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INTRODUCTION

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The first edition of Goodman & Gilman 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 chemical 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 section provides the underpinnings for these definitions by exploring the processes of drug invention, followed by the basic properties of the interactions between the drug and biological systems: pharmacodynamics, pharmacokinetics (including drug transport and metabolism), and pharmacogenomics. Subsequent sections deal with the use of drugs as therapeutic agents in human subjects.

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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 conventional term discovery, is intentional. 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.

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FROM EARLY EXPERIENCES WITH PLANTS TO MODERN CHEMISTRY

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The human fascination—and sometimes infatuation—with chemicals that alter biological function is ancient and results from long experience with and dependence on plants. Many plants produce harmful compounds for defense that animals have learned to avoid and humans to exploit.

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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 and the deadly nightshade plant by professional poisoners; of belladonna ("beautiful lady") to dilate pupils; of the Chinese herb ma huang (containing ephedrine) as a circulatory stimulant; of curare by South American Indians to paralyze and kill animals hunted for food; and of poppy juice (opium) containing morphine (from the Greek Morpheus, the god of dreams) for pain relief and control of dysentery. Morphine, of course, has well-known addicting properties, mimicked in some ways by other problematic ("recreational") natural products—nicotine, cocaine, and ethanol.

Although terrestrial and marine organisms remain valuable sources of compounds with pharmacological activities, drug invention became more allied with synthetic organic chemistry as that discipline flourished over the past 150 years, beginning in the dye industry. Dyes are colored 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 invention of arsphenamine in 1907, which was patented as "salvarsan," suggestive of the hope ...

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