration of drug. Achieves 100% bioavailability. expensive than other routes.
Parenteral Administration 7 days. Two examples of transdermal preparations are the skin
Parenteral administration refers to drug administration with patches called fentanyl transdermal (Duragesic), used to
a needle and syringe or with an intravenous infusion pump. treat severe chronic pain, and nitroglycerin ointment, used
The most commonly used parenteral routes are the intrave- to treat heart failure and angina pectoris.
nous, intramuscular, and subcutaneous routes.
Intravenous administration bypasses the process of drug Inhalational Administration
absorption and provides the greatest reliability and con- Inhalational administration can be used to produce either a
trol over the dose of drug reaching the systemic circula- localized or a systemic drug effect. A localized effect on the
tion. Because the drug is delivered directly into the blood, respiratory tract is achieved with drugs used to treat asthma
it has 100% bioavailability (see Chapter 2). The route is or rhinitis, whereas a systemic effect is observed when a
often preferred for administration of drugs with short half- general anesthetic such as sevoflurane is inhaled.
lives and drugs whose dose must be carefully titrated to the
physiologic response, such as agents used to treat hypoten- Topical Administration
sion, shock, and acute heart failure. The intravenous route Topical administration refers to the application of drugs to
is widely used to administer antibiotics and antineoplastic the surface of the body to produce a localized effect. It is
drugs to critically ill patients, as well as to treat various types often used to treat disease and trauma of the skin, eyes, nose,
of medical emergencies. The intravenous route is poten- mouth, throat, rectum, and vagina.
tially the most dangerous because rapid administration of
drugs by this route can cause serious toxicity. DRUG NAMES
Intramuscular administration and subcutaneous admin- A drug often has several names, including a chemical name,
istration are suitable for treatment with drug solutions and a nonproprietary (generic) name, and a proprietary name
particle suspensions. Solutions are absorbed more rapidly (or trade or brand name).
than particle suspensions, so suspensions are often used to The chemical name, which specifies the chemical struc-
extend the duration of action of a drug over many hours or ture of the drug, uses standard chemical nomenclature.
days. Most drugs are absorbed more rapidly after intramus- Some chemical names are short and easily pronounceable
cular than after subcutaneous administration because of the (e.g., the chemical name of aspirin is acetylsalicylic acid).
greater circulation of blood to the muscle. Others are long and hard to pronounce owing to the size and
Intrathecal administration refers to injection of a drug complexity of the drug molecule. For most drugs, medicinal
through the thecal covering of the spinal cord and into the chemists primarily use the chemical name.
subarachnoid space. In cases of meningitis, the intrathecal The generic name (nonproprietary name) is the type of
route is useful in administering antibiotics that do not cross drug name most suitable for use by health care profession-
the blood-brain barrier. Epidural administration, common als. In the United States, the generic names of drugs are the
in labor and delivery, targets analgesics into the space above United States Adopted Name (USAN) designations. These
the dural membranes of the spinal cord. designations, which are often derived from the chemical names
Other, less common parenteral routes include intra- of drugs, provide some indication of the class to which a par-
articular administration of drugs used to treat arthritis, ticular drug belongs. For example, oxacillin can be easily rec-
intradermal administration for allergy tests, and insuffla- ognized as a type of penicillin. The designations are selected by
tion (intranasal administration) for sinus medications. the USAN Council, which is a nomenclature committee rep-
resenting the medical and pharmacy professions and the United
Transdermal Administration States Pharmacopeial Convention (see Chapter 4). Students tak-
Transdermal administration is the application of drugs to the ing various board examinations including pharmacology (e.g.,
skin for absorption into the circulation. Application can be via nursing boards, medical boards) will also be most attentive to
a skin patch or, less commonly, via an ointment. Transdermal the generic names of drugs.
administration, which bypasses first-pass metabolism, is a reli- The brand name (proprietary name, trade name) for a
able route of administration for drugs that are effective when drug is the registered trademark belonging to a particular drug
given at a relatively low dosage and that are highly soluble manufacturer and is used to designate a drug product mar-
in lipid membranes. Transdermal skin patches slowly release keted by that manufacturer. Heavily marketed brand names
medication for periods of time that typically range from 1 to become common knowledge to patients, such as Prozac and
Viagra. Many drugs are marketed under two or more brand • T he sources of drugs are natural products (including
names, especially after the manufacturer loses patent exclu- plants, microbes, animal tissues, and minerals) and
sivity. For example, ibuprofen (generic name) is marketed in chemical synthesis. Drugs can exist as crude drug
the United States with the brand names of Advil, Motrin, preparations, pure drug compounds, or pharmaceuti-
and Midol. Drugs can also be marketed under their USAN cal preparations used to administer a specific dose to
designation. For these reasons, it is often less confusing and a patient.
more precise to use the USAN rather than a brand name • The primary routes of administration are enteral (e.g.,
for a drug. However, the brand name may provide a better oral ingestion), parenteral (e.g., intravenous, intra-
indication of the drug’s pharmacologic or therapeutic effect. muscular, and subcutaneous injection), transdermal,
For example, Diuril is a brand name for chlorothiazide, a inhalational, and topical. Most routes produce sys-
diuretic; Flomax for tamsulosin, a drug used to increase urine temic effects. Topical administration produces a local-
flow; and Maxair for pirbuterol, a drug used to treat asthma. ized effect at the site of administration.
• All drugs (pure compounds) have a nonproprietary
Generic Drug Substitution for Branded Drugs name (or generic name, such as a USAN designation)
When a new drug is developed and brought to market by and a chemical name. Some drugs also have one or
a pharmaceutical manufacturer, the US Food and Drug more proprietary names (trade names or brand names)
Administration (FDA) approval comes with an exclusivity under which they are marketed by their manufacturer.
patent for the next 17 to 20 years. During this time, no other
company can manufacture or sell the same drug. When the
original drug loses exclusivity, generic drug manufacturers Review Questions
can file for a brief form of drug approval, limited to showing
that the generic formulation exhibits the same absorption 1. Which route of drug administration is used with potent
and bioavailability as the original, branded drug. Generic and lipophilic drugs in a patch formulation and avoids
drugs are much cheaper because the second manufacturer first-pass metabolism?
does not have to recoup the costs of drug discovery, devel- (A) topical
opment, clinical trials, and the FDA new drug application. (B) sublingual
Although the FDA does not regulate when to use generic (C) rectal
drugs, most states have passed laws on generic substitution. (D) oral
Because use of generic medications instead of branded drugs (E) transdermal
can save millions of dollars in health care costs, some states 2. Which one of the following routes of administration does
mandate generic substitution without patient or physician not have an absorption phase?
approval, although physicians can override generic substitu- (A) subcutaneous
tions in some cases. Other states need the approval of the (B) intramuscular
patient or physician to switch from a branded drug prescrip- (C) intravenous
tion to a generic substitute. (D) sublingual
Both patient and physician misconceptions affect the (E) inhalation
underutilization of generic drugs. Scientific studies show 3. Which of the following correctly describes the intramus-
that the overwhelming majority of generic medicines are cular route of parenteral drug administration?
bioequivalent to the branded, originator drug. The FDA (A) drug absorption is erratic and unpredictable
has identified certain drugs that may be more dangerous (B) used to administer drug suspensions that are slowly
to switch, called narrow therapeutic index (NTI) drugs, absorbed
which may warrant further drug blood monitoring after a (C) bypasses the process of drug absorption to achieve
generic to branded drug substitution. an immediate effect
In this textbook, the generic name of a drug is given in (D) cannot be used for drugs that undergo a high degree
the normal-sized font and its brand name in Small Caps of first-pass metabolism
font. Note that not all generic drugs have a brand name (E) poses more risks than intravenous administration
counterpart. 4. An elderly patient has problems remembering to take her
medication 3 times a day. Which one of the drug formu-
lations might be particularly useful in this case?
SUMMARY OF IMPORTANT POINTS
(A) extended release
• T he development of pharmacology was made possible (B) suspension
by important advances in chemistry and physiology (C) suppository
that enabled scientists to isolate and synthesize pure (D) skin patch
chemical compounds (drugs) and to design methods (E) enteric coated
for identifying and quantifying the physiologic actions 5. Which form of a drug name is most likely known by
of the compounds. patients from exposure to drug advertisements?
• Pharmacology has two main subdivisions. Pharmaco (A) nonproprietary name
dynamics is concerned with the mechanisms of drug (B) British Approved Name
action and the dose-response relationship, whereas (C) chemical name
pharmacokinetics is concerned with the relationship (D) generic name
between the drug dose and the plasma drug concen- (E) trade name
tration over time.

CHAPTER
Pharmacokinetics or What the
2 Body Does to the Drug
OVERVIEW A few drugs are absorbed by active transport or by facili-

Pharmacokinetics is the study of drug disposition in the tated diffusion. Active transport requires a carrier mol-
body and focuses on the changes in drug plasma concen- ecule and a form of energy, provided by hydrolysis of the
tration. For any given drug and dose, the plasma concentra- terminal high-energy phosphate bond of adenosine triphos-
tion of the drug will rise and fall according to the rates of phate (ATP). Active transport can transfer drugs against
four processes: absorption, distribution, metabolism, and a concentration gradient. For example, the antineoplastic
excretion (ADME). Absorption is the movement of drug drug 5-fluorouracil undergoes active transport. Facilitated
from the site of administration to the bloodstream. The diffusion also requires a carrier molecule, but no energy
rate and extent of absorption are dependent on the physical is needed. Thus drugs or substances cannot be transferred
characteristics of the drug and its formulation. Distribution against a concentration gradient but diffuse faster than
is the process of a drug leaving the bloodstream and being without a carrier molecule present. Some cephalosporin
distributed throughout the body, into the organs and tis- antibiotics, such as cephalexin, undergo facilitated diffusion
sues. Metabolism, also called biotransformation, is the by an oligopeptide transporter protein located in intestinal
process of converting a drug to one or more metabolites, epithelial cells.
primarily in the liver. Excretion is the removal of a drug
or its metabolites from the body, primarily by the kidneys Effect of pH on Absorption of Weak Acids and Bases
and urination. Sometimes the term elimination of a drug is Many drugs are weak acids or bases that exist in both ion-
used; this refers to the processes of metabolism and excre- ized and nonionized forms in the body. Only the nonionized
tion combined. The relationship between these pharmaco- form of these drugs is sufficiently soluble in membrane lip-
kinetic processes is explained more fully later and is shown ids to cross cell membranes (Box 2.1). The ratio of the two
in Fig. 2.1. forms at a particular site influences the rate of absorption
and is also a factor in distribution and elimination.
DRUG ABSORPTION The protonated form of a weak acid is nonionized, whereas
Drug absorption refers to the passage of drug molecules from the protonated form of a weak base is ionized. The ratio of
the site of administration into the circulation. The process the protonated form to the nonprotonated form of these
of drug absorption applies to all routes of administration, drugs can be calculated using the Henderson-Hasselbalch
except for the topical route, in which drugs are applied equation (see Box 2.1). The pKa is the negative log of the
directly on the target tissue, and intravenous administra- ionization constant, particular for each acidic or basic drug.
tion, in which the drug is given directly in the bloodstream. At a pH equal to the pKa, equal amounts of the protonated
Drug absorption requires that drugs cross one or more layers and nonprotonated forms are present. If the pH is less than
of cells and cell membranes. Drugs injected into the subcu- the pKa, the protonated form predominates. If the pH is
taneous tissue and muscle bypass the epithelial barrier and greater than the pKa, the nonprotonated form predominates.
are more easily absorbed through spaces between capillary In the stomach, with a pH of 1, weak acids and bases are
endothelial cells. In the gut, lungs, and skin, drugs must highly protonated. At this site, the nonionized form of weak
first be absorbed through a layer of epithelial cells that have acids (pKa = 3–5) and the ionized form of weak bases (pKa =
tight junctions. For this reason, drugs face a greater barrier 8–10) will predominate. Hence weak acids are more readily
to absorption after oral administration than after parenteral absorbed from the stomach than are weak bases. In the intes-
administration. tines, with a pH of 7, weak bases are also mostly ionized but
much less so than in the stomach, and weak bases are absorbed
Processes of Absorption more readily from the intestines than from the stomach.
Most drugs are absorbed by passive diffusion across a bio- However, weak acids can also be absorbed more readily
logic barrier and into the circulation. The rate of absorption from the intestines than from the stomach, despite their
is proportional to the drug concentration gradient across the greater ionization in the intestines, because the intestines
barrier and the surface area available for absorption at that have a greater surface area than the stomach for absorption
site, known as Fick’s law. Drugs can be absorbed passively of the nonionized form of a drug, and this outweighs the
through cells either by lipid diffusion or by aqueous diffu- influence of greater ionization in the intestines.
sion. Lipid diffusion is a process by which the drug dissolves
in the lipid components of the cell membranes. This process DRUG DISTRIBUTION
is facilitated by a high degree of lipid solubility of the drug. Drugs are distributed to organs and tissues via the circu-
Aqueous diffusion occurs by passage through aqueous pores lation, diffusing into interstitial fluid and into cells from
in cell membranes. Because aqueous diffusion is restricted to the bloodstream. Most drugs are not uniformly distributed
drugs with low molecular weights, many drugs are too large throughout total body water, and some drugs are restricted
to be absorbed by this process. to the extracellular fluid or the plasma compartment. Drugs
11
Pill taken Drug concentration in blood Removed in urine
Plasma protein binding
Absorption Excretion
Distribution Metabolism
Tissues
and organs Liver
Fig. 2.1 The absorption, distribution, biotransformation (metabolism), and excretion of a typical drug after its oral administration.
BOX 2.1 EFFECT OF PH ON THE ABSORPTION OF A WEAK ACID AND A WEAK BASE
Weak acids (HA) donate a proton (H+) to form anions (A−), whereas weak bases (B) accept a proton to form cations (HB+).
HA H+ + A– For weak acids, the protonated

form is nonionized.
B + H+ HB+ For weak bases, the protonated

form is ionized.
Only the nonionized form of a drug can readily penetrate The pKa of a weak acid or weak base is the pH at which there are
cell membranes. equal amounts of the protonated form and the nonprotonated
form. The Henderson-Hasselbalch equation can be used to
determine the ratio of the two forms:
[protonate form]
HA HA log = pKa − pH
[non protonate form]
A–
For salicylic acid, which is a weak acid with a pKa of 3,
log [HA]/[A–] is 3 minus the pH. At a pH of 2, then, log
[HA]/[A–] = 3 – 2 = 1. Therefore [HA]/[A–] = 10/1.
B B
HB+ COOH COO–
+ H+
OH OH
Cell membrane
Protonated Nonprotonated
For amphetamine, which is a weak base with a pKa of 10, log [HB+]/[B] is 10 minus the pH. At a pH of 8, then, log [HB+]/[B]
= 10 − 8 = 2. Therefore [HB+]/[B] = 100/1.
CH2 CH NH2 CH2 CH NH3+

+ H+
CH3 CH3
Nonprotonated Protonated
The following are the ratios of the protonated form to the nonprotonated form at different pH levels:
Salicylic acid Amphetamine
10 1 1 1 1 1000 100 10 1
Protonated
pH 2 3 4 5 6 7 8 9 10
Nonprotonated 1 1 10 100 1000 1 1 1 1

Chapter 2 Pharmacokinetics or What the Body Does to the Drug 13
with sufficient lipid solubility can simply diffuse through where the blood-brain barrier restricts the penetration of
membranes into cells. Other drugs are concentrated in cells polar and ionized molecules. The barrier is formed by tight
by the phenomenon of ion trapping, which is described junctions between the capillary endothelial cells and also
later. Drugs can also be actively transported into cells. For by the glial cells that surround the capillaries, which inhibit
example, some drugs are actively transported into hepatic the penetration of polar molecules into brain neurons.
cells, where they undergo metabolism.
Opposing the distribution of drugs to tissues are a num- DRUG METABOLISM
ber of ATP-driven drug efflux pumps, known as ABC trans- Drug metabolism (biotransformation) and excretion are
porters (ABC is an acronym for “ATP-binding cassette”). the two processes responsible for the decline of the plasma
The most studied of these proteins, called permeability gly- drug concentration over time. Both of these processes con-
coprotein or simply P-glycoprotein (Pgp), is expressed on tribute to the elimination of active drug from the body. As
the luminal side of endothelial cells lining the intestines, discussed later in the chapter, clearance is a measure of the
brain capillaries, and a number of other tissues. Drug trans- rate of elimination. Drug metabolism is the enzyme-cata-
port in the blood-to-lumen direction leads to a secretion of lyzed conversion of drugs to their metabolites. Most drug
various drugs into the intestinal tract, thereby serving as a biotransformation takes place in the liver, but drug-metab-
detoxifying mechanism. Pgp also serves to exclude drugs olizing enzymes are found in many other tissues, including
from the brain. The Pgp proteins may exclude drugs from the gut, kidneys, brain, lungs, and skin.
tissues throughout the body, including anticancer agents
from tumors, leading to chemotherapeutic drug resistance. Role of Drug Biotransformation
Inhibition of Pgp by amiodarone, erythromycin, proprano- The fundamental role of drug-metabolizing enzymes is to
lol, and other agents can increase tissue levels of these drugs inactivate and detoxify drugs and other foreign substances
and augment their pharmacologic effects (see Fig. 45.2). (xenobiotics) that can enter the body. Drug metabolites are
usually more water soluble than is the parent molecule, and
Factors Affecting Distribution therefore they are more readily excreted by the kidneys.
Organ Blood Flow No particular relationship exists between metabolism and
The rate at which a drug is distributed to various organs pharmacologic activity. Some drug metabolites are active,
after a drug dose is administered depends largely on the whereas others are inactive. Many drug molecules undergo
proportion of cardiac output received by the organs. Drugs attachment of polar groups, a process called conjugation,
are rapidly distributed to highly perfused tissues, namely the for more rapid excretion. As a general rule, most conjugated
brain, heart, liver, and kidney. This enables a rapid onset of drug metabolites are inactive, but a few exceptions exist.
action of drugs affecting these tissues. Drugs are distributed
more slowly to less perfused tissues such as skeletal muscle Formation of Active Metabolites
and even more slowly to those with the lowest blood flow, Many pharmacologically active drugs, such as the sedative-
such as skin, bone, and adipose (fat) tissue. hypnotic agent diazepam (Valium), are biotransformed to
active metabolites. Some agents, known as prodrugs, are
Plasma Protein Binding administered as inactive compounds and then biotrans-
Almost all drugs are reversibly bound to plasma proteins, formed to active metabolites. This type of agent is usually
primarily albumin, but also lipoproteins, glycoproteins, and developed because the prodrug is better absorbed than its
β-globulins. The extent of binding depends on the affinity active metabolite. For example, the antiglaucoma agent
of a particular drug for protein-binding sites and ranges from dipivefrin (Propine) is a prodrug converted to its active
less than 10% to as high as 99% of the plasma concentra- metabolite, epinephrine, by corneal enzymes after topical
tion. As the free (unbound) drug diffuses into interstitial ocular administration. Orally administered prodrugs, such
fluid and cells, drug molecules dissociate from plasma pro- as the antihypertensive agent enalapril (Vasotec), are con-
teins to maintain the equilibrium between free drug and verted to their active metabolite by hepatic enzymes during
bound drug. In general, acidic drugs bind to albumin and their first pass through the liver.
basic drugs to glycoproteins and β-globulins.
Plasma protein binding is saturable, and a drug can be First-Pass Biotransformation
displaced from binding sites by other drugs that have a high Drugs that are absorbed from the gut reach the liver via the
affinity for such sites. However, most drugs are not used at hepatic portal vein before entering the systemic circulation
high enough plasma concentrations to occupy the vast num- (Fig. 2.2). Many drugs, such as the antihypertensive agent
ber of plasma protein binding sites. There are a few agents felodipine (Plendil), are extensively converted to inactive
that may cause drug interactions by competing for plasma metabolites during their first pass through the gut wall and
protein binding sites, as highlighted in Chapter 4. liver and have low bioavailability (see later) after oral admin-
istration. This phenomenon is called the first-pass effect.
Molecular Size Drugs administered by the sublingual or rectal route undergo
Molecular size is a factor affecting the distribution of less first-pass metabolism and have a higher degree of bio-
extremely large molecules, such as those of the anticoagu- availability than do drugs administered by the oral route.
lant heparin. Heparin is largely confined to the plasma com-
partment, although it does undergo some biotransformation Phases of Drug Biotransformation
in the liver. Drug biotransformation can be divided into two phases,
Lipid Solubility. Lipid solubility is a major factor affect- each carried out by a unique set of metabolic enzymes. In
ing the extent of drug distribution, particularly to the brain, many cases, phase I enzymatic reactions create or unmask a
Direct IV
administration
Oral drug
Active drug administration
Drug
metabolite
First pass Liver

effect
Enterohepatic Stomach
cycling
Fig. 2.2 First-pass drug biotransformation. Drugs that are absorbed from the gut can be biotransformed by enzymes in the gut wall and liver before reach-
ing the systemic circulation. This process lowers their degree of bioavailability. Enterohepatic cycling can occur when drugs and drug metabolites with
molecular weights greater than 300 are excreted via the bile, stored in the gallbladder, delivered to the intestines by the bile duct, and then reabsorbed into
the hepatic portal system. This process reduces the elimination of a drug and prolongs its half-life and duration of action in the body.
chemical group required for a phase II reaction. However, in Many CYP isozymes have been identified and cloned,
some cases, drugs bypass phase I biotransformation and go and their role in metabolizing specific drugs elucidated.
directly to phase II. Although some phase I drug metabolites Each isozyme catalyzes a different but overlapping spectrum
are pharmacologically active, most phase II drug metabo- of oxidative reactions. Most drug metabolism is catalyzed by
lites are inactive. three CYP families named CYP1, CYP2, and CYP3. The
different CYP families are likely related by gene duplica-
Phase I Biotransformation tion, and each family is divided into subfamilies, also clearly
Phase I biotransformation includes oxidative, hydrolytic, related by homologous protein sequences. The CYP3A
and reductive reactions (Fig. 2.3). subfamily catalyzes more than half of all microsomal drug
Oxidative Reactions. Oxidative reactions are the most oxidation reactions.
common type of phase I biotransformation. They are cata- Many drugs alter drug metabolism by inhibiting or induc-
lyzed by enzymes isolated in the microsomal fraction of liver ing CYP enzymes, and drug interactions can occur when
homogenates (the fraction derived from the endoplasmic these drugs are administered concurrently with other drugs
reticulum) and by cytoplasmic enzymes. that are metabolized by CYP (see Chapter 4). Two examples
The microsomal cytochrome P450 (CYP) mono- of inducers of CYP are the barbiturate phenobarbital and
oxygenase system is a family of enzymes that catalyze the the antitubercular drug rifampin. The inducers stimulate
biotransformation of drugs with a wide range of chemi- the transcription of genes encoding CYP enzymes, result-
cal structures. The microsomal monooxygenase reaction ing in increased messenger RNA (mRNA) and protein syn-
requires the following: CYP (a hemoprotein); a flavoprotein thesis. Drugs that induce CYP enzymes activate the binding
reduced by nicotinamide adenine dinucleotide phosphate of transcription factors to the promoter domains of CYP
(NADPH), called NADPH CYP reductase; and membrane genes, increasing their rate of gene transcription.
lipids in which the system is embedded. In the drug-oxidiz- A few drugs are oxidized by cytoplasmic enzymes. For
ing reaction, one atom of oxygen is used to form a hydroxyl- example, ethanol is oxidized to aldehyde by alcohol dehy-
ated metabolite of a drug, whereas the other atom of oxygen drogenase, and caffeine and the bronchodilator theophyl-
forms water when combined with electrons contributed by line are metabolized by xanthine oxidase. Other cytoplasmic
NADPH. The hydroxylated metabolite may be the end oxidases include monoamine oxidase, a site of action for
product of the reaction or serve as an intermediate that some psychotropic medications.
leads to the formation of another metabolite. Hydrolytic Reactions. Esters and amides are hydrolyzed
The most common chemical reactions catalyzed by CYP by a variety of enzymes. These include cholinesterase and
enzymes are aliphatic hydroxylation, aromatic hydroxyl- other plasma esterases that inactivate choline esters, local
ation, N-dealkylation, and O-dealkylation. anesthetics, and drugs such as esmolol (Brevibloc), an
Description Reaction Examples
Oxidative reactions
OH
Ibuprofen, pentobarbital,
Aliphatic hydroxylation Drug CH2 CH3 Drug CH CH3 and tolbutamide
OH
Phenobarbital, phenytoin,
Aromatic hydroxylation Drug Drug and propranolol
Codeine, imipramine, and

N-Dealkylation Drug NH CH3 Drug NH2 + CH2=O theophylline
Codeine, dextromethorphan,
O-Dealkylation Drug O CH3 Drug OH + CH2=O and indomethacin
O
Amphetamine and
Deamination Drug CH–CH3 Drug C– CH3 + NH2 diazepam
NH2
N-Oxidation Drug N H Drug N OH Chlorpheniramine
Chlorpromazine and
S-Oxidation Drug S H Drug S OH cimetidine
Hydrolytic reactions
O O
Lidocaine and
Amide hydrolysis Dr C N ug Dr C OH + NH2 ug procainamide
O O
Aspirin, esmolol,
Ester hydrolysis Dr C O ug Dr C OH + OH ug and procaine
Reductive reactions
Nitro reduction Drug N O Drug NH2 Chloramphenicol
O O
Reductive hydrolysis Drug O N O Drug OH + N O Nitroglycerin
Fig. 2.3 Phase I drug biotransformation. Many drugs are biotransformed by oxidative, hydrolytic, or reductive reactions and then undergo conjugation
with endogenous substances. A few drugs bypass phase I reactions and directly enter phase II biotransformation.
Description Reaction Examples
Conjugation reactions Acetyl CoA

S O SH
Hydralazine,
Acetylation Drug NH2 + O C Drug N C + isoniazid
CH3 CH3
Morphine,
Glucuronidation Drug OH + GA UDP Drug GA + UDP oxazepam
UDP-glucoronic acid (GA)
O O
Acetaminophen,
Sulfation Drug OH + O S O Drug O S O + minoxidil
O O
3 -Phosphoadenosine-5 -
phosphosulfate (PAPS)
Fig. 2.4 Phase II drug biotransformation. Many drugs undergo conjugation with endogenous substances as shown in the figure. UDP, Uridine diphosphate.
agent for the treatment of tachycardia that blocks cardiac drug-metabolizing enzymes. Modern genetic studies were
β1-adrenoceptors. There are few CYP enzymes that carry out triggered by rare fatalities in children being treating for
hydrolytic reactions. leukemia using the thiopurine agent 6-mercaptopurine
Reductive Reactions. Reductive reactions are less (6-MP). It was discovered that the children died as a result
common than are oxidative and hydrolytic reactions. of drug toxicity because they expressed a faulty variant of
Chloramphenicol, an antimicrobial agent, and a few other thiopurine methyltransferase, the enzyme that metabolizes
drugs are partly metabolized by a hepatic nitroreductase, 6-MP.
and this process involves CYP enzymes. Nitroglycerin, a
vasodilator, undergoes reductive hydrolysis catalyzed by Variations in Acetyltransferase Activity
glutathione-organic nitrate reductase. Individuals exhibit slow or fast acetylation of some
drugs because of genetically determined differences in
Phase II Biotransformation N-acetyltransferase. Slow acetylators (SAs) were first iden-
In phase II biotransformation, drug molecules undergo tified by neuropathic effects of isoniazid, a drug to treat
conjugation reactions with an endogenous substance such tuberculosis (see Chapter 41). These patients had higher
as acetate, glucuronate, sulfate, or glycine (Fig. 2.4). plasma levels of isoniazid compared with other patients
Conjugation enzymes, which are present in the liver and classified as rapid acetylators (RAs). The SA phenotype
other tissues, join various drug molecules with one of these is autosomal recessive, although more than 20 allelic vari-
endogenous substances to form water-soluble metabolites ants of the gene for N-acetyltransferase have been identi-
that are more easily excreted. Except for microsomal gluc- fied. In individuals with one wild-type enzyme and one
uronosyltransferases, these enzymes are located in the faulty variant, an intermediate phenotype is observed. The
cytoplasm. Most conjugated drug metabolites are pharma- distribution of these phenotypes varies from population to
cologically inactive. population. Approximately 15% of Asians, 50% of Whites
Glucuronide Formation. Glucuronide formation, the and Africans, and more than 80% of Mideast populations
most common conjugation reaction, uses glucuronosyl- have the SA phenotype. Other drugs that may cause toxic-
transferases to conjugate a glucuronate molecule with the ity in the SA patient are sulfonamide antibiotics, the anti-
parent drug molecule. dysrhythmic agent procainamide, and the antihypertensive
Acetylation. Acetylation is accomplished by agent hydralazine.
N-acetyltransferase enzymes that use acetyl coenzyme A
(acetyl CoA) as a source of the acetate group. Variations in CYP2D6 and CYP2C19 Activity
Sulfation. Sulfotransferases catalyze the conjugation Variations in oxidation of some drugs have been attributed
of several drugs, including the vasodilator minoxidil and to genetic differences in certain CYP enzymes. Genetic
the potassium-sparing diuretic triamterene, whose sulfate polymorphisms of CYP2D6 and CYP2C19 enzymes are
metabolites are pharmacologically active. well characterized, and human populations of “extensive
metabolizers” and “poor metabolizers” have been identi-
Pharmacogenomics fied. These differences are caused by more than 70 identified
Since the completion of the Human Genome Project, it is variants in the CYP2D6 gene and more than 25 variants
now fully realized that there is a great degree of individual of the CYP2C19 genes, resulting from point mutations,
variation, called polymorphism, in the genes coding for deletions, or additions; gene rearrangements; or deletion or
duplication of the entire gene. This gives rise to an increase, primarily in proximal tubular cells. This process is competi-
reduction, or complete loss of enzyme activity and to differ- tively inhibited by other drugs of the same chemical class.
ent levels of enzyme expression that result in altered rates For example, the secretion of penicillins and other weak
of enzymatic reactions. acids is inhibited by probenecid, an agent used to treat gout.
Most individuals are extensive metabolizers of CYP2D6 Active tubular secretion is not affected by plasma protein
substrates, but 10% of Whites and a smaller fraction of binding. This is a result of the equilibrium of free drug and
Asians and Africans are poor metabolizers of substrates for bound drug, such that when free drug is actively transported
CYP2D6. Psychiatric patients who are poor metabolizers across the renal tubule, this fraction of free drug is replaced
of CYP2D6 drugs have been found to have a higher rate by a fraction that dissociates from plasma proteins.
of adverse drug reactions than do those who are extensive
metabolizers, because of higher psychotropic drug plasma Passive Tubular Reabsorption
levels. In addition, poor metabolizers of CYP2D6 drugs The extent to which a drug undergoes passive reabsorption
have a reduced ability to metabolize codeine to morphine across renal tubular cells and into the circulation depends
sufficiently to obtain adequate pain relief when codeine is on the lipid solubility of the drug. Drug biotransformation
administered for analgesia. facilitates drug elimination by forming polar drug metabo-
Poor metabolizers of CYP2C19 substrates have higher lites that are not as readily reabsorbed as the less-polar par-
plasma levels of proton pump inhibitors, such as omeprazole ent molecules.
(Prilosec), whereas some extensive metabolizers of CYP2C19 Most nonelectrolytes, including ethanol, are passively
drugs require larger doses of omeprazole to treat peptic ulcer. reabsorbed across tubular cells. Ionized weak acids and bases
are not reabsorbed across renal tubular cells, and they are
Other Variations in Drug Metabolism Enzymes more rapidly excreted in the urine than are nonionized
Approximately 1 in 3000 individuals exhibits a familial drugs that undergo passive reabsorption. The proportion of
atypical cholinesterase that will not metabolize succinyl- ionized and nonionized drugs is affected by renal tubular
choline, a neuromuscular blocking agent, at a normal rate. pH, which can be manipulated to increase the excretion of
Affected individuals are subject to prolonged apnea after a drug after a drug overdose (Box 2.3).
receiving the usual dose of the drug. For this reason, patients
should be screened for atypical cholinesterase before receiv- Biliary Excretion and Enterohepatic Cycling
ing succinylcholine. Many drugs are excreted in the bile as the parent compound
There are many more polymorphisms in both phase I and or a drug metabolite. Biliary excretion favors compounds
phase II metabolic enzymes. With more than 30 families of with molecular weights greater than 300 and with both
drug-metabolizing enzymes, all with genetic variants, a major polar and lipophilic groups; smaller molecules are excreted
development in pharmacotherapy will be the individual tai- only in negligible amounts. Conjugation, particularly with
loring of drug and dose to each patient’s genomic identity. glucuronate, increases biliary excretion.
Numerous conjugated drug metabolites, including both
DRUG EXCRETION the glucuronate and sulfate metabolites of steroids, are
Excretion is the removal of drug from body fluids and occurs excreted in the bile. After the bile empties into the intes-
primarily in the urine. Other routes of excretion from the tines, a fraction of the drug may be reabsorbed into the
body include in bile, sweat, saliva, tears, feces, breast milk, circulation and eventually return to the liver. This phenom-
and exhaled air. enon is called enterohepatic cycling (see previous Fig. 2.2).
Excreted conjugated drugs can be hydrolyzed back to the
Renal Drug Excretion parent drug by intestinal bacteria, and this facilitates the
Most drugs are excreted in the urine, either as the parent drug’s reabsorption. Thus biliary excretion eliminates sub-
compound or as a drug metabolite. Drugs are handled by the stances from the body only to the extent that enterohepatic
kidneys in the same manner as are endogenous substances, cycling is incomplete (i.e., when some of the excreted drug
undergoing processes of glomerular filtration, active tubular is not reabsorbed from the intestine).
secretion, and passive tubular reabsorption. The amount of
drug excreted is the sum of the amounts filtered and secreted Other Routes of Excretion
minus the amount reabsorbed. The relationship among Sweat and saliva are minor routes of excretion for some
these processes, the rate of drug excretion, and renal clear- drugs. In pharmacokinetic studies, saliva measurements are
ance is shown in Box 2.2. sometimes used because the saliva concentration of a drug
often reflects the intracellular concentration of the drug in
Glomerular Filtration target tissues.
Glomerular filtration is the first step in renal drug excretion.
In this process, the free drug enters the renal tubule as a dis- QUANTITATIVE PHARMACOKINETICS
solved solute in the plasma filtrate (see Box 2.2). If a drug To derive and use expressions for pharmacokinetic param-
has a large fraction bound to plasma proteins, as is the case eters, the first step is to establish a mathematical model
with the anticoagulant warfarin, it will have a low rate of that accurately relates the plasma drug concentration to the
glomerular filtration. rates of drug absorption, distribution, and elimination. The
one-compartment model is the simplest model of drug dis-
Active Tubular Secretion position, but the two-compartment model provides a more
Some drugs, particularly weak acids and bases, undergo accurate representation of the pharmacokinetic behavior of
active tubular secretion by transport systems located many drugs (Fig. 2.5). With the one-compartment model, a
BOX 2.2 THE RENAL EXCRETION AND CLEARANCE OF A WEAK ACID, PENICILLIN G
DESCRIPTION AND CHEMICAL STRUCTURE rate (1080 mg/min) minus the drug reabsorption rate
Penicillin G (benzylpenicillin) is an example of a weak acid. (<1 mg/min).
It has a pKa of 2.8 and is primarily excreted via renal tubular
secretion. Approximately 60% of penicillin G is bound to Nephron
plasma proteins. The pharmacokinetic calculations that
follow are based on a urine pH of 5.8, a plasma drug
concentration of 3 mg/mL, a glomerular filtration rate of
100 mL/min, and a measured drug excretion rate of 1200
mg/min. Because 40% of penicillin G is free (unbound), the
free drug plasma concentration is 0.4 × 3 mg/mL = 1.2
mg/mL. 1
S CH3
CH2 C NH
CH3 2
O N
O COOH
3
RENAL EXCRETION
The discussion and accompanying figure illustrate the
relationship among the rates of glomerular filtration, active
tubular secretion, passive tubular reabsorption, and excretion.
1. Filtration. The drug filtration rate is calculated by
multiplying the glomerular filtration rate by the free drug
plasma concentration: 100 mL/min × 1.2 mg/mL = 120
mg/min. 4
2. Secretion. The drug secretion rate is calculated by
subtracting the drug filtration rate from the drug excretion Urine
rate: 1200 mg/min − 120 mg/min = 1080 mg/min. This
amount indicates that 90% of the drug’s excretion occurs
by the process of tubular secretion.
3. Reabsorption. The ratio of the nonionized form to the
ionized form of the drug in the urine is equal to the antilog Bound drug
of the pKa minus the pH: antilog of 2.8 − 5.8 = antilog of
Free drug
−3 = 1:1000. Because most of the drug is ionized in the
urine, the drug reabsorption rate is probably less than 1
mg/min.
4. Excretion. The drug excretion rate was initially given as
1200 mg/min. It was determined by measuring the drug RENAL CLEARANCE
concentration in urine and multiplying it by the urine Renal clearance is calculated by dividing the excretion rate
flow rate. Note that the drug excretion rate is equal to the (1200 mg/min) by the plasma drug concentration (3 mg/mL).
drug filtration rate (120 mg/min) plus the drug secretion The result is 400 mL/min, which is equal to 24 L/h.
BOX 2.3 URINE ACIDIFICATION AND ALKALINIZATION IN THE TREATMENT OF DRUG OVERDOSE
If a drug or other compound is a weak acid or base, its degree kidneys, so urine alkalinization is useful in treating an overdose
of ionization and rate of renal excretion will depend on its pKa of this drug. Urine acidification to enhance the elimination of
and on the pH of the renal tubular fluid. The rate of excretion weak bases (e.g., amphetamine) has been largely abandoned
of a weak acid can be accelerated by alkalinizing the because it does not significantly increase the elimination of
urine, whereas the rate of excretion of a weak base can be these drugs and poses a serious risk of metabolic acidosis.
accelerated by acidifying the urine. These procedures have In cases involving an overdose of aspirin or other
been used to enhance the excretion of drugs and poisons, salicylate, alkalinization of the urine produces the dual
but they are not without risk to the patient, and their benefits benefits of increasing drug excretion and counteracting the
have been established for only a few drugs. metabolic acidosis that occurs with serious aspirin toxicity.
To make manipulation of the urine pH worthwhile, a drug For patients with phenobarbital overdose or herbicide
must be excreted to a large degree by the kidneys. The short- 2,4-dichlorophenoxyacetic acid poisoning, alkalinization of
acting barbiturates (e.g., secobarbital) are eliminated almost the urine is also helpful; this is accomplished by administering
entirely via biotransformation to inactive metabolites, so sodium bicarbonate intravenously every 3 to 4 hours to
modification of the urine pH has little effect on their excretion. increase the urinary pH to 7 to 8.
In contrast, phenobarbital is excreted to a large degree by the
A
One-compartment model
Drug concentration Amount of drug

Dose of drug (D) eliminated
ka in body
administered ke
C = D/V
Absorption Metabolism + Excretion = Elimination

B
Two-compartment model
Drug concentration Amount of drug

Dose of drug (D) eliminated
ka in blood
administered ke
Absorption Metabolism + Excretion = Elimination

Distribution kd
Drug concentration
in tissues and organs
Fig. 2.5 Two models of the processes of drug absorption, distribution, and elimination: ka, kd, and ke are the rate constants, representing the fractional
completion of each process per unit of time. (A) In the one-compartment model, the drug concentration at any time, C, is the amount of drug in the body
at that time, D, divided by the volume of the compartment, V. Thus D is a function of the dose administered and the rates of absorption and elimination rep-
resented by ka and ke, respectively. (B) In the two-compartment model, the drug concentration in the central compartment (the blood) is a function of the
dose administered and the rates of drug absorption, distribution to the peripheral compartment (the tissues), and elimination from the central compartment.
A B
Plasma drug concentration (mg/mL)
IV drug given AUCoral

40 40 f=
Duration AUCIV
of action
30 Cmax 30
20 20
AUCIV
MEC
10 AUCoral 10 AUCoral
Tmax
0 0
0 1 2 3 4 5 6 7 8 0 1 2 3 4 5 6 7 8
Pill taken Time after administration (h) Time after administration (h)
Fig. 2.6 Plasma drug concentration and drug bioavailability. The plasma drug concentration curve for a single dose of a drug given orally (A) shows
maximum concentration (Cmax), the time needed to reach the maximum (Tmax), the minimum effective concentration (MEC), the duration of action, and
the area under the curve (AUC). (B) To determine bioavailability, F, the AUC of the AUCoral is divided by the AUC of the intravenously administered
drug, AUCIV.
drug undergoes absorption into the blood according to the for other pharmacokinetic parameters, such as the elimi-
rate constant ka and elimination from the blood with the nation half-life (t½) of a drug. In this section, the most
rate constant ke. In the two-compartment model, drugs are important parameters of pharmacokinetics are explained in
absorbed into the central compartment (blood), distributed greater detail.
from the central compartment to the peripheral compart-
ment (the tissues), and eliminated from the central compart- Drug Plasma Concentration Curves
ment. Regardless of the model used, rate constants can be Fig. 2.6A shows a standardized drug plasma concentration
determined for each process and used to derive expressions curve over time after oral administration of a typical drug.
Calculation of the volume of distribution (Vd)

IV dose
50.00 Vd=
CT=0
Distribution phase (alpha phase)
In this example, a straight line
5.00 from the beta phase part of the
curve intersects the vertical axis
CT=0 Elimination phase (beta phase) at 5.00 mg/L, the concentration
0.50 at time zero(CT=0). Given the IV
dose is 500 mg, the Vd for this
drug is:
0.05
500 mg
V d= =100L
5 mg/L
0.00
0 1 2 3 4 5 6 7 8 9 10 11 12
IV dose Time after administration (h)
given
Fig. 2.7 Calculating the volume of distribution (Vd) of a drug. The graph provides an example of how the Vd is calculated. A dose of 500 mg was injected
intravenously at time zero, and plasma drug concentrations were measured over time. The terminal elimination curve (β elimination phase) was extrapo-
lated back to time zero to determine that the plasma drug concentration at time zero, CT=0, was 5 mg/L. Then the Vd was calculated by dividing the dose
by the CT=0. In this case the result was 100 L.
The y-axis is a linear scale of drug plasma concentration, Volume of Distribution

often expressed in micrograms per milliliter or milligrams The volume of distribution (Vd) is defined as the volume of
per liter, and the x-axis is a scale of time, usually expressed fluid in which a dose of a drug would need to be dissolved
in hours. Parameters of the plasma drug concentration curve to have the same concentration as it does in plasma. The
are the maximum concentration (Cmax), the time needed Vd does not necessarily represent the volume in a particular
to reach the maximum (Tmax), the minimum effective body fluid compartment. Instead, the Vd is an apparent vol-
concentration (MEC), and the duration of action. A mea- ume that represents the relationship between the dose of a
sure of the total amount of drug during the time course is drug and the resulting plasma concentration of the drug, to
given by the area under the curve (AUC). These measures account for the immediate distribution of the drug out of the
are useful for comparing the bioavailability of different blood after absorption.
pharmaceutical formulations or of drugs given by different
routes of administration. Calculation of the Volume of Distribution
After intravenous drug administration, the plasma drug
Bioavailability concentration falls rapidly at first as the drug is distributed
Bioavailability is defined as the fraction (F) of the admin- from the central compartment to the peripheral compart-
istered dose of a drug that reaches the systemic circulation ment. The Vd is calculated by dividing the dose of a drug
in an active form. As shown in Fig. 2.6B, the oral bioavail- given intravenously by the plasma drug concentration
ability of a particular drug is determined by dividing the immediately after the initial or alpha (α) distribution phase.
AUC of an orally administered dose of the drug (AUCoral) As shown in Fig. 2.7, this drug concentration can be deter-
by the AUC of an intravenously administered dose of the mined by extrapolating the plasma drug concentration back
same drug (AUCIV). By definition, an intravenously admin- to time zero from the linear part of the latter or beta (β)
istered drug has 100% bioavailability. The bioavailability of elimination phase. Note that the y-axis in this case is plot-
drugs administered intramuscularly or via other routes can ted on a log scale so that the exponential decay curve of
be determined in the same manner as the bioavailability of the elimination phase is converted to a straight line. The
drugs administered orally. plasma drug concentration at time zero (CT=0) represents
The bioavailability of orally administered drugs is of par- the plasma concentration of a drug that would be obtained if
ticular concern because it can be reduced by many pharma- it were instantaneously dissolved in its Vd. The equation for
ceutical and biologic factors. Pharmaceutical factors include calculating Vd is rearranged to determine the dose of a drug
the rate and extent of tablet disintegration and drug dis- required to establish a specified plasma drug concentration
solution. Biologic factors include the effects of food, which and to calculate a loading dose (Box 2.4).
can sequester or inactivate a drug; the effects of gastric acid,
which can inactivate a drug; and the effects of gut and liver Interpretation of the Volume of Distribution
enzymes, which can metabolize a drug during its absorption Although the Vd does not correspond to an actual body fluid
and first pass through the liver. The CYP3A4 isozyme found compartment, it does provide a measure of the extent of dis-
in intestinal enterocytes and hepatic cells is a particularly tribution of a drug. A low Vd that approximates plasma vol-
important catalyst of first-pass drug metabolism. CYP3A4 ume or extracellular fluid volume usually indicates that the
works in conjunction with Pgp (described in the section drug’s distribution is restricted to a particular compartment
discussing drug distribution), as the 3A4 isozyme located in (the plasma or extracellular fluid). The anticoagulant war-
enterocytes inactivates drugs transported into the intestinal farin has a Vd of approximately 8 L, which reflects a high
lumen by Pgp. degree of plasma protein binding. When the Vd of a drug
BOX 2.4 DRUG DOSAGE CALCULATIONS

LOADING DOSE The maintenance dose is designed to establish or maintain
The loading dose, or priming dose, of a drug is determined a desired steady state C. The amount of drug to be given
by multiplying the volume of distribution (Vd) of the drug is based on the principle that at the steady state, the rate
by the desired plasma drug concentration (desired C). of drug administration equals the rate of drug elimination.
(This information can be found in the medical literature.) The rate of elimination is equal to the clearance multiplied
For example, for theophylline, the estimated Vd for an adult by the steady-state drug concentration. For example, if the
weighing 70 kg is 35 L, and the desired C is 15 mg/L. The steady-state gentamicin concentration is 2 mg/L and the
calculation is as follows: clearance rate for gentamicin is 100 mL/min (0.1 L/min), then
the elimination rate is 0.1 L/min × 2 mg/L = 0.2 mg/min. If
Loading dose = Vd × C the drug is to be administered every 8 hours, then the dosage
= 35 L × 15 mg / L would be calculated as follows:
= 525 mg
Maintenance dose = Hourly rate × dosage interval in hours
As is discussed in Chapter 4 (see Table 4.5), the patient’s = 0.2 mg / min × 60 minutes in an hour
age can affect the Vd and therefore should be considered in × 8 hours
determining the appropriate loading dose for a particular = 96 mg every 8 hours
patient.
MAINTENANCE DOSE If a drug is to be administered orally, the calculated dose
Calculations of the maintenance dose must take into consid- must be divided by the fractional bioavailability to determine
eration the intended frequency of drug administration. the administered dose.
With intermittent administration, the fluctuations in C in- DOSAGE ADJUSTMENT USING PHARMACOKINETIC VALUES
crease as the dosage interval increases. A twofold fluctuation First, choose the target C and administer the initial dose on
in C will occur when the dosage interval is equal to the drug’s the basis of the standard published values (general population
half-life. This is because the C will fall 50% between doses. values) for clearance or Vd. Second, measure the patient’s
For many drugs, the half-life is a convenient and acceptable plasma drug levels and calculate the patient’s Vd and clearance.
dosage interval. Third, revise the dosage based on the patient’s Vd and clearance.
is equivalent to total body water (approximately 40 L, as in an adult. A renal drug clearance higher than the creati-
occurs with ethanol), this usually indicates that the drug has nine clearance indicates that the drug is a substance that
reached the intracellular fluid as well. undergoes tubular secretion. A renal drug clearance lower
Some drugs have a Vd that is much larger than total body than the creatinine clearance suggests that the drug is
water. A large Vd may indicate that the drug is concen- highly bound to plasma proteins or that it undergoes passive
trated intracellularly, with a resulting low concentration in reabsorption from the renal tubules.
the plasma. Many weak bases, such as the antidepressant
fluoxetine (Prozac), have a large Vd (40–55 L) because Hepatic Clearance
of the phenomenon of intracellular ion trapping. Weak Hepatic clearance is more difficult to determine than
bases are less ionized within plasma than they are within renal clearance. This is because hepatic drug elimination
cells because intracellular fluid usually has a lower pH than includes the biotransformation and biliary excretion of par-
extracellular fluid. After a weak base diffuses into a cell, a ent compounds. For this reason, hepatic clearance is usually
larger fraction is ionized in the more acidic intracellular determined by multiplying hepatic blood flow by the arte-
fluid. This restricts its diffusion out of a cell and results in riovenous drug concentration difference.
a large Vd.
A large Vd may also result from sequestration into fat tis- SINGLE-DOSE PHARMACOKINETICS
sue, such as occurs with the antimalarial agent chloroquine. First-Order Kinetics
Most drugs exhibit first-order kinetics, in which the rate
Drug Clearance of drug elimination (amount of drug eliminated per unit
Clearance (Cl) is the most fundamental expression of drug time) is proportional to the plasma drug concentration and
elimination. It is defined as the volume of body fluid (blood) follows an exponential decay function. Note that the rate
from which a drug is removed per unit of time. Although of drug elimination is not the same as the elimination rate
the clearance of a particular drug is constant, it is important constant, ke (fraction of drug eliminated per unit time). A
to note that the amount of drug contained in the clearance few drugs (e.g., ethanol) exhibit zero-order kinetics, in
volume will vary with the plasma drug concentration. which the rate of drug elimination is constant and indepen-
dent of plasma drug concentration (Fig. 2.8).
Renal Clearance For drugs that exhibit first-order kinetics, the plasma
Renal clearance can be calculated as the renal excretion drug concentration can be determined from the dose of a
rate divided by the plasma drug concentration (see Box 2.2). drug and its clearance. Because the plasma drug concentra-
Drugs that are eliminated primarily by glomerular filtration is often correlated with the magnitude of a drug’s effect,
tion, with little tubular secretion or reabsorption, will have it is possible to use pharmacokinetic expressions to deter-
a renal clearance approximately equal to the creatinine mine and adjust drug dosages to achieve a desired therapeu-
clearance, which is normally approximately 100 mL/min tic effect (see Box 2.4).
A B

No constant t1/2
40 Constant t1/2 40
30 Elimination half-life (t1/2) = 1h 30 t1/2 = 4h
20 20
t1/2 = 1h t1/2 = 2h
10 10
0 0
0 1 2 3 4 5 6 7 8 0 1 2 3 4 5 6 7 8
Time after administration (h) Time after administration (h)
Fig. 2.8 The kinetic order of drugs. In first-order kinetics (A) the rate of drug elimination is proportional to the plasma drug concentration. In zero-order
kinetics (B) the rate of drug elimination is constant. The kinetic order of a drug is derived from the exponent n in the following expression:
Δ[Drug]/ Δt = −ke [Drug]n
where Δ represents change, [Drug] represents the plasma drug concentration, and t is time. If n is 1, then Δ[Drug]/ Δt is proportional to [Drug]. If n is 0, then
Δ[Drug]/ Δt is constant (ke), because [Drug]0 equals 1.
The following principles pertain to first-order kinet- CONTINUOUS-DOSE AND MULTIPLE-DOSE

ics: A drug’s rate of elimination is equal to the plasma KINETICS
drug concentration multiplied by the drug clearance; Drug Accumulation and the Steady-State Principle
the elimination rate declines as the plasma concentra- When a drug that exhibits first-order pharmacokinetics is
tion declines; and the half-life and clearance of the drug administered to a patient continuously or intermittently,
remain constant as long as renal and hepatic function do the drug will accumulate until it reaches a plateau or steady-
not change. state plasma drug concentration.
The basis for this accumulation to a steady state is shown
Elimination Half-Life in Fig. 2.10. When the drug is first administered, the rate
Elimination half-life (t½) is the time required to reduce the of administration is much greater than the rate of elimina-
plasma drug concentration by 50%. It can be calculated tion because the plasma concentration is so low. As the
from the elimination rate constant, but it is usually deter- drug continues to be administered, the rate of drug elimina-
mined from the plasma drug concentration curve (Fig. 2.9). tion gradually increases, whereas the rate of administration
The half-life can also be expressed in terms of the drug’s remains constant. Eventually, as the plasma concentration
clearance and Vd, indicating that the drug’s half-life will rises sufficiently, the rate of drug elimination equals the rate
change when either of these factors is altered. The formula of drug administration. At this point, the steady-state equi-
for relating half-life to clearance and Vd is given in the leg- librium is achieved.
end of Fig. 2.9. Disease, age, and other physiologic variables
can alter drug clearance or Vd and thereby change the elimi- Time Required to Reach the Steady-State Condition
nation half-life (see Chapter 4). Drug accumulation to a steady state is a first-order pro-
cess and therefore obeys the rule that half of the process
Zero-Order Kinetics is completed in a defined time. Because the time to reach
The following principles pertain to zero-order kinetics: The the steady state is dependent on the time it takes for the
rate of drug elimination is constant (see Fig. 2.8B); the rate of drug elimination to equal to the rate of drug admin-
drug’s elimination half-life is proportional to the plasma istration, the time to reach the steady state is a function
drug concentration; the clearance is inversely proportional of the elimination half-life of the drug. Any first-order pro-
to the drug concentration; and a small increase in dosage cess requires approximately five half-lives to be completed;
can produce a disproportionate increase in the plasma drug thus the time to reach the steady-state drug concentration
concentration. is approximately five drug half-lives. If the half-life of a
In many cases, the reason that the rate of drug elimina- drug changes, then the time required to reach the steady
tion is constant is that the elimination process becomes state also changes. Note that the time required to reach the
saturated. This occurs, for example, at most plasma con- steady state is independent both of the drug dose and the
centrations of ethanol. In some cases, drugs exhibit zero- rate or frequency of drug administration.
order elimination when high doses are administered, which
occurs, for example, with aspirin and the anticonvulsant Steady-State Drug Concentration
phenytoin (Dilantin) or when a hepatic or renal disease The steady-state drug concentration depends on the drug
has impaired the drug elimination processes. dose administered per unit of time and on the half-life of the
Ct = C0 . eket
Ct = C at any time, t
C0 = C at time zero
ke = Elimination rate constant
e = Base of natural logarithms
10 C0
Plasma drug concentration (mg/L)
5 Ct1/2
0
t1/2 Time
Plasma
drug
concentration
Clearance
volume
Amount of
drug excreted
per unit of time
Fig. 2.9 Drug half-life and clearance. The elimination half-life (t½) is the time required to reduce the plasma drug concentration (C) by 50%. The for-
mula is as follows:
t1/2 = 0.693 / ke
where 0.693 is the natural logarithm of 2, and ke is the elimination rate constant. The half-life is often determined from the plasma drug concentration curve
shown here. The clearance (Cl) is the volume of fluid from which a drug is eliminated per unit of time. It can be calculated as the product of the volume of
distribution, Vd, and ke. If 0.693/t½ is substituted for ke, the equation is as follows:
Cl = 0.693Vd / t1/2
Thus a drug’s clearance is directly proportional to its volume of distribution and is inversely proportional to its half-life.
drug. Fig. 2.11 illustrates typical plasma concentration curves single oral dose is shown in Fig. 2.11D. With intermittent
after drugs are administered continuously or intermittently. oral administration, the bioavailability of the drug will also
If the dose is doubled, the steady-state concentration is also influence the steady-state plasma concentration.
doubled (Fig. 2.11A). Likewise, if the half-life is doubled, the
steady-state concentration is doubled (Fig. 2.11B). Dosage Calculations
A drug administered intermittently will accumulate to a The methods for calculating both the loading dose and the
steady state at the same rate as a drug given by continuous maintenance dose are given in Box 2.4.
infusion, but the plasma drug concentration will fluctuate as
each dose is absorbed and eliminated. The average steady- Loading Dose
state plasma drug concentration with intermittent intrave- A loading dose, or priming dose, is given to rapidly estab-
nous administration will be the same as if the equivalent lish a therapeutic plasma drug concentration. The loading
dose were administered by continuous infusion (Fig. 2.11C). dose can be calculated by multiplying the Vd by the desired
A comparison of the steady-state drug levels following con- plasma drug concentration. The loading dose, which is
tinuous intravenous infusion, multiple oral doses, and a larger than the maintenance dose, is generally administered
Steady-state concentration after continuous IV infusion
IV infusion Steady-state reached in five t1/2

stopped
40
30 1st t1/2
20
2nd t1/2 Drug eliminated in five t1/2
10 3rd t1/2
4th t1/2
t1/2 t1/2 t1/2 t1/2 t1/2 5th t1/2
0
0 1 2 3 4 5 6 7 8 9 10 11 12
IV infusion Time after administration (h)
given
Fig. 2.10 Drug accumulation to the steady state. The time required to reach the steady state depends on the half-life (t½); it does not depend on the dose
or dosage interval. The steady-state drug concentration depends on the drug dose administered per unit of time and on the drug’s clearance or t½.
as a single dose, but it can be divided into fractions that are plasma. It is calculated by dividing the drug dose by
given over several hours. A divided loading dose is some- the plasma drug concentration at time zero.
times used for drugs that are more toxic (e.g., digitalis gly- • Many drugs are metabolized (biotransformed) before
cosides used to treat congestive heart failure). excretion. Drug metabolites can be pharmacologically
active or inactive. Phase I reactions include oxidative,
Maintenance Dose reductive, and hydrolytic reactions, whereas phase II
A maintenance dose is given to establish or maintain the reactions conjugate a drug with an endogenous sub-
desired steady-state plasma drug concentration. For drugs stance. The CYP enzymes located in the endoplasmic
given intermittently, the maintenance dose is one of a series reticulum of liver cells are the most important oxida-
of doses administered at regular intervals. The amount of tive metabolic enzymes.
drug to be given is based on the principle that, at the steady • Most drugs are excreted in the urine, either as the
state, the rate of drug administration equals the rate of drug parent compound and/or as drug metabolites, and
elimination. To determine the rate of drug elimination, undergo the processes of glomerular filtration, active
the drug clearance is multiplied by the average steady-state tubular secretion, and passive tubular reabsorption.
plasma drug concentration. The maintenance dose is then The renal clearance of a drug can be calculated by
calculated as the rate of drug elimination multiplied by the dividing the renal excretion rate by the plasma drug
dosage intervals. If the drug is administered orally, its bio- concentration.
availability must also be included in the equation. • Most drugs exhibit first-order kinetics, in which the
rate of drug elimination is proportional to the plasma
drug concentration at any given time. If drug elimi-
SUMMARY OF IMPORTANT POINTS
nation mechanisms (biotransformation and excretion)
• M ost drugs are absorbed by passive diffusion across become saturated, a drug can exhibit zero-order kinet-
cell membranes or between cells. The rate of passive ics, in which the rate of drug elimination is constant.
diffusion of a drug across cell membranes is propor- • In first-order kinetics, a drug’s half-life and clearance
tional to the drug’s lipid solubility and the surface area are constant as long as elimination processes are con-
available for absorption. Only the nonionized form of stant. The half-life is the time required for the plasma
weak acids and bases is lipid soluble. drug concentration to decrease by 50%. The clear-
• The ratio of the ionized form to the nonionized form ance is the volume of plasma from which a drug is
of a weak acid or base can be determined from the eliminated per unit of time.
pKa of the drug and the pH of the body fluid in which • The oral bioavailability of a drug is the fraction of the
the drug is dissolved. administered dose that reaches the bloodstream in
• The distribution of a drug is influenced by organ blood an active form. It is determined by dividing the AUC
flow and by the plasma protein binding, molecular after oral administration by the AUC after intravenous
size, and lipid solubility of the drug. Only drugs with administration. Factors that reduce bioavailability
high lipid solubility can penetrate the blood-brain include incomplete tablet disintegration and first-pass
barrier. and gastric inactivation of a drug.
• The volume of distribution is the volume of fluid in • With continuous or intermittent drug administra-
which a drug would need to be dissolved to have tion, the plasma drug concentration increases until it
the same concentration in that volume as it does in reaches a steady-state condition, in which the rate of
A B
16 16

Dose = 10 mg/min
t1/2 = 4 hours
Dose = 5 mg/min
8 8
Dose = 5 mg/min t1/2 = 2 hours
Dose = 5 mg/min
0 0
0 1 2 3 4 5 6 0 4 8 12 16 20 24
IV infusion Time (hr) Time (hr)

IV infusion
started
started
C Continuous infusion of D Intravenous infusion

three units of drug a day
Injection of three units Single dose
of drug once a day
Injection of one unit of Multiple doses
drug three times a day
40 16
32
24
8
16
0 0
0 12 24 36 48 0 1 2 3 4 5 6
Time (hr) Time (hr)
Fig. 2.11 Plasma drug concentrations after continuous or intermittent drug administration. (A) The steady-state plasma drug concentration is propor-
tional to the dose administered per unit of time. (B) The steady-state plasma drug concentration is directly proportional to the half-life (and is inversely
related to clearance). (C) The average steady-state concentration is the same for intermittent infusion as it is for continuous infusion. However, with
intermittent drug administration, the plasma concentrations fluctuate between doses, and the size of fluctuations increases as the dosage interval increases.
(D) Plasma drug concentrations after intermittent oral administration are affected by the rates of drug absorption, distribution, and elimination. If only one
dose is given, the peak in plasma drug concentration is followed by a continuous decline in the curve.
drug elimination is equal to the rate of drug adminis- Review Questions

tration. It takes approximately four to five drug half-
lives to achieve the steady-state condition. 1. If food decreases the rate but not the extent of the
• The steady-state drug concentration can be calculated absorption of a particular drug from the gastrointesti-
as the dose per unit of time divided by the clearance, nal tract, then taking the drug with food will result in a
and this equation can be rearranged to determine the smaller
dose per unit of time required to establish a specified (A) area under the plasma drug concentration time
steady-state drug concentration. curve.
• A loading dose is a single or divided dose given to (B) maximal plasma drug concentration.
rapidly establish a therapeutic plasma drug concentra- (C) time at which the maximal plasma drug concentra-
tion. The dose can be calculated by multiplying the tion occurs.
volume of distribution by the desired plasma drug (D) fractional bioavailability.
concentration. (E) total clearance.
2. If a drug exhibits first-order elimination, then 4. What dose of a drug should be injected intravenously
(A) the elimination half-life is proportional to the every 8 hours to obtain an average steady-state plasma
plasma drug concentration. drug concentration of 5 mg/L if the drug’s volume of dis-
(B) the drug is eliminated at a constant rate. tribution is 30 L and its clearance is 8 L/h?
(C) hepatic drug metabolizing enzymes are saturated. (A) 40 mg
(D) drug clearance will increase if the plasma drug con- (B) 80 mg
centration increases. (C) 160 mg
(E) the rate of drug elimination (mg/min) is propor- (D) 320 mg
tional to the plasma drug concentration. (E) 400 mg
3. After a person ingests an overdose of an opioid analgesic, 5. The volume of distribution of a drug will be greater if the
the plasma drug concentration is found to be 32 mg/L. drug
How long will it take to reach a safe plasma concentra- (A) is more ionized inside cells than in plasma.
tion of 2 mg/L if the drug’s half-life is 6 hours? (B) is administered very rapidly.
(A) 12 hours (C) is highly ionized in plasma.
(B) 24 hours (D) has poor lipid solubility.
(C) 48 hours (E) has a high molecular weight.
(D) 72 hours
(E) 1 week
CHAPTER
Pharmacodynamics or What the
3 Drug Does to the Body
OVERVIEW Drugs can also bind at a different site, called an allosteric

Pharmacodynamics is the study of the detailed mecha- site, which alters the response of the endogenous ligand
nism of action by which drugs produce their pharmacologic at the ligand-gated ion channel and increases or decreases
effects. This study of a drug’s mechanism of action begins the flow of ions. Some drugs directly bind and inactivate
with the binding of a drug to its target receptor, enzyme, or voltage-gated ion channels; these are ion-channel proteins
other protein. With some drugs, such as a receptor antago- that do not have an endogenous ligand (as ligand-gated ion
nist, this simple action may be the complete description of channels do) but open or close as a function of the mem-
the drug’s mechanism of action. For other drugs, binding brane voltage potential. Neurotransmitter transporter
to a receptor or other target initiates a molecular chain of proteins are large, 12-transmembrane domain proteins that
events, called the signal transduction pathway. The sig- transfer neurotransmitter molecules out of the synapse and
nal transduction pathway may activate second messenger back into the neuron. A large group of agents, known gener-
molecules, which then activate or inhibit other molecules. ally as reuptake inhibitors, target these transport proteins.
In this case, the mechanism of action is complex and com- Steroid hormone receptors are intracellular proteins
plete only when an ultimate description of all intracellular that translocate to the nucleus on ligand (steroid) bind-
processes altered by a drug are known. Pharmacodynamics ing. In the nucleus, the steroid-receptor complex alters
provides a scientific basis for the selection and use of drugs the transcription rate of specific genes (Fig. 3.2). DNA is
to counteract specific pathologic changes caused by disease, also a receptor site for ligands that bind directly to nucleic
trauma, or genetic anomalies. acids, most notably the antineoplastic agents. Other macro-
There is also a quantitative aspect to pharmacodynam- molecules that serve as receptors include the various lipids
ics in characterizing the dose-response curve, which is the and phospholipids that make up the membrane. Some of
relationship between the drug dose and the magnitude of the effects of general anesthetics and alcohol are caused by
the pharmacologic effect. This dose-response curve trans- interaction with membrane lipids.
lates a drug’s mechanism of action into an observable effect
that can be measured in tissues and the whole patient. Receptor Classification
Drug receptors are classified according to drug specificity,
NATURE OF DRUG RECEPTORS tissue location, and, more recently, their primary amino
Drugs produce their effects by interacting with specific cell acid sequence. For example, adrenoceptors were initially
molecules called receptors. By far, most ligands (drugs or divided into two types (α and β) based on their affinity for
neurotransmitters) bind to protein molecules, although norepinephrine, epinephrine, and other agents in different
some agents act directly on DNA or membrane lipids (Table tissues. Subsequently, the distinction between the types was
3.1). confirmed by the development of selective antagonists that
blocked either α-adrenoceptors or β-adrenoceptors. Later,
Types of Drug Receptors the two types of receptors were divided into subtypes (α1,
The largest family of receptors for pharmaceutical agents α2, β1, β2, etc.) based on more subtle differences in agonist
is G protein–coupled receptors (GPCRs). These mem- potency, tissue distribution, and varying effects.
brane-spanning proteins consist of four extracellular, seven At present, most receptors for drug targets and endog-
transmembrane, and four intracellular domains (Fig. 3.1). enous ligands are cloned and their amino acid sequences
Extracellular domains and, to some extent, transmem- determined. There are also numerous other receptor-like
brane regions determine ligand binding and selectivity. proteins predicted from the human genome for which an
Intracellular loops, especially the third one, mediate the endogenous ligand is not identified, called orphan recep-
receptor interaction with its effector molecule, a guanine tors. The orphan receptors are of great interest to phar-
nucleotide binding protein (G protein). maceutical companies as they represent targets for the
A number of ligands inhibit the function of specific development of new drugs. Families of receptor types are
enzymes by competitive or noncompetitive inhibition. A grouped by their sequence similarity using bioinformatics,
ligand that binds to the same active, catalytic site as the and this classification supports results from earlier in vivo
endogenous substrate is called a competitive inhibitor. Ligands and in vitro functional studies. In many cases, each type of
that bind at a different site on the enzyme and alter the receptor corresponds to a single, unique gene with subtypes
shape of the molecule, thereby reducing its catalytic activ- of receptors arising from different transcripts of the same
ity, are called noncompetitive inhibitors. gene by the process of alternative splicing.
Drugs also target membrane transport proteins, includ-
ing ligand- and voltage-gated ion channels and neurotrans- DRUG-RECEPTOR INTERACTIONS
mitter transporters. At ligand-gated ion channels, drugs Receptor Binding and Affinity
can bind at the same site as the endogenous ligand (called To initiate a cellular response, a drug must first bind to
an orthosteric site) and directly compete for the receptor. a receptor. In most cases, drugs bind to their receptor by
27
TABLE 3.1 Drug Receptors forming hydrogen, ionic, or hydrophobic (van der Waals)
TYPES OF DRUG EXAMPLES OF DRUGS THAT bonds with a receptor site. These weak bonds are reversible
RECEPTORS BIND RECEPTORS and enable the drug to dissociate from the receptor as the
Hormone and Neurotransmitter Receptors tissue concentration of the drug declines. The binding of
drugs to receptors often exhibits stereospecificity, so that
Adrenoceptors Epinephrine and propranolol
only one of the stereoisomers (R- or L-enantiomers) of
Histamine receptors Cimetidine and a drug with a chiral center will bind to the receptor and
diphenhydramine activate its signaling. In a few cases, drugs form relatively
5-Hydroxytryptamine (serotonin) Lysergic acid diethylamide (LSD) permanent covalent bonds with a specific receptor. This
receptors and sumatriptan occurs, for example, with antineoplastic drugs that bind to
Insulin receptors Insulin DNA and with drugs that irreversibly inhibit the enzyme
Muscarinic receptors Atropine and bethanechol cholinesterase.
The ability of a drug to bind with its receptor or target
Opioid receptors Morphine and naltrexone
is called affinity, which is a measure of the strength of the
Steroid receptors Cortisol and tamoxifen drug-receptor complex. According to the law of mass action,
Enzymes the number of receptors (R) occupied by a drug depends on
Carbonic anhydrase Acetazolamide
the drug concentration (D) and the drug-receptor associa-
tion and dissociation rate constants (k1 and k2):
Cholinesterase Donepezil and physostigmine k1
[D ] + [ R ] k2
[D-R ] → Effect
Cyclooxygenase Aspirin and celecoxib
DNA polymerase Acyclovir and zidovudine The ratio of k2 to k1 is known as the drug’s dissocia-
tion constant (KD) and represents the drug concentration
DNA topoisomerase Ciprofloxacin
required to occupy 50% of its receptors in a controlled
Human immunodeficiency virus Indinavir in vitro tissue or cell preparation. The lower the KD, the
(HIV) protease greater the drug’s affinity for the receptor, as it takes less
Monoamine oxidase Phenelzine drug to occupy 50% of its receptors. Most drugs have a KD
Na+K+-adenosine triphosphatase Digoxin in the micromolar to nanomolar (10−6 to 10−9 M) range of
drug concentrations. As discussed later, receptor affinity is
Xanthine oxidase Allopurinol
the primary determinant of drug potency.
Membrane Transport Proteins
Ligand-gated ion channels Diazepam and ondansetron Signal Transduction
Voltage-gated ion channels Lidocaine and verapamil Signal transduction describes the pathway from ligand
binding to conformational changes in the receptor, recep-
Ion transporters Furosemide and
hydrochlorothiazide
tor interaction with an effector molecule (if present), and
other downstream molecules called second messengers. This
Neurotransmitter transporters Fluoxetine and cocaine cascade of receptor-mediated biochemical events ultimately
Other Macromolecules leads to one or more pharmacologic effects (Table 3.2).
Membrane lipids Alcohol and amphotericin B
G Protein–Coupled Receptors
Nucleic acids Cyclophosphamide and
doxorubicin The signal transduction pathway for GPCRs is well under-
stood. These receptors constitute a superfamily of receptors
Transmembrane
N-term α-helices
EL1 EL2 EL3
Extracellular
1 2 3 4 5 6 7
Intracellular
C-term
IL1 IL2 IL3
Fig. 3.1 Structure of a typical G protein–coupled receptor (GPCR). All GPCRs consist of a long polypeptide chain of amino acids threaded through the
cell membrane with seven transmembrane (TM) domains. These TM domains are arranged in α-helices composed of hydrophobic residues. The N-terminal
of the receptor protein is outside the cell and the C-terminal is on the inside. Three extracellular loops (EL) and three intracellular loops (IL) are formed
by this configuration. The protein in the cell membrane forms a circle with TM1 and TM7 in close proximity but is shown here in a two-dimensional view
for clarity.
Chapter 3 Pharmacodynamics or What the Drug Does to the Body 29
Steroid
hormone
Cell membrane
Receptor
hsp
New protein
Hormone-receptor
complex
mRNA
DNA
Nucleus Cytoplasm
Fig. 3.2 Signal transduction with a steroid hormone receptor. Steroid hormones diffuse through the cell membrane and bind to steroid receptors in the
cytoplasm. Binding of the steroid ligand displaces accessory heat-shock proteins (hsp) and allows steroid receptor dimerization. The dimerized steroid hor-
mone–receptor complex is translocated to the nucleus and binds to specific sequences on the DNA upstream of a gene, leading to increased transcription of
a gene, messenger RNA (mRNA), and translation of proteins.
TABLE 3.2 Examples of Receptors and Signal Transduction Pathways

MECHANISM OF SIGNAL EXAMPLE OF EFFECT IN TISSUE OR
FAMILY AND TYPE OF RECEPTOR TRANSDUCTION CELL
G Protein–Coupled Receptors
α1-Adrenoceptor Activation of phospholipase C Vasoconstriction
α2-Adrenoceptor Inhibition of adenylyl cyclase Release of norepinephrine decreased
β-Adrenoceptor Stimulation of adenylyl cyclase Heart rate increased
Muscarinic receptor Activation of phospholipase C Glandular secretion increased
Ligand-Gated Ion Channels
GABAA receptors Chloride ion flux Hyperpolarization of neuron
Nicotinic receptors Sodium ion flux Skeletal muscle contraction
Membrane-Bound Enzymes
Atrial natriuretic factor receptors Stimulation of guanylyl cyclase Sodium excretion increased
Insulin receptors Activation of tyrosine kinase Glucose uptake stimulated
Nuclear Receptors
Steroid receptors Activation of gene transcription Reduced cytokine production
Thyroid hormone receptors Activation of gene transcription Oxygen consumption increased
GABA, Gamma-aminobutyric acid.
for many endogenous ligands and drugs, including receptors and thereby stimulates the production of cyclic adenosine
for acetylcholine, epinephrine, histamine, opioids, and sero- monophosphate (cyclic AMP, or cAMP). The Gαi (inhibi-
tonin. Fig. 3.3 illustrates the inactive state and the active tory) subunit decreases adenylyl cyclase activity and inhibits
state with signal transduction for a typical GPCR, the mu the production of cAMP. Another G protein (Gαq) activates
opioid receptor. phospholipase C and leads to the formation of inositol tri-
The heterotrimeric G proteins have three subunits, phosphate (IP3) and diacylglycerol (DAG) from membrane
known as Gα, Gβ and Gγ. The Gα subunit serves as the site phospholipids. IP3 and DAG further cause an elevation of
of guanosine triphosphate (GTP) hydrolysis, a process cata- Ca+2 ions inside the cell. Several other types of Gα subunits
lyzed by innate GTPase activity, which acts to terminate are also present in cells and activated by receptors. The Gβ
the signal. Several types of Gα subunits exist, each of which and Gγ subunits are so tightly bound together that they do
determines a specific cellular response. For example, the Gαs not dissociate and are therefore written as Gβγ. The Gβγ sub-
(stimulating) subunit increases adenylyl cyclase activity unit also has signaling function when separated from Gα
Calcium ions
Cell Morphine
membrane
µ opioid receptor
cAMP Calcium chanel

Gαi Gβ Gγ G protein ATP
GTP
GDP
Morphine binds to
receptor causing GTP
to replace GDP on Gαi
and the break-up of the
G protein
GTP–Gαi inhibits Gαi Gβγ binds to

activity of adenylate calcium channels
cyclase decreasing blocking inward flow Gβ Gγ
GTP
cAMP levels of calcium ions
Fig. 3.3 Signal transduction with a G protein–coupled receptor. (A) The inactive state of a GPCR using the example of a mu opioid receptor. The recep-
tor is shown in a linear pose; it exists as an enclosed circle in real life. The G protein is next with its heterotrimeric structure, in this case containing an
inhibitory Gαi subunit, bound to GDP. Other molecules in the signal transduction pathway include adenylate cyclase, which converts ATP to cAMP, and a
calcium channel protein. (B) When an agonist ligand (morphine in this example) binds to the receptor, the receptor interacts with the G protein, enabling
the dissociation of GDP and facilitation of GTP binding. The extra power of the additional phosphate bond on GTP causes Gαi to separate from the Gβ and
Gγ subunits. The inhibitory Gαi subunit then inhibits adenylate cyclase activity and decreases levels of cAMP. The conjoined Gβ and Gγ subunits inhibit
the inward flow of Ca2+ at calcium channel proteins. GTP hydrolysis, catalyzed by Gα subunit GTPase, leads to reassociation of Gαi with Gβ and Gγ subunits
and returns the receptor to an inactive state.
on ligand-receptor activation, for example, by altering K+ processes such as ion channel activity, release of neurotrans-
or Ca+2 channel conductance (see Fig. 3.3B). The recep- mitter, regulation of transcription, and numerous other pro-
tor sequence of its C-terminal inside the cell determines cesses. For example, one of the best studied kinases, protein
which type of G-protein will interact with a given GPCR. kinase A, is activated by the increase of cAMP produced by
Additionally, beta-arrestins are intracellular protein part- epinephrine binding to β2-adrenoceptors in muscle. Protein
ners with GPCRs and are activated by agonist binding to kinase A phosphorylates the enzyme glycogen phosphory-
produce their own signaling pathways. lase, which then increases the breakdown of glycogen to free
Recently, the demonstration that some receptor agonists glucose, providing the fuel needed by the muscles to respond
will shunt the signaling pathway of GPCRs to either the to the event that initiated the release of epinephrine.
G-protein pathway or beta-arrestin signaling pathway led to IP3 and DAG evoke the release of calcium from intra-
the concept of biased agonism. Drugs that show selective cellular storage sites and thereby augment calcium-mediated
bias towards one signaling pathway or the other may have processes such as muscle contraction, glandular secretion,
increased clinical efficacy with reduced adverse effects. For and neurotransmitter release. The increased intracellular
example, it is thought that G-protein biased agonists at the Ca+2 ions also activate calcium-dependent kinases and a
opioid receptor may increase the Gα pathway to produce number of other enzyme cascades.
analgesia with reduced stimulation of the beta-arrestin
pathways which is associated with respiratory depression Ligand-Gated Ion Channels
and constipation (see Chapter 23). Ligand-gated ion channels are a large class of membrane
The second messengers cAMP, IP3, DAG, and Ca+2 proteins that share similar subunit structure and are assem-
activate or inhibit unique cellular enzymes in each target bled in tetrameric or pentameric structures. Drugs that bind
cell. cAMP activates a number of tissue-specific cAMP- to ligand-gated ion channels alter the conductance (g) of
dependent protein kinases. These kinases phosphorylate ions through the channel protein. In this case, there are no
other enzymes or proteins that ultimately affect intracellular second messengers directly activated by the drug binding
Another random document with
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soucie peu, Michel, de l’approbation ou de la désapprobation des
hommes, ce n’est pas pour venir approuver ou désapprouver à mon
tour ; ces mots n’ont pour moi pas grand sens. J’ai parlé beaucoup
trop de moi tout à l’heure ; de me croire compris m’entraînait… Je
voulais simplement vous dire que pour quelqu’un qui n’a pas le sens
de la propriété, vous semblez posséder beaucoup ; c’est grave.
— Que possédé-je tant ?
— Rien, si vous le prenez sur ce ton… Mais n’ouvrez-vous pas
votre cours ? N’êtes-vous pas propriétaire en Normandie ? Ne
venez-vous pas de vous installer, et luxueusement, à Passy ? Vous
êtes marié. N’attendez-vous pas un enfant ?
— Eh bien ! dis-je impatienté, cela prouve simplement que j’ai su
me faire une vie plus « dangereuse » (comme vous dites) que la
vôtre.
— Oui, simplement, redit ironiquement Ménalque ; puis, se
retournant brusquement, et me tendant la main :
— Allons, adieu ; voilà qui suffit pour ce soir et nous ne dirions
rien de mieux. Mais, à bientôt.
Je restai quelque temps sans le revoir.
De nouveaux soins, de nouveaux soucis m’occupèrent ; un

savant italien me signala des documents nouveaux qu’il mit au jour
et que j’étudiai longuement pour mon cours. Sentir ma première
leçon mal comprise avait éperonné mon désir d’éclairer
différemment et plus puissamment les suivantes ; je fus par là porté
à poser en doctrine ce que je n’avais fait d’abord que hasarder à titre
d’ingénieuse hypothèse. Combien d’affirmateurs doivent leur force à
cette chance de n’avoir pas été compris à demi-mot ! Pour moi, je ne
peux discerner, je l’avoue, la part d’entêtement qui peut-être vint se
mêler au besoin d’affirmation naturelle. Ce que j’avais de neuf à dire
me parut d’autant plus urgent que j’avais plus de mal à le dire, et
surtout à le faire entendre.
Mais combien les phrases, hélas ! devenaient pâles près des
actes ! La vie, le moindre geste de Ménalque n’était-il pas plus
éloquent mille fois que mon cours ? Ah ! que je compris bien, dès
lors, que l’enseignement presque tout moral des grands philosophes
antiques ait été d’exemple autant et plus encore que de paroles !
Ce fut chez moi que je revis Ménalque, près de trois semaines

après notre première rencontre. Ce fut presque à la fin d’une réunion
trop nombreuse. Pour éviter un dérangement quotidien, Marceline et
moi préférions laisser nos portes grandes ouvertes le jeudi soir ;
nous les fermions ainsi plus aisément les autres jours. Chaque jeudi,
ceux qui se disaient nos amis venaient donc ; la belle dimension de
nos salons nous permettait de les recevoir en grand nombre et la
réunion se prolongeait fort avant dans la nuit. Je pense que les
attirait surtout l’exquise grâce de Marceline et le plaisir de converser
entre eux, car, pour moi, dès la seconde de ces soirées, je ne trouvai
plus rien à écouter, rien à dire, et dissimulai mal mon ennui. J’errais
du fumoir au salon, de l’antichambre à la bibliothèque, accroché
parfois par une phrase, observant peu et regardant comme au
hasard.
Antoine, Étienne et Godefroy discutaient le dernier vote de la
Chambre, vautrés sur les délicats fauteuils de ma femme. Hubert et
Louis maniaient sans précaution et froissaient d’admirables eaux-
fortes de la collection de mon père. Dans le fumoir, Mathias, pour
écouter mieux Léonard, avait posé son cigare ardent sur une table
en bois de rose. Un verre de curaçao s’était répandu sur le tapis.
Les pieds boueux d’Albert, impudemment couché sur un divan,
salissaient une étoffe. Et la poussière qu’on respirait était faite de
l’horrible usure des choses… Il me prit une furieuse envie de
pousser tous mes invités par les épaules. Meubles, étoffes,
estampes, à la première tache perdaient pour moi toute valeur ;
choses tachées, choses atteintes de maladie et comme désignées
par la mort. J’aurais voulu tout protéger, mettre tout sous clef pour
moi seul. Que Ménalque est heureux, pensai-je, qui n’a rien ! Moi,
c’est parce que je veux conserver que je souffre. Que m’importe au
fond tout cela ?
Dans un petit salon moins éclairé, séparé par une glace sans
tain, Marceline ne recevait que quelques intimes ; elle était à demi
étendue sur des coussins ; elle était affreusement pâle, et me parut
si fatiguée que j’en fus effrayé soudain et me promis que cette
réception serait la dernière. Il était déjà tard. J’allais regarder l’heure
à ma montre quand je sentis dans la poche de mon gilet les petits
ciseaux de Moktir.
— Et pourquoi les avait-il volés, celui-là, si c’était aussitôt pour
les abîmer, les détruire ?
A ce moment, quelqu’un frappa sur mon épaule ; je me retournai
brusquement : c’était Ménalque.
Il était, presque le seul, en habit. Il venait d’arriver. Il me pria de
le présenter à ma femme ; je ne l’eusse certes pas fait de moi-
même. Ménalque était élégant, presque beau ; d’énormes
moustaches, tombantes, déjà grises, coupaient son visage de
pirate ; la flamme froide de son regard indiquait plus de courage et
de décision que de bonté. Il ne fut pas plus tôt devant Marceline que
je compris qu’il ne lui plaisait pas. Après qu’il eut avec elle échangé
quelques banales phrases de politesse, je l’entraînai dans le fumoir.
J’avais appris le matin même la nouvelle mission dont le
ministère des colonies le chargeait ; divers journaux, rappelant à ce
sujet son aventureuse carrière, semblaient oublier leurs basses
insultes de la veille et ne trouvaient pas de termes assez vifs pour le
louer. Ils exagéraient à l’envi les services rendus au pays, à
l’humanité tout entière par les profitables découvertes de ses
dernières explorations, tout comme s’il n’entreprenait rien que dans
un but humanitaire : et l’on vantait de lui des traits d’abnégation, de
dévouement, de hardiesse, tout comme s’il devait chercher une
récompense en ces éloges.
Je commençais de le féliciter ; il m’interrompit dès les premiers
mots :
— Eh quoi ! vous aussi, cher Michel ; vous ne m’aviez pourtant
pas d’abord insulté, dit-il. Laissez donc aux journaux ces bêtises. Ils
semblent s’étonner aujourd’hui qu’un homme de mœurs décriées
puisse pourtant avoir encore quelques vertus. Je ne sais faire en moi
les distinctions et les réserves qu’ils prétendent établir, et n’existe
qu’en totalité. Je ne prétends à rien qu’au naturel, et pour chaque
action, le plaisir que j’y prends m’est signe que je devais la faire.
— Cela peut mener loin, lui dis-je.
— J’y compte bien, reprit Ménalque. Ah ! si tous ceux qui nous
entourent pouvaient se persuader de cela. Mais la plupart d’entre
eux pensent n’obtenir d’eux-mêmes rien de bon que par la
contrainte ; ils ne se plaisent que contrefaits. C’est à soi-même que
chacun prétend le moins ressembler. Chacun se propose un patron,
puis l’imite ; même il ne choisit pas le patron qu’il imite ; il accepte un
patron tout choisi. Il y a pourtant, je le crois, d’autres choses à lire,
dans l’homme. On n’ose pas. On n’ose pas tourner la page. Lois de
l’imitation ; je les appelle : lois de la peur. On a peur de se trouver
seul ; et l’on ne se trouve pas du tout. Cette agoraphobie morale
m’est odieuse ; c’est la pire des lâchetés. Pourtant c’est toujours seul
qu’on invente. Mais qui cherche ici d’inventer ? Ce que l’on sent en
soi de différent, c’est précisément ce que l’on possède de rare, ce
qui fait à chacun sa valeur ; et c’est là ce que l’on tâche de
supprimer. On imite. Et l’on prétend aimer la vie.
Je laissais Ménalque parler ; ce qu’il disait, c’était précisément ce
que, le mois d’avant, je disais à Marceline ; et j’aurais donc dû
l’approuver. Pourquoi, par quelle lâcheté l’interrompis-je, et lui dis-je,
imitant Marceline, la phrase mot pour mot par laquelle elle m’avait
alors interrompu :
— Vous ne pouvez pourtant, cher Ménalque, demander à chacun
de différer de tous les autres.
Ménalque se tut brusquement, me regarda d’une façon bizarre,
puis, comme Eusèbe précisément s’approchait pour prendre congé
de moi, il me tourna le dos sans façon et alla s’entretenir avec
Hector.
Aussitôt dite, ma phrase m’avait paru stupide ; et je me désolai
surtout qu’elle pût faire croire à Ménalque que je me sentais attaqué
par ses paroles. Il était tard ; mes invités partaient. Quand le salon
fut presque vide, Ménalque revint à moi :
— Je ne puis vous quitter ainsi, me dit-il. Sans doute j’ai mal
compris vos paroles. Laissez-moi du moins l’espérer.
— Non, répondis-je. Vous ne les avez pas mal comprises ; mais
elles n’avaient aucun sens ; et je ne les eus pas plus tôt dites que je
souffris de leur sottise, et surtout de sentir qu’elles allaient me ranger
à vos yeux précisément parmi ceux dont vous faisiez le procès tout à
l’heure, et qui, je vous l’affirme, me sont odieux comme à vous. Je
hais tous les gens à principes.
— Ils sont, reprit Ménalque en riant, ce qu’il y a de plus
détestable en ce monde. On ne saurait attendre d’eux aucune
espèce de sincérité ; car ils ne font jamais que ce que leurs principes
ont décrété qu’ils devaient faire, ou, sinon, regardent ce qu’ils font
comme mal fait. Au seul soupçon que vous pouviez être un des
leurs, j’ai senti la parole se glacer sur mes lèvres. Le chagrin qui m’a
pris aussitôt m’a révélé combien mon affection pour vous est vive ;
j’ai souhaité m’être mépris, non dans mon affection, mais dans le
jugement que je portais.
— En effet, votre jugement était faux.
— Ah ! n’est-ce pas ? dit-il en me prenant la main brusquement.
Écoutez ; je dois partir bientôt, mais je voudrais vous voir encore.
Mon voyage sera, cette fois, plus long et hasardeux que tous les
autres ; je ne sais quand je reviendrai. Je dois partir dans quinze
jours ; ici, chacun ignore que mon départ est si proche ; je vous
l’annonce secrètement. Je pars dès l’aube. La nuit qui précède un
départ est pour moi chaque fois une nuit d’angoisses affreuses.
Prouvez-moi que vous n’êtes pas homme à principes ; puis-je
compter que vous voudrez bien passer cette dernière nuit près de
moi ?
— Mais nous nous reverrons avant, lui dis-je, un peu surpris.
— Non. Durant ces quinze jours, je n’y serai plus pour personne,
et ne serai même pas à Paris. Demain je pars pour Budapest ; dans
six jours je dois être à Rome. Ici et là sont des amis que je veux
embrasser avant de quitter l’Europe. Un autre m’attend à Madrid.
— C’est entendu, je passerai cette nuit de veille avec vous.
— Et nous boirons du vin de Chiraz, dit Ménalque.
Quelques jours après cette soirée, Marceline commença d’aller

moins bien. J’ai déjà dit qu’elle était souvent fatiguée ; mais elle
évitait de se plaindre, et comme j’attribuais à son état cette fatigue,
je la croyais très naturelle et j’évitais de m’inquiéter. Un vieux
médecin assez sot, ou insuffisamment renseigné, nous avait tout
d’abord rassurés à l’excès. Cependant des troubles nouveaux,
accompagnés de fièvre, me décidèrent à appeler le Docteur Tr. qui
passait alors pour le plus avisé spécialiste. Il s’étonna que je ne
l’eusse pas appelé plus tôt, et prescrivit un régime strict que, depuis
quelque temps déjà, elle eût dû suivre. Par un très imprudent
courage, Marceline s’était jusqu’à ce jour surmenée ; jusqu’à la
délivrance, qu’on attendait vers la fin de janvier, elle devait garder la
chaise longue. Sans doute un peu inquiète et plus dolente qu’elle ne
voulait l’avouer, Marceline se plia très doucement aux prescriptions
les plus gênantes ; une sorte de résignation religieuse rompit la
volonté qui la soutenait jusqu’alors, de sorte que son état empira
brusquement durant les quelques jours qui suivirent.
Je l’entourai de plus de soins encore et la rassurai de mon
mieux, me servant des paroles mêmes de Tr. qui ne voyait en son
état rien de bien grave ; mais la violence de ses craintes finit par
m’alarmer à mon tour. Ah ! combien dangereusement déjà notre
bonheur se reposait sur l’espérance ! et de quel futur incertain ! Moi
qui d’abord ne trouvais de goût qu’au passé, la subite saveur de
l’instant m’a pu griser un jour, pensai-je, mais le futur désenchante
l’heure présente, plus encore que le présent ne désenchanta le
passé ; et depuis notre nuit de Sorrente, déjà tout mon amour, toute
ma vie se projettent sur l’avenir.
Cependant le soir vint que j’avais promis à Ménalque ; et malgré
mon ennui d’abandonner toute une nuit d’hiver Marceline, je lui fis
accepter de mon mieux la solennité du rendez-vous, la gravité de
ma promesse. Marceline allait un peu mieux ce soir-là, et pourtant
j’étais inquiet ; une garde me remplaça près d’elle. Mais, sitôt dans la
rue, mon inquiétude prit une force nouvelle ; je la repoussai, luttai
contre elle, m’irritant contre moi de ne pas mieux m’en libérer. Je
parvins ainsi peu à peu à un état de surtension, d’exaltation
singulière, très différente et très proche à la fois de l’inquiétude
douloureuse qui l’avait fait naître, mais plus proche encore du
bonheur. Il était tard ; je marchais à grands pas ; la neige commença
de tomber abondante ; j’étais heureux de respirer enfin un air plus
vif, de lutter contre le froid, heureux contre le vent, la nuit, la neige ;
je savourais mon énergie.
Ménalque, qui m’entendit venir, parut sur le palier de l’escalier. Il
m’attendait sans patience. Il était pâle et paraissait un peu crispé. Il
me débarrassa de mon manteau, et me força de changer mes bottes
mouillées contre de molles pantoufles persanes. Sur un guéridon,
près du feu, étaient posées des friandises. Deux lampes éclairaient
la pièce, moins que ne le faisait le foyer. Ménalque, dès l’abord,
s’informa de la santé de Marceline. Pour simplifier, je répondis
qu’elle allait très bien.
— Votre enfant, vous l’attendez bientôt ? reprit-il.
— Dans deux mois.
Ménalque s’inclina vers le feu, comme s’il eût voulu cacher son
visage. Il se taisait. Il se tut si longtemps que j’en fus à la fin tout
gêné, ne sachant non plus que lui dire. Je me levai, fis quelques
pas, puis, m’approchant de lui, posai ma main sur son épaule. Alors,
comme s’il continuait sa pensée :
— Il faut choisir, murmura-t-il. L’important, c’est de savoir ce que
l’on veut.
— Eh ! ne voulez-vous pas partir ? lui demandai-je, incertain du
sens que je devais donner à ses paroles.
— Il paraît.
— Hésiteriez-vous donc ?
— A quoi bon ? Vous qui avez femme et enfant, restez. Des mille
formes de la vie, chacun ne peut connaître qu’une. Envier le
bonheur d’autrui, c’est folie ; on ne saurait pas s’en servir. Le
bonheur ne se veut pas tout fait, mais sur mesure. Je pars demain ;
je sais : j’ai tâché de tailler ce bonheur à ma taille. Gardez le
bonheur calme du foyer.
— C’est à ma taille aussi que j’avais taillé mon bonheur, m’écriai-
je. Mais j’ai grandi. A présent mon bonheur me serre. Parfois, j’en
suis presque étranglé !
— Bah ! vous vous y ferez ! dit Ménalque ; puis il se campa
devant moi, plongea son regard dans le mien, et comme je ne
trouvais rien à dire, il sourit un peu tristement : — On croit que l’on
possède, et l’on est possédé, reprit-il. — Versez-vous du Chiraz,
cher Michel ; vous n’en goûterez pas souvent ; et mangez de ces
pâtes roses que les Persans prennent avec. Pour ce soir je veux
boire avec vous, oublier que je pars demain, et causer comme si
cette nuit était longue. Savez-vous ce qui fait de la poésie
aujourd’hui et de la philosophie surtout, lettres mortes ? C’est
qu’elles se sont séparées de la vie. La Grèce, elle, idéalisait à même
la vie ; de sorte que la vie de l’artiste était elle-même déjà une
réalisation poétique ; la vie du philosophe, une mise en action de sa
philosophie ; de sorte aussi que, mêlées à la vie, au lieu de s’ignorer,
la philosophie alimentant la poésie, la poésie exprimant la
philosophie, cela était d’une persuasion admirable. Aujourd’hui la
beauté n’agit plus ; l’action ne s’inquiète plus d’être belle ; et la
sagesse opère à part.
— Pourquoi, dis-je, vous qui vivez votre sagesse, n’écrivez-vous
pas vos mémoires ? — ou simplement, repris-je en le voyant sourire,
les souvenirs de vos voyages ?
— Parce que je ne veux pas me souvenir, répondit-il. Je croirais,
ce faisant, empêcher d’arriver l’avenir et faire empiéter le passé.
C’est du parfait oubli d’hier que je crée la nouvelleté de chaque
heure. Jamais, d’avoir été heureux, ne me suffit. Je ne crois pas aux
choses mortes, et confonds n’être plus, avec n’avoir jamais été.
Je m’irritais enfin de ces paroles, qui précédaient trop ma
pensée ; j’eusse voulu tirer arrière, l’arrêter ; mais je cherchais en
vain à contredire, et d’ailleurs m’irritais contre moi-même plus encore
que contre Ménalque. Je restai donc silencieux. Lui, tantôt allant et
venant à la façon d’un fauve en cage, tantôt se penchant vers le feu,
tantôt se taisait longuement, puis tantôt, brusquement, disait :
— Si encore nos médiocres cerveaux savaient bien embaumer
les souvenirs ! Mais ceux-ci se conservent mal. Les plus délicats se
dépouillent ; les plus voluptueux pourrissent ; les plus délicieux sont
les plus dangereux dans la suite. Ce dont on se repent était délicieux
d’abord.
De nouveau, long silence ; et puis il reprenait :
— Regrets, remords, repentirs, ce sont joies de naguère, vues de
dos. Je n’aime pas regarder en arrière, et j’abandonne au loin mon
passé, comme l’oiseau, pour s’envoler, quitte son ombre. Ah !
Michel, toute joie nous attend toujours, mais veut toujours trouver la
couche vide, être la seule, et qu’on arrive à elle comme un veuf. Ah !
Michel, toute joie est pareille à cette manne du désert qui se
corrompt d’un jour à l’autre ; elle est pareille à l’eau de la source
Amélès qui, raconte Platon, ne se pouvait garder dans aucun vase.
Que chaque instant emporte tout ce qu’il avait apporté.
Ménalque parla longtemps encore ; je ne puis rapporter ici toutes
ses phrases ; beaucoup pourtant se gravèrent en moi, d’autant plus
fortement que j’eusse désiré les oublier plus vite ; non qu’elles
m’apprissent rien de bien neuf, mais elles mettaient à nu
brusquement ma pensée ; une pensée que je couvrais de tant de
voiles, que j’avais presque pu l’espérer étouffée. Ainsi s’écoula la
veillée.
Quand, au matin, après avoir conduit Ménalque au train qui
l’emporta, je m’acheminai seul pour rentrer près de Marceline, je me
sentis plein d’une tristesse abominable, de haine contre la joie
cynique de Ménalque ; je voulais qu’elle fût factice ; je m’efforçais de
la nier. Je m’irritais de n’avoir rien su lui répondre : je m’irritais
d’avoir dit quelques mots qui l’eussent fait douter de mon bonheur,
de mon amour. Et je me cramponnais à mon douteux bonheur, à
mon « calme bonheur », comme disait Ménalque ; je ne pouvais,
hélas ! en écarter l’inquiétude, mais prétendais que cette inquiétude
servît d’aliment à l’amour. Je me penchais vers l’avenir où déjà je
voyais mon petit enfant me sourire ; pour lui se reformait et se
fortifiait ma morale. Décidément je marchais d’un pas ferme.
Hélas ! quand je rentrai, ce matin-là, un désordre inaccoutumé
me frappa dès la première pièce. La garde vint à ma rencontre et
m’apprit, à mots tempérés, que d’affreuses angoisses avaient saisi
ma femme dans la nuit, puis des douleurs, bien qu’elle ne se crût
pas encore au terme de sa grossesse ; que se sentant très mal, elle
avait envoyé chercher le docteur, que celui-ci, bien qu’arrivé en hâte
dans la nuit, n’avait pas encore quitté la malade ; puis, voyant ma
pâleur je pense, elle voulut me rassurer, me disant que tout allait
déjà bien mieux, que… Je m’élançai vers la chambre de Marceline.
La chambre était peu éclairée ; et d’abord je ne distinguai que le
docteur qui, de la main, m’imposa silence ; puis, dans l’ombre une
figure que je ne connaissais pas. Anxieusement, sans bruit, je
m’approchai du lit. Marceline avait les yeux fermés ; elle était si
terriblement pâle que d’abord je la crus morte ; mais, sans ouvrir les
yeux, elle tourna vers moi la tête. Dans un coin sombre de la pièce,
la figure inconnue rangeait, cachait divers objets ; je vis des
instruments luisants, de l’ouate ; je vis, crus voir, un linge taché de
sang… Je sentis que je chancelais. Je tombai presque vers le
docteur ; il me soutint. Je comprenais ; j’avais peur de comprendre.
— Le petit ? demandai-je anxieusement.
Il eut un triste haussement d’épaules. — Sans plus savoir ce que
je faisais, je me jetai contre le lit, en sanglotant. Ah ! subit avenir ! Le
terrain cédait brusquement sous mon pas ; devant moi n’était plus
qu’un trou vide où je trébuchais tout entier.
Ici tout se confond en un ténébreux souvenir. Pourtant Marceline
sembla d’abord assez vite se remettre. Les vacances du début de
l’année me laissant un peu de répit, je pus passer près d’elle
presque toutes les heures du jour. Près d’elle je lisais, j’écrivais, ou
lui faisais doucement la lecture. Je ne sortais jamais sans lui
rapporter quelques fleurs. Je me souvenais des tendres soins dont
elle m’avait entouré alors que moi j’étais malade, et l’entourais de
tant d’amour que parfois elle en souriait, comme heureuse. Pas un
mot ne fut échangé au sujet du triste accident qui meurtrissait nos
espérances.
Puis la phlébite se déclara : et quand elle commença de décliner,
une embolie, soudain, mit Marceline entre la vie et la mort. C’était la
nuit ; je me revois penché sur elle, sentant, avec le sien, mon cœur
s’arrêter ou revivre. Que de nuits la veillai-je ainsi ! le regard
obstinément fixé sur elle, espérant, à force d’amour, insinuer un peu
de ma vie en la sienne. Et si je ne songeais plus beaucoup au
bonheur, ma seule triste joie était de voir parfois sourire Marceline.
Mon cours avait repris. Où trouvai-je la force de préparer mes
leçons, de les dire ? Mon souvenir se perd et je ne sais comment se
succédèrent les semaines. Pourtant un petit fait que je veux vous
redire :
C’est un matin, peu de temps après l’embolie ; je suis auprès de
Marceline ; elle semble aller un peu mieux, mais la plus grande
immobilité lui est encore prescrite ; elle ne doit même pas remuer les
bras. Je me penche pour la faire boire, et lorsqu’elle a bu et que je
suis encore penché près d’elle, d’une voix que son trouble rend plus
faible encore, elle me prie d’ouvrir un coffret que son regard me
désigne ; il est là, sur la table ; je l’ouvre ; il est plein de rubans, de
chiffons, de petits bijoux sans valeur. Que veut-elle ? J’apporte près
du lit la boîte ; je sors un à un chaque objet. Est-ce ceci ? cela ?…
Non ; pas encore ; et je la sens qui s’inquiète un peu. — Ah !
Marceline ! c’est ce petit chapelet que tu veux ! Elle s’efforce de
sourire.
— Tu crains donc que je ne te soigne pas assez ?
— Oh ! mon ami ! murmure-t-elle. — Et je me souviens de notre
conversation de Biskra, de son craintif reproche en m’entendant
repousser ce qu’elle appelle « l’aide de Dieu ». Je reprends un peu
rudement :
— J’ai bien guéri tout seul.
— J’ai tant prié pour toi, répond-elle. Elle dit cela tendrement,
tristement ; je sens dans son regard une anxiété suppliante. Je
prends le chapelet et le glisse dans sa main affaiblie qui repose sur
le drap, contre elle. Un regard chargé de larmes et d’amour me
récompense, mais auquel je ne puis répondre ; un instant encore je
m’attarde, ne sais que faire, suis gêné ; enfin, n’y tenant plus :
— Adieu, lui dis-je ; et je quitte la chambre, hostile, et comme si
l’on m’en avait chassé.
Cependant l’embolie avait amené des désordres assez graves ;
l’affreux caillot de sang, que le cœur avait rejeté, fatiguait et
congestionnait les poumons, obstruait la respiration, la faisait difficile
et sifflante. La maladie était entrée en Marceline, l’habitait
désormais, la marquait, la tachait. C’était une chose abîmée.
III
La saison devenait clémente. Dès que mon cours fut terminé, je

transportai Marceline à la Morinière, le Docteur affirmant que tout
danger pressant était passé et que, pour achever de la remettre, il
ne fallait rien tant qu’un air meilleur. J’avais moi-même grand besoin
de repos. Ces veilles que j’avais tenu à supporter presque toutes
moi-même, cette angoisse prolongée, et surtout cette sorte de
sympathie physique qui, lors de l’embolie de Marceline, m’avait fait
ressentir en moi les affreux sursauts de son cœur, tout cela m’avait
fatigué comme si j’avais moi-même été malade.
J’eusse préféré emmener Marceline dans la montagne ; mais elle
me montra le désir le plus vif de retourner en Normandie, prétendit
que nul climat ne lui serait meilleur, et me rappela que j’avais à
revoir ces deux fermes, dont je m’étais un peu témérairement
chargé. Elle me persuada que je m’en étais fait responsable, et que
je me devais d’y réussir. Nous ne fûmes pas plus tôt arrivés qu’elle
me poussa donc de courir sur les terres… Je ne sais si, dans son
amicale insistance, beaucoup d’abnégation n’entrait pas ; la crainte
que, sinon, me croyant retenu près d’elle par les soins qu’il fallait
encore lui donner, je ne sentisse pas assez grande ma liberté…
Marceline pourtant allait mieux ; du sang recolorait ses joues ; et rien
ne me reposait plus que de sentir moins triste son sourire ; je
pouvais la laisser sans crainte.
Je retournai donc sur les fermes. On y faisait les premiers foins.
L’air chargé de pollens, de senteurs, m’étourdit tout d’abord comme
une boisson capiteuse. Il me sembla que, depuis l’an passé, je
n’avais plus respiré, ou respiré que des poussières, tant pénétrait
mielleusement en moi l’atmosphère. Du talus où je m’étais assis,
comme grisé, je dominais la Morinière ; je voyais ses toits bleus, les
eaux dormantes de ses douves ; autour, des champs fauchés,
d’autres pleins d’herbes ; plus loin, la courbe du ruisseau ; plus loin,
les bois où l’automne dernier je me promenais à cheval avec
Charles. Des chants que j’entendais depuis quelques instants se
rapprochèrent ; c’étaient des faneurs qui rentraient, la fourche ou le
râteau sur l’épaule. Ces travailleurs, que je reconnus presque tous,
me firent fâcheusement souvenir que je n’étais point là en voyageur
charmé, mais en maître. Je m’approchai, leur souris, leur parlai,
m’enquis de chacun longuement. Déjà Bocage le matin m’avait pu
renseigner sur l’état des cultures ; par une correspondance régulière,
il n’avait d’ailleurs pas cessé de me tenir au courant des moindres
incidents des fermes. L’exploitation n’allait pas mal ; beaucoup mieux
que Bocage ne me le laissait d’abord espérer. Pourtant on
m’attendait pour quelques décisions importantes, et, durant
quelques jours, je dirigeai tout de mon mieux, sans plaisir, mais
raccrochant à ce semblant de travail ma vie défaite.
Dès que Marceline fut assez bien pour recevoir, quelques amis
vinrent habiter avec nous. Leur société affectueuse et point bruyante
sut plaire à Marceline, mais fit que je quittai d’autant plus volontiers
la maison. Je préférais la société des gens de la ferme ; il me
semblait qu’avec eux je trouverais mieux à apprendre ; non point que
je les interrogeasse beaucoup ; non, et je sais à peine exprimer cette
sorte de joie que je ressentais auprès d’eux : il me semblait sentir à
travers eux ; et tandis que la conversation de nos amis, avant qu’ils
commençassent de parler, m’était déjà toute connue, la seule vue de
ces gueux me causait un émerveillement continuel.
Si d’abord l’on eût dit qu’ils mettaient à me répondre toute la
condescendance que j’évitais de mettre à les interroger, bientôt ils
supportèrent mieux ma présence. J’entrais toujours plus en contact
avec eux. Non content de les suivre au travail, je voulais les voir à
leurs jeux ; leurs obtuses pensées ne m’intéressaient guère, mais
j’assistais à leurs repas, j’écoutais leurs plaisanteries, surveillais
amoureusement leurs plaisirs. C’était, dans une sorte de sympathie,
pareille à celle qui faisait sursauter mon cœur aux sursauts de celui
de Marceline, c’était un immédiat écho de chaque sensation
étrangère, non point vague, mais précis, aigu. Je sentais en mes
bras la courbature du faucheur ; j’étais las de sa lassitude ; la gorgée
de cidre qu’il buvait me désaltérait ; je la sentais glisser dans sa
gorge ; un jour, en aiguisant sa faux, l’un s’entailla profondément le
pouce : je ressentis sa douleur, jusqu’à l’os.
Il me semblait, ainsi, que ma vue ne fût plus seule à m’enseigner
le paysage, mais que je le sentisse encore par une sorte
d’attouchement qu’illimitait cette bizarre sympathie.
La présence de Bocage me gênait, il me fallait, quand il venait,
jouer au maître, et je n’y trouvais plus aucun goût. Je commandais
encore, il le fallait, et dirigeais à ma façon les travailleurs ; mais je ne
montais plus à cheval par crainte de les dominer trop. Mais, malgré
les précautions que je prenais pour qu’ils ne souffrissent plus de ma
présence et ne se contraignissent plus devant moi, je restais devant
eux, comme auparavant, plein de curiosité mauvaise. L’existence de
chacun d’eux me demeurait mystérieuse. Il me semblait toujours
qu’une partie de leur vie se cachât. Que faisaient-ils, quand je n’étais
plus là ? Je ne consentais pas qu’ils ne s’amusassent pas plus. Et je
prêtais à chacun d’eux un secret que je m’entêtais à désirer
connaître. Je rôdais, je suivais, j’épiais. Je m’attachais de préférence
aux plus frustes natures, comme si, de leur obscurité, j’attendais,
pour m’éclairer, quelque lumière.
Un surtout m’attirait : il était assez beau, grand, point stupide,
mais uniquement mené par l’instinct ; il ne faisait jamais rien que de
subit, et cédait à toute impulsion de passage. Il n’était pas de ce
pays ; on l’avait embauché par hasard. Excellent travailleur deux
jours, il se soûlait à mort le troisième. Une nuit, j’allai furtivement le
voir dans la grange ; il était vautré dans le foin ; il dormait d’un épais
sommeil ivre. Que de temps je le regardai !… Un beau jour, il partit
comme il était venu. J’eusse voulu savoir sur quelles routes. J’appris
le soir même que Bocage l’avait renvoyé. Je fus furieux contre
Bocage, le fis venir.
— Il paraît que vous avez renvoyé Pierre, commençai-je. Voulez-
vous me dire pourquoi ?
Un peu interloqué par ma colère, que pourtant je tempérais de
mon mieux :
— Monsieur ne voulait pourtant pas garder chez lui un sale
ivrogne, qui débauchait les meilleurs ouvriers.
— Je sais mieux que vous ceux que je désire garder.
— Un galvaudeur ! On ne sait même pas d’où qu’il vient. Dans le
pays, ça ne faisait pas bon effet. Quand, une nuit, il aurait mis le feu
à la grange, Monsieur aurait peut-être été content.
— Mais enfin cela me regarde, et la ferme est à moi, peut-être ;
j’entends la diriger comme il me plaît. A l’avenir, vous voudrez bien
me faire part de vos motifs, avant d’exécuter personne.
Bocage, je l’ai dit, m’avait connu tout enfant ; quelque blessant
que fût le ton de mes paroles, il m’aimait trop pour beaucoup s’en
fâcher. Et même il ne me prit pas suffisamment au sérieux. Le
paysan normand demeure trop souvent sans créance pour ce dont il
ne pénètre pas le mobile, c’est-à-dire pour ce que ne conduit pas
l’intérêt. Bocage considérait simplement comme une lubie cette
querelle.
Pourtant je ne voulus pas rompre l’entretien sur un blâme, et,
sentant que j’avais été trop vif, je cherchais ce que je pourrais
ajouter.
— Votre fils Charles ne doit-il pas bientôt revenir ? me décidai-je
à demander après un instant de silence.
— Je pensais que Monsieur l’avait oublié, à voir comme il
s’inquiétait peu après lui, dit Bocage encore blessé.
— Moi, l’oublier, Bocage ! et comment le pourrais-je, après tout
ce que nous avons fait ensemble l’an passé ? Je compte même
beaucoup sur lui pour les fermes.
— Monsieur est bien bon. Charles doit revenir dans huit jours.
— Allons, j’en suis heureux, Bocage ; et je le congédiai.
Bocage avait presque raison : je n’avais certes pas oublié
Charles, mais je ne me souciais plus de lui que fort peu. Comment
expliquer qu’après une camaraderie si fougueuse, je ne sentisse
plus à son égard qu’une chagrine incuriosité ? C’est que mes
occupations et mes goûts n’étaient plus ceux de l’an passé. Mes
deux fermes, il me fallait me l’avouer, ne m’intéressaient plus autant
que les gens que j’y employais ; et pour les fréquenter, la présence
de Charles allait être gênante. Il était bien trop raisonnable et se
faisait trop respecter. Donc, malgré la vive émotion qu’éveillait en
moi son souvenir, je voyais approcher son retour avec crainte.
Il revint. Ah ! que j’avais raison de craindre et que Ménalque
faisait bien de renier tout souvenir ! Je vis entrer, à la place de
Charles, un absurde Monsieur, coiffé d’un ridicule chapeau melon.
Dieu ! qu’il était changé ! Gêné, contraint, je tâchai pourtant de ne
pas répondre avec trop de froideur à la joie qu’il montrait de me
revoir ; mais même cette joie me déplut ; elle était gauche et ne me
parut pas sincère. Je l’avais reçu dans le salon, et, comme il était
tard, je ne distinguais pas bien son visage ; mais, quand on apporta
la lampe, je vis avec dégoût qu’il avait laissé pousser ses favoris.
L’entretien, ce soir-là, fut plutôt morne ; puis, comme je savais
qu’il serait sans cesse sur les fermes, j’évitai, durant près de huit
jours, d’y aller, et je me rabattis sur mes études et sur la société de
mes hôtes. Puis, sitôt que je recommençai de sortir, je fus requis par
une occupation très nouvelle :
Des bûcherons avaient envahi les bois. Chaque année, on en
vendait une partie ; partagés en douze coupes égales, les bois
fournissaient chaque année, avec quelques arbres de haut jet dont
on n’espérait plus de croissance, un taillis de douze ans qu’on
mettait en fagots.
Ce travail se faisait l’hiver, puis, avant le printemps, selon les
clauses de la vente, les bûcherons devaient avoir vidé la coupe.
Mais l’incurie du père Heurtevent, le marchand de bois qui dirigeait
l’opération, était telle, que, parfois, le printemps entrait dans la coupe
encore encombrée ; on voyait alors de nouvelles pousses fragiles
s’allonger au travers des ramures mortes, et, lorsque enfin les
bûcherons faisaient vidange, ce n’était point sans abîmer bien des
bourgeons. Cette année, la négligence du père Heurtevent,
l’acheteur, passa nos craintes. En l’absence de toute surenchère,
j’avais dû lui laisser la coupe à très bas prix ; aussi, sûr d’y trouver
toujours son compte, se pressait-il fort peu de débiter un bois qu’il
avait payé si peu cher. Et, de semaine en semaine, il différait le
travail, prétextant une fois l’absence d’ouvriers, une autre fois le
mauvais temps, puis un cheval malade, des prestations, d’autres
travaux… que sais-je ? Si bien qu’au milieu de l’été rien n’était
encore enlevé.
Ce qui, l’an précédent, m’eût irrité au plus haut point, cette année
me laissait assez calme, je ne me dissimulais pas le tort que
Heurtevent me faisait ; mais ces bois ainsi dévastés étaient beaux,
et je m’y promenais avec plaisir, épiant, surveillant le gibier,
surprenant les vipères, et, parfois, m’asseyant longuement sur un
des troncs couchés, qui semblait vivre encore et par ses plaies jetait
quelques vertes brindilles.
Puis, tout à coup, vers le milieu de la première quinzaine d’août,
Heurtevent se décida à envoyer ses hommes. Ils vinrent six à la fois,
prétendant achever tout l’ouvrage en dix jours. La partie des bois
exploitée touchait presque à la Valterie ; j’acceptai, pour faciliter
l’ouvrage des bûcherons, qu’on apportât leur repas de la ferme.
Celui qui fut chargé de ce soin était un loustic nommé Bute, que le
régiment venait de nous renvoyer tout pourri — j’entends quant à
l’esprit, car son corps allait à merveille ; c’était un de ceux de mes
gens avec qui je causais le plus volontiers. Je pus donc ainsi le
revoir sans aller pour cela sur la ferme. Car c’est précisément alors
que je recommençai de sortir. Et durant quelques jours, je ne quittai
guère les bois, ne rentrant à la Morinière que pour les heures des
repas, et souvent me faisant attendre. Je feignais de surveiller le
travail, mais en vérité ne voyais que les travailleurs.
Il se joignait parfois, à cette bande de six hommes, deux des fils
Heurtevent ; l’un âgé de vingt ans, l’autre de quinze, élancés,
cambrés, les traits durs. Ils semblaient de type étranger, et j’appris
plus tard, en effet, que leur mère était Espagnole. Je m’étonnai
d’abord qu’elle eût pu venir jusqu’ici, mais Heurtevent, un vagabond
fieffé dans sa jeunesse, l’avait, paraît-il, épousée en Espagne. Il était
pour cette raison assez mal vu dans le pays. La première fois que
j’avais rencontré le plus jeune des fils, c’était, il m’en souvient, sous
la pluie ; il était seul, assis sur une charrette au plus haut d’un
entassement de fagots ; et là, tout renversé parmi les branches, il
chantait, ou plutôt gueulait, une espèce de chant bizarre et tel que je
n’en avais jamais ouï dans le pays. Les chevaux qui traînaient la
charrette, connaissant le chemin, avançaient sans être conduits. Je
ne puis dire l’effet que ce chant produisit sur moi ; car je n’en avais
entendu de pareil qu’en Afrique. Le petit, exalté, paraissait ivre ;
quand je passai, il ne me regarda même pas. Le lendemain, j’appris
que c’était un fils de Heurtevent. C’était pour le revoir, ou du moins
pour l’attendre que je m’attardais ainsi dans la coupe. On acheva
bientôt de la vider. Les garçons Heurtevent n’y vinrent que trois fois.
Ils semblaient fiers, et je ne pus obtenir d’eux une parole.
Bute, par contre, aimait à raconter ; je fis en sorte que bientôt il
comprît ce qu’avec moi l’on pouvait dire ; dès lors il ne se gêna
guère et déshabilla le pays. Avidement je me penchai sur mon
mystère. Tout à la fois il dépassait mon espérance, et ne me
satisfaisait pas. Était-ce là ce qui grondait sous l’apparence ? ou
peut-être n’était-ce encore qu’une nouvelle hypocrisie ? N’importe !
Et j’interrogeais Bute, comme j’avais fait les informes chroniques des
Goths. De ses récits sortait une trouble vapeur, d’abîme qui déjà me
montait à la tête et qu’inquiètement je humais. Par lui, j’appris
d’abord que Heurtevent couchait avec sa fille. Je craignais, si je
manifestais le moindre blâme, d’arrêter toute confidence ; je souris
donc ; la curiosité me poussait.
— Et la mère ? Elle ne dit rien ?
— La mère ! voilà douze ans pleins qu’elle est morte… Il la
battait.
— Combien sont-ils dans la famille ?
— Cinq enfants. Vous avez vu l’aîné des fils et le plus jeune. Il y
en a encore un de seize ans, qui n’est pas fort, et qui veut se faire
curé. Et puis la fille aînée a déjà deux enfants du père…
Et j’appris peu à peu bien d’autres choses, qui faisaient de la
maison Heurtevent un lieu brûlant, à l’odeur forte, autour duquel,
malgré que j’en eusse, mon imagination, comme une mouche à
viande, tournoyait : — Un soir, le fils aîné tenta de violer une jeune
servante ; et comme elle se débattait, le père intervenant aida son
fils, et de ses mains énormes la contint ; cependant que le second
fils, à l’étage au-dessus, continuait tendrement ses prières, et que le
cadet, témoin du drame, s’amusait. Pour ce qui est du viol, je me
figure qu’il n’avait pas été bien difficile, car Bute racontait encore
que, peu de temps après, la servante, y ayant pris goût, avait tenté
de débaucher le petit prêtre.
— Et l’essai n’a pas réussi ? demandai-je.
— Il tient encore, mais plus bien dru, répondit Bute.
— N’as-tu pas dit qu’il y avait une autre fille ?
— Qui en prend bien tant qu’elle en trouve ; et encore sans
demander rien. Quand ça la tient, c’est elle qui paierait plutôt. Par
exemple, faudrait pas coucher chez le père ; il cognerait. Il dit
comme ça qu’en famille on a le droit de faire ce qui vous plaît, mais
que ça ne regarde pas les autres. Pierre, le gars de la ferme que
vous avez fait renvoyer, ne s’en est pas vanté, mais, une nuit, il n’en
est pas sorti sans un trou dans la tête. Depuis ce temps-là, c’est
dans le bois du château qu’on travaille.
Alors, en l’encourageant du regard :
— Tu en as essayé ? demandai-je.
Il baissa les yeux pour la forme et dit en rigolant :
— Quelquefois. Puis, relevant vite les yeux :
— Le petit au père Bocage aussi.
— Quel petit au père Bocage ?
— Alcide, celui qui couche sur la ferme. Monsieur ne le connaît
donc pas ?
J’étais absolument stupéfait d’apprendre que Bocage avait un
autre fils.
— C’est vrai, continua Bute, que, l’an passé, il était encore chez
son oncle. Mais c’est bien étonnant que Monsieur ne l’ait pas déjà

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BRENNER AND STEVENS’ PHARMACOLOGY, SIXTH EDITION  ISBN: 978-0-323-75898-7

Previous editions copyrighted 2018, 2013, 2010, 2006, and 2000

Content Strategist: Alexandra Mortimer

Last digit is the print number: 9 8 7 6 5 4 3 2 1

Section I 21 L ocal and General Anesthetics 233

41  ntimycobacterial Drugs for Treating

Dose of drug Drug concentration Magnitude of

Absorption Receptor binding

Natural drug source Opium poppy

Crude drug preparation Raw opium

Pure drug extract Morphine sulfate

Pharmaceutical formulation Morphine tablets

OVERVIEW A few drugs are absorbed by active transport or by facili-

Pill taken Drug concentration in blood Removed in urine

Plasma protein binding

HA H+ + A– For weak acids, the protonated

B + H+ HB+ For weak bases, the protonated

CH2 CH NH2 CH2 CH NH3+

Salicylic acid Amphetamine

Nonprotonated 1 1 10 100 1000 1 1 1 1

First pass Liver

Description Reaction Examples

Codeine, imipramine, and

N-Oxidation Drug N H Drug N OH Chlorpheniramine

Nitro reduction Drug N O Drug NH2 Chloramphenicol

Reductive hydrolysis Drug O N O Drug OH + N O Nitroglycerin

Description Reaction Examples

Conjugation reactions Acetyl CoA

UDP-glucoronic acid (GA)

Drug concentration Amount of drug

Absorption Metabolism + Excretion = Elimination

Drug concentration Amount of drug

Absorption Metabolism + Excretion = Elimination

Plasma drug concentration (mg/mL)

IV drug given AUCoral

Calculation of the volume of distribution (Vd)

The y-axis is a linear scale of drug plasma concentration, Volume of Distribution

BOX 2.4 DRUG DOSAGE CALCULATIONS

Plasma drug concentration (mg/mL)

30 Elimination half-life (t1/2) = 1h 30 t1/2 = 4h

The following principles pertain to first-order kinet- CONTINUOUS-DOSE AND MULTIPLE-DOSE

Plasma drug concentration (mg/L)

Steady-state concentration after continuous IV infusion

IV infusion Steady-state reached in five t1/2

BRENNER AND STEVENS’ PHARMACOLOGY, SIXTH EDITION ISBN: 978-0-323-75898-7

Section I 21 L ocal and General Anesthetics 233

41 ntimycobacterial Drugs for Treating