Modern Pharmacology With Clinical Applications pdf
I. GENERAL PRINCIPLES OF PHARMACOLOGY
7. Principles of Toxicology
20. Antihypertensive Drugs 225 David P. Westfall
21. Diuretic Drugs 239 Peter A. Friedman and William O. Berndt
22. Anticoagulant, Antiplatelet, and Fibrinolytic (Thrombolytic) Drugs 256 Jeffrey S. Fedan
23. Hypocholesterolemic Drugs and Coronary Heart Disease 268 Richard J. Cenedella IV.
DRUGS AFFECTING THE CENTRAL NERVOUS SYSTEM
24. Introduction to Central Nervous System Pharmacology 281 Charles R. Craig
T a b l e o f C o n t e n t s
8. Contemporary Bioethical Issues in Pharmacology and Pharmaceutical Research
63 Mary E. Davis and Mark J. Reasor
56 Jeane McCarthy
1. Progress in Therapeutics
6. Drug Metabolism and Disposition in Pediatric and Gerontological Stages of Life
48 Timothy S. Tracy
5. Pharmacokinetics
34 Timothy S. Tracy
4. Metabolism and Excretion of Drugs
20 Timothy S. Tracy
3. Drug Absorption and Distribution
10 William W. Fleming
2. Mechanisms of Drug Action
03 Robert E. Stitzel and Joseph J. McPhillips
19. Calcium Channel Blockers 218 Vijay C. Swamy and David J. Triggle
73 Janet Fleetwood II.
Drugs Affecting the Cardiovascular System
28. Agents Affecting Neuromuscular Transmission 338 Michael D. Miyamoto
DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM
37. Drugs Used in Gout 441 Knox Van Dyke
36. Antiinflammatory and Antirheumatic Drugs 423 Karen A. Woodfork and Knox Van Dyke
THERAPEUTIC ASPECTS OF INFLAMMATORY AND SELECTED OTHER CLINICAL DISORDERS
35. Contemporary Drug Abuse 406 Billy R. Martin and William L. Dewey V.
34. Antipsychotic Drugs 397 Stephen M. Lasley
33. Drugs Used in Mood Disorders 385 Herbert E. Ward and Albert J. Azzaro
32. Antiepileptic Drugs 374 Charles R. Craig
31. Drugs Used in Neurodegenerative Disorders 364 Patricia K. Sonsalla
30. Sedative–Hypnotic and Anxiolytic Drugs 355 John W. Dailey
29. Central Nervous System Stimulants 348 David A. Taylor
27. Local Anesthetics 336 J. David Haddox
14. Ganglionic Blocking Drugs and Nicotine 141 Thomas C. Westfall III.
26. Opioid and Nonopioid Analgesics 310 Sandra P. Welch and Billy R. Martin
25. General Anesthesia: Intravenous and Inhalational Agents 291 David J. Smith and Michael B. Howie
9. General Organization and Functions of the Nervous System
83 William W. Fleming
10. Adrenomimetic Drugs
96 Tony J.-F. Lee and Robert E. Stitzel
11. Adrenoceptor Antagonists 109 David P. Westfall
12. Directly and Indirectly Acting Cholinomimetics 121 William F. Wonderlin
13. Muscarinic Blocking Drugs 134 William F. Wonderlin
18. The Renin–Angiotensin–Aldosterone System and Other Vasoactive Substances 206 Lisa A. Cassis
17. Antianginal Drugs 196 Garrett J. Gross
16. Antiarrhythmic Drugs 160 Peter S. Fischbach and Benedict R. Lucchesi
15. Pharmacologic Management of Chronic Heart Failure 151 Mitchell S. Finkel and Humayun Mirza
38. Histamine and Histamine Antagonists 449 Knox Van Dyke and Karen A. Woodfork
39. Drugs Used in Asthma 458 Theodore J. Torphy and Douglas W. P. Hay
40. Drugs Used in Gastrointestinal Disorders 470 Lisa M. Gangarosa and Donald G. Seibert
41. Drugs Used in Dermatological Disorders 484 Eric L. Carter, Mary-Margaret Chren, and David R. Bickers
42. Drugs for the Control of Supragingival Plaque 499 Angelo Mariotti and Arthur F. Hefti VI.
58. Gene Therapy 666 John S. Lazo and Jennifer Rubin Grandis VII.
57. Immunomodulating Drugs 657 Leonard J. Sauers
56. Antineoplastic Agents 638 Branimir I. Sikic
55. The Rational Basis for Cancer Chemotherapy 630 Branimir I. Sikic
DRUGS AFFECTING THE ENDOCRINE SYSTEM
47. Tetracyclines, Chloramphenicol, Macrolides, and Lincosamides 544 Richard P. O’Connor
60. Adrenocortical Hormones and Drugs Affecting the Adrenal Cortex 686 Ronald P. Rubin
Index xii
TABLE OF CONTENTS
69. Herbal Medicine 785 Gregory Juckett
68. Vitamins 777 Suzanne Barone
67. Insulin and Oral Drugs for Diabetes Mellitus 763 Michael J. Thomas and John A. Thomas
66. Parathyroid Hormone, Calcitonin, Vitamin D, and Other Compounds Related to Mineral Metabolism 754 Frank L. Schwartz
65. Thyroid and Antithyroid Drugs 742 John Connors
64. Drugs Used in the Treatment of Erectile Dysfunction 735 John A. Thomas and Michael J. Thomas
63. Androgens, Antiandrogens, and Anabolic Steroids 724 Frank L. Schwartz and Roman J. Miller
62. Uterine Stimulants and Relaxants 716 Leo R. Brancazio and Robert E. Stitzel
61. Estrogens, Progestins, and SERMs 704 Jeannine S. Strobl
59. Hypothalamic and Pituitary Gland Hormones 677 Priscilla S. Dannies
48. Bacitracin, Glycopeptide Antibiotics, and the Polymyxins 552 Mir Abid Husain
CHEMOTHERAPY
43. Introduction to Chemotherapy 509 Steven M. Belknap
44. Synthetic Organic Antimicrobials: Sulfonamides, Trimethoprim, Nitrofurans, Quinolones, Methenamine 515 Marcia A. Miller-Hjelle, Vijaya Somaraju, and J. Thomas Hjelle
45. -Lactam Antibiotics 526 James F. Graumlich
46. Aminoglycoside Antibiotics 538 Steven Belknap
53. Antiprotozoal Drugs 606 Leonard William Scheibel
52. Antifungal Drugs 596 David C. Slagle
51. Therapy of Human Immunodeficiency Virus 584 Knox Van Dyke and Karen Woodfork
50. Antiviral Drugs 567 Knox Van Dyke and Karen Woodfork
49. Drugs Used in Tuberculosis and Leprosy 557 Vijaya Somaraju
54. Anthelmintic Drugs 621 Mir Abid Husain and Leonard William Scheibel T
he sixth edition of Modern Pharmacology With
Clinical Applications continues our commitment
to enlisting experts in pharmacology to provide a textbook that is up-to-date and comprehensive. De- signed to be used during a single semester, the book fo- cuses on the clinical application of drugs within a con- text of the major principles of pharmacology. It is meant to serve students in medicine, osteopathy, dentistry, pharmacy, and advanced nursing, as well as undergrad- uate students.
This edition includes a number of new or updated fea- tures that further enhance the appeal of the text.
Study Questions: Each chapter includes five to
seven examination questions (following the United States Medical Licensing Examination guidelines) with detailed answers to help students test their knowledge of the covered material.
Case Studies: Appearing at the end of each chapter,
case studies present students with real-life examples of clinical scenarios and require them to apply their knowledge to solve the problem.
Refined Focus: In this edition, we chose to focus
more on drug classes rather than on individual drugs, eliminate unnecessary detail such as chemical struc- tures, and maintain emphasis on structure–activity rela- tionships in drug action and development.
Updated Information: This edition also includes new information from the clinic and the laboratory.
Emerging information has been added within chapters and when appropriate (as in the case of herbal drugs and erectile dysfunction), through the addition of new chapters.
SUMMARY OF FEATURES
With these revisions, we hope we have provided a book that is readable, up-to-date, comprehensive but not exhaustive, and accurate—a text that supplies both students and faculty with a clear introduction to mod- ern pharmacotherapeutics.
Charles R. Craig Robert E. Stitzel P r e f a c e
Albert J. Azzaro, PhD Chief Scientific Officer, Clinical Development
Priscilla S. Dannies, PhD Professor of Pharmacology
John M. Connors, PhD Associate Professor
Department of Physiology and Pharmacology West Virginia University School of Medicine Morgantown, WV 26506-9229
Charles R. Craig, PhD Director of West Virginia University Research Compliance
Professor of Neurobiology and Anatomy West Virginia University School of Medicine Morgantown, WV 26506-9142
John W. Dailey, PhD Professor Emeritus
Department of Basic Science University of Illinois College of Medicine PO Box 1649 Peoria, IL 61656
Department of Pharmacology School of Medicine Yale University 333 Cedar Street New Haven, CT 06510
Mary-Margaret Chren, MD Associate Professor in Residence
Mary E. Davis, PhD Professor of Physiology and Pharmacology
West Virginia University School of Medicine Morgantown, WV 26506-9229
William L. Dewey, PhD Professor of Pharmacology and Toxicology
Virginia Commonwealth University 310 N. 12th Street PO Box 980613 Richmond, VA 23219-0613
Jeffrey S. Fedan, PhD Professor of Physiology and Pharmacology
West Virginia University School of Medicine Research Pharmacologist National Institute for Occupational Safety and Health Morgantown, WV 26506
University of California at San Francisco San Francisco VAMC 190 4150 Clement Street San Francisco, CA 94121
Kirksville College of Osteopathic Medicine 800 West Jefferson Street
Somerset Pharmaceuticals 2202 North West Shore Blvd., Suite 450 Tampa, FL 33607
David R. Bickers, MD Carl Truman Nelson Professor and Chairman
Suzanne Barone, PhD
9710 Bellevue Drive Bethesda, MD 20814
Steven M. Belknap, MD Associate Professor
Department of Biomedical & Therapeutic Sciences University of Illinois College of Medicine at Peoria PO Box 1649 Peoria, Ill 61656
William O. Berndt, PhD Vice Chancellor, Academic Affairs
Dean, Graduate Studies and Research Professor of Pharmacology University of Nebraska Medical Center 986810 Nebraska Medical Center Omaha, NE 68198-6810
Department of Dermatology College of Physicians & Surgeons of Columbia University New York, NY 10032
Richard J. Cenedella, PhD Professor and Chairman, Department of Biochemistry
Leo R. Brancazio, PhD Instructor, Division of Maternal/Fetal Medicine
4010 Hospital South Duke University Medical Center Durham, NC 27710-3967
Eric L. Carter, MD Assistant Clinical Professor of Dermatology
Columbia University College of Physicians and Surgeons 151 Ft. Washington Avenue New York, NY 10032
Lisa A. Cassis, PhD Professor, Division of Pharmaceutical Sciences
University of Kentucky, College of Pharmacy Lexington, KY 40536-0082
C o n t r i b u t i n g A u t h o r s
CONTRIBUTING AUTHORS
Gregory Juckett, MD Professor of Family Medicine
Research and Graduate Studies Ohio State University College of Medicine and Dentistry 305 W. 12th Ave.
Columbus, OH 43210
J. Thomas Hjelle, PhD Associate Professor of Pharmacology
Department of Biomedical and Therapeutic Sciences University of Illinois College of Medicine at Peoria One Illini Drive Peoria, IL 61605
Michael B. Howie, MD Professor of Anesthesia
The Ohio State University College of Medicine Columbus, OH 43210
Mir Abid Husain, MD Saint Francis Medical Center
530 NE Glen Oak Avenue Peoria, IL 61637
West Virginia University Health Sciences Center Morgantown, WV 26506-9247
SmithKline Beecham Pharmaceuticals King of Prussia, PA 19406-0639 Arthur F. Hefti, D.MD, P.D.
Stephen M. Lasley, PhD Department of Biomedical & Therapeutic Sciences
University of Illinois College of Medicine PO Box 1649 Peoria, IL 61656-1649
John S. Lazo, PhD Professor and Chair, Department of Pharmacology
University of Pittsburgh School of Medicine E1340 Biomedical Sciences Tower Pittsburgh, PA 15261-0001
Tony J.-F. Lee Professor of Pharmacology
Southern Illinois University School of Medicine Springfield, IL 62794-9629
Benedict R. Lucchesi, MD, PhD Professor of Pharmacology
Department of Pharmacology University of Michigan Medical School 1301 MSRB III Ann Arbor, MI 48109-0632
Associate Dean
viii
Mitchell S. Finkel, MD Professor of Medicine and Biochemistry and Molecular Pharmacology
Department of Physiology and Pharmacology West Virginia University School of Medicine Morgantown, WV 26506-9229
West Virginia University School of Medicine Morgantown, WV 26506-9157
Peter S. Fischbach, MD Department of Pediatric & Communicable Diseases
Division of Pediatric Cardiology F1310 Mott Children’s Hospital Ann Arbor, MI 48109-0204
Janet Fleetwood, PhD Director, Medical Humanities Program
Medical College of Pennsylvania 3300 Henry Avenue Philadelphia, PA 19129
Peter A. Friedman, PhD Professor of Pharmacology
University of Pittsburgh School of Medicine Pittsburgh, PA 15261
William W. Fleming, PhD Professor Emeritus
Lisa M. Gangarosa, MD Assistant Professor
Purdue Pharmaceuticals 100 Connecticut Avenue Norwalk, CT 06850-3590
Section of Gastroenterology C.B. 7080 University of North Carolina Burnett-Womack Bldg., Room 724 Chapel Hill, NC 27599
Jennifer Rubin Grandis, M.D Associate Professor of Otolaryngology
University of Pittsburgh School of Medicine Pittsburgh, PA 15261
James F. Graumlich, MD Assistant Professor of Biomedical & Therapeutic Sciences
University of Illinois College of Medicine One Illini Drive, Box 1649 Peoria, IL 61656-1649
Garrett J. Gross, PhD Professor of Pharmacology & Toxicology
Medical College of Wisconsin 8701 Watertown Plank Road Milwaukee, WI 53226 David Haddox, D.D.S., MD, F.A.C.P.M.
Medical Director, Internal Analgesics
Douglas W. P. Hay, PhD Associate Fellow, Department of Pulmonary Pharmacology
Contributing Authors
ixDonald G. Seibert, MD Gastroenterology Associates of Southwest Virginia
Department of Pharmacology and Toxicology State University of New York at Buffalo School of Medicine 102 Farber Hall Buffalo, NY 14214-3000 Leonard J. Sauers, PhD, D.A.B.T.
Director, Product Safety, Regulatory Affairs, & Analytical Sciences
The Procter & Gamble Company Ivorydale Technical Center 5299 Spring Grove Avenue Cincinnati, OH 45217
Leonard William Scheibel, MD Chief, Section of Clinical Pharmacology
University of Illinois College of Medicine Department of Biomedical & Therapeutic Sciences PO Box 1649 Peoria, IL 61656-1649
Frank L. Schwartz, MD Associate Professor of Medicine
West Virginia University School of Medicine Morgantown, WV 26506 Medical Director, Diabetes Center Camden Clark Memorial Hospital Parkersburg, WV 26101
2012 Stephenson Ave SW Roanoke, VA 24014
West Virginia University School of Medicine
Branimir I. Sikic, MD, PhD Professor of Medicine (Oncology) and Clinical Pharmacology
Stanford University Medical Center Stanford, CA 94305-5151
David C. Slagle, MD Saint Francis Medical Center
530 N. E. Glen Oak Avenue Peoria, IL 61637
David J. Smith, PhD Professor of Biochemistry and Molecular Pharmacology
West Virginia University School of Medicine Morgantown, WV 26506-9142
Vijaya Somaraju, MD Saint Francis Medical Center
Ronald P. Rubin, PhD Professor and Chair
Mark Reasor, PhD Professor of Physiology and Pharmacology
Angelo Mariotti, D.D.S., PhD Chair, Department of Periodontology
Current address: 20611 Highland Hall Drive Montgomery Village, MD 20886-4024
Ohio State University College of Medicine and Dentistry 305 W. 12th Ave.
Columbus, OH 43210
Billy R. Martin, PhD Professor and Chair
Department of Pharmacology & Toxicology Virginia Commonwealth University 410 N. 12th St., 7th floor, Room 760 PO Box 980613 Richmond, VA 23298-0377
Jeane McCarthy, MD Clinical Professor of Pediatrics
University of South Florida All Children’s Hospital St. Petersburg, FL 33701
Joseph J. McPhillips, PhD Retired, formerly Director of Clinical Research Boehringer Mannheim Pharmaceuticals Corp.
Marcia A. Miller-Hjelle, PhD Chief, Section of Medical Microbiology and Infectious Diseases
PO Box 600 Mossville, IL 61552-0600
Department of Biomedical and Therapeutic Sciences University of Illinois College of Medicine One Illini Drive, Box 1649 Peoria, IL 61656-1649
Roman J. Miller, PhD Professor of Biology
Eastern Mennonite College Harrisonburg, VA 22801
Humayun Mirza, MD Interventional Fellow
Section of Cardiology, Department of Medicine West Virginia University School of Medicine Morgantown, WV 26506-9157
Michael D. Miyamoto, PhD Professor of Pharmacology
East Tennessee State University College of Medicine Johnson City, TN 37614-0577
Richard P. O’Connor, MD C/o Caterpillar Corporate Medical Caterpillar Inc.
530 N. E. Glen Oak Avenue Peoria, IL 61637
CONTRIBUTING AUTHORS
x
University of Nevada-Reno, MS318 Reno, NV 89557-0046
West Virginia University School of Medicine Morgantown, WV 26506-9142
Herbert E. Ward, MD Department of Psychiatry
University of Florida PO Box 100256 Gainesville, FL 32610-0256
Sandra P. Welch, PhD Professor of Pharmacology & Toxicology
Virginia Commonwealth University PO Box 980613 Richmond, VA 23298-0613
David P. Westfall, PhD Professor of Pharmacology
Thomas C. Westfall, PhD Professor and Chair
School of Pharmacy 126 Cooke Buffalo, NY 14260-0001
Department of Pharmacology and Physiological Sciences St. Louis University School of Medicine 1402 S. Grand Blvd.
St. Louis, MO 63104-1083
William F. Wonderlin, PhD Associate Professor of Biochemistry and Molecular Pharmacology
West Virginia University School of Medicine Morgantown, WV 26506-9142
Karen A. Woodfork, PhD Adjunct Associate Professor in Biochemistry and Molecular Pharmacology
West Virginia University School of Medicine Morgantown, WV 26506-9142
Knox Van Dyke, PhD Professor of Biochemistry and Molecular Pharmacology
David Triggle, PhD Dean, State University of New York at Buffalo
Patricia K. Sonsalla, PhD Associate Professor of Neurology
West Virginia University School of Medicine Morgantown, WV 26506-9142
UMDNJ-RW Johnson Medical School 675 Hoes Lane Piscataway, NJ 08854-5635
Robert E. Stitzel, PhD Director of University Graduate Education
Professor and Associate Chair Department of Biochemistry and Molecular Pharmacology West Virginia University School of Medicine Morgantown, WV 26506-9142
Jeannine Strobl, PhD Professor of Biochemistry and Molecular Pharmacology
V. C. Swamy, PhD
219 Wood Shadow San Antonio, TX 78216-1633
John A. Thomas, PhD
West Virginia University School of Pharmacy Morgantown, WV 26506-9530
David A. Taylor, PhD Professor and Chair of Pharmacology
School of Pharmacy State University of New York at Buffalo 313 Hochstetter Hall Buffalo, NY 14260
Chair, Biomedical Pharmacology
Michael J. Thomas, MD, PhD Associate Professor of Medicine, Division of Endocrinology
University of North Carolina School of Medicine 6101 Thurston Bowles, CB #7170 Chapel Hill, NC 27599-7170
Theodore J. Torphy, PhD Vice President and Director of Pharmacology Centocor, Inc.
200 Great Valley Parkway Malvern, PA 19355
Timothy S. Tracy, PhD Associate Professor of Basic Pharmaceutical Sciences
East Carolina University School of Medicine Greenville, NC 27858-4353
SECTION
I
I GENERAL PRINCIPLESOF PHARMACOLOGY
6. Drug Metabolism and Disposition in
1. Progress in Therapeutics
3 Robert E. Stitzel and Joseph J. McPhillips Pediatric and Gerontological Stages
- of Life
2. Mechanisms of Drug Action
10 William W. Fleming Jeane McCarthy
- 7. Principles of Toxicology
3. Drug Absorption and Distribution
20 Timothy S. Tracy Mary E. Davis and Mark J. Reasor
8. Contemporary Bioethical Issues in
- 4. Metabolism and Excretion of Drugs
Timothy S. Tracy Pharmacology & Pharmaceutical
- Research ••
5. Pharmacokinetics
Timothy S. Tracy Janet Fleetwood
Early in human history a natural bond formed be- tween religion and the use of drugs. Those who became most proficient in the use of drugs to treat disease were the “mediators” between this world and the spirit world, namely, the priests, shamans, holy persons, witches, and soothsayers. Much of their power within the community was derived from the cures that they could effect with drugs. It was believed that the sick were possessed by demons and that health could be re- stored by identifying the demon and finding a way to cast it out.
Progress in Therapeutics
Robert E. Stitzel and Joseph J. McPhillips
1
1
CONTRIBUTIONS OF MANY CULTURES
B . C
. and contained classifications of individual me- dicinal plants as well as compilations of plant mixtures to be used for medical purposes. The Chinese doctrine
of signatures
Originally, religion dominated its partnership with
Ancient Egyptian medical papyri contain numerous prescriptions. The largest and perhaps the most impor- tant of these, the Ebers papyrus (1550
B . C
.), contains about 800 prescriptions quite similar to those written today in that they have one or more active substances as well as vehicles (animal fat for ointments; and water, milk, wine, beer, or honey for liquids) for suspending or dissolving the active drug. These prescriptions also com- monly offer a brief statement of how the preparation is to be prepared (mixed, pounded, boiled, strained, left overnight in the dew) and how it is to be used (swal- lowed, inhaled, gargled, applied externally, given as an enema). Cathartics and purgatives were particularly in vogue, since both patient and physician could tell al- most immediately whether a result had been achieved. It was reasoned that in causing the contents of the gas- trointestinal tract to be forcibly ejected, one simultane- ously drove out the disease-producing evil spirits that had taken hold of the unfortunate patient.
The level of drug usage achieved by the Egyptians undoubtedly had a great influence on Greek medicine
The ancient Chinese wrote extensively on medical subjects. The Pen Tsao, for instance, was written about 2700
and divine intervention was called upon for every treatment. However, the use of drugs to effect cures led to a profound change in both religious thought and structure. As more became known about the effects of drugs, the importance of divine intervention began to recede, and the treatment of patients effectively became a province of the priest rather than the gods whom the priest served. This process lead to a growing under- standing of the curative powers of natural products and a decreasing reliance on supernatural intervention and forever altered the relationship between humanity and its gods. Furthermore, when the priests began to apply the information learned from treating one patient to the treatment of other patients, there was a recognition that a regularity prevailed in the natural world independent of supernatural whim or will. Therapeutics thus evolved from its roots in magic to a foundation in experience. This was the cornerstone for the formation of a science- based practice of medicine.
therapeutics,
(like used to treat like) enables us to un- derstand why medicines of animal origin were of such great importance in the Chinese pharmacopoeia. various natural substances are found in both the Iliad and the Odyssey. Battle wounds frequently were cov- ered with powdered plant leaves or bark; their astrin- gent and pain-reducing actions were derived from the tannins they contained. It may have been mandrake root (containing atropinelike substances that induce a twilight sleep) that protected Ulysses from Circe. The oriental hellebore, which contains the cardiotoxic
Veratrum
By the first century
4
Although the availability of a laboratory devoted to pharmacological investigations was important, much more was required to raise this discipline to the same prominent position occupied by other basic sciences; this
One of the first laboratories devoted almost exclu- sively to drug research was established in Dorpat, Estonia, in the late 1840s by Rudolph Bucheim (1820– 1879) (Fig. 1.1). The laboratory, built in Bucheim’s home, was devoted to studying the actions of agents such as cathartics, alcohol, chloroform, anthelmintics, and heavy metals. Bucheim believed that “the investi- gation of drugs . . . is a task for a pharmacologist and not for a chemist or pharmacist, who until now have been expected to do this.”
Until the nineteenth century, the rapid development of pharmacology as a distinct discipline was hindered by the lack of sophisticated chemical methodology and by limited knowledge of physiological mechanisms. The significant advances made through laboratory studies of animal physiology accomplished by early investigators such as Françoise Magendie and Claude Bernard pro- vided an environment conducive to the creation of sim- ilar laboratories for the study of pharmacological phe- nomena.
The isolation and use of pure substances allowed for an analysis of what was to become one of the basic con- cerns of pharmacology, that is, the quantitative study of drug action. It was soon realized that drug action is pro- duced along a continuum of effects, with low doses pro- ducing a less but essentially similar effect on organs and tissues as high doses. It also was noted that the appear- ance of toxic effects of drugs was frequently a function of the dose–response relationship.
At the turn of the nineteenth century, methods be- came available for the isolation of active principles from crude drugs. The development of chemistry made it pos- sible to isolate and synthesize chemically pure com- pounds that would give reproducible biological results. In 1806, Serturner (1783–1841) isolated the first pure ac- tive principle when he purified morphine from the opium poppy. Many other chemically pure active com- pounds were soon obtained from crude drug prepara- tions, including emetine by Pelletier (1788–1844) from ipecacuanha root; quinine by Carentou (1795–1877) from cinchona bark; strychnine by Magendie (1783– 1855) from nux vomica; and, in 1856, cocaine by Wohler (1800–1882) from coca.
. it was clear to both physi- cian and protopharmacologist alike that there was much variation to be found from one biological extract to another, even when these were prepared by the same individual. It was reasoned that to fashion a rational and reproducible system of therapeutics and to study phar- macological activity one had to obtain standardized and uniform medicinal agents.
A . D
. 131–201), who was considered the greatest European physician after Hippocrates. Galen believed that drugs had cer- tain essential properties, such as warmth, coldness, dry- ness, or humidity, and that by using several drugs he could combine these properties to adjust for deficien- cies in the patient. Unfortunately, he often formulated general rules and laws before sufficient factual informa-
alkaloids, was smeared on arrow tips to in- crease their killing power. The fascination of the Greeks with the toxic effects of various plant extracts led to an increasing body of knowledge concerned primarily with the poisonous aspects of drugs (the science of toxicol-
A . D
(the identification and preparation of crude drugs from natural sources). There has long been a tendency of some physicians to prescribe large numbers of drugs where one or two would be sufficient. We can trace the history of this polypharmaceutical approach to Galen (
nosy
Individuals who searched for improved product formu- lations were largely responsible for the founding of the disciplines of pharmacy (the science of preparing, com- pounding, and dispensing medicines) and pharmacog-
Early drug practitioners, both in Europe and South America, gathered herbs, plants, animals, and minerals and often blended them into a variety of foul-smelling and ill-flavored concoctions. The fact that many of these preparations were so distasteful led to an attempt to improve on the “cosmetic” properties of these mixtures to ensure that patients would actually use them.
The Indian cultures of Central and South America, although totally isolated from the Old World, developed drug lore and usage in a fashion almost parallel with that of the older civilization. The use of drugs played an inti- mate part in the rites, religions, history, and knowledge of the South American Indians. New World medicine also was closely tied to religious thought, and Indian cultures treated their patients with a blend of religious rituals and herbal remedies. Incantations, charms, and appeals to various deities were as important as the appropriate ap- plication of poultices, decoctions, and infusions.
). Plato’s description of the death of Socrates is an accurate description of the toxicological properties of the juice of the hemlock fruit. His description of the paralysis of sensory and motor nerves, followed eventu- ally by central nervous system depression and respira- tory paralysis, precisely matches the known actions of the potent hemlock alkaloid, coniine.
ogy
I GENERAL PRINCIPLES OF PHARMACOLOGY
1 Progress in Therapeutics
5 F I G U R E 1 . 1 The three important figures in the early history of pharmacology are (left to right) Rudolf Bucheim, Oswald Schmiedeberg, and John Jacob Abel. They not only created new laboratories devoted to the laboratory investigation of drugs but also firmly established the new discipline through the training of future faculty, the writing of textbooks, and the founding of scientific journals and societies.
academic institutions and the training of a sufficient num- cal to the rise of experimental pharmacology in the ber of talented investigators to occupy these positions. United States. The latter task was accomplished largely by Bucheim’s Pharmacology, as a separate and vital discipline, has pupil and successor at Dorpat, Oswald Schmiedeberg interests that distinguish it from the other basic sciences (1838–1921), undoubtedly the most prominent pharma- and pharmacy. Its primary concern is not the cataloguing cologist of the nineteenth century (Fig. 1.1). In addition to of the biological effects that result from the administra- conducting his own outstanding research on the pharma- tion of chemical substances but rather the dual aims of cology of diuretics, emetics, cardiac glycosides, and so (1) providing an understanding of normal and abnormal forth, Schmiedeberg wrote an important medical text- human physiology and biochemistry through the appli- book and trained approximately 120 pupils from more cation of drugs as experimental tools and (2) applying to than 20 countries. Many of these new investigators either clinical medicine the information gained from funda- started or developed laboratories devoted to experimen- mental investigation and observation. tal pharmacology in their own countries. A report in the Status of Research in Pharmacology
One of Schmiedeberg’s most outstanding students has described some of the founding principles on which was John Jacob Abel, who has been called the founder of the discipline is based and that distinguish pharmacol- American pharmacology (Fig 1.1). Abel occupied the ogy from other fields of study. These principles include chair of pharmacology first at the University of Michigan the study of the following: and then at Johns Hopkins University. Among his most
- important research accomplishments is an examination The relationship between drug concentration
of the chemistry and isolation of the active principles and biological response Drug action over time • from the adrenal medulla (a monobenzyl derivative of
- epinephrine) and the pancreas (crystallization of in- Factors affecting absorption, distribution, bind-
sulin). He also examined mushroom poisons, investigated ing, metabolism, and elimination of chemicals
- the chemotherapeutic actions of the arsenicals and anti- Structure-activity relationships
- monials, conducted studies on tetanus toxin, and de- Biological changes that result from repeated
signed a model for an artificial kidney. In addition, Abel drug use: tolerance, addiction, adverse reactions, founded the Journal of Experimental Medicine, the altered rates of drug metabolism, and so forth
and the Journal of Antagonism of the effects of one drug by an- Pharmacology and Experimental Therapeutics.
- Journal of Biological Chemistry,
His devo- other tion to pharmacological research, his enthusiasm for the The process of drug interaction with cellular • training of students in this new discipline, and his estab- macromolecules (receptors) to alter physiolog- In the past 100 years there has been extraordinary growth in medical knowledge. This expansion of infor- mation has come about largely through the contribu- tions of the biological sciences to medicine by a system- atic approach to the understanding and treatment of disease. The experimental method and technological advances are the foundations upon which modern med- icine is built.
Before the twentieth century, most government controls were concerned not with drugs but with impure and adulterated foods. Medicines were thought to pose problems similar to those presented by foods. Efficacy was questioned in two respects: adulteration of active medicines by addition of inert fillers and false claims made for the so-called patent (secret) medicines or nos- trums. Indeed, much of the development of the science of pharmacy in the nineteenth century was standardiz- ing and improving prescription drugs.
A landmark in the control of drugs was the 1906 Pure Food and Drug Act. Food abuses, however, were the primary target. Less than one quarter of the first thousand decisions dealt with drugs, and of these, the majority were concerned with patent medicines.
1 . 1
T A B L E
Phases of Clinical Investigation
IV Obtain additional data following approval
III Verify efficacy and detect adverse affects
II Establish efficacy and dose
I Establish safety
I GENERAL PRINCIPLES OF PHARMACOLOGY Phase Purpose
6
Drug regulation in the United States is continuing to evolve rapidly, both in promulgation of specific regula- tions and in the way regulations are implemented (Table 1.1). The abolition of patent medicines is an outstanding example, as is control over the accuracy of claims made for drugs. Since the 1962 amendments, the advertising of prescription drugs in the United States has been in- creasingly controlled—to a greater extent than in most other countries. All new drugs introduced since 1962 have some proof of efficacy. This is not to say that mis- leading drug advertisements no longer exist; manufac- turers still occasionally make unsubstantiated claims.
The 1938 act required manufacturers to submit a New Drug Application (NDA) to the FDA for its ap- proval before the company was permitted to market a new drug. Efficacy (proof of effectiveness) became a re- quirement in 1962 with the Kefauver-Harris drug amendments. These amendments established a require- ment that drugs show “substantial evidence” of efficacy before receiving NDA approval. Substantial evidence was defined in the amendments as evidence consisting of adequate and well-controlled investigations, includ- ing clinical investigations, by experts qualified by scien- tific training and experience to evaluate the effective- ness of the drug, on the basis of which such experts could fairly and responsibly conclude that the drug would have the claimed effect under the conditions of use named on the label.
A major defect of the generally strong 1938 law was its inadequate control of advertising. Regulations now require that the “labeling on or within the package from which the drug is to be dispensed” contain adequate in- formation for the drug’s use; this requirement explains the existence of the package insert. If the pharmaceuti- cal manufacturer makes claims for its product beyond those contained in an approved package insert, the FDA may institute legal action against the deviations in advertising.
DRUG CONTROL AND DEVELOPMENT
The modern history of United States drug regulation began with the Food, Drug and Cosmetic Act of 1938, which superseded the 1906 Pure Food and Drug Act. The 1938 act was viewed as a means of preventing the obscure provision of the 1938 act was destined to be the starting point for some of the most potent controls the Food and Drug Administration (FDA) now exercises in the drug field. This provision allowed the prescription drug to come under special control by requiring that it carry the legend “Caution—to be used only by or on the prescription of a physician.”
For the next 30 years, drug control was viewed pri- marily as a problem of prohibiting the sale of dangerous drugs and tightening regulations against misbranding. Until the 1930s, new drugs posed little problem because there were few of them.
Prescription drugs also were subject to control un- der the 1906 law. In fact, until 1953 there was no fixed legal boundary between prescription and nonprescrip- tion medications. Prescription medications received a lower priority, since food and patent medicine abuses were judged to be the more urgent problems.
equal recognition as authorities for drug specifications. In the first contested criminal pros- ecution under the law, action was taken against the maker of a headache mixture bearing the beguiling name of Cuforhedake-Brane-Fude. In 1912, Congress passed an amendment to the Pure Food and Drug Act that banned false and fraudulent therapeutic claims for patent medicines.
National Formulary
The 1906 law defined drug broadly and governed the labeling but not the advertising of any substance used to affect disease. This law gave the Pharmacopoeia and the
MODERN DRUG LEGISLATION
1 Progress in Therapeutics
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CLINICAL TESTING OF DRUGS
Experiments conducted on animals are essential to the development of new chemicals for the management of disease. The safety and efficacy of new drugs, however, can be established only by adequate and well-controlled studies on human subjects. Since findings in animals do not always accurately predict the human response to drugs, subjects who participate in clinical trials are put at some degree of risk. The risk comes not only from the potential toxicity of the new drug but also from possible lack of efficacy, with the result that the condition under treatment becomes worse. Since risk is involved, the pri- mary consideration in any clinical trial should be the welfare of the subject. As a consequence of unethical or questionably ethical practices committed in the past, most countries have established safeguards to protect the rights and welfare of persons who participate in clinical trials. Two of the safeguards that have been es- tablished are the institutional review board (IRB) and the requirement for informed consent.
One of the goals of drug development is to provide suffi-
Controlled and uncontrolled studies often are con- ducted after a drug is approved and marketed. Such studies are intended to broaden the experience with the drug and compare it with other drugs.
Phase IV
and to detect effects that may not have sur- faced in the phase I and II trials, during which exposure to the drug was limited. A new drug application is sub- mitted at the end of phase III. However, for drugs in- tended to treat patients with life-threatening or severely debilitating illnesses, especially when no satisfactory therapy exists, the FDA has established procedures de- signed to expedite development, evaluation, and mar- keting of new therapies. In the majority of cases, the procedure applies to drugs being developed for the treatment of cancer and acquired immunodeficiency syndrome (AIDS). Under this procedure, drugs can be approved on the basis of phase II studies conducted in a limited number of patients.
The purpose of phase III studies is to verify the efficacy of the drug
When an effective dose range has been established and no serious adverse reactions have occurred, large num- bers of subjects can be exposed to the drug. In phase III studies the number of subjects may range from several hundred to several thousand, depending on the drug.
Phase III
Ideally, these individuals should have no medical problems other than the condition for which the new drug is intended. Efforts are concentrated on evalu- ating efficacy and on establishing an optimal dose range. Therefore, dose–response studies are a critical part of phase II studies. Monitoring subjects for adverse effects is also an integral part of phase II trials. The number of subjects in phase II studies is usually between 80 and 100.
for the first time.
If the results of phase I studies show that it is reasonably safe to continue, the new drug is administered to patients
Phase II
The initial studies consist of administering a sin- gle dose of the test drug and closely observing the sub- ject in a hospital or clinical pharmacology unit with emergency facilities. If no adverse reactions occur, the dose is increased progressively until a predetermined dose or serum level is reached or toxicity supervenes. Phase I studies are usually confined to a group of 20 to 80 subjects. If no untoward effects result from single doses, short-term multiple-dose studies are initiated.
is to establish the dose level at which signs of toxicity first appear.
When a drug is administered to humans for the first time, the studies generally have been conducted in healthy men between 18 and 45 years of age; this prac- tice is coming under increasing scrutiny and criticism. For certain types of drugs, such as antineoplastic agents, it is not appropriate to use healthy subjects because the risk of injury is too high. The purpose of phase I studies
Phase I
The clinical development of new drugs usually takes place in steps or phases conventionally described as clinical pharmacology (phase I), clinical investigation (phase II), clinical trials (phase III), and postmarketing studies (phase IV). Table 1.1 summarizes the four phases of clinical evaluation.