Goodman & Gilman's: The Pharmacological Basis of Therapeutics / Edition 9 available in Hardcover
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Chapter 1: PharmacokineticsThe potential nonequivalence of different drug preparations has been a matter of concern. Strengthened regulatory requirements have resulted in few, if any, documented cases of nonequivalence between approved drug products. The significance of possible nonequivalence of drug preparations is further discussed in connection with drug nomenclature and the choice of drug name in writing prescription orders (see Appendix 1).
Distribution of Drugs
After a drug is absorbed or injected into the bloodstream, it may be distributed into interstitial and cellular fluids. Patterns of drug distribution reflect certain physiological factors and physicochemical properties of drugs. An initial phase of distribution may be distinguished that reflects cardiac output and regional blood flow. Heart, liver, kidney, brain, and other well-perfused organs receive most of the drug during the first few minutes after absorption. Delivery of drug to muscle, most viscera, skin, and fat is slower, and these tissues may require several minutes to several hours before steady state is attained. A second phase of drug distribution may therefore be distinguished; this is also limited by blood flow, and it involves a far larger fraction of the body mass than does the first phase. Superimposed on patterns of distribution of blood flow are factors that determine the rate at which drugs diffuse into tissues. Diffusion into the interstitial compartment occurs rapidly because of the highly permeable nature of capillary endothelial membranes (except in the brain). Lipid-insoluble drugs that permeate membranes poorly are restricted in their distribution and hence in theirpotential sites of action. Distribution also may be limited by drug binding to plasma proteins, particularly albumin for acidic drugs and al-acid glycoprotein for basic drugs. An agent that is extensively and strongly bound has limited access to cellular sites of action, and it may be metabolized and eliminated slowly. Drugs may accumulate in tissues in higher concentrations than would be expected from diffusion equilibria as a result of pH gradients, binding to intracellular constituents, or partitioning into lipid.
Drug that has accumulated in a given tissue may serve as a reservoir that prolongs drug action in that same tissue or at a distant site reached through the circulation. An example that illustrates many of these factors is the use of the intravenous anesthetic thiopental, a highly lipid-soluble drug. Because blood flow to the brain is so high, the drug reaches its maximal concentration in brain within a minute after it is injected intravenously. After injection is concluded, the plasma concentration falls as thiopental diffuses into other tissues, such as muscle. The concentration of the drug in brain follows that of the plasma, because there is little binding of the drug to brain constituents. Thus, onset of anesthesia is rapid, but so is its termination. Both are directly related to the concentration of drug in the brain. A third phase of distribution for this drug is due to the slow, blood-flow-limited uptake by fat. With administration of successive doses of thiopental, accumulation of drug takes place in fat and other tissues that can store large amounts of the compound. These can become reservoirs for the maintenance of the plasma concentration, and therefore the brain concentration, at or above the threshold required for anesthesia. Thus, a drug that is short acting because of rapid redistribution to sites at which the agent has no pharmacological action can become long acting when these storage sites are "filled" and termination of the drug's action becomes dependent on biotransformation and excretion (see Benet, 1978).
Since the difference in pH between intracellular and extracellular fluids is small (7.0 vs. 7.4), this factor can result in only a relatively small concentration gradient of drug across the plasma membrane. Weak bases are slightly concentrated inside of cells, while the concentration of weak acids is slightly lower in the cells than in extracellular fluids. Lowering the pH of extracellular fluid increases the intracellular concentration of weak acids and decreases that of weak bases, provided that the intracellular pH does not also change and that the pH change does not simultaneously affect the binding, biotransformation, or excretion of the drug. Elevating the pH produces the opposite effects (see Figure 1-2).
Central Nervous System and Cerebrospinal Fluid.
The distribution of drugs to the CNS from the bloodstream is unique, mainly in that entry of drugs into the cerebrospinal fluid and extracellular space of the CNS is restricted. The restriction is similar to that across the gastrointestinal epithelium. Endothelial cells of the brain capillaries differ from their counterparts in most tissues by the absence of intercellular pores and pinocytotic vesicles. Tight junctions predominate, and aqueous bulk flow thus is severely restricted. This is not unique to the CNS capillaries (tight junctions appear in many muscle capillaries as well). It is likely that the unique arrangement of pericapillary glial cells also contributes to the slow diffusion of organic acids and bases into the CNS. The drug molecules probably must traverse not only endothelial but also perivascular cell membranes before reaching neurons or other target cells in the CNS. Cerebral blood flow is the only limitation to permeation of the CNS by highly lipidsoluble drugs. The rate of diffusion of drugs with increasing polarity into the CNS is proportional to the lipid solubility of the nonionized species.
Strongly ionized agents such as quaternary amines are normally unable to enter the CNS from the circulation. In addition, organic ions are extruded from the cerebrospinal fluid into blood at the choroid plexus by transport processes similar to those in the renal tubule. Lipid-soluble substances leave the brain by diffusion through the capillaries and the blood-choroid plexus boundary. Drugs and endogenous metabolites, regardless of lipid solubility and molecular size, also exit with bulk flow of the cerebrospinal fluid through the arachnoid villi.
The blood-brain barrier is adaptive in that exclusion of drugs and other foreign agents such as penicillin or tubocurarine protects the CNS against severely toxic effects. However, the barrier is neither absolute nor invariable. Very large doses of penicillin may produce seizures; meningeal or encephalic inflammation increases the local permeability. Maneuvers to increase permeability of the bloodbrain barrier potentially are important to enhance the efficacy of chemotherapeutic agents that are used to treat infections or tumors localized in the brain.
Drug Reservoirs. As mentioned, the body compartments in which a drug accumulates are potential reservoirs for the drug. If stored drug is in equilibrium with that in plasma and is released as the plasma concentration declines, a concentration of the drug in plasma and at its locus of action is sustained, and pharmacological effects of the drug are prolonged. However, if the reservoir for the drug has a large capacity and fills rapidly, it so alters the distribution of the drug that larger quantities of the drug are required initially to provide a therapeutically effective concentration in the target organ.
Plasma Proteins. Many drugs are bound to plasma proteins, mostly to plasma albumin for acidic drugs and to atacid glycoprotein for basic drugs; binding to other plasma proteins generally occurs to a much smaller extent. The binding is usually reversible; covalent binding of reactive drugs such as alkylating agents occurs occasionally.
The fraction of total drug in plasma that is bound is determined by the drug concentration, its affinity for the binding sites, and the number of binding sites. Simple mass-action equations are used to describe the free and bound concentrations (see Chapter 2). At low concentrations of drug (less than the plasma protein-binding dissociation constant), the fraction bound is a function of the concentration of binding sites and the dissociation constant. At high drug concentrations (greater than the dissociation constant), the fraction bound is a function of the number of binding sites and the drug concentration. Therefore, statements that a given drug is bound to a specified extent apply only over a limited range of concentrations. The percentage values listed in Appendix II refer only to the therapeutic range of concentrations for each drug...
Table of ContentsPharmacokinetics
Principles of Toxicology
Principles of Therapeutics
Cholinergic Agonists and Antimuscarinic Drugs
Neuromuscular Junction Agents and Antonomic Ganglia
Catecholamines, Sympathomimetric Drugs and Adrenergic Receptor Antagonists
5-Hydroxytryptamine (Serotonim) and Receptor Antagonists
Neurohumoral Transmission and The Central Nervous System
History and Principles of Anesthesiology
Hypnotics and Sedatives, Ethanol
Drugs and The Treatment of Psychiatric Disorders-Mood Disorders
Drugs Effective in the Therapy of The Epilepsies
Drugs Effective in the Therapy of Migraines
Treatment of CNS Degenerative Diseases
Opioid Analgesics and Antagonists
Drug Addiction and Drug Abuse
Histamine, Bradykinin and Theur Antagonists
Drugs Used in the Treatment of Asthma
Analgesic-Antipyretics and Anti-Inflammatory Agents
Diuretics and Other Agents Employed in the Mobilization of Edema Fluid
Agents Affecting the Renal Conservation of Water
Renin and Angiotensin
Drugs Used for the Treatment of Angina
Antihypertensive Agents and the Drug Therapy of Hypertension
Drug Therapy of Congestive Heart Failure
Drugs Used in the Treatment of Hyperlipoproteinemias
Agents for Control of Gastric Acidity and Treatment of Peptic Ulcers
Agents Affecting Gastrointestinal Water Flux and Motility, Digestants and Bile Acids
Oxytocin, Prostaglandins, Ergot Alkaloids and Other Drugs: TocolyticAgents
Drugs Used in the Chemotherapy of Heiminthiasis
Drugs Used in the Chemotherapy of Protozoal Infections
Anticoagulant, Thromboly-Tic and Antiplatelet Drugs
Adenophyseal Hormones and Related Substances
Thyroid and Antithyroid Drugs
Estrogens and Progestins
Adrenocorticotrophic Hormone: Adrenocortical Steroids and Their Synthetic Analogs
Insulin, Oral Hypoglycemic Agents and The Pharmacology of the Endocrine Pancreas
Agents Affecting Calcification and Bone Turnover
Heavy Metals and Heavy Metal Antagonists
Nonmetallic Environmental Toxicants
Appendices: Principles of Prescription Order Writing and Patient Compliance Instructions
Design and Optimization of Dosage Regimens
Some changes have been made in this edition to facilitate achievement of these objectives. For example, each of the chapters has been reviewed by at least one physician, expert in the clinical areas treated by the agents discussed, and by a pharmacist. These physician and pharmacist reviewers, to whom the editors are grateful, are identified in the pages following the list of contributing authors. Each chapter begins with a Synopsis in an effort to link the contents of that chapter with other chapters in the book where complementary material is discussed. The pace at which new knowledge is being obtained is ever accelerating and has led to the addition of a Prospectus at the end of most chapters. It is largely in these sections that conceptual advances or therapeutic agents in early clinical trials are mentioned, with the intent of helping readers of this book search the biomedical literature for updated information during the period before the publication of the tenth edition.
Several new chapters have been added. In the section "General Principles" (SectionI), a chapter has been added on the principles of gene therapy. Whether or not gene therapy ultimately achieves all that is hoped for it, its clinical strategies nonetheless may reveal insights into the molecular bases of disease in a setting that otherwise could not be achieved by studies in animal models or in healthy human volunteers. The identification of diverse serotonin receptor subtypes and clarification of the roles of different subtypes in the central nervous system and gastrointestinal tract encouraged us to include a new chapter on serotonin receptor agonists and antagonists. We also have added new chapters on the treatment of migraine and on ocular pharmacology. As in previous editions, each chapter in the book emphasizes therapeutic advances permitted by newly marketed drugs and some investigational agents. The compilation of pharmacokinetic data (Appendix II) includes 335 agents, of which 91 are new entries.
We are grateful to Dr. Perry B. Molinoff and Dr. Raymond W. Ruddon, our editorial colleagues, whose insightful advice and dedicated efforts in editing this volume were essential to its completion. We, of course, are greatly indebted to all of the contributors to this edition, in particular to those who delivered their chapters by or before the requested deadline. In addition to the editors and contributors, three other individuals played a vital role in the production of this edition. Edna M. Kunkel worked as both graphic artist and editorial assistant and was assisted in the latter role by Jane C. Almon. Lauralea Edwards, D.Ph., was exhaustive in her efforts to document the references and to assure accuracy of pharmaceutical information included in this edition, particularly agents released for clinical use in the United States during the course of the book's preparation and agents in use in other countries. Without the tireless and highly skillful work of these three individuals, the timely completion of this book would not have been possible. We also appreciate the encouragement, efforts, and "final push" provided by Martin Wonsiewicz and Peter McCurdy of McGraw-Hill.
Finally, we are extremely grateful for the enthusiasm, wisdom, encouragement, and friendship of our consulting editor. Dr. Alfred Goodman Gilman. We were and remain, even at its conclusion, intimidated by the daunting task of editing this book. Now fully aware of the effort required, we are even more in awe of Dr. Gilman's editing of previous editions of this book and flattered by his willingness to entrust the editing of this edition to us. The ninth edition is dedicated to Dr. Alfred Goodman Gilman in recognition of his contributions to this and previous editions of this book, to the field of pharmacology, and to science in general.
Joel G. Hardman
Lee E. Limbird