GOODMAN & GILMAN'S THE PHARMACOLOGICAL Basis of THERAPEUTICS THIRTEENTH EDITION

GOODMAN & GILMAN'S THE PHARMACOLOGICAL Basis of THERAPEUTICS THIRTEENTH EDITION

The first edition of this book appeared in 1941, the product of a collaboration between two friends and professors at Yale, Louis Goodman and Alfred Gilman. Their purpose, stated in the preface to that edition, was 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 applications of pharmacodynamics to therapeutics, and to create a book that would be useful to students of pharmacology and to physicians. We continue to follow these principles in the 13th edition.

The 1st edition was quite successful despite its high price, $12.50, and soon became known as the “blue bible of pharmacology.” The book was evidence of the deep friendship between its authors, and when the Gilmans’ son was born in 1941, he was named Alfred Goodman Gilman. World War II and the relocation of both authors—Goodman to Utah, Gilman to Columbia—postponed a second edition until 1955. The experience of writing the second edition during a period of accelerating basic research and drug development persuaded the authors to become editors, relying on experts whose scholarship they trusted to contribute individual chapters, a pattern that has been followed ever since. 

Alfred G. Gilman, the son, served as an associate editor for the 5th edition (1975), became the principal editor for the 6th (1980), 7th (1985), and 8th (1990) editions, and consulting editor for the 9th and 10th editions that were edited by Lee Limbird and Joel Hardman. After an absence in the 11th edition, Al Gilman agreed to co-author the introductory chapter in the 12th edition. His final contribution to G&G, a revision of that chapter, is the first chapter in this edition, which we dedicate to his memory. 

A multi-authored text of this sort grows by accretion, posing challenges to editors but also offering 75 years of wisdom, memorable pearls, and flashes of wit. Portions of prior editions persist in the current edition, and we have given credit to recent former contributors at the end of each chapter. Such a text also tends to grow in length with each edition, as contributors add to existing text and as pharmacotherapy advances. To keep the length manageable and in a single volume, Dr. Randa Hilal-Dandan and I prepared a shortened version of each chapter and then invited contributors to add back old material that was essential and to add new material. We also elected to discard the use of extract (very small) type and to use more figures to explain signaling pathways and mechanisms of drug action. Not wanting to favor one company’s preparation of an agent over that of another, we have ceased to use trade names except as needed to refer to drug combinations or to distinguish multiple formulations of the same agent with distinctive pharmacokinetic or pharmacodynamic properties. Counter-balancing this shortening are five new chapters that reflect advances in the therapeutic manipulation of the immune system, the treatment of viral hepatitis, and the pharmacotherapy of cardiovascular disease and pulmonary artery hypertension. 

Editing such a book brings into view a number of overarching issues: Over-prescribing of antibiotics and their excessive use in agricultural animal husbandry continues to promote the development of antimicrobial resistance; the application of CRISPR/cas9 will likely provide new therapeutic avenues; global warming and the sheer size of the human population require medical scientists and practitioners to promote remedial and preventive action based on data, not ideology.

A number of people have made invaluable contributions to the preparation of this edition. My thanks to Randa Hilal-Dandan and Bjorn Knollmann for their editorial work; to Harriet Lebowitz of McGraw-Hill, who guided our work, prescribed the updated style, and kept the project moving to completion; to Vastavikta Sharma of Cenveo Publishers Services, who oversaw the copy editing, typesetting, and preparation of the artwork; to Nelda Murri, our consulting pharmacist, whose familiarity with clinical pharmacy is evident throughout the book; to James Shanahan, publisher at McGraw-Hill, for supporting the project; and to the many readers who have written to critique the book and offer suggestions.

Drug Invention and the Pharmaceutical Industry

The first edition of Goodman & Gilman, published in 1941, helped to organize the field of pharmacology, giving it intellectual validity and an academic identity. That edition began: “The subject of pharmacology is a broad one and embraces the knowledge of the source, physical and chem-ical properties, compounding, 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.” This General Principles sec-tion provides the underpinnings for these definitions by exploring the processes of drug invention, development, and regulation, followed by the basic properties of the interactions between the drug and biological systems: pharmacodynamics, pharmacokinetics (including drug transport and metabolism), and pharmacogenomics, with a brief foray into drug toxicity and poisoning. Subsequent sections deal with the use of drugs as therapeutic agents in human subjects.

Use of the term invention to describe the process by which a new drug is identified and brought to medical practice, rather than the more con-ventional term discovery, is intentional. Today, useful drugs are rarely discovered hiding somewhere waiting to be found. The term invention emphasizes the process by which drugs are sculpted and brought into being based on experimentation and optimization of many independent properties; there is little serendipity.

Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, Metabolism, and Elimination

The human body restricts access to foreign molecules; therefore, to reach its target within the body and have a therapeutic effect, a drug molecule must cross a number of restrictive barriers en route to its target site. Fol-lowing administration, the drug must be absorbed and then distributed, usually via vessels of the circulatory and lymphatic systems; in addition to crossing membrane barriers, the drug must survive metabolism (pri-marily hepatic) and elimination (by the kidney and liver and in the feces). ADME, the absorption, distribution, metabolism, and elimination of drugs, are the processes of pharmacokinetics (Figure 2–1). Understand-ing these processes and their interplay and employing pharmacokinetic principles increase the probability of therapeutic success and reduce the occurrence of adverse drug events.

The absorption, distribution, metabolism, and excretion of a drug involve its passage across numerous cell membranes. Mechanisms by which drugs cross membranes and the physicochemical properties of mol-ecules and membranes that influence this transfer are critical to under-standing the disposition of drugs in the human body. The characteristics of a drug that predict its movement and availability at sites of action are its molecular size and structural features, degree of ionization, relative lipid solubility of its ionized and nonionized forms, and its binding to serum and tissue proteins. Although physical barriers to drug movement may be a single layer of cells (e.g., intestinal epithelium) or several layers of cells and associated extracellular protein (e.g., skin), the plasma membrane is the basic barrier.

Pharmacodynamics: Molecular Mechanisms of Drug Action

Pharmacodynamics is the study of the biochemical, cellular, and physio-logical effects of drugs and their mechanisms of action. The effects of most drugs result from their interaction with macromolecular components of the organism. The term drug receptor or drug target denotes the cellular macromolecule or macromolecular complex with which the drug interacts to elicit a cellular or systemic response. Drugs commonly alter the rate or magnitude of an intrinsic cellular or physiological response rather than create new responses. Drug receptors are often located on the surface of cells but may also be located in specific intracellular compartments, such as the nucleus, or in the extracellular compartment, as in the case of drugs that target coagulation factors and inflammatory mediators. Many drugs also interact with acceptors (e.g., serum albumin), which are entities that do not directly cause any change in biochemical or physiological response but can alter the pharmacokinetics of a drug’s actions.

A large percentage of the new drugs approved in recent years are therapeutic biologics, including genetically engineered enzymes and mono-clonal antibodies. Going far beyond the traditional concept of a drug are genetically modified viruses and microbes. One recently approved agent for treating melanoma is a genetically modified live oncolytic herpes virus that is injected into tumors that cannot be removed completely by surgery. Gene therapy products using viruses as vectors to replace genetic mutations that give rise to lethal and debilitating diseases have already been approved in China and Europe. The next generation of gene therapy products will be those capable of targeted genome editing using antisense oligonucleotides and RNAi and by delivering the CRISPR/Cas9 genome-editing system using viruses or genetically modified microorganisms. These new agents will have pharmacological properties that are distinctly different from tra-ditional small-molecule drugs.

Drug Toxicity and Poisoning

There is a graded dose-response relationship in an individual and a quan-tal dose-response relationship in the population (see Figures 3–2, 3–3, and 3–6). Graded doses of a drug given to an individual usually result  in a greater magnitude of response as the dose increases. In a quantal dose-response relationship, the percentage of the population affected increases as the dose is increased; the relationship is quantal in that the effect is judged to be either present or absent in a given individual. This quantal dose-response phenomenon is used to determine the LD50 of drugs, as defined in Figure 4–1A.

One can also determine a quantal dose-response curve for the ther-apeutic effect of a drug to generate ED50, the concentration of drug at which 50% of the population will have the desired response, and a quantal dose-response curve for lethality by the same agent (Figure 4–1B). These two curves can be used to generate a TI, which quantifies the relative safety of a drug.



  

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