The first edition of this textbook, published in 1941, is often credited with organizing the field of pharmacology, giving it intellectual validity and an academic identity. That first 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." 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 development into a therapeutic entity, 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.
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 suggested to us by our colleague Michael S. Brown, MD, and it is appropriate. In the past, drugs were discovered as natural 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.
*Alfred G. Gilman serves on the Board of Directors of Eli Lilly & Co. and Regeneron Pharmaceuticals, and acknowledges potential conflicts of interests.
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 syntheses, 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 alkaloids atropine and scopolamine) by professional poisoners, 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 products—nicotine, cocaine, and ethanol.
While many terrestrial and marine organisms remain valuable sources of naturally occurring compounds with various pharmacological activities, especially 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 revolution began in the dye industry. Dyes, by definition, 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 that the chemical would be the salvation of humankind. This arsenic-containing 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 infections. 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.
Small Molecules Are the Tradition
With the exception of a few naturally occurring hormones 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, starting in the 1980s. The usual approach to invention of a small-molecule drug is to screen a collection of chemicals ("library") for compounds with the desired features. 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 animals or ingested by man, the approach today relies on high-throughput screening of libraries containing hundreds of thousands or even millions of compounds for their 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 synthetic 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, ...