Goodman  Gilmans The Pharmacological Basis of Therapeutics 12th Ed.

Goodman  Gilmans The Pharmacological Basis of Therapeutics 12th Edition (www.webofpharma.com)

The publication of the twelfth edition of this book is a testament to the vision and ideals of the original authors, Alfred Gilman and Louis Goodman, who, in 1941 set forth the principles that have guided the book through eleven editions: to correlate pharmacology with related medical sciences, to reinterpret the actions and uses of drugs in light of advances in medicine and the basic biomedical sciences, to emphasize the appli-cations of pharmacodynamics to therapeutics, and to create a book that will be useful to students of pharma-cology and to physicians. These precepts continue to guide the current edition. 

As with editions since the second, expert scholars have contributed individual chapters. A multiauthored book of this sort grows by accretion, posing challenges to editors but also offering memorable pearls to the reader. Thus, portions of prior editions persist in the current edition, and I hasten to acknowledge the con-tributions of previous editors and authors, many of whom will see text that looks familiar. However, this edition differs noticeably from its immediate predeces-sors. Fifty new scientists, including a number from out-side the U.S., have joined as contributors, and all chapters have been extensively updated. The focus on basic principles continues, with new chapters on drug invention, molecular mechanisms of drug action, drug toxicity and poisoning, principles of antimicrobial ther-apy, and pharmacotherapy of obstetrical and gynecol-ogical disorders. Figures are in full color. The editors have continued to standardize the organization of chap-ters; thus, students should easily find the basic physiol-ogy, biochemistry, and pharmacology set forth in regular type; bullet points highlight important lists within the text; the clinician and expert will find details in extract type under clear headings.

Online features now supplement the printed edi-tion. The entire text, updates, reviews of newly approved drugs, animations of drug action, and hyperlinks to rel-evant text in the prior edition are available on the Good-man & Gilman section of McGraw-Hill’s websites, AccessMedicine.com and AccessPharmacy.com. An Image Bank CD accompanies the book and makes all tables and figures available for use in presentations.

The process of editing brings into view many remarkable facts, theories, and realizations. Three stand out: the invention of new classes of drugs has slowed to a trickle; therapeutics has barely begun to capitalize on the information from the human genome project; and, the development of resistance to antimicrobial agents, mainly through their overuse in medicine and agriculture, threatens to return us to the pre-antibiotic era. We have the capacity and ingenuity to correct these shortcomings.

Many, in addition to the contributors, deserve thanks for their work on this edition; they are acknowl-edged on an accompanying page. In addition, I am grateful to Professors Bruce Chabner (Harvard Medical School/Massachusetts General Hospital) and Björn Knollmann (Vanderbilt University Medical School) for agreeing to be associate editors of this edition at a late date, necessitated by the death of my colleague and friend Keith Parker in late 2008. Keith and I worked together on the eleventh edition and on planning this edi-tion. In anticipation of the editorial work ahead, Keith submitted his chapters before anyone else and just a few weeks before his death; thus, he is well represented in this volume, which we dedicate to his memory.


Three objectives have guided the writing of this book—the correlation of pharmacology with related medical sciences, the reinterpretation of the actions and uses of drugs from the viewpoint of important advances in medicine, and the placing of emphasis on the applica-tions of pharmacodynamics to therapeutics.

Although pharmacology is a basic medical sci-ence in its own right, it borrows freely from and con-tributes generously to the subject matter and technics of many medical disciplines, clinical as well as preclin-ical. Therefore, the correlation of strictly pharmacolog-ical information with medicine as a whole is essential for a proper presentation of pharmacology to students and physicians. Further more, the reinterpretation of the actions and uses of well-established therapeutic agents in the light of recent advances in the medical sciences is as important a function of a modern text book of pharmacology as is the description of new drugs. In many instances these new interpretations necessitate radical departures from accepted but outworn concepts of the actions of drugs. Lastly, the emphasis throughout the book, as indicated in its title, has been clinical. This is mandatory because medical students must be taught pharmacology from the standpoint of the actions and uses of drugs in the prevention and treatment of disease. To the student, pharmacological data per se are value less unless he/she is able to apply this information inthe practice of medicine. This book has also been writ-ten for the practicing physician, to whom it offers an opportunity to keep abreast of recent advances in ther-apeutics and to acquire the basic principles necessary for the rational use of drugs in his/her daily practice.

The criteria for the selection of bibliographic ref-erences require comment. It is obviously unwise, if not impossible, to document every fact included in the text. Preference has therefore been given to articles of a review nature, to the literature on new drugs, and to original contributions in controversial fields. In most instances, only the more recent investigations have been cited. In order to encourage free use of the bibliography, references are chiefly to the available literature in the English language.

The authors are greatly indebted to their many colleagues at the Yale University School of Medicine for their generous help and criticism. In particular they are deeply grateful to Professor Henry Gray Barbour, whose constant encouragement and advice have been invaluable.

Drug Invention and the Pharmaceutical Industry

The first edition of this textbook, published in 1941, is often credited with organizing the field of pharmacol-ogy, giving it intellectual validity and an academic iden-tity. That first edition began: “The subject of pharma-cology is a broad one and embraces the knowledge of the source, physical and chemical properties, com-pounding, physiological actions, absorption, fate, and excretion, and therapeutic uses of drugs. A drug may be broadly defined as any chemical agent that affects living protoplasm, and few substances would escape inclusion by this definition.” These two sentences still serve us well. This first section of the 12th edition of this textbook provides the underpinnings for these definitions by exploring the processes of drug invention and develop-ment into a therapeutic entity, followed by the basic properties of the interactions between the drug and bio-logical systems: pharmacodynamics, pharmacokinetics (including drug transport and metabolism), and phar-macogenomics. Subsequent sections deal with the use of drugs as therapeutic agents in human subjects.

We intentionally use the term invention to describe the process by which a new drug is identified and brought to medical practice, rather than the more conventional term discovery. This significant semantic change was sug-gested to us by our colleague Michael S. Brown, MD, and it is appropriate. In the past, drugs were discovered as nat-ural products and used as such. Today, useful drugs are rarely discovered hiding somewhere waiting to be found; rather, they are sculpted and brought into being based on experimentation and optimization of many independent properties. The term invention emphasizes this process; there is little serendipity. 


FROM EARLY EXPERIENCES WITH PLANTS TO MODERN CHEMISTRY


Man’s fascination—and sometimes infatuation—with chemicals (i.e., drugs) that alter biological function is ancient and arose as a result of experience with and dependence on plants. Most plants are root-bound, and many have become capable of elaborate chemical syn-theses, producing harmful compounds for defense that animals learned to avoid and man learned to exploit. Many examples are described in earlier editions of this text: the appreciation of coffee (caffeine) by the prior of an Arabian convent who noted the behavior of goats that gamboled and frisked through the night after eating the berries of the coffee plant, the use of mushrooms or the deadly nightshade plant (containing the belladonna alka-loids atropine and scopolamine) by professional poison-ers, and a rather different use of belladonna (“beautiful lady”) to dilate pupils. Other examples include the uses of the Chinese herb ma huang (containing ephedrine) for over 5000 years as a circulatory stimulant, curare-containing arrow poisons used for centuries by South American Indians to paralyze and kill animals hunted for food, and poppy juice (opium) containing morphine (from the Greek Morpheus, the god of dreams) for pain relief and control of dysenteries. Morphine, of course, has well-known addicting properties, mimicked in some ways by other problematic (“recreational”) natural prod-ucts—nicotine, cocaine, and ethanol.

While many terrestrial and marine organisms remain valuable sources of naturally occurring com-pounds with various pharmacological activities, espe-cially including lethal effects on both microorganisms and eukaryotic cells, drug invention became more allied with synthetic organic chemistry as that discipline flourished over the past 150 years. This revolutionored compounds with selective affinity for biological tissues. Study of these interactions stimulated Paul Ehrlich to postulate the existence of chemical receptors in tissues that interacted with and “fixed” the dyes. Similarly, Ehrlich thought that unique receptors on microorganisms or parasites might react specifically with certain dyes and that such selectivity could spare normal tissue. Ehrlich’s work culminated in the inven-tion of arsphenamine in 1907, which was patented as “salvarsan,” suggestive of the hope that the chemical would be the salvation of humankind. This arsenic-con-taining compound and other organic arsenicals were invaluable for the chemotherapy of syphilis until the discovery of penicillin. During that period and thanks to the work of Gerhard Domagk, another dye, prontosil (the first clinically useful sulfonamide) was shown to be dramatically effective in treating streptococcal infec-tions. The era of antimicrobial chemotherapy was born, and the fascination with dyes soon spread to the entire and nearly infinite spectrum of organic chemicals. The resulting collaboration of pharmacology with chemistry on the one hand, and with clinical medicine on the other, has been a major contributor to the effective treatment of disease, especially since the middle of the 20th century.


SOURCES OF DRUGS


Small Molecules Are the Tradition

With the exception of a few naturally occurring hor-mones such as insulin, most drugs were small organic molecules (typically <500 Da) until recombinant DNA technology permitted synthesis of proteins by various organisms (bacteria, yeast) and mammalian cells, start-ing in the 1980s. The usual approach to invention of a small-molecule drug is to screen a collection of chem-icals (“library”) for compounds with the desired fea-tures. An alternative is to synthesize and focus on close chemical relatives of a substance known to participate in a biological reaction of interest (e.g., congeners of a specific enzyme substrate chosen to be possible inhibitors of the enzymatic reaction), a particularly important strategy in the discovery of anticancer drugs. While drug discovery in the past often resulted from serendipitous observations of the effects of plant extracts or individual chemicals administered to ani-mals or ingested by man, the approach today relies on high-throughput screening of libraries containing hun-dreds of thousands or even millions of compounds fortheir ability to interact with a specific molecular target or elicit a specific biological response (see “Targets of Drug Action” later in the chapter). Chemical libraries are synthesized using modern organic chemical syn-thetic approaches such as combinatorial chemistry to create large collections of related chemicals, which can then be screened for activity in high-throughput systems. Diversity-oriented synthetic approaches also are of obvious value, while natural products (plant or marine animal collections) are sources of novel and sometimes exceedingly complex chemical structures. 

Automated screening procedures employing robotic systems can process hundreds of thousands of samples in just a few days. Reactions are carried out in small trays containing a matrix of tiny wells (typically 384 or 1536). Assay reagents and samples to be tested are coated onto plates or distributed by robots, using ink-jet technology. Tiny volumes are used and chemical samples are thus conserved. The assay must be sensitive, specific, and designed to yield a readily detectable signal, usually a change in absorption or emission of light (fluorescence, luminescence, phosphorescence) or alteration of a radioactive substrate. The signal may result from the interaction of a candidate chemical with a specific protein target, such as an enzyme or a biological receptor protein that one hopes to inhibit or activate with a drug. Alternatively, cell-based high-throughput screens may be performed. For example, a cell may be engineered to emit a fluorescent signal when Ca2+ fluxes into the cell as a result of a ligand-receptor interaction. Cellular engineering is accomplished by transfecting the necessary genes into the cell, enabling it to perform the functions of interest. It is of enormous value that the specific protein target in an assay or the molecules used to engineer a cell for a high-throughput screen are of human origin, obtained by transcription and translation of the cloned human gene. The potential drugs that are identified in the screen (“hits”) are thus known to react with the human protein and not just with its rel-ative (ortholog) obtained from mouse or another species. 

Several variables affect the frequency of hits obtained in a screen. Among the most important are the “drugability” of the target and the stringency of the screen in terms of the concentrations of compounds that are tested. The slang term “drugability” refers to the ease with which the function of a target can be altered in the desired fashion by a small organic molecule. If the protein target has a well-defined binding site for a small molecule (e.g., a catalytic or allosteric site), chances are excellent that hits will be obtained. If the goal is to employ a small molecule to mimic or disrupt the interaction between two proteins, the challenge is much greater. 


From Hits to Leads


Only rarely do any of the initial hits in a screen turn out to be marketable drugs. Initial hits often have modest

affinity for the target, and lack the desired specificity and pharmacological properties of a successful phar-maceutical. Skilled medicinal chemists synthesize derivatives of the hits, making substitutions at accessi-ble positions, and begin in this way to define the rela-tionship between chemical structure and biological activity. Many parameters may require optimization, including affinity for the target, agonist/antagonist activity, permeability across cell membranes, absorp-tion and distribution in the body, metabolism of the drug, and unwanted effects. While this approach was driven largely by instinct and trial and error in the past, modern drug development frequently takes advantage of determination of a high-resolution structure of the putative drug bound to its target. X-ray crystallography offers the most detailed structural information if the tar-get protein can be crystallized with the lead drug bound to it. Using techniques of molecular modeling and com-putational chemistry, the structure provides the chemist with information about substitutions likely to improve the “fit” of the drug with the target and thus enhance the affinity of the drug for its target (and, hopefully, optimize selectivity of the drug simultaneously). Nuclear magnetic resonance (NMR) spectroscopy is another valuable technique for learning the structure of a drug-receptor complex. NMR studies are done in solution, with the advantage that the complex need not be crystallized. However, the structures obtained by NMR spectroscopy usually are not as precise as those from X-ray crystallography, and the protein target must not be larger than roughly 35–40 kDa. 

The holy grail of this approach to drug invention will be to achieve success entirely through computation. Imagine a database containing detailed chemical infor-mation about millions of chemicals and a second data-base containing detailed structural information about all human proteins. The computational approach is to “roll” all the chemicals over the protein of interest to find those with high-affinity interactions. The dream gets bolder if we acquire the ability to roll the chemicals that bind to the target of interest over all other human proteins to discard compounds that have unwanted interactions. Finally, we also will want to predict the structural and functional consequences of a drug bind-ing to its target (a huge challenge), as well as all rele-vant pharmacokinetic properties of the molecules of interest. We are a long way from realization of this fab-ulous dream; however, we are sufficiently advanced to imagine it and realize that it could someday be a reality. Indeed, computational approaches have suggested new uses for old drugs and offered explanations for recentfailures of drugs in the later stages of clinical develop-ment (e.g., torcetrapib; see below) (Kim et al., 2010; Kinnings et al., 2009; Xie et al., 2007, 2009).

Large Molecules Are Increasingly

Important

Protein therapeutics were uncommon before the advent of recombinant DNA technology. Insulin was intro-duced into clinical medicine for the treatment of dia-betes following the experiments of Banting and Best in 1921. Insulin could be produced in great quantities by purification from porcine or bovine pancreas obtained from slaughter houses. These insulins are active in man, although antibodies to the foreign proteins are occa-sionally problematic.

Growth hormone, used to treat pituitary dwarfism, is a case of more stringent species specificity: only the human hormone could be used after purification from pituitary glands harvested during autopsy. The danger of this approach was highlighted when patients who had received the human hormone developed Creutzfeldt-Jakob disease (the human equivalent of mad cow dis-ease), a fatal degenerative neurological disease caused by prion proteins that contaminated the drug prepara-tion. Thanks to gene cloning and the ability to produce large quantities of proteins by expressing the cloned gene in bacteria or eukaryotic cells grown in enormous (30,000-liter) bioreactors, protein therapeutics now uti-lize highly purified preparations of human (or human-ized) proteins. Rare proteins can now be produced in quantity, and immunological reactions are minimized. Proteins can be designed, customized, and optimized using genetic engineering techniques. Other types of macromolecules may also be used therapeutically. For example, antisense oligonucleotides are used to block gene transcription or translation, as are small interfering RNAs (siRNAs). 

Proteins utilized therapeutically include various hormones, growth factors (e.g., erythropoietin, granulo-cyte-colony stimulating factor), and cytokines, as well as a rapidly increasing number of monoclonal antibodies now widely used in the treatment of cancer and autoim-mune diseases. Murine monoclonal antibodies can be “humanized” (by substituting human for mouse amino acid sequences). Alternatively, mice have now been “engineered” by replacement of critical mouse genes with their human equivalents, such that they make com-pletely human antibodies. Protein therapeutics are administered parenterally, and their receptors or targets must be accessible extracellularly. 

The earliest drugs came from observation of the effects of plants after their ingestion by animals. One could observe at least some of the effects of the chemical(s) in the plant and, as a side benefit, know that the plant extract was active when taken orally. Valuable drugs were discovered with no knowledge of their mechanism or site of action. While this approach is still useful (e.g., in screening for the ability of natural products to kill microorganisms or malignant cells), modern drug invention usually takes the opposite approach—starting with a statement (or hypothesis) that a certain protein or pathway plays a critical role in the pathogenesis of a certain disease, and that altering the protein’s activity would therefore be effective against that disease. Crucial questions arise:

can one find a drug that will have the desired effect against its target?

does modulation of the target protein affect the course of disease?

does this project make sense economically?


    


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