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Preface
The fourteenth edition of Basic & Clinical Pharmacology continues Significant revisions in this edition include:
the extensive use of full-color illustrations and expanded coverage
of transporters, pharmacogenomics, and new drugs of all types • Major revisions of the chapters on immunopharmacology,
emphasized in prior editions. In addition, it reflects the major antiseizure, antipsychotic, antidepressant, antidiabetic, anti-
expansion of large-molecule drugs in the pharmacopeia, with inflammatory, and antiviral drugs, prostaglandins, and central
nervous system neurotransmitters.
numerous new monoclonal antibodies and other biologic agents.
• Continued expansion of the coverage of general concepts relat-
Case studies accompany most chapters, and answers to ques- ing to newly discovered receptors, receptor mechanisms, and
tions posed in the case studies appear at the end of each chapter. drug transporters.
The book is designed to provide a comprehensive, authoritative, • Descriptions of important new drugs released through May 2017.
and readable pharmacology textbook for students in the health • Many revised illustrations in full color that provide significantly
sciences. Frequent revision is necessary to keep pace with the rapid more information about drug mechanisms and effects and help
changes in pharmacology and therapeutics; the 2–3 year revision to clarify important concepts.
cycle of this text is among the shortest in the field, and the avail-
An important related educational resource is Katzung &
ability of an online version provides even greater currency. The
Trevor’s Pharmacology: Examination & Board Review, (Trevor AJ,
book also offers special features that make it a useful reference for
Katzung BG, & Kruidering-Hall, M: McGraw-Hill). This book
house officers and practicing clinicians.
provides a succinct review of pharmacology with approximately
This edition continues the sequence used in many pharmacol-
one thousand sample examination questions and answers. It is
ogy courses and in integrated curricula: basic principles of drug
especially helpful to students preparing for board-type examina-
discovery, pharmacodynamics, pharmacokinetics, and pharma-
tions. A more highly condensed source of information suitable for
cogenomics; autonomic drugs; cardiovascular-renal drugs; drugs
review purposes is USMLE Road Map: Pharmacology, second edi-
with important actions on smooth muscle; central nervous system
tion (Katzung BG, Trevor AJ: McGraw-Hill, 2006). An extremely
drugs; drugs used to treat inflammation, gout, and diseases of
useful manual of toxicity due to drugs and other products
the blood; endocrine drugs; chemotherapeutic drugs; toxicology;
is Poisoning & Drug Overdose, by Olson KR, ed; 7th edition,
and special topics. This sequence builds new information on a
McGraw-Hill, 2017.
foundation of information already assimilated. For example, early
This edition marks the 35th year of publication of Basic &
presentation of autonomic nervous system pharmacology allows
Clinical Pharmacology. The widespread adoption of the first
students to integrate the physiology and neuroscience they have
thirteen editions indicates that this book fills an important need.
learned elsewhere with the pharmacology they are learning and
We believe that the fourteenth edition will satisfy this need even
prepares them to understand the autonomic effects of other drugs.
more successfully. Chinese, Croatian, Czech, French, Georgian,
This is especially important for the cardiovascular and central ner-
Indonesian, Italian, Japanese, Korean, Lithuanian, Portuguese,
vous system drug groups. However, chapters can be used equally
Spanish, Turkish, and Ukrainian translations of various editions
well in courses and curricula that present these topics in a different
are available. The publisher may be contacted for further
sequence.
information.
Within each chapter, emphasis is placed on discussion of drug
I wish to acknowledge the prior and continuing efforts of
groups and prototypes rather than offering repetitive detail about
my contributing authors and the major contributions of the
individual drugs. Selection of the subject matter and the order
staff at Lange Medical Publications, Appleton & Lange, and
of its presentation are based on the accumulated experience of
McGraw-Hill, and of our editors for this edition, Caroline
teaching this material to thousands of medical, pharmacy, dental,
Define and Greg Feldman. I also wish to thank Alice Camp and
podiatry, nursing, and other health science students.
Katharine Katzung for their expert proofreading contributions.
Major features that make this book particularly useful in
Suggestions and comments about Basic & Clinical Pharmacology
integrated curricula include sections that specifically address the
are always welcome. They may be sent to me in care of the
clinical choice and use of drugs in patients and the monitoring of
publisher.
their effects—in other words, clinical pharmacology is an integral
part of this text. Lists of the trade and generic names of commer-
Bertram G. Katzung, MD, PhD
cial preparations available are provided at the end of each chapter
San Francisco
for easy reference by the house officer or practitioner evaluating a
June 2017
patient’s drug list or writing a prescription.
vii
Authors
Michael J. Aminoff, MD, DSc, FRCP Edward Chu, MD

Professor, Department of Neurology, University of Professor of Medicine and Pharmacology & Chemical
California, San Francisco Biology; Chief, Division of Hematology-Oncology,
Director, University of Pittsburgh Cancer Institute,
Allan I. Basbaum, PhD
University of Pittsburgh School of Medicine, Pittsburgh
Professor and Chair, Department of Anatomy and W.M.
Keck Foundation Center for Integrative Neuroscience, Valerie B. Clinard, PharmD
University of California, San Francisco Associate Professor, Department of Clinical Pharmacy,
School of Pharmacy, University of California,
Camille E. Beauduy, PharmD
San Francisco
Assistant Clinical Professor, School of Pharmacy,
University of California, San Francisco Robin L. Corelli, PharmD
Clinical Professor, Department of Clinical Pharmacy,
Neal L. Benowitz, MD
School of Pharmacy, University of California,
Professor of Medicine and Bioengineering &
San Francisco
Therapeutic Science, University of California,
San Francisco Maria Almira Correia, PhD
Professor of Pharmacology, Pharmaceutical Chemistry
Italo Biaggioni, MD
and Biopharmaceutical Sciences, Department of Cellular
Professor of Pharmacology, Vanderbilt University School
& Molecular Pharmacology, University of California,
of Medicine, Nashville
San Francisco
Daniel D. Bikle, MD, PhD
Charles DeBattista, MD
Professor of Medicine, Department of Medicine, and
Professor of Psychiatry and Behavioral Sciences, Stanford
Co-Director, Special Diagnostic and Treatment Unit,
University School of Medicine, Stanford
University of California, San Francisco, and Veterans
Affairs Medical Center, San Francisco Cathi E. Dennehy, PharmD
Professor, Department of Clinical Pharmacy, University
Homer A. Boushey, MD
of California, San Francisco School of Pharmacy,
Chief, Asthma Clinical Research Center and Division
San Francisco
of Allergy & Immunology; Professor of Medicine,
Department of Medicine, University of California, Betty J. Dong, PharmD, FASHP, FCCP, FAPHA
San Francisco Professor of Clinical Pharmacy and Clinical Professor
of Family and Community Medicine, Department of
Adrienne D. Briggs, MD
Clinical Pharmacy and Department of Family and
Clinical Director, Bone Marrow Transplant Program,
Community Medicine, Schools of Pharmacy and
Banner Good Samaritan Hospital, Phoenix
Medicine, University of California, San Francisco
Hakan Cakmak, MD
Kenneth Drasner, MD
Department of Medicine, University of California,
Professor of Anesthesia and Perioperative Care,
San Francisco
University of California, San Francisco
Lundy Campbell, MD
Helge Eilers, MD
Professor, Department of Anesthesiology and
Professor of Anesthesia and Perioperative Care,
Perioperative Medicine, University of California
San Francisco, School of Medicine, San Francisco
Daniel E. Furst, MD
George P. Chrousos, MD
Carl M. Pearson Professor of Rheumatology, Director,
Professor & Chair, First Department of Pediatrics,
Rheumatology Clinical Research Center, Department of
Athens University Medical School, Athens, Greece
Rheumatology, University of California, Los Angeles
ix
x AUTHORS
Joshua M. Galanter, MD Michael J. Kosnett, MD, MPH

Department of Medicine, University of California, Associate Clinical Professor of Medicine, Division of
San Francisco Clinical Pharmacology and Toxicology, University of
Colorado Health Sciences Center, Denver
Kathleen M. Giacomini, PhD
Professor of Bioengineering and Therapeutic Sciences, Marieke Kruidering-Hall, PhD
Schools of Pharmacy and Medicine, University of Academy Chair in Pharmacology Education; Professor,
California, San Francisco Department of Cellular and Molecular Pharmacology,
Augustus O. Grant, MD, PhD
Professor of Medicine, Cardiovascular Division, Duke Douglas F. Lake, PhD
University Medical Center, Durham Associate Professor, The Biodesign Institute, Arizona
State University, Tempe
John A. Gray, MD, PhD
Associate Professor, Department of Neurology, Center for Harry W. Lampiris, MD
Neuroscience, University of California, Davis Professor of Clinical Medicine, UCSF, Interim Chief,
Robert D. Harvey, PhD ID Section, Medical Service, San Francisco VA Medical
Professor of Pharmacology and Physiology, University of Center, San Francisco
Nevada School of Medicine, Reno
Paul W. Lofholm, PharmD
Jennifer E. Hibma, PharmD Clinical Professor of Pharmacy, School of Pharmacy,
Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco
Schools of Pharmacy and Medicine, University of
Roger K. Long, MD
California, San Francisco
Professor of Pediatrics, Department of Pediatrics,
Nicholas H. G. Holford, MB, ChB, FRACP University of California, San Francisco
Professor, Department of Pharmacology and Clinical
Christian Lüscher, MD
Pharmacology, University of Auckland Medical School,
Departments of Basic and Clinical Neurosciences,
Auckland
Medical Faculty, University Hospital of Geneva, Geneva,
John R. Horn, PharmD, FCCP Switzerland
Professor of Pharmacy, School of Pharmacy, University
Daniel S. Maddix, PharmD
of Washington; Associate Director of Pharmacy Services,
Associate Clinical Professor of Pharmacy, University of
Department of Medicine, University of Washington
California, San Francisco
Medicine, Seattle
Howard I. Maibach, MD
John Hwa, MD, PhD
Professor of Dermatology, Department of Dermatology,
Professor of Medicine and Pharmacology, Yale University
School of Medicine, New Haven
Mary J. Malloy, MD
Harlan E. Ives, MD, PhD
Clinical Professor of Pediatrics and Medicine,
Professor Emeritus of Medicine, Department of
Departments of Pediatrics and Medicine, Cardiovascular
Medicine, University of California, San Francisco
Research Institute, University of California,
Samie R. Jaffrey, MD, PhD San Francisco
Greenberg-Starr Professor of Pharmacology,
Kathleen Martin, PhD
Department of Pharmacology, Cornell University Weill
Associate Professor, Yale Cardiovascular Center, Yale
Medical College, New York City
University, New Haven
John P. Kane, MD, PhD
Umesh Masharani, MBBS, MRCP (UK)
Professor of Medicine, Department of Medicine;
Professor of Medicine, Department of Medicine,
Professor of Biochemistry and Biophysics; Associate
Director, Cardiovascular Research Institute, University of
California, San Francisco Kenneth R. McQuaid, MD
Professor of Clinical Medicine, University of California,
Bertram G. Katzung, MD, PhD
San Francisco; Chief of Gastroenterology, San Francisco
Professor Emeritus, Department of Cellular & Molecular
Veterans Affairs Medical Center, San Francisco
Pharmacology, University of California, San Francisco
Ramana K. Naidu, MD
Gideon Koren, MD, FRCPC, FACMT
Department of Anesthesia and Perioperative Care,
Consultant, Kiryat Ono, Israel
AUTHORS xi
Ahmed A. Negm, MD Sharon Safrin, MD

Department of Medicine, University of California, Associate Clinical Professor, Department of Medicine,
Los Angeles University of California, San Francisco; President, Safrin
Clinical Research, Hillsborough
Martha S. Nolte Kennedy, MD
Clinical Professor, Department of Medicine, University Ramin Sam, MD
of California, San Francisco Associate Professor, Department of Medicine, University
of California, San Francisco
Kent R. Olson, MD
Clinical Professor, Department of Medicine, Schools of Mark A. Schumacher, PhD, MD
Medicine and Pharmacy, University of California, San Professor, Department of Anesthesia and Perioperative
Francisco; Medical Director, San Francisco Division, Care, University of California, San Francisco
California Poison Control System, San Francisco
Daniel T. Teitelbaum, MD
Achilles J. Pappano, PhD Adjunct Professor of Occupational and Environmental
Professor Emeritus, Department of Cell Biology and Health, Colorado School of Public Health, Denver;
Calhoun Cardiology Center, University of Connecticut and Adjunct Professor, Civil and Environmental
Health Center, Farmington Engineering, Colorado School of Mines, Golden
David Pearce, MD Anthony J. Trevor, PhD
Professor of Medicine, University of California, Professor Emeritus, Department of Cellular & Molecular
San Francisco Pharmacology, University of California, San Francisco
Roger J. Porter, MD Candy Tsourounis, PharmD
Adjunct Professor of Neurology, University of Professor of Clinical Pharmacy, Medication Outcomes
Pennsylvania, Philadelphia; Adjunct Professor of Center, University of California, San Francisco School of
Pharmacology, Uniformed Services University of the Pharmacy, San Francisco
Health Sciences, Bethesda
Mark von Zastrow, MD, PhD
Ian A. Reid, PhD Professor, Departments of Psychiatry and Cellular &
Professor Emeritus, Department of Physiology, Molecular Pharmacology, University of California,
University of California, San Francisco San Francisco
David Robertson, MD Lisa G. Winston, MD
Elton Yates Professor of Medicine, Pharmacology and Clinical Professor, Department of Medicine, Division
Neurology, Vanderbilt University; Director, Clinical & of Infectious Diseases, University of California,
Translational Research Center, Vanderbilt Institute for San Francisco; Hospital Epidemiologist, San Francisco
Clinical and Translational Research, Nashville General Hospital, San Francisco
Dirk B. Robertson, MD Spencer Yost, MD
Professor of Clinical Dermatology, Department of Professor, Department of Anesthesia and Perioperative
Dermatology, Emory University School of Medicine, Care, University of California, San Francisco; Medical
Atlanta Director, UCSF-Mt. Zion ICU, Chief of Anesthesia,
UCSF-Mt. Zion Hospital, San Francisco
Michael A. Rogawski, MD, PhD
Professor of Neurology, Department of Neurology, James L. Zehnder, MD
University of California, Davis Professor of Pathology and Medicine, Pathology
Department, Stanford University School of Medicine,
Philip J. Rosenthal, MD
Stanford
Professor of Medicine, San Francisco General Hospital,
S C H E D U L E O F C O N T R O L L E D D R U G S1
SCHEDULE I Depressants:
Schedule II barbiturates in mixtures with noncontrolled drugs or in
(All nonresearch use illegal under federal law.) suppository dosage form
Flunitrazepam (Rohypnol) Barbiturates (butabarbital [Butisol], butalbital [Fiorinal])
Narcotics: Ketamine (Ketalar)
Heroin and many nonmarketed synthetic narcotics
Cannabinoids:
Hallucinogens: Dronabinol (Marinol)
LSD
Anabolic Steroids:
MDA, STP, DMT, DET, mescaline, peyote, bufotenine, ibogaine, Fluoxymesterone (Androxy), Methyltestosterone (Android, Testred),
psilocybin, phencyclidine (PCP; veterinary drug only) Oxandrolone (Oxandrin), Oxymetholone (Androl-50),
Marijuana Testosterone and its esters (Androgel)
Methaqualone
SCHEDULE II SCHEDULE IV
(Prescription must be rewritten after 6 months or five refills; differs from
(No telephone prescriptions, no refills.)2 Schedule III in penalties for illegal possession.)
Opioids: Opioids:
Opium: Opium alkaloids and derived phenanthrene alkaloids: Butorphanol (Stadol)
codeine, morphine (Avinza, Kadian, MSContin, Roxanol),
hydrocodone and hydrocodone combinations (Zohydro ER, Difenoxin 1 mg + atropine 25 mcg (Motofen)
Hycodan, Vicodin, Lortab), hydromorphone (Dilaudid), Pentazocine (Talwin)
oxymorphone (Exalgo), oxycodone (dihydroxycodeinone, a Stimulants:
component of Oxycontin, Percodan, Percocet, Roxicodone, Tylox) Armodafinil (Nuvigil)
Designated synthetic drugs: meperidine (Demerol), methadone, Diethylpropion (Tenuate) not in USA
levorphanol (Levo-Dromoran), fentanyl (Duragesic, Actiq, Modafinil (Provigil)
Fentora), alfentanil (Alfenta), sufentanil (Sufenta), remifentanil Phentermine (Adipex-P)
(Ultiva), tapentadol (Nycynta) Depressants:
Stimulants: Benzodiazepines: Alprazolam (Xanax), Chlordiazepoxide (Librium),
Coca leaves and cocaine Clobazam (Onfi), Clonazepam (Klonopin), Clorazepate (Tranxene),
Amphetamines: Amphetamine complex (Biphetamine), Diazepam (Valium), Estazolam, Flurazepam (Dalmane), Lorazepam
Amphetamine salts (Adderall), Dextroamphetamine (Dexedrine, (Ativan), Midazolam (Versed), Oxazepam, Quazepam (Doral),
Procentra), Lisdexamfetamine (Vyvanse), Methamphetamine Temazepam (Restoril), Triazolam (Halcion)
(Desoxyn), Methylphenidate (Ritalin, Concerta, Methylin, Carisoprodol (Soma)
Daytrana, Medadate), Above in mixtures with other controlled or Chloral hydrate
uncontrolled drugs
Eszopiclone (Lunesta)
Cannabinoids:
Nabilone (Cesamet) Lacosamide (Vimpat)
Depressants: Meprobamate
Amobarbital (Amytal) Methohexital (Brevital)
Pentobarbital (Nembutal) Paraldehyde not in USA
Secobarbital (Seconal) Phenobarbital
Tramadol (Ultram)
Zaleplon (Sonata)
SCHEDULE III Zolpidem (Ambien)
(Prescription must be rewritten after 6 months or five refills.)
Opioids:
Buprenorphine (Buprenex, Subutex) SCHEDULE V
Mixture of above Buprenorphine and Naloxone (Suboxone) (As any other nonopioid prescription drug)
The following opioids in combination with one or more active Codeine: 200 mg/100 mL
nonopioid ingredients, provided the amount does not exceed that Difenoxin preparations: 0.5 mg + 25 mcg atropine
shown: Dihydrocodeine preparations: 10 mg/100 mL
Codeine and dihydrocodeine: not to exceed 1800 mg/dL or 90 mg/ Diphenoxylate (not more than 2.5 mg and not less than 0.025 mg of
tablet or other dosage unit atropine per dosage unit, as in Lomotil)
Opium: 500 mg/dL or 25 mg/5 mL or other dosage unit (paregoric) Opium preparations: 100 mg/100 mL
Stimulants: Pregabalin (Lyrica)
Benzphetamine (Regimex)
Phendimetrazine
1
See https://www.deadiversion.usdoj.gov/schedules.
2
Emergency prescriptions may be telephoned if followed within 7 days by a valid written prescription annotated to indicate that it was previously placed by
telephone. CMEA (Combat Methamphetamine Epidemic Act of 2005) establishes regulations for ephedrine, pseudoephedrine, and phenylpropanolamine
over-the-counter sales and purchases.
SECTION I BASIC PRINCIPLES
1
C H A P T E R
Introduction: The Nature of

Drugs & Drug Development
& Regulation
Bertram G. Katzung, MD, PhD*
C ASE STUDY
A 78-year-old woman is brought to the hospital because of In the emergency department, samples of venous and arterial
suspected aspirin overdose. She has taken aspirin for joint pain blood are obtained while the airway, breathing, and circulation
for many years without incident, but during the past year, she are evaluated. An intravenous (IV) drip is started, and gastro-
has exhibited many signs of cognitive decline. Her caregiver intestinal decontamination is begun. After blood gas results are
finds her confused, hyperventilating, and vomiting. The care- reported, sodium bicarbonate is administered via the IV. What
giver finds an empty bottle of aspirin tablets and calls 9-1-1. is the purpose of the sodium bicarbonate?
Pharmacology can be defined as the study of substances that the patient. Such deliberate therapeutic applications may be con-
interact with living systems through chemical processes. These sidered the proper role of medical pharmacology, which is often
interactions usually occur by binding of the substance to regula- defined as the science of substances used to prevent, diagnose, and
tory molecules and activating or inhibiting normal body processes. treat disease. Toxicology is the branch of pharmacology that deals
These substances may be chemicals administered to achieve a with the undesirable effects of chemicals on living systems, from
beneficial therapeutic effect on some process within the patient or individual cells to humans to complex ecosystems (Figure 1–1).
for their toxic effects on regulatory processes in parasites infecting The nature of drugs—their physical properties and their inter-
actions with biological systems—is discussed in part I of this
*
The author thanks Barry Berkowitz, PhD, for contributions to the chapter. The development of new drugs and their regulation by
second part of this chapter. government agencies are discussed in part II.
1
2 SECTION I Basic Principles
drug preparation and the medical uses of drugs—began to develop

Chemical
as the precursor to pharmacology. However, any real understand-
ing of the mechanisms of action of drugs was prevented by the
absence of methods for purifying active agents from the crude
Pharmacokinetics
Patient Environment materials that were available and—even more—by the lack of
methods for testing hypotheses about the nature of drug actions.
In the late 18th and early 19th centuries, François Magendie
and his student Claude Bernard began to develop the methods
Intended Unintended Other of experimental physiology and pharmacology. Advances in
target targets organisms chemistry and the further development of physiology in the
tissues
18th, 19th, and early 20th centuries laid the foundation needed
Pharmacodynamics
for understanding how drugs work at the organ and tissue levels.
Food Paradoxically, real advances in basic pharmacology during this
chain time were accompanied by an outburst of unscientific claims by
Therapeutic
effects
manufacturers and marketers of worthless “patent medicines.” Not
until the concepts of rational therapeutics, especially that of the
controlled clinical trial, were reintroduced into medicine—only
Toxic More about 60 years ago—did it become possible to adequately evaluate
effects organisms therapeutic claims.
Around the 1940s and 1950s, a major expansion of research
Medical pharmacology Environmental
and toxicology toxicology efforts in all areas of biology began. As new concepts and new
techniques were introduced, information accumulated about drug
FIGURE 1–1 Major areas of study in pharmacology. The actions action and the biologic substrate of that action, the drug receptor.
of chemicals can be divided into two large domains. The first (left During the last 60 years, many fundamentally new drug groups
side) is that of medical pharmacology and toxicology, which is aimed and new members of old groups were introduced. The last four
at understanding the actions of drugs as chemicals on individual decades have seen an even more rapid growth of information
organisms, especially humans and domestic animals. Both beneficial and understanding of the molecular basis for drug action. The
and toxic effects are included. Pharmacokinetics deals with the molecular mechanisms of action of many drugs have now been
absorption, distribution, and elimination of drugs. Pharmacodynamics identified, and numerous receptors have been isolated, structurally
concerns the actions of the chemical on the organism. The second characterized, and cloned. In fact, the use of receptor identifica-
domain (right side) is that of environmental toxicology, which is tion methods (described in Chapter 2) has led to the discovery
concerned with the effects of chemicals on all organisms and their
of many orphan receptors—receptors for which no ligand has
survival in groups and as species.
been discovered and whose function can only be guessed. Stud-
ies of the local molecular environment of receptors have shown
THE HISTORY OF PHARMACOLOGY that receptors and effectors do not function in isolation; they are
strongly influenced by other receptors and by companion regula-
Prehistoric people undoubtedly recognized the beneficial or toxic tory proteins.
effects of many plant and animal materials. Early written records Pharmacogenomics—the relation of the individual’s genetic
list remedies of many types, including a few that are still recog- makeup to his or her response to specific drugs—is becoming an
nized as useful drugs today. Most, however, were worthless or important part of therapeutics (see Chapter 5). Decoding of the
actually harmful. In the last 1500 years, sporadic attempts were genomes of many species—from bacteria to humans—has led
made to introduce rational methods into medicine, but none to the recognition of unsuspected relationships between recep-
was successful owing to the dominance of systems of thought tor families and the ways that receptor proteins have evolved.
(“schools”) that purported to explain all of biology and disease Discovery that small segments of RNA can interfere with protein
without the need for experimentation and observation. These synthesis with extreme selectivity has led to investigation of small
schools promulgated bizarre notions such as the idea that disease interfering RNAs (siRNAs) and micro-RNAs (miRNAs) as ther-
was caused by excesses of bile or blood in the body, that wounds apeutic agents. Similarly, short nucleotide chains called antisense
could be healed by applying a salve to the weapon that caused the oligonucleotides (ANOs), synthesized to be complementary to
wound, and so on. natural RNA or DNA, can interfere with the readout of genes and
Around the end of the 17th century, reliance on observation the transcription of RNA. These intracellular targets may provide
and experimentation began to replace theorizing in physiology the next major wave of advances in therapeutics.
and clinical medicine. As the value of these methods in the study Unfortunately, the medication-consuming public is still
of disease became clear, physicians in Great Britain and on the exposed to vast amounts of inaccurate or unscientific information
Continent began to apply them to the effects of traditional drugs regarding the pharmacologic effects of chemicals. This has resulted
used in their own practices. Thus, materia medica—the science of in the irrational use of innumerable expensive, ineffective, and
CHAPTER 1 Introduction: The Nature of Drugs & Drug Development & Regulation 3
sometimes harmful remedies and the growth of a huge “alternative location distant from its intended site of action, eg, a pill given
health care” industry. Furthermore, manipulation of the legislative orally to relieve a headache. Therefore, a useful drug must have
process in the United States has allowed many substances pro- the necessary properties to be transported from its site of admin-
moted for health—but not promoted specifically as “drugs”—to istration to its site of action. Finally, a practical drug should be
avoid meeting the Food and Drug Administration (FDA) stan- inactivated or excreted from the body at a reasonable rate so that
dards described in the second part of this chapter. Conversely, its actions will be of appropriate duration.
lack of understanding of basic scientific principles in biology and Drugs may be solid at room temperature (eg, aspirin, atro-
statistics and the absence of critical thinking about public health pine), liquid (eg, nicotine, ethanol), or gaseous (eg, nitrous oxide).
issues have led to rejection of medical science by a segment of the These factors often determine the best route of administration.
public and to a common tendency to assume that all adverse drug The most common routes of administration are described in
effects are the result of malpractice. Chapter 3, Table 3–3. The various classes of organic compounds—
General principles that the student should remember are carbohydrates, proteins, lipids, and smaller molecules—are all rep-
(1) that all substances can under certain circumstances be toxic; resented in pharmacology. As noted above, oligonucleotides, in the
(2) that the chemicals in botanicals (herbs and plant extracts, form of small segments of RNA, have entered clinical trials and are
“nutraceuticals”) are no different from chemicals in manufactured on the threshold of introduction into therapeutics.
drugs except for the much greater proportion of impurities in A number of useful or dangerous drugs are inorganic elements,
botanicals; and (3) that all dietary supplements and all therapies eg, lithium, iron, and heavy metals. Many organic drugs are weak
promoted as health-enhancing should meet the same standards of acids or bases. This fact has important implications for the way
efficacy and safety as conventional drugs and medical therapies. they are handled by the body, because pH differences in the vari-
That is, there should be no artificial separation between scientific ous compartments of the body may alter the degree of ionization
medicine and “alternative” or “complementary” medicine. Ideally, of weak acids and bases (see text that follows).
all nutritional and botanical substances should be tested by the
same types of randomized controlled trials (RCTs) as synthetic Drug Size
compounds.
The molecular size of drugs varies from very small (lithium ion,
molecular weight [MW] 7) to very large (eg, alteplase [t-PA], a
protein of MW 59,050). However, most drugs have molecular
■■ I GENERAL PRINCIPLES OF weights between 100 and 1000. The lower limit of this narrow
PHARMACOLOGY range is probably set by the requirements for specificity of action.
To have a good “fit” to only one type of receptor, a drug molecule
THE NATURE OF DRUGS must be sufficiently unique in shape, charge, and other properties
to prevent its binding to other receptors. To achieve such selective
In the most general sense, a drug may be defined as any sub- binding, it appears that a molecule should in most cases be at least
stance that brings about a change in biologic function through 100 MW units in size. The upper limit in molecular weight is
its chemical actions. In most cases, the drug molecule interacts determined primarily by the requirement that drugs must be able
as an agonist (activator) or antagonist (inhibitor) with a specific to move within the body (eg, from the site of administration to
target molecule that plays a regulatory role in the biologic system. the site of action). Drugs much larger than MW 1000 do not dif-
This target molecule is called a receptor. The nature of recep- fuse readily between compartments of the body (see Permeation,
tors is discussed more fully in Chapter 2. In a very small number in following text). Therefore, very large drugs (usually proteins)
of cases, drugs known as chemical antagonists may interact must often be administered directly into the compartment where
directly with other drugs, whereas a few drugs (osmotic agents) they have their effect. In the case of alteplase, a clot-dissolving
interact almost exclusively with water molecules. Drugs may be enzyme, the drug is administered directly into the vascular
synthesized within the body (eg, hormones) or may be chemicals compartment by intravenous or intra-arterial infusion.
not synthesized in the body (ie, xenobiotics). Poisons are drugs
that have almost exclusively harmful effects. However, Paracelsus Drug Reactivity & Drug-Receptor Bonds
(1493–1541) famously stated that “the dose makes the poison,”
Drugs interact with receptors by means of chemical forces or
meaning that any substance can be harmful if taken in the wrong
bonds. These are of three major types: covalent, electrostatic, and
dosage. Toxins are usually defined as poisons of biologic origin, ie,
hydrophobic. Covalent bonds are very strong and in many cases
synthesized by plants or animals, in contrast to inorganic poisons
not reversible under biologic conditions. Thus, the covalent bond
such as lead and arsenic.
formed between the acetyl group of acetylsalicylic acid (aspirin)
and cyclooxygenase, its enzyme target in platelets, is not readily
The Physical Nature of Drugs broken. The platelet aggregation–blocking effect of aspirin lasts
To interact chemically with its receptor, a drug molecule must long after free acetylsalicylic acid has disappeared from the blood-
have the appropriate size, electrical charge, shape, and atomic stream (about 15 minutes) and is reversed only by the synthesis
composition. Furthermore, a drug is often administered at a of new enzyme in new platelets, a process that takes several days.
Other examples of highly reactive, covalent bond-forming drugs TABLE 1–1 Dissociation constants (Kd) of the
include the DNA-alkylating agents used in cancer chemotherapy enantiomers and racemate of carvedilol.
to disrupt cell division in the tumor.
Electrostatic bonding is much more common than covalent ` Receptors a Receptors
Form of Carvedilol (Kd, nmol/L1) (Kd, nmol/L)
bonding in drug-receptor interactions. Electrostatic bonds vary
from relatively strong linkages between permanently charged R(+) enantiomer 14 45
ionic molecules to weaker hydrogen bonds and very weak induced S(−) enantiomer 16 0.4
dipole interactions such as van der Waals forces and similar R,S(±) enantiomers 11 0.9
phenomena. Electrostatic bonds are weaker than covalent bonds. 1
The Kd is the concentration for 50% saturation of the receptors and is inversely
Hydrophobic bonds are usually quite weak and are probably proportionate to the affinity of the drug for the receptors.
important in the interactions of highly lipid-soluble drugs with Data from Ruffolo RR et al: The pharmacology of carvedilol. Eur J Clin Pharmacol
the lipids of cell membranes and perhaps in the interaction of 1990;38:S82.
drugs with the internal walls of receptor “pockets.”
The specific nature of a particular drug-receptor bond is of less Finally, because enzymes are usually stereoselective, one drug
practical importance than the fact that drugs that bind through enantiomer is often more susceptible than the other to drug-
weak bonds to their receptors are generally more selective than metabolizing enzymes. As a result, the duration of action of one
drugs that bind by means of very strong bonds. This is because enantiomer may be quite different from that of the other. Simi-
weak bonds require a very precise fit of the drug to its receptor larly, drug transporters may be stereoselective.
if an interaction is to occur. Only a few receptor types are likely Unfortunately, most studies of clinical efficacy and drug elimina-
to provide such a precise fit for a particular drug structure. Thus, tion in humans have been carried out with racemic mixtures of drugs
if we wished to design a highly selective short-acting drug for a rather than with the separate enantiomers. At present, only a small
particular receptor, we would avoid highly reactive molecules that percentage of the chiral drugs used clinically are marketed as the
form covalent bonds and instead choose a molecule that forms active isomer—the rest are available only as racemic mixtures. As a
weaker bonds. result, most patients receive drug doses of which 50% is less active or
A few substances that are almost completely inert in the inactive. Some drugs are currently available in both the racemic and
chemical sense nevertheless have significant pharmacologic the pure, active isomer forms. However, proof that administration of
effects. For example, xenon, an “inert” gas, has anesthetic effects the pure, active enantiomer decreases adverse effects relative to those
at elevated pressures. produced by racemic formulations has not been established.
Drug Shape Rational Drug Design

The shape of a drug molecule must be such as to permit binding to Rational design of drugs implies the ability to predict the appro-
its receptor site via the bonds just described. Optimally, the drug’s priate molecular structure of a drug on the basis of information
shape is complementary to that of the receptor site in the same way about its biologic receptor. Until recently, no receptor was known
that a key is complementary to a lock. Furthermore, the phenom- in sufficient detail to permit such drug design. Instead, drugs
enon of chirality (stereoisomerism) is so common in biology that were developed through random testing of chemicals or modifica-
more than half of all useful drugs are chiral molecules; that is, they tion of drugs already known to have some effect. However, the
can exist as enantiomeric pairs. Drugs with two asymmetric centers characterization of many receptors during the past three decades
have four diastereomers, eg, ephedrine, a sympathomimetic drug. has changed this picture. A few drugs now in use were developed
through molecular design based on knowledge of the three-
In most cases, one of these enantiomers is much more potent than
dimensional structure of the receptor site. Computer programs
its mirror image enantiomer, reflecting a better fit to the receptor
are now available that can iteratively optimize drug structures
molecule. If one imagines the receptor site to be like a glove into
to fit known receptors. As more becomes known about receptor
which the drug molecule must fit to bring about its effect, it is
structure, rational drug design will become more common.
clear why a “left-oriented” drug is more effective in binding to a
left-hand receptor than its “right-oriented” enantiomer.
The more active enantiomer at one type of receptor site may Receptor Nomenclature
not be more active at another receptor type, eg, a type that may be The spectacular success of newer, more efficient ways to identify
responsible for some other effect. For example, carvedilol, a drug and characterize receptors (see Chapter 2) has resulted in a variety
that interacts with adrenoceptors, has a single chiral center and of differing, and sometimes confusing, systems for naming them.
thus two enantiomers (Table 1–1). One of these enantiomers, the This in turn has led to a number of suggestions regarding more
(S)(–) isomer, is a potent β-receptor blocker. The (R)(+) isomer rational methods of naming receptors. The interested reader is
is 100-fold weaker at the β receptor. However, the isomers are referred for details to the efforts of the International Union of
approximately equipotent as α-receptor blockers. Ketamine is an Pharmacology (IUPHAR) Committee on Receptor Nomenclature
intravenous anesthetic. The (+) enantiomer is a more potent anes- and Drug Classification (reported in various issues of Pharma-
thetic and is less toxic than the (–) enantiomer. Unfortunately, the cological Reviews and elsewhere) and to Alexander SP et al: The
drug is still used as the racemic mixture. Concise Guide to PHARMACOLOGY 2015/16: Overview.
Br J Pharmacol 2015;172:5729. The chapters in this book mainly inactive state (or some state other than the acetylcholine-activated
use these sources for naming receptors. state). These agents reduce the effects of acetylcholine and similar
molecules in the body (Figure 1–2B), but their action can be over-
come by increasing the dosage of agonist. Some antagonists bind
DRUG-BODY INTERACTIONS very tightly to the receptor site in an irreversible or pseudoirre-
versible fashion and cannot be displaced by increasing the agonist
The interactions between a drug and the body are conveniently concentration. Drugs that bind to the same receptor molecule but
divided into two classes. The actions of the drug on the body are do not prevent binding of the agonist are said to act allosterically
termed pharmacodynamic processes (Figure 1–1); the principles and may enhance (Figure 1–2C) or inhibit (Figure 1–2D) the
of pharmacodynamics are presented in greater detail in Chapter 2. action of the agonist molecule. Allosteric inhibition is not usually
These properties determine the group in which the drug is classi- overcome by increasing the dose of agonist.
fied, and they play the major role in deciding whether that group is
appropriate therapy for a particular symptom or disease. The actions B. Agonists That Inhibit Their Binding Molecules
of the body on the drug are called pharmacokinetic processes and Some drugs mimic agonist drugs by inhibiting the molecules
are described in Chapters 3 and 4. Pharmacokinetic processes gov- responsible for terminating the action of an endogenous ago-
ern the absorption, distribution, and elimination of drugs and are nist. For example, acetylcholinesterase inhibitors, by slowing the
of great practical importance in the choice and administration of a destruction of endogenous acetylcholine, cause cholinomimetic
particular drug for a particular patient, eg, a patient with impaired effects that closely resemble the actions of cholinoceptor agonist
renal function. The following paragraphs provide a brief introduc- molecules even though cholinesterase inhibitors do not bind or
tion to pharmacodynamics and pharmacokinetics. only incidentally bind to cholinoceptors (see Chapter 7). Because
they amplify the effects of physiologically released agonist ligands,
Pharmacodynamic Principles their effects are sometimes more selective and less toxic than those
of exogenous agonists.
Most drugs must bind to a receptor to bring about an effect.
However, at the cellular level, drug binding is only the first in a C. Agonists, Partial Agonists, and Inverse Agonists
sequence of steps:
Figure 1–3 describes a useful model of drug-receptor interaction.
• Drug (D) + receptor-effector (R) → drug-receptor-effector As indicated, the receptor is postulated to exist in the inactive,
complex → effect nonfunctional form (Ri) and in the activated form (Ra). Ther-
• D + R → drug-receptor complex → effector molecule → effect modynamic considerations indicate that even in the absence of
• D + R → D-R complex → activation of coupling molecule → any agonist, some of the receptor pool must exist in the Ra form
effector molecule → effect some of the time and may produce the same physiologic effect
as agonist-induced activity. This effect, occurring in the absence
• Inhibition of metabolism of endogenous activator → increased
of agonist, is termed constitutive activity. Agonists have a much
activator action on an effector molecule → increased effect
higher affinity for the Ra configuration and stabilize it, so that a
Note that the final change in function is accomplished by an large percentage of the total pool resides in the Ra–D fraction and
effector mechanism. The effector may be part of the receptor a large effect is produced. The recognition of constitutive activity
molecule or may be a separate molecule. A very large number may depend on the receptor density, the concentration of cou-
of receptors communicate with their effectors through coupling pling molecules (if a coupled system), and the number of effectors
molecules, as described in Chapter 2. in the system.
Many agonist drugs, when administered at concentrations
A. Types of Drug-Receptor Interactions sufficient to saturate the receptor pool, can activate their receptor-
Agonist drugs bind to and activate the receptor in some fashion, effector systems to the maximum extent of which the system is
which directly or indirectly brings about the effect (Figure 1–2A). capable; that is, they cause a shift of almost all of the receptor pool
Receptor activation involves a change in conformation in the to the Ra–D pool. Such drugs are termed full agonists. Other
cases that have been studied at the molecular structure level. Some drugs, called partial agonists, bind to the same receptors and acti-
receptors incorporate effector machinery in the same molecule, so vate them in the same way but do not evoke as great a response, no
that drug binding brings about the effect directly, eg, opening of matter how high the concentration. In the model in Figure 1–3,
an ion channel or activation of enzyme activity. Other receptors partial agonists do not stabilize the Ra configuration as fully as
are linked through one or more intervening coupling molecules full agonists, so that a significant fraction of receptors exists in
to a separate effector molecule. The major types of drug-receptor- the Ri–D pool. Such drugs are said to have low intrinsic efficacy.
effector coupling systems are discussed in Chapter 2. Pharmaco- Because they occupy the receptor, partial agonists can also prevent
logic antagonist drugs, by binding to a receptor, compete with access by full agonists. Thus, pindolol, a β-adrenoceptor partial
and prevent binding by other molecules. For example, acetylcho- agonist, may act either as an agonist (if no full agonist is present)
line receptor blockers such as atropine are antagonists because or as an antagonist (if a full agonist such as epinephrine is pres-
they prevent access of acetylcholine and similar agonist drugs to ent). (See Chapter 2.) Intrinsic efficacy is independent of affinity
the acetylcholine receptor site and they stabilize the receptor in its (as usually measured) for the receptor.
Drug Receptor Effects
Agonist +
A+C A alone
Response
–
A+B
B
A+D
Log Dose
Competitive
inhibitor
Allosteric
activator
Allosteric inhibitor
FIGURE 1–2 Drugs may interact with receptors in several ways. The effects resulting from these interactions are diagrammed in the
dose-response curves at the right. Drugs that alter the agonist (A) response may activate the agonist binding site, compete with the agonist
(competitive inhibitors, B), or act at separate (allosteric) sites, increasing (C) or decreasing (D) the response to the agonist. Allosteric activators
(C) may increase the efficacy of the agonist or its binding affinity. The curve shown reflects an increase in efficacy; an increase in affinity would
result in a leftward shift of the curve.
In the same model, conventional antagonist action can be as benzodiazepines also facilitate the receptor-effector system and
explained as fixing the fractions of drug-bound Ri and Ra in cause GABA-like inhibition with sedation as the therapeutic result.
the same relative amounts as in the absence of any drug. In this This sedation can be reversed by conventional neutral antagonists
situation, no change in activity will be observed, so the drug will such as flumazenil. Inverse agonists of this receptor system cause
appear to be without effect. However, the presence of the antago- anxiety and agitation, the inverse of sedation (see Chapter 22).
nist at the receptor site will block access of agonists to the receptor Similar inverse agonists have been found for β adrenoceptors,
and prevent the usual agonist effect. Such blocking action can be histamine H1 and H2 receptors, and several other receptor systems.
termed neutral antagonism.
What will happen if a drug has a much stronger affinity for the D. Duration of Drug Action
Ri than for the Ra state and stabilizes a large fraction in the Ri–D Termination of drug action can result from several processes. In
pool? In this scenario the drug will reduce any constitutive activity, some cases, the effect lasts only as long as the drug occupies the
thus resulting in effects that are the opposite of the effects produced receptor, and dissociation of drug from the receptor automatically
by conventional agonists at that receptor. Such drugs are termed terminates the effect. In many cases, however, the action may
inverse agonists (Figure 1–3). One of the best documented exam- persist after the drug has dissociated because, for example, some
ples of such a system is the γ-aminobutyric acid (GABAA) receptor- coupling molecule is still present in activated form. In the case
effector (a chloride channel) in the nervous system. This receptor is of drugs that bind covalently to the receptor site, the effect may
activated by the endogenous transmitter GABA and causes inhibi- persist until the drug-receptor complex is destroyed and new recep-
tion of postsynaptic cells. Conventional exogenous agonists such tors or enzymes are synthesized, as described previously for aspirin.
these endogenous molecules are regulatory molecules. Binding of a

Effect drug to a nonregulatory molecule such as plasma albumin will result
Ri Ra in no detectable change in the function of the biologic system, so
this endogenous molecule can be called an inert binding site. Such
D D binding is not completely without significance, however, because it
affects the distribution of drug within the body and determines the
amount of free drug in the circulation. Both of these factors are of
Ri – D Ra – D pharmacokinetic importance (see also Chapter 3).
Effect
Pharmacokinetic Principles
In practical therapeutics, a drug should be able to reach its intended
Ra + Da site of action after administration by some convenient route. In many
Full agonist cases, the active drug molecule is sufficiently lipid-soluble and stable
to be given as such. In some cases, however, an inactive precursor
chemical that is readily absorbed and distributed must be adminis-
Response
Ra + Dpa tered and then converted to the active drug by biologic processes—
Partial agonist inside the body. Such a precursor chemical is called a prodrug.
Ra + Ri In only a few situations is it possible to apply a drug directly to its
Ra + Dant + Ri + Dant
Antagonist
target tissue, eg, by topical application of an anti-inflammatory agent
Constitutive
activity to inflamed skin or mucous membrane. Most often, a drug is admin-
Ri + Di
Inverse agonist istered into one body compartment, eg, the gut, and must move to
Log Dose its site of action in another compartment, eg, the brain in the case of
an antiseizure medication. This requires that the drug be absorbed
into the blood from its site of administration and distributed to its
FIGURE 1–3 A model of drug-receptor interaction. The
hypothetical receptor is able to assume two conformations. In the
site of action, permeating through the various barriers that separate
Ri conformation, it is inactive and produces no effect, even when these compartments. For a drug given orally to produce an effect
combined with a drug molecule. In the Ra conformation, the receptor in the central nervous system, these barriers include the tissues that
can activate downstream mechanisms that produce a small observ- make up the wall of the intestine, the walls of the capillaries that per-
able effect, even in the absence of drug (constitutive activity). In the fuse the gut, and the blood-brain barrier, the walls of the capillaries
absence of drugs, the two isoforms are in equilibrium, and the Ri that perfuse the brain. Finally, after bringing about its effect, a drug
form is favored. Conventional full agonist drugs have a much higher should be eliminated at a reasonable rate by metabolic inactivation,
affinity for the Ra conformation, and mass action thus favors the by excretion from the body, or by a combination of these processes.
formation of the Ra–D complex with a much larger observed effect.
Partial agonists have an intermediate affinity for both Ri and Ra forms.
A. Permeation
Conventional antagonists, according to this hypothesis, have equal
affinity for both receptor forms and maintain the same level of Drug permeation proceeds by several mechanisms. Passive dif-
constitutive activity. Inverse agonists, on the other hand, have a fusion in an aqueous or lipid medium is common, but active
much higher affinity for the Ri form, reduce constitutive activity, and processes play a role in the movement of many drugs, especially
may produce a contrasting physiologic result. those whose molecules are too large to diffuse readily (Figure 1–4).
Drug vehicles can be very important in facilitating transport and
permeation, eg, by encapsulating the active agent in liposomes
In addition, many receptor-effector systems incorporate desen- and in regulating release, as in slow release preparations. Newer
sitization mechanisms for preventing excessive activation when methods of facilitating transport of drugs by coupling them to
agonist molecules continue to be present for long periods. (See nanoparticles are under investigation.
Chapter 2 for additional details.)
1. Aqueous diffusion—Aqueous diffusion occurs within the
E. Receptors and Inert Binding Sites larger aqueous compartments of the body (interstitial space, cyto-
To function as a receptor, an endogenous molecule must first be sol, etc) and across epithelial membrane tight junctions and the
selective in choosing ligands (drug molecules) to bind; and second, endothelial lining of blood vessels through aqueous pores that—in
it must change its function upon binding in such a way that the some tissues—permit the passage of molecules as large as MW
function of the biologic system (cell, tissue, etc) is altered. The 20,000–30,000.* See Figure 1–4A.
selectivity characteristic is required to avoid constant activation of
*
the receptor by promiscuous binding of many different ligands. The capillaries of the brain, the testes, and some other tissues are
The ability to change function is clearly necessary if the ligand is characterized by the absence of pores that permit aqueous diffusion.
They may also contain high concentrations of drug export pumps
to cause a pharmacologic effect. The body contains a vast array of (MDR pumps; see text). These tissues are therefore protected or
molecules that are capable of binding drugs, however, and not all of “sanctuary” sites from many circulating drugs.
Lumen
Interstitium
A B C D
FIGURE 1–4 Mechanisms of drug permeation. Drugs may diffuse passively through aqueous channels in the intercellular junctions (eg,
tight junctions, A), or through lipid cell membranes (B). Drugs with the appropriate characteristics may be transported by carriers into or out of
cells (C). Very impermeant drugs may also bind to cell surface receptors (dark binding sites), be engulfed by the cell membrane (endocytosis),
and then be released inside the cell or expelled via the membrane-limited vesicles out of the cell into the extracellular space (exocytosis, D).
Aqueous diffusion of drug molecules is usually driven by the too insoluble in lipid to diffuse passively through membranes, eg,
concentration gradient of the permeating drug, a downhill move- peptides, amino acids, and glucose. These carriers bring about
ment described by Fick’s law (see below). Drug molecules that are movement by active transport or facilitated diffusion and, unlike
bound to large plasma proteins (eg, albumin) do not permeate passive diffusion, are selective, saturable, and inhibitable. Because
most vascular aqueous pores. If the drug is charged, its flux is also many drugs are or resemble such naturally occurring peptides,
influenced by electrical fields (eg, the membrane potential and— amino acids, or sugars, they can use these carriers to cross mem-
in parts of the nephron—the transtubular potential). branes. See Figure 1–4C.
Many cells also contain less selective membrane carriers that
2. Lipid diffusion—Lipid diffusion is the most important are specialized for expelling foreign molecules. One large family
limiting factor for drug permeation because of the large number of such transporters binds adenosine triphosphate (ATP) and
of lipid barriers that separate the compartments of the body. is called the ABC (ATP-binding cassette) family. This family
Because these lipid barriers separate aqueous compartments, the includes the P-glycoprotein or multidrug resistance type 1
lipid:aqueous partition coefficient of a drug determines how (MDR1) transporter found in the brain, testes, and other tis-
readily the molecule moves between aqueous and lipid media. In sues, and in some drug-resistant neoplastic cells (Table 1–2).
the case of weak acids and weak bases (which gain or lose electri- Similar transport molecules from the ABC family, the multidrug
cal charge-bearing protons, depending on the pH), the ability to resistance-associated protein (MRP) transporters, play impor-
move from aqueous to lipid or vice versa varies with the pH of the tant roles in the excretion of some drugs or their metabolites
medium, because charged molecules attract water molecules. The into urine and bile and in the resistance of some tumors to
ratio of lipid-soluble form to water-soluble form for a weak acid chemotherapeutic drugs. Several other transporter families have
or weak base is expressed by the Henderson-Hasselbalch equation been identified that do not bind ATP but use ion gradients to
(described in the following text). See Figure 1–4B. drive transport. Some of these (the solute carrier [SLC] family)
are particularly important in the uptake of neurotransmitters
3. Special carriers—Special carrier molecules exist for many across nerve-ending membranes. The latter carriers are discussed
substances that are important for cell function and too large or in more detail in Chapter 6.
TABLE 1–2 Some transport molecules important in pharmacology.

Transporter Physiologic Function Pharmacologic Significance
NET Norepinephrine reuptake from synapse Target of cocaine and some tricyclic antidepressants
SERT Serotonin reuptake from synapse Target of selective serotonin reuptake inhibitors and some tricyclic
antidepressants
VMAT Transport of dopamine and norepinephrine into Target of reserpine and tetrabenazine
adrenergic vesicles in nerve endings
MDR1 Transport of many xenobiotics out of cells Increased expression confers resistance to certain anticancer drugs;
inhibition increases blood levels of digoxin
MRP1 Leukotriene secretion Confers resistance to certain anticancer and antifungal drugs
MDR1, multidrug resistance protein-1; MRP1, multidrug resistance-associated protein-1; NET, norepinephrine transporter; SERT, serotonin reuptake transporter; VMAT, vesicular
monoamine transporter.
4. Endocytosis and exocytosis—A few substances are so large For example, pyrimethamine, an antimalarial drug, undergoes the
or impermeant that they can enter cells only by endocytosis, the following association-dissociation process:
process by which the substance is bound at a cell-surface recep-
tor, engulfed by the cell membrane, and carried into the cell by
pinching off of the newly formed vesicle inside the membrane.
The substance can then be released into the cytosol by breakdown
of the vesicle membrane, Figure 1–4D. This process is responsible
for the transport of vitamin B12, complexed with a binding protein Note that the protonated form of a weak acid is the neutral,
(intrinsic factor) across the wall of the gut into the blood. Simi- more lipid-soluble form, whereas the unprotonated form of a weak
larly, iron is transported into hemoglobin-synthesizing red blood base is the neutral form. The law of mass action requires that these
cell precursors in association with the protein transferrin. Specific reactions move to the left in an acid environment (low pH, excess
receptors for the binding proteins must be present for this process protons available) and to the right in an alkaline environment. The
to work. Henderson-Hasselbalch equation relates the ratio of protonated to
The reverse process (exocytosis) is responsible for the secretion unprotonated weak acid or weak base to the molecule’s pKa and
of many substances from cells. For example, many neurotransmit- the pH of the medium as follows:
ter substances are stored in membrane-bound vesicles in nerve
endings to protect them from metabolic destruction in the cyto-
plasm. Appropriate activation of the nerve ending causes fusion
of the storage vesicle with the cell membrane and expulsion of its
contents into the extracellular space (see Chapter 6). This equation applies to both acidic and basic drugs. Inspec-
tion confirms that the lower the pH relative to the pKa, the greater
B. Fick’s Law of Diffusion will be the fraction of drug in the protonated form. Because the
The passive flux of molecules down a concentration gradient is uncharged form is the more lipid-soluble, more of a weak acid will
given by Fick’s law: be in the lipid-soluble form at acid pH, whereas more of a basic
drug will be in the lipid-soluble form at alkaline pH.
Application of this principle is made in the manipulation of
drug excretion by the kidney (see Case Study). Almost all drugs
are filtered at the glomerulus. If a drug is in a lipid-soluble form
during its passage down the renal tubule, a significant fraction
where C1 is the higher concentration, C2 is the lower concentra- will be reabsorbed by simple passive diffusion. If the goal is to
tion, area is the cross-sectional area of the diffusion path, permea- accelerate excretion of the drug (eg, in a case of drug overdose),
bility coefficient is a measure of the mobility of the drug molecules it is important to prevent its reabsorption from the tubule.
in the medium of the diffusion path, and thickness is the length of This can often be accomplished by adjusting urine pH to make
the diffusion path. In the case of lipid diffusion, the lipid:aqueous certain that most of the drug is in the ionized state, as shown
partition coefficient is a major determinant of mobility of the in Figure 1–5. As a result of this partitioning effect, the drug
drug because it determines how readily the drug enters the lipid is “trapped” in the urine. Thus, weak acids are usually excreted
membrane from the aqueous medium. faster in alkaline urine; weak bases are usually excreted faster in
acidic urine. Other body fluids in which pH differences from
C. Ionization of Weak Acids and Weak Bases; the blood pH may cause trapping or reabsorption are the contents of
Henderson-Hasselbalch Equation the stomach (normal pH 1.9–3) and small intestine (pH 7.5–8),
breast milk (pH 6.4–7.6), aqueous humor (pH 6.4–7.5), and
The electrostatic charge of an ionized molecule attracts water dipoles
vaginal and prostatic secretions (pH 3.5–7).
and results in a polar, relatively water-soluble and lipid-insoluble
As indicated by Table 1–3, a large number of drugs are weak
complex. Because lipid diffusion depends on relatively high lipid
bases. Most of these bases are amine-containing molecules. The
solubility, ionization of drugs may markedly reduce their ability to
nitrogen of a neutral amine has three atoms associated with it
permeate membranes. A very large percentage of the drugs in use are
plus a pair of unshared electrons (see the display that follows).
weak acids or weak bases; Table 1–3 lists some examples. For drugs,
The three atoms may consist of one carbon or a chain of carbon
a weak acid is best defined as a neutral molecule that can reversibly
atoms (designated “R”) and two hydrogens (a primary amine),
dissociate into an anion (a negatively charged molecule) and a proton
two carbons and one hydrogen (a secondary amine), or three
(a hydrogen ion). For example, aspirin dissociates as follows:
carbon atoms (a tertiary amine). Each of these three forms
may reversibly bind a proton with the unshared electrons. Some
drugs have a fourth carbon-nitrogen bond; these are quaternary
amines. However, the quaternary amine is permanently charged
and has no unshared electrons with which to reversibly bind a
A weak base can be defined as a neutral molecule that can form a proton. Therefore, primary, secondary, and tertiary amines may
cation (a positively charged molecule) by combining with a proton. undergo reversible protonation and vary their lipid solubility with
TABLE 1–3 Ionization constants of some common drugs.

1 1 1
Drug pKa Drug pKa Drug pKa
Weak acids Weak bases Weak bases (cont’d)

Acetaminophen 9.5 Albuterol (salbutamol) 9.3 Isoproterenol 8.6
2
Acetazolamide 7.2 Allopurinol 9.4, 12.3 Lidocaine 7.9
Ampicillin 2.5 Alprenolol 9.6 Metaraminol 8.6
Aspirin 3.5 Amiloride 8.7 Methadone 8.4
Chlorothiazide 6.8, 9.42 Amiodarone 6.6 Methamphetamine 10.0
Chlorpropamide 5.0 Amphetamine 9.8 Methyldopa 10.6
Ciprofloxacin 6.1, 8.72 Atropine 9.7 Metoprolol 9.8
Cromolyn 2.0 Bupivacaine 8.1 Morphine 7.9
Ethacrynic acid 2.5 Chlordiazepoxide 4.6 Nicotine 7.9, 3.12
Furosemide 3.9 Chloroquine 10.8, 8.4 Norepinephrine 8.6
Ibuprofen 4.4, 5.22 Chlorpheniramine 9.2 Pentazocine 7.9
Levodopa 2.3 Chlorpromazine 9.3 Phenylephrine 9.8
Methotrexate 4.8 Clonidine 8.3 Physostigmine 7.9, 1.82
Methyldopa 2.2, 9.22 Cocaine 8.5 Pilocarpine 6.9, 1.42
Penicillamine 1.8 Codeine 8.2 Pindolol 8.6
Pentobarbital 8.1 Cyclizine 8.2 Procainamide 9.2
Phenobarbital 7.4 Desipramine 10.2 Procaine 9.0
Phenytoin 8.3 Diazepam 3.0 Promethazine 9.1
Propylthiouracil 8.3 Diphenhydramine 8.8 Propranolol 9.4
Salicylic acid 3.0 Diphenoxylate 7.1 Pseudoephedrine 9.8
Sulfadiazine 6.5 Ephedrine 9.6 Pyrimethamine 7.0–7.33
Sulfapyridine 8.4 Epinephrine 8.7 Quinidine 8.5, 4.42
Theophylline 8.8 Ergotamine 6.3 Scopolamine 8.1
2
Tolbutamide 5.3 Fluphenazine 8.0, 3.9 Strychnine 8.0, 2.32
Warfarin 5.0 Hydralazine 7.1 Terbutaline 10.1
Imipramine 9.5 Thioridazine 9.5
1
The pKa is that pH at which the concentrations of the ionized and nonionized forms are equal.
2
More than one ionizable group.
3
Isoelectric point.
pH, but quaternary amines are always in the poorly lipid-soluble actions and in their pharmacokinetic properties as well. For most
charged form. groups, one or two prototype drugs can be identified that typify
the most important characteristics of the group. This permits clas-
sification of other important drugs in the group as variants of the
prototype, so that only the prototype must be learned in detail and,
for the remaining drugs, only the differences from the prototype.
■■ II DRUG DEVELOPMENT &

DRUG GROUPS REGULATION
To learn each pertinent fact about each of the many hundreds of A truly new drug (one that does not simply mimic the structure
drugs mentioned in this book would be an impractical goal and, and action of previously available drugs) requires the discovery of
fortunately, is unnecessary. Almost all the several thousand drugs a new drug target, ie, the pathophysiologic process or substrate of a
currently available can be arranged into about 70 groups. Many of disease. Such discoveries are usually made in public sector institu-
the drugs within each group are very similar in pharmacodynamic tions (universities and research institutes), and molecules that have
Cells of the
Interstitium nephron Urine
pH 7.4 pH 6.0
Lipid H
H diffusion
R N H
0.001 mg R N H 0.001 mg
H+ H+
H H
+ +
0.398 mg R N H R N H 10 mg
H H
0.399 mg 10 mg
total total
FIGURE 1–5 Trapping of a weak base (methamphetamine) in the urine when the urine is more acidic than the blood. In the hypothetical
case illustrated, the diffusible uncharged form of the drug has equilibrated across the membrane, but the total concentration (charged plus
uncharged) in the urine (more than 10 mg) is 25 times higher than in the blood (0.4 mg).
beneficial effects on such targets are often discovered in the same NEW DRUG DEVELOPMENT
laboratories. However, the development of new drugs usually takes
place in industrial laboratories because optimization of a class of The development of a new drug usually begins with the discovery
new drugs requires painstaking and expensive chemical, pharmaco- or synthesis of a potential new drug compound or the elucidation
logic, and toxicologic research. In fact, much of the recent progress of a new drug target. After a new drug molecule is synthesized or
in the application of drugs to disease problems can be ascribed to the extracted from a natural source, subsequent steps seek an under-
pharmaceutical industry including “big pharma,” the multibillion- standing of the drug’s interactions with its biologic targets. Repeated
dollar corporations that specialize in drug development and application of this approach leads to synthesis of related compounds
marketing. These companies are uniquely skilled in translating with increased efficacy, potency, and selectivity (Figure 1–6). In the
basic findings into successful therapeutic breakthroughs and United States, the safety and efficacy of drugs must be established
profit-making “blockbusters” (see http://www.pharmacytimes. before marketing can be legally carried out. In addition to in vitro
com/news/10-best-selling-brand-name-drugs-in-2015/). studies, relevant biologic effects, drug metabolism, pharmacokinetic
Such breakthroughs come at a price, however, and the escalating profiles, and relative safety of the drug must be characterized in vivo
cost of drugs has become a significant contributor to the inflation- in animals before human drug trials can be started. With regulatory
ary increase in the cost of health care. Development of new drugs approval, human testing may then go forward (usually in three
is enormously expensive, but considerable controversy surrounds phases) before the drug is considered for approval for general use. A
drug pricing. Critics claim that the costs of development and mar- fourth phase of data gathering and safety monitoring is becoming
keting are grossly inflated by marketing activities, advertising, and increasingly important and follows after approval for marketing.
other promotional efforts, which may consume as much as 25% or Once approved, the great majority of drugs become available for
more of a company’s budget. Furthermore, profit margins for big use by any appropriately licensed practitioner. Highly toxic drugs
pharma are relatively high. Recent drug-pricing scandals have been that are nevertheless considered valuable in lethal diseases may be
reported in which the right to an older, established drug has been approved for restricted use by practitioners who have undergone
purchased by a smaller company and the price increased by several special training in their use and who maintain detailed records.
hundred or several thousand percent. This “price gouging” has
caused public outrage and attracted regulatory attention that may
result in more legitimate and rational pricing mechanisms. Finally, DRUG DISCOVERY
pricing schedules for many drugs vary dramatically from country
to country and even within countries, where large organizations Most new drugs or drug products are discovered or developed
can negotiate favorable prices and small ones cannot. Some coun- through the following approaches: (1) screening for biologic activity
tries have already addressed these inequities, and it seems likely that of large numbers of natural products, banks of previously discovered
all countries will have to do so during the next few decades. chemical entities, or large libraries of peptides, nucleic acids, and
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spekulierender Neffen, sind eine Plage seiner alten Tage.
Neuerdings hat er eine Tochter aus Fayyāds Haus, ein
fünfzehnjähriges Mädchen, geheiratet, aber sie hat ihm kein Kind
geboren. Übrigens kursiert in Damaskus eine hübsche Geschichte
von ihm, auf die jedoch in seinem Beisein nicht angespielt wird.
Beim Ausbruch des letzten Drusenkrieges wurde Djerūdi, der
zufälligerweise gerade mit der Regierung auf gutem Fuße stand und
sich im Gebirge wohl auskannte, mit 30 oder 40 Mann ausgeschickt,
um zu rekognoszieren und Bericht zu erstatten. Das Heer folgte ihm
auf dem Fuße. Als er durch ein Dörfchen nahe bei Ormān zog, lud
ihn der Scheich, sein alter Bekannter, zu Tische. Während er noch
im Mak'ad des Mahles harrte, hörte er die Drusen draußen beraten,
ob es nicht geraten sei, ihn bei dieser Gelegenheit als Beauftragten
der türkischen Armee zu töten. Er wünschte sehnlichst, den Ort zu
verlassen, aber die Regeln des guten Tones forderten, daß er das
Mahl auch verzehrte, welches eben bereitet wurde. Als es endlich
erschien, beförderte er es in größter Hast, denn die Lebhaftigkeit der
Beratung draußen erfüllte ihn mit ernster Besorgnis, bestieg alsdann
sein Pferd und ritt davon, ehe noch die Drusen zu einem Entschluß
gekommen waren. Aber plötzlich befand er sich zwischen zwei
Feuern, denn das türkische Heer war eingetroffen, und das erste
Gefecht war im Gange. Djerūdi und seine Genossen suchten in ihrer
Verwirrung hinter einigen Felsen Schutz, und schließlich schlich sich
einer nach dem andern zu dem türkischen Nachtrab zurück. Die
Drusen haben den Vorfall in einem Liede verewigt; es beginnt:
»Djerūdis goldne Rosse sind berühmt,

und schön die Reiter auf der wirren Flucht!
Mohammed Pascha, sage deinem Herrn,
wo sind die Mannen, wo die Waffen?«
Das Lied wird nicht oft vor ihm gesungen.

Tekyah des Nakschibendi.
Mein nächster Gast war Scheich Hassan Nakschibendi, der mit

dem glatten und schlauen Frömmlergesicht. Er wußte sogar die
zehn Minuten gut auszunützen, die er im Gastzimmer des
Wirtshauses verbrachte. Denn als er einen prunkvollen Ring an
Sēlim Begs Finger erspähte, wünschte er ihn zu sehen und fand so
großen Gefallen daran, daß er ihn in die Tasche steckte und
bemerkte, Sēlim würde gewiß gern seiner khānum (jüngsten Frau),
die er vor ein oder zwei Jahren geheiratet, ein Geschenk damit
machen. Sēlim schlug darauf vor, sofort nach seinem Hause in
Salahijjeh zu fahren, um das Präsent zu überbringen, und da
Scheich Hassan und Mohammed Pascha ihre Landauer an der Tür
hatten, stiegen wir ein und fuhren durch die freundlichen, festtägigen
Straßen nach Salahijjeh. Vor der Tür des Hauses meinte Sēlim, ich
möchte mich erst vom Vāli, der ganz nahe wohnte, verabschieden,
und er borgte Djerūdis Wagen, »des Pompes halber«. Dann sagte
Sēlim zu Mohammed Pascha:
»Ihr kommt nicht mit uns?« Eine sarkastische Frage, denn er
wußte gar wohl, daß Djerūdi gerade in Ungnade und eben erst aus
wohlverdienter Haft entlassen worden war.
Djerūdi schüttelte den Kopf, kam dann ganz nahe heran an uns,
die wir im Landauer saßen, und flüsterte:
»Sagt etwas zu meinem Gunsten beim Pascha!«
Wir versprachen das lachend. Im Fortfahren vertraute mir Sēlim
an, daß auch kein einziger Mann zu ihm selbst gehalten hätte, als er
in Ungnade war (»nur Intrigen meiner Feinde waren daran schuld«),
kein einziger hätte ihm helfen wollen; jetzt aber, wo er in Gunst
stand, würde er von allen Seiten um seine Vermittlung gebeten. Und,
die Rockschöße um sich breitend, lehnte er sich in stolzem
Selbstbewußtsein in Djerūdis Wagen zurück.
Nāzim Pascha stand auf der Türschwelle und verabschiedete
sich eben vom Oberbefehlshaber. Er stieg die Stufen herunter und
lud uns mit der größten Freundlichkeit in sein Haus. Und dieser
zweite Besuch bei ihm (er hatte mich inzwischen aufgesucht) war
weit weniger förmlich als der erste. Wir unterhielten uns über den
Krieg in Japan, ein Stoff, der meinen jungen und alten Partnern im
Gespräch überhaupt nie fern lag, und ich erkühnte mich, ihn um
seine Ansicht zu befragen.
»Offiziell bin ich neutral,« lautete die Antwort.
»Aber unter Freunden?«
»Natürlich bin ich auf Seiten der Japaner. Die Engländer haben
durch ihren Sieg gewonnen,« fügte er noch hinzu.
Worauf ich: »Und werden Sie nicht auch gewinnen?«
»Bis jetzt haben wir noch nicht gewonnen,« erwiderte er düster,
»in Mazedonien noch gar nicht.«
Dann erkundigte er sich, wie mir mein Aufenthalt in Damaskus
gefallen hätte. Da fuhr Sēlim hastig dazwischen:
»Heute hat sie eine große Enttäuschung erfahren.«
Der Vāli sah betroffen drein.
»Ja,« fuhr Sēlim fort, »sie hoffte einen Räuberhauptmann zu
sehen und fand nur einen friedlichen Untertan, Ew. Exzellenz.«
»Und der wäre?« forschte Nāzim.
»Mohammed Pascha Djerūdi,« sagte Sēlim. Damit war das gute
Wort sehr geschickt angebracht.
Vor den Toren von Damaskus.
In Scheich Hassans Haus zurückgekehrt, teilten wir diesen Teil

der Unterhaltung dem Gegenstand derselben mit. Djerūdi zog ein
schiefes Gesicht, erklärte sich aber zufrieden. Dann führte mich
Hassan zu seiner Frau — seiner fünften, die er geheiratet hatte,
nachdem er sich von seiner gesetzmäßigen vierten hatte scheiden
lassen. Er ist so diskret, jeder einzelnen ihren besonderen
Hausstand zu halten, und ohne Frage wird ihm dafür auch durch
Frieden in seinen Häuslichkeiten gelohnt. Drei Frauen befanden sich
im inneren Gemach, außer der Gattin noch eine andre, die offenbar
nicht zum Haushalt gehörte, denn bei Scheich Hassans Eintritt
verbarg sie das Gesicht in den Betten, und eine Christin, die sich um
die Bedürfnisse der männlichen Gäste verdient machte (außer
Djerūdi und Sēlim waren noch andre anwesend), und die in den
Bazaren, wo sie sich freier bewegen kann als ihre
mohammedanischen Schwestern, die Einkäufe besorgt. Im Harem
sah es entsetzlich wüst aus. Wofern die Frauen nicht Besuch
erwarten und darauf vorbereitet haben, herrscht in der Tat überall
eine unvergleichliche Unordnung. Es läßt sich dieselbe teilweise
dadurch erklären, daß weder Schubladen noch Schränke vorhanden
sind, und alle Habseligkeiten in großen grünen oder vergoldeten
Kästen aufbewahrt werden, die man auspacken muß, so oft auch
nur ein Taschentuch gebraucht wird, und die häufig auch ausgepackt
bleiben. Scheich Hassans Frau war jung und hübsch; freilich hing ihr
das Haar in Strähnen um Gesicht und Hals, und ein schmutziger
Morgenrock umkleidete eine Gestalt, die leider schon verfallen war.
Die Aussicht von Nakschibendis Balkon ist mir unvergeßlich. Zu
unsern Füßen die große, prächtige Stadt Damaskus mit ihren
Gärten, Kuppeln und Minarets, und weiterhin die Wüste, die fast bis
an ihre Tore heranreicht. Und das ist der Kernpunkt der ganzen
Sache.
Dies meine Erlebnisse in Damaskus. Was die Kirchen und
Kastells betrifft, diese können die Herrschaften selbst sehen.
Wasserverkäufer.
Achtes Kapitel.
Als ich dem Vāli (Generalgouverneur) auf seine Fragen, wohin
ich von Damaskus aus zu reisen gedächte, Ba'albek als Ziel nannte,
äußerte er die Absicht, eine Schar Bewaffneter zum Schutze einer
so vornehmen Dame mitzuschicken. Um dieses Thema
abzubrechen, erwiderte ich kurzerhand, ich würde die Bahn
benutzen. Da ich aber im Ernste nicht die geringste Lust zu diesem
Beförderungsmittel verspürte, blieb mir, wollte ich allein reisen, nur
ein möglichst früher Aufbruch übrig. Es war ein freundlicher,
sonniger Morgen, als wir durch die bereits von einer Schar fröhlicher
Menschen belebten Straßen ritten; unsre Pferde zerrten ungeduldig
am Zaumzeug nach ihrer achttägigen Ruhe. An Amīr Omars Haus in
der Wādi Barada vorüberkommend, erblickten wir diesen Herrn in
der Morgensonne auf seinem Dach sich gütlich tun. Er rief mir zu,
doch heraufzukommen, aber ich erklärte, daß Geschäfte vorlägen,
und er mich ziehen lassen müßte.
»So zieht in Frieden!« gab er zurück, »so Gott will, reiten wir
eines Tages zusammen.«
»So Gott will!« sagte ich und »Gott mit euch!«
Als sich nach ein oder zwei Meilen der Weg teilte, schlug ich die
direkte Richtung nach dem Antilibanon ein, denn mir lag daran, der
Aufmerksamkeit behördlicher Personen zu entgehen, die
angewiesen worden waren, mir ihre Achtung zu bezeigen. Wir
kamen durch das schöne, mit Aprikosenbäumen bestandene Tal der
Barada (noch war die Zeit der Blüte nicht gekommen), kreuzten den
Fluß oberhalb der prächtigen Schlucht Barada, und ritten über eine
zwischen schneebedeckten Bergen liegende Ebene nach dem durch
seine Äpfel berühmten Zebdāny. Hier schlugen wir auf einer grünen
Wiese neben einem Brunnen unser Lager auf; nach Süden zu
begrenzten die schneeigen Flanken des Hermon das Bild, nach
Norden lagen die Dorfhäuser verstreut auf den Hügelwellen; kein
einziger aus Zebdāny bekümmerte sich um die kleinen Zelte. Am
nächsten Tage passierten wir im Sturmgeheul den Antilibanon. Eine
weite Tour war es von 8¼ Meilen, aber reizvoll und unterhaltend. Wir
mußten auf der großen Römerstraße von Damaskus nach Ba'albek
sein; das ganze Tal entlang sah man ab und zu lateinische
Inschriften an den Felswänden. Ganz durchnäßt, denn die letzten
Meilen wurden durch kahle Gegend in strömendem Regen
zurückgelegt, gelangten wir endlich in Ba'albek an. Es war fast zu
stürmisch, um ein Lager auszuschlagen, und doch lehnte sich alles
in mir gegen den Gedanken an ein Hotel auf. Aber Michaïl wußte
Rat. Er kannte eine anständige, christliche Frau, die am Eingang des
Dorfes wohnte, die würde uns sicherlich Obdach geben. Und so
geschah es auch. Die Frau war hocherfreut, uns zu sehen, und
richtete sofort einen sauberen leeren Raum für mein Zeltzubehör
ein, während Michaïl sich mit seinen Kochutensilien in einem
anderen niederließ. Mochte nun der Regen wütend gegen die
Fenster schlagen — wir waren geborgen.
Meine Wirtin, Kurunfuleh, die Nelke, mit Namen, hatte zum
Gatten einen gewissen Jūsef el 'Awais, der gerade in Amerika sein
Glück suchte, wohin sie ihm zu folgen gedachte. Ich verbrachte
einige Stunden in ihrer Gesellschaft; auch ihr Sohn und ihre Tochter
waren da, und ein paar Verwandte, die ihre Lauten mitgebracht
hatten. Man plauderte und musizierte. Wie sie sagten, macht ihnen
die Zukunft viel Sorge, denn die Bevölkerung von Ba'albek und der
Umgegend gehört größtenteils zu den Metāwileh, einer freisinnigen
und wegen ihres Fanatismus und ihrer Unwissenheit berüchtigten
Sekte des Islam. So oft die Japaner siegreich waren, pflegten diese
Leute zu kommen, ballten ihre Fäuste drohend gegen die
Christennachbarn und riefen: »Die Christen sind geschlagen
worden! Hütet euch, wir werden euch auch bald davonjagen und
eure Habe nehmen.« »Und ganz so geht es in Jerusalem her,« fiel
Michaïl ein (ob seine Worte auf Wahrheit beruhten, weiß ich nicht),
»dort haben die Muselmänner dem Mufti durch eine Deputation
sagen lassen: ‚Die Zeit ist für uns gekommen, die Christen zu
verjagen.’ Aber der Mufti versetzte: ‚Wenn ihr Unruhen
heraufbeschwört, werden die europäischen Mächte sich einmischen,
denn Jerusalem ist ihr Augapfel; sie werden das ganze Land
einnehmen, und wir werden schlimmer dran sein als zuvor.’«
Ich suchte Kurunfuleh zu trösten, indem ich sagte, es sei
undenkbar, daß die Christen in Syrien verfolgt werden könnten, da
das Land so wohl bekannt und von Touristen viel besucht sei, die
sicherlich entrüstet sein würden. Der alljährlich wiederkehrende
Strom von Touristen bietet in der Tat eine der besten Garantien für
die Aufrechterhaltung der Ordnung. Aber warum kehrte denn
Kurunfuleh nicht in den Libanon, ihre Heimat, zurück, wo sie unter
dem direkten Schutz der Mächte stand und keine Gefahr zu
befürchten brauchte? Sie antwortete:
Suk Wādi, Barada.
»O meine Dame, das Haus hier ist auf meines Gatten Namen
eingetragen, es darf vor seiner Rückkehr nicht verkauft werden noch
unbewohnt bleiben, und außerdem lebt es sich in der Ebene so ganz
anders, als im Libanon; ich könnte es nicht wieder ertragen, dort zu
wohnen. Dort tun die Leute weiter nichts als ihre Nachbarn
beobachten, und zieht man einen neuen Rock an, so stecken sie die
Köpfe zusammen und spotten: Hast die feine Dame gesehen? Und
lassen Sie sich auch nur sagen, wie man im Libanon lebt: ich esse in
Ba'albek jeden Tag Fleisch, die im Libanon aber nur einmal in der
Woche. Sie teilen eine Zwiebel in drei Teile und würzen drei Abende
hintereinander ihren burghul (geschroteter Weizen) damit; ich aber
werfe Abend für Abend eine ganze Handvoll Zwiebeln in den
Kochtopf. Ja, es geht karg her im Libanon.«
Sie hatte recht. Es geht so karg dort her, daß jeder, der nur
irgendwie das Reisegeld erschwingen kann, nach den Vereinigten
Staaten auswandert, so daß es in den Kulturen von Getreide, Wein
und Maulbeerbäumen entsetzlich an Arbeitskräften mangelt. »Es ist
kein Vorwärtskommen«, wie der Syrer sagt. Die Provinz ist eine
Sackgasse ohne eignen Hafen, ohne Handel. Du brauchst dort nicht
gerade zu verhungern, aber was hast du von einem Leben, das dir
nicht mehr als den dritten Teil einer Zwiebel zum Abendbrot bietet?
Die Hohe Pforte ist den Mächten einmal wieder übergewesen. Sie
hat alles bewilligt, was von ihr gefordert worden ist, o ja, auch mit
Freuden, aber die Zugeständnisse, welche die Türen zum
Wohlstand anscheinend erschlossen, haben in Wirklichkeit den Pfad
denen versperrt, die Nutzen daraus ziehen sollten.
Am nächsten Tage hatte der Regen noch nicht nachgelassen. Ich
empfing den Polizeikommissar, der mich hergeleitet hatte, und
stattete dann in dem meiner Wohnung nahegelegenen Hotel einer
vielköpfigen Portugiesenfamilie einen Besuch ab. Monsieur Luiz de
Sommar war mit Gattin, Töchtern und Neffen über den Djebel Druz
von Jerusalem nach Damaskus gereist. In Salchad hatte ich von
ihrer Ankunft in Sueda gehört und mich gewundert, wie sie sich
Zulaß verschafft haben mochten. Ich hörte eine seltsame
Geschichte, die sehr zugunsten Sommars spricht, gleichzeitig aber
auch dartut, wie ängstlich die Regierung das Bergland vor den
spionierenden Augen der Touristen zu hüten bestrebt ist. Die
Portugiesen hatten Mr. Mark Sykes in 'Ammān getroffen, der ihnen
riet, ihre Tour lieber über Kanawāt im Djebel Druz zu nehmen, da sie
keinerlei Schwierigkeit haben würden, die Erlaubnis dazu zu
erhalten. Monsieur Sommar war denn auch gutes Mutes
vorwärtsmarschiert, aber in Sueda, dem Hauptsitz der Regierung,
angekommen, hatte ihn der Kāimakām angehalten und zwar höflich
aber fest angedeutet, daß er auf demselben Wege, den er
gekommen, wieder zurückreisen müsse. Der Herr verweigerte das in
ebenso bestimmter Weise und sandte Telegramme an seinen Konsul
in Damaskus und seinen Minister in Konstantinopel. Und nun
erfolgte ein erregter Depeschenaustausch mit dem Endergebnis,
daß Monsieur Sommar nach Kanawāt weiterreisen dürfte, falls er
hundert Zaptiehs mitnehmen würde. »Denn«, sagte der Kāimakām,
»das Land ist über die Maßen gefährlich.« (Ein Land, durch welches,
wie ich weiß, eine Frau in der alleinigen Begleitung eines
Drusenjungen, ja, ganz allein reiten kann, selbst wenn ihre
Satteltaschen mit Gold angefüllt sind!) Aber Monsieur de Sommar
war ein kluger Mann. Er erwiderte, daß er die hundert Zaptiehs
schon mitnehmen wolle, aber keinen Piaster würden sie von ihm
bekommen. Man feilschte, der Kāimakām änderte seinen Beschluß
und setzte die Eskorte auf zwanzig fest, unter welchem Schutz die
Sommars glücklich in Kanawāt landeten. Ich beglückwünschte sie zu
diesem Abenteuer und mich selber, die ich meinen Passierschein
von Fellāh ul 'Isa und nicht vom syrischen Vāli erwirkt hatte.
Ba'albek.
Trotz des Regens war der Tag in Ba'albek nicht verloren. Die
Deutschen hatten seit meinem letzten Besuch den Tempel der
Sonne ausgegraben und Altäre, Fontänen, Teile von Dekorationen
sowie Grundmauern von Kirchen bloßgelegt, die von höchstem
Interesse waren. Und außerdem erweckt die große Gruppe von
Tempeln mit den sie umschließenden Mauern, die zwischen dem
Doppelgebirge des Libanon und Antilibanon liegt, einen Eindruck,
der nur von der Tempelgruppe der athenischen Akropolis übertroffen
wird, die ja wirklich ihresgleichen sucht. Die Ausführungen im
einzelnen sind weniger gut als die athenischen. Das unendlich
Würde- und Maßvolle in dieser Krone unter den Schöpfungen der
Architekten kann nicht erreicht werden, wie auch die prachtvolle, das
blaue Meer und den Golf von Salamis beherrschende Lage einzig in
ihrer Art ist. Aber im großen ganzen kommt Ba'albek der Akropolis
näher als irgend ein anderer Gebäudekomplex, und der Gelehrte
findet reichlich Material zu Betrachtungen über die griechisch-
asiatische Kunst, die Ba'albek erbaut und seine Pfosten, Architrave
und Kapitäle mit Ornamenten versehen hat, die ebenso
abwechslungsreiche Entwürfe zeigen, wie sie herrlich ausgeführt
sind. Der Archäologe kennt weder rein noch unrein. Jedes Werk der
menschlichen Phantasie nimmt bei ihm den ihm bestimmten Platz in
der Geschichte der Kunst ein, leitet und erweitert sein eigenes
Verständnis. Befriedigt das Ergebnis sein Auge, so freut er sich, in
jedem Falle aber liefert es ihm ein neues unerwartetes Band
zwischen dieser und jener Kunst und führt ihn eine Stufe weiter
empor auf der Leiter der Geschichte. Das macht ihn fähig, mit allem
zufrieden zu sein, was er sieht, und sicher wird er nicht sagen: »O
weh — o weh! Diese Dummköpfe von Syrern ... Phidias würde das
so und so gemacht haben!« Denn ihm gewährt es Befriedigung,
einen neuen Versuch auf dem Pfade künstlerischen Schaffens zu
entdecken, einen frischen Hauch, der die Akanthusblätter und
Weinranken an den Kapitälen bewegt.
Der große Hof, Ba'albek.
Unsre Abreise von Ba'albek wurde durch ein sehr betrübliches

Vorkommnis gekennzeichnet: mein Hund Kurt war in der Nacht
verschwunden. Im Gegensatz zu den meisten syrischen
Pariahunden offenbarte er ein höchst anschmiegendes Wesen, war
auch (und darin unterschied er sich wiederum nicht von seinen
halbverhungerten Stammesgenossen) unersättlich gefräßig, weshalb
die Wahrscheinlichkeit nahelag, daß er mit einem Knochen
weggelockt und eingesperrt worden war, bis wir glücklich aus dem
Wege sein würden. Während Habīb nach der einen Richtung hin das
Dorf durchstreifte, und Michaïl nach der anderen, erschien der
Polizeikommissar auf dem Schauplatz und suchte Balsam in die
Wunde meines Schmerzes zu träufeln. Nach einiger Zeit erschien
Habīb wieder, hinter ihm Kurt, schweifwedelnd und an einer Kette
befestigt. Wie jener atemlos berichtete, hatte er das Tier, an eben
diese Kette gefesselt, bei jemand entdeckt, der es hatte stehlen
wollen.
»Und als Kurt meine Stimme hörte, bellte er; ich ging in den Hof
und sah ihn. Und der Herr der Kette verlangte sie von mir, aber bei
Gott! ich gab sie ihm nicht, sondern schlug ihn zu Boden damit.
Gottes Zorn über den diebischen Metawīleh!«
Und so habe ich das Vergnügen zu berichten, daß die Metawīleh
eine ganz so unehrliche Gesellschaft sind, wie das Gerücht von
ihnen geht, daß ihre Anschläge aber von umsichtigen Christen
vereitelt werden können.
Wir ritten das weite und öde Tal zwischen Libanon und
Antilibanon dahin. Ich hätte ja mit der Bahn nach Homs und weiter
bis Hamah reisen können, aber ich zog es vor, je nach Laune von
einer Seite des Tales nach der anderen zu kreuzen, um alle
interessanten Stätten der Gegend aufzusuchen, und das war mir nur
zu Pferde möglich. Das nördlich von Ba'albek gelegene Syrien war
mir unbekannt, es war auch insofern ein Abschnitt, als hier die Karte
von Palästina aufhörte. Ich mußte nun meine Zuflucht zu Kieperts
kleiner aber vortrefflicher Karte nehmen, die ich aus dem in Saleh
verbliebenen Werke Oppenheims entfernt hatte. Es gibt keine andre
genügende Karte, bis etliche dreißig Meilen südlich von Aleppo
Kieperts großer kleinasiatischer Atlas im Maßstabe von 1 : 400000
einsetzt; diesem Übelstand wird hoffentlich abgeholfen sein, sobald
die Amerikanische Princeton-Expedition ihr Werk herausgibt. Nach
4½ Stunden erreichten wir Lebweh, wo der Hauptquell des Orontes
in einer Menge kleiner Brünnchen dem Boden entspringt — ein
entzückender Anblick. Hier war es, wo wir von zwei Soldaten
eingeholt wurden, die der Kāimakām uns mit der höflichen Frage
nachgeschickt hatte, ob mir eine Eskorte erwünscht wäre. Ich
schickte den einen Mann zurück, behielt aber den anderen, um den
Kāimakām nicht zu verletzen. Unser neuer Begleiter nannte sich
Derwisch und erwies sich als sehr nützlich und angenehm, wie in der
Tat die ganze lange Reihe seiner Nachfolger, die uns eskortierten,
bis ich den Zug in Konia bestieg. Einige von ihnen trugen viel dazu
bei, die Reise unterhaltend zu gestalten: während wir Stunde um
Stunde nebeneinander dahinritten, erzählten sie mir vielerlei von
ihren Erfahrungen und Abenteuern. Diese Unterbrechung des
Garnisonlebens behagte ihnen nicht wenig; gar wohl gefiel ihnen
auch der Medschideh (etwa vier Mark) täglich, der ihnen viel sicherer
war als der Sold des Sultans. Nach Ablauf ihrer Dienstzeit
beschenkte ich sie überdies noch mit einem kleinen Trinkgeld, und
sie erhielten sich und ihre Pferde mit den Nahrungsmitteln und dem
Futter, die sie, wie ich starken Verdacht hege, dem Bauernvolk
gewaltsam abnahmen — eine Art offizieller Erpressung, gegen die
einzuschreiten der Reisende keine Macht hat.
Säulen des Sonnentempels, Ba'albek.
In Lebweh befinden sich die Ruinen eines Tempels, der in
derselben massigen Bauweise wie Ba'albek errichtet war. Ein aus
vier Steinlagen bestehendes Podium, das von einem einfachen
Sims, lediglich einer krummgezogenen Fläche, überragt wird, ist
alles, was davon übriggeblieben. Das Dorf gehört Asad Beg, einem
reichen Metawīleh, dem Bruder des in ganz Nordsyrien
wohlbekannten Dr. Haida. Er ist in der Tat überall zu finden. Komme
ich doch nie nach Damaskus, ohne ihn zu treffen, und immer
gewährt es mir Befriedigung, denn er ist außerordentlich intelligent
und in der Literatur Arabiens gut zu Hause. Neuerdings ist er zu
irgend einem Posten an der Bahn von Mekka berufen worden;
meines Wissens ist er der einzige Mann seines Stammes, der eine
gute Erziehung genossen und sich hervorgetan hat.
Wir schlugen unser Lager in Rās Ba'albek, 1½ Stunde von
Lebweh entfernt auf, wo sich eine vortreffliche Quelle in einer
Schlucht der östlichen Hügel befindet. Der beißende Frost hatte
eines Morgens aufgehört — dem Himmel sei Dank! — aber noch
war es kalt. Die Graupeln schlugen an die Zeltwand, als wir in der
Morgendämmerung aufstanden, und den ganzen Tag ritten wir in
einem teuflischen Wetter dahin. Und dies war der 8. März! Ja, der
Frühling reist gemächlich in das nördliche Syrien! Ich ließ mein
Lagergerät auf dem direkten Wege gehen, um mit Derwisch ein
Denkmal aufzusuchen, welches sich auf einer kleinen Anhöhe
inmitten des Orontes-Tales erhebt und auf dieser trostlosen Fläche
von jeder Seite her auf eine Tagereise weit sichtbar ist. Es ist ein
hoher Turm aus massivem Steingemäuer mit einer Pyramide auf der
Spitze; viereckige Wandpfeiler und ein grober Fries mit
Kriegstrophäen und Jagdszenen in Basrelief bilden die Dekoration.
Die Syrer nennen es nach einem nahegelegenen Dorfe Kāmu'a
Hurmul (Turm von Hurmul), und die Gelehrten vermuten, daß es
zum Gedächtnis an irgend eine große Schlacht der Römer errichtet
wurde. Ob sie recht haben oder nicht, läßt sich durch keinerlei
Inschrift nachweisen. Es liegt zwei Wegstunden westlich von Rās
Ba'albek. Von dem fürchterlichen Wind gepeitscht, ritten wir noch 1½
Stunden weiter bis zu einer Reihe kleinerer Erdwälle, welche die
Luftlöcher eines unterirdischen Kanals deckten. In Persien nennt
man es einen Kanāt, und ich glaube, so heißt es auch auf Arabisch.
2½ weitere Stunden brachten uns nach Kseir; und als eine
Viertelstunde später auch die Maultiere eingetroffen waren, schlugen
wir unser Lager dicht an der Begräbnisstätte außerhalb der
häßlichen, aus Lehm erbauten Stadt auf. Nach Sonnenuntergang
legte sich der Wind, und Friede, physischer sowohl als moralischer,
zog ins Lager ein. Hatte doch sogar Michaïls gute Laune unter der
Wut der Elemente gelitten, während Habīb, heiter wie gewöhnlich,
hereingekommen war, und ich mich — ich freue mich, das
konstatieren zu können — in philosophisches Schweigen gehüllt
hatte, sobald ich fühlte, daß der Orkan sich mit meinem Humor
entfernen wollte. Mohammed der Druse war nicht mehr bei uns; wir
hatten ihn in Damaskus zurückgelassen. Mochte es seine eigne
Schuld sein, oder hatten sich die anderen gegen ihn
zusammengetan — jedenfalls nahmen die Verdrießlichkeiten und
der Streit kein Ende, und es war besser, ein Glied des Stabes zu
opfern, um die Karawane in Einigkeit zu erhalten. In Damaskus, wo
unser Vertrag endete, schieden wir als die besten Freunde, und eine
Reihe von Mietlingen, die sich — in meinen Augen wenigstens —
durch nichts voneinander unterschieden, nahm seinen Platz ein.
Das Tal des Orontes war früher arabischer Lagerplatz; noch jetzt
lassen sich in trocknen Zeiten einige Scheichs der Haseneh und der
'Anazeh dort nieder, aus dem letzteren Stamme hauptsächlich die
Ruwalla; aber die große Masse der Beduinen ist von der Zivilisation
verdrängt worden. Der Kāmua wahrt ihr Gedächtnis in Gestalt alter
Stammeszeichen. Seltsam mutete es an, daß wir uns in den
Niederlassungen der alten Hittiter (wer sie auch gewesen sein
mögen) befanden; die berühmten Proben ihrer noch bis jetzt nicht
entzifferten Schrift, die in Hamah aufgefunden wurden, sind jetzt in
dem Museum von Konstantinopel untergebracht und spotten der
Bemühungen der Gelehrten. Die jetzigen Einwohner von Kseir
bestehen teilweise aus Christen und aus Gliedern einer die
»Nosairijjeh« genannten Sekte. Der Islam erkennt sie zwar nicht als
Rechtgläubige an, aber sie geben sich, wie alle die kleineren Sekten,
die größte Mühe, den äußeren Unterschied zwischen sich und dem
herrschenden Glauben zu verwischen. Sie halten ihre
Glaubenslehren möglichst geheim, aber Dussaud hat ihnen
gründlich nachgespürt und manche Anklänge an den alten
Phönizierglauben entdeckt. Abgeschlossen in ihren Bergfesten
lebend, haben die Nosairijjeh ihren alten semitischen Kultus
beibehalten und nehmen als direkte Abkömmlinge des Heidentums
eine hohe Stellung in den Augen der Syriologen ein, während sie
selbst über ihre Abstammung völlig im Dunklen sind. Im Lande
sprach man Übles von ihrer Religion, wie man ja überhaupt immer
über Dinge, die man nicht versteht, Böses zu flüstern pflegt, und als
sichtbaren Beweis sagte man mir, daß das Leben dieser Sekte alles
zu wünschen übrig lasse. Aber Dussaud hat den Fleck
weggewaschen, der auf ihrem Glauben lag, und ich meinerseits
beobachte, nach meinen Erfahrungen über ihr Verhalten Fremden
gegenüber, eine wohlwollende Neutralität. Habe ich doch fünf Tage
in dem Bergland westlich von Homs verlebt und eine Woche in der
Nähe Antiochiens, in welch beiden Distrikten sie besonders vertreten
sind, und habe keinen Grund zur Klage gehabt. Weniger war mein
Hund Kurt mit der Gesellschaft zufrieden, die er in Kseir antraf. Er
bellte die ganze Nacht hindurch unaufhörlich, fast hätte ich ihn in
den Hof des Metawīleh zurückgewünscht.
Tempel des Jupiter, Ba'albek.

Der folgende Tag brachte herrliches Wetter. Ich machte mit
Michaïl einen weiten Umweg, um den Tell Nebi Mendu aufzusuchen,
wo Kadesch am Orontes, die südliche Hauptstadt der Hittiter, lag.
Kadesch muß seinerzeit eine schöne Stadt gewesen sein. Der
Hügel, auf dem es erbaut wurde, erhebt sich aus einer großen
Getreideebene. Nach Süden zu zieht sich zwischen den
Zwillingsketten des Libanon das breite Orontestal dahin, im Westen
wird es durch den Djebel Nosairijjeh gegen das Meer hin geschützt,
und der Libanon umschließt mit den Nosairijjehbergen ein blühendes
Flachland, durch welches die Kaufleute mit ihren Waren an das Meer
gelangen können. Nach dem nördlichen Horizont erstrecken sich die
Ebenen von Zölesyrien, und die Steppen der palmyrischen Wüste
begrenzen den Blick nach Osten. Der Fuß des Tell wird von dem
kleinen aber reißenden Orontes (der »Rebell« bedeutet sein
arabischer Name) bespült, ganz im Vordergrund aber liegt der sechs
Meilen lange See Homs. Man nähert sich dem Hügel Kadesch auf
grasbewachsenen Flächen; zwischen Weidengebüsch dreht sich ein
Mühlrad lustig in dem rauschenden Strom. Die Gegend muß seit den
Zeiten der Hittiter beinahe ununterbrochen bewohnt gewesen sein,
denn die Geschichte erwähnt eine Seleucidenstadt Laodicea ad
Orontem, auch finden sich Spuren einer christlichen Stadt. Jede
nachfolgende Generation hat auf dem Staube derer gebaut, die vor
ihr gewesen. So ist der Berg höher und höher geworden und sicher
auch reicher und reicher an Spuren von denjenigen, die darauf
wohnten. Aber er kann nicht gänzlich durchgraben werden wegen
der armseligen Lehmhütten, die den Ruhm von Laodicea und
Kadesch geerbt haben. Und da ist ja auch der kleine Kirchhof am
Nordende des Dorfes, der, so will es der Islam, ungestört bleiben
muß, bis die Posaune Gabriels die Schläfer weckt. Ich sah wohl
Fragmente von Säulen und recht rohen Kapitälen umherliegen, aber
als ich so auf dem Berge stand, war meine Phantasie zu lebhaft
beschäftigt, ein Bild von der Schlacht bei Kadesch zu weben, wo der
König der Hittiter seinerzeit gegen Pharao kämpfte, und von der uns
eine wundervolle Reihe Hieroglyphen in Ägypten erzählt. Ein
viertelstündiger Ritt führte von Tell Nebi Mendu an eine seltsame
Erdarbeit, die von den Arabern für Sefinet Nuh (Noahs Arche), von
den Archäologen dagegen für eine assyrische Befestigung erklärt

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Basic and Clinical Pharmacology 14th

Edition (eBook PDF)

Basic and Clinical Pharmacology 14th Edition (eBook

Basic & Clinical Pharmacology, 14th Edition Bertram G.

Basic & Clinical Pharmacology, 14th Edition Bertram G.

Basic and Clinical Pharmacology, 15th Edition Bertram

Basic & Clinical Pharmacology, 15th Edition Bertram G.

(eBook PDF) Basic Pharmacology for Nurses 17th Edition

(eBook PDF) Pharmacology and Physiology for Anesthesia:

Clinical Pharmacology 12th Edition Morris J. Brown

Michael J. Aminoff, MD, DSc, FRCP Edward Chu, MD

Joshua M. Galanter, MD Michael J. Kosnett, MD, MPH

Ahmed A. Negm, MD Sharon Safrin, MD

Introduction: The Nature of

drug preparation and the medical uses of drugs—began to develop

Drug Shape Rational Drug Design

Drug Receptor Effects

these endogenous molecules are regulatory molecules. Binding of a

TABLE 1–2 Some transport molecules important in pharmacology.

TABLE 1–3 Ionization constants of some common drugs.

Weak acids Weak bases Weak bases (cont’d)

■■ II DRUG DEVELOPMENT &

»Djerūdis goldne Rosse sind berühmt,

Das Lied wird nicht oft vor ihm gesungen.

Mein nächster Gast war Scheich Hassan Nakschibendi, der mit

Vor den Toren von Damaskus.

In Scheich Hassans Haus zurückgekehrt, teilten wir diesen Teil

Der große Hof, Ba'albek.

Unsre Abreise von Ba'albek wurde durch ein sehr betrübliches

Tempel des Jupiter, Ba'albek.

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