Goodman and Gilman Clinical Pharmacology - G. Gilman - Practical Guide
Goodman & Gilman Clinical Pharmacology is the leading guide to pharmacology, one of a kind, covering all areas of modern pharmacology, from molecular biology, genetics, biochemistry to physiology and clinical disciplines. This is both a textbook in which the fundamentals of all the listed disciplines are laid out in an extremely clear and concise manner, and a monograph with the appropriate rigor of presentation and citation, and a practical guide suitable for use at the patient's bedside, and an encyclopedia of modern pharmacology written by leading scientists, including several laureates Nobel Prize... One of them is the chief editor of the book, Alfred Goodman Gilman. Goodman and Gilman Clinical Pharmacology is republished every five years, with each new edition being radically updated. The reader is offered modern concepts that set the way for the development of science for many years to come. "Clinical Pharmacology according to Goodman and Gilman" - the second part of the dilogy, ...
Read completelyGoodman & Gilman Clinical Pharmacology is the leading guide to pharmacology, one of a kind, covering all areas of modern pharmacology, from molecular biology, genetics, biochemistry to physiology and clinical disciplines. This is both a textbook in which the fundamentals of all the listed disciplines are set out in an extremely clear and concise manner, and a monograph with appropriate severity of presentation and citation, and a practical guide suitable for use at the patient's bedside, and an encyclopedia of modern pharmacology written by leading scientists, including several Nobel laureates. awards. One of them is the chief editor of the book, Alfred Goodman Gilman. Goodman and Gilman Clinical Pharmacology is republished every five years, with each new edition being radically updated. The reader is offered modern concepts that set the way for the development of science for many years to come. "Clinical Pharmacology according to Goodman and Gilman" is the second part of the dilogy, the first part of which is "Internal Medicine according to Tinsley R. Harrison".
Designed for doctors of all specialties and medical students.
Hormones and their antagonists.
Vitamins.
Dermatological agents.
Ophthalmic agents.
Toxicology.
Modern pharmacology is a huge area of knowledge. It includes physiology, biochemistry, physics and chemistry - without them it is impossible to understand the mechanisms of action of drugs, molecular biology and genetics - without them physiology and biochemistry and, finally, clinical disciplines are unthinkable today.
Pharmacology is closely related to other, non-drug, forms of treatment, since the doctor's task is not to affect a specific cellular receptor, but to lead the patient to recovery, using all available means.
"Clinical Pharmacology according to Goodman and Gilman" is a one-of-a-kind book, for it comprehensively and organically embraces all these aspects. This is both a textbook, in which the fundamentals of all the listed disciplines are set out very clearly and at the same time concisely, and a monograph with the appropriate rigor of presentation and citation, a rich bibliography and critical analysis of modern data, and a practical guide suitable for use at the patient's bedside, and an encyclopedia modern pharmacology, articles of which were written by leading scientists, including several Nobel Prize winners. One of them is the chief editor of the book, Alfred Goodman Gilman.
In subsections " Historical reference"rigor and academicism are combined with a fascinating presentation of vivid episodes from the history of science, cults, rituals - everything that is associated with the use of medicinal substances.
In the sections devoted to the mechanisms of action of drugs, modern genetic, physiological and biochemical theories are presented; thus, the part of the book devoted to vegetative agents begins with a chapter on the physiology of the autonomic nervous system, which examines both the classical concepts of this system and the latest advances in this area. The mechanisms of action are followed by pharmacokinetics and drug interactions - the most important information from a practical point of view, which is not always given due attention.
Finally, the sections devoted to practical issues - indications for the use of drugs, their doses and modes of administration, are written with the expectation of direct practical application, these sections are based primarily on data from controlled trials, but at the same time give the doctor the breadth of outlook that is necessary for freedom of action.
The most subtle and modern therapy will not achieve the goal if the patient does not follow the doctor's prescriptions, therefore, measures are constantly being discussed aimed at creating a convenient regimen for taking medications.
Pharmacology is one of the most rapidly developing areas of medicine.
By the time large monographs are published, many of the data presented in them are beginning to become outdated, but such monographs are nevertheless necessary - not every doctor is able to navigate the huge flow of information published in original articles and reviews. To compensate for this shortcoming, "Clinical Pharmacology" is republished every five years, with each new edition being radically updated. This renewal is not limited to a listing of new facts, because facts become outdated quickly - the reader is offered modern concepts that set the way for the development of science for many years to come.
Many of the data given in the book, especially from the field of molecular and cellular biology, at the time of writing the book have not yet led to the development of new drugs, but their appearance is a matter of the near future, and the doctor, having read the book, will be ready for this. "Clinical Pharmacology according to Goodman and Gilman" is the second part of the most popular dilogy among Western doctors, and the first is "Internal Medicine according to Tinsley R. Harrison".
By publishing the book, the Praktika Publishing House completes the cycle of work on this dilogy, providing the reader with a complete description of the foundations of modern medicine.
Hormones and anti-hormonal agents. Pituitary and hypothalamic hormones. Thyroid hormones and antithyroid drugs. Estrogens and progestogens. Androgens. Adrenocorticotropic hormone, glucocorticoids and their antagonists. Insulin and other pancreatic hormones. Oral hypoglycemic drugs. Agents affecting calcium metabolism and bone metabolism
Vitamins... Water-soluble vitamins. Fat-soluble vitamins
Dermatological agents
Ophthalmic agents
Clinical toxicology. Heavy metal poisoning. Other poisoning
Goodman & Gilman Clinical Pharmacology is the leading manual of pharmacology, one of a kind, covering all areas of modern pharmacology - from molecular biology, genetics, biochemistry to physiology and clinical disciplines. It is also a textbook in which it is extremely clear and concise sets out the fundamentals of all the disciplines listed, a monograph with appropriate severity of presentation and citation, and a practical guide suitable for use at the patient's bedside, and an encyclopedia of modern pharmacology, written by leading scientists, including several Nobel laureates, one of whom is the editor-in-chief of the book, Alfred Goodman Gilman. "Clinical Pharmacology" is reprinted every five years, with each new edition being radically updated. The reader is offered modern concepts that set the way for the development of science for many years to come. "" Clinical Pharmacology "is the second part of the dilogy, the first part of which are "" Internal b diseases according to Tinsley R. Harrison "". Designed for doctors of all specialties and medical students. ISBN (Russian) - 5-89816-063-9 (volume 2), 5-89816-069-8 (edition) ISBN (English) - 0-07-135469-7 This volume includes: ANTI-INFLAMMATORY AND ANTI-ALLERGIC DRUGS AFFECTING THE EXTRACTIVE AND CARDIOVASCULAR SYSTEM MEANS AFFECTING THE DIGESTIVE SYSTEM
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D GOODMAN AND GILMAN "S ARMACOLOGICA BASIS OF RA D CS Tenth edition Editors Joel G. Hardman, Ph.D. Professor of Pharmacology, Emeritus Vanderbilt University Medical Center Nashville, Tennessee Lee E. Limbird, Ph.D. Professor of Pharmacology Associate Vice Chancellor for Research Vanderbilt University Medical Center Nashville, Tennessee Consulting Editor Alfred Goodman Gilman, MD, Ph.D., D.Sc. (Hon .; Raymond and Ellen Willie Distinguished Chair in Molecular Neuropharmacology Regental Professor and Chairman, Department of Pharmacology University of Texas Southwestern Medical Center Dallas, Texas McGraw-Hill Medical Publishing Division New York Chicago San Francisco Lisbon London Madrid Mexico City Milan New Delhi San Juan Seoul Singapore Sydney Toronto u EC KAYA ARMAKOLOSHYA by Goodman and Gilman Book Two Edited by A. Gilman Editors J. Hardman and L. Limberd Translation from English under the general editorship of the candidate medical sciences N. N. Alipova Translation editors: T. V. Meleshenko, Ph.D. D. S. Benevolensky, E. M. Makarenko practice Moscow 2006 LBC 52.8 K 49 Medicine is a rapidly renewing science. Research is underway, clinical experience is accumulating, new drugs and treatment methods are emerging. The authors and editor have done everything possible to ensure that the book includes the most up-to-date and comprehensive information. But due to the fact that no one is immune from mistakes, and medical science is constantly developing, neither the authors, nor the editor, nor other persons who worked on the book can guarantee its absolute flawlessness and do not take responsibility for any errors or omissions. and also for the consequences of using the information given in the book. We strongly encourage readers to consult other sources of information in addition to this book. When prescribing medicines, especially new or rarely used medicines, carefully read the instructions included in the package. The editors would like to thank Dr.M. Zh.Yu. Alyabyev, Ph.D. n. M. A. Slinkina, Ph.D. n. E.R. Timofeev and N.A.Fyodorov for their help in the work on the book. Consultant Ph.D. US Abdurakhmanov Technical editor D. V. Prishchepa Artists E. R. Gor, O. L. Lozovskaya Proofreaders N. N. Yudina, Yu. M. Gizatullina License ЛР№ 065635 dated 19.01.1998 Publishing house "Praktika", 119048, Moscow, P.O. Box 421. Tel .: 101-22-04, 203-97-62. Signed for printing on 11.01.2006. Format 84x108 / 16. Circulation 10,000 copies. Order No. 1658. Printed at OJSC “Printing House“ Novosti ”105005, Moscow, st. Fr. Engels, 46 Series "Classics of modern medicine" No. 5 Clinical pharmacology according to Goodman and Gilman. Edited by A. G. Gilman, editors J. Hardman and L. Limberd. In four volumes. Per. from English - M .. Practice, 2006. - 336 p. K 49 Goodman & Gilman Clinical Pharmacology is the leading guide to pharmacology, one of a kind, covering all areas of modern pharmacology - from molecular biology, genetics, biochemistry to physiology and clinical disciplines. This is both a textbook in which the fundamentals of all the listed disciplines are set out in an extremely clear and concise manner, and a monograph with appropriate severity of presentation and citation, and a practical guide suitable for use at the patient's bedside, and an encyclopedia of modern pharmacology written by leading scientists, including several Nobel laureates. awards. One of them is the chief editor of the book, Alfred Goodman Gilman. "Clinical Pharmacology" is reprinted every five years, with each new edition being radically updated. The reader is offered modern concepts that set the way for the development of science for many years to come. "Clinical Pharmacology" is the second part of the dilogy, the first part of which is "Tinsley R. Harrison's Internal Medicine". Designed for doctors of all specialties and medical students. © 2001 by The McGraw-Hill Companies, Inc. © Russian translation and design, Praktika Publishing House, 2006 ISBN (Russian) - 5-89816-063-9 (volume 2), 5-89816-069-8 (edition) TSRN * 89816061 9 ISBN (English .) - 0-07-135469-7 9 785898 160630> CONTENTS Abbreviations and units of measurement VII Authors and translators IX Preface XII Preface to the first edition XIII Part IV ANTI-INFLAMMATORY AND ANTI-ALLERGIC MEDICINES Introduction 502 2 5 Histamine, kinins and drugs suppressing them 502 26 Eicosanoids and platelet activating factor 519 27 Non-steroidal anti-inflammatory drugs and drugs used for gout 533 28 Drugs used for bronchial asthma 566 TJTU DRUGS THAT HAVE EXPERIMENTAL AND CARDIAC SOCIETY 31 DIURETUMORBS1 Drugs acting on the renin-angiotensin system 622 32 Antianginal drugs 649 33 Antihypertensive drugs 671 34 Drugs used in heart failure 694 35 Antiarrhythmic drugs tva 718 36 Lipid-lowering agents 749 Part VI SRVDSHA AFFECTING THE DIGESTIVE SYSTEM 37 Means used for increased acidity of gastric contents, reflux esophagitis and peptic ulcer 777 3 8 Prokinetic and antiemetics. Drugs used in irritable bowel syndrome 787 39 Antidiarrheals and laxatives. Drugs used in chronic inflammatory bowel diseases. Pancreatic enzymes 582 and bile acids 798 607 Index U-1 ABBREVIATIONS AND UNITS OF MEASUREMENT Abbreviations A AV AD ADH ADP ACTH ALA ALAT AMP APF Apr AsAT Asn Asp ATP AHE APTV BCNP Val i / m v WHO vp HIV vp -6-PD GABA HDF Gis G-CSF Gly Gln Glu HMG-CoA reductase GM-CSF GMP GTP DAG two DDT DZLA DNA DOPA dTMP GIT IHD IVL IL Ile IMF IF3 IGF cDNA CoA COMT ld ctglyar Lactose Lys blood pressure antidiuretic hormone HDL LDL VLDL adenosine adrenocorticotropic hormone LPPP alanine LSD alanine adenosine LFK angiotensin-converting enzyme MAO MAK arginine aspartate MBC asparagine aspartic acid Met ICD adenosine M-CSF acetylcholinesterase activated partial tromboplastino- MHO howling time bacille Calmette-Guerin MOD valine IPC intravenous mRNA vasoactive intestinal polypeptide MRI human immunodeficiency virus MSH intramuscularly NAD World Organization health care NADP excitatory postsynaptic potential - NSAIDs cyal guanosine OPN glucose-6-phosphate dehydrogenase OPSS y-aminobutyric acid guanosine diphosphate O CK histidine PV granulocyte colony-stimulating p / c factor Pro glycine PTH-glutamic acid PFC gluta - Macrophage column - rRNA stimulating factor Ser guanosine monophosphate GFR guanosine triphosphate CSF 1,2-diacylglycerol ESR disseminated intravascular coagulation - AIDS coagulation STH dichlorodiphenyltrichloroethane T pressure of pulmonary artery wedging TGPA gastric acid deoxyribonite RNA lung Trp interleukin TSH isoleucine TTF inosine monophosphate TELA inositol-1,4,5-triphosphate Y insulin-like growth factor UDP complementary DNA ^ Ultrasound coenzyme A UMP catechol-O-methyltransferase UTP computed tomography UV-A cream Tin phosphokinase luteinizing hormone lactate dehydrogenase leucine lysine high-density lipoproteins low-density lipoproteins international very low-density lipoproteins intermediate density lipoproteins lysergic acid diethylamide (LSD) physiotherapy exercise minimal alveoxolar concentration minimal concentration of diseases macrophage Respiratory minimum inhibitory concentration messenger RNA (messenger RNA) magnetic resonance imaging melanocyte-stimulating hormone nicotinamide adenine dinucleotide nicotinamide adenine dinucleotide nonsteroidal anti-inflammatory drugs acute renal failure total peripheral vascular resistance circulating time subcutaneous prothrombin area nd adult distress syndrome radioimmunoassay ribonucleic acid ribosomal RNA series glomerular filtration rate cerebrospinal fluid erythrocyte sedimentation rate p syndrome self-discipline ... The book owes such high praise not to a systematic presentation of individual facts, but to an attempt to summarize pharmacological knowledge and apply scientific concepts in clinical practice. The early authors of Clinical Pharmacology, Louis S. Goodman and Alfred Gilman, were outstanding scientists, brilliant educators and wise mentors, yet many consider this book to be their greatest achievement. The truth of this opinion is supported by the very fact that Clinical Pharmacology has already gone through 10 editions. 7th edition A985) was dedicated to Alfred Gilman, who died shortly before the book was published. The eighth edition of A990) was dedicated to Louis Goodman, who had by that time ceased his work as principal editor of the book. Louis Goodman passed away in November 2000. We will forever remember his brilliant mind, the highest erudition, sharp humor, impeccable taste and ability to captivate and lead. We again dedicate the next edition of Clinical Pharmacology to Louis Goodman and Alfred Gilman - with gratitude for their wise mentoring and with the hope that the goals set for the first edition of the book will be achieved in this and subsequent editions. If the successors of these two eminent scientists abide by their foundations, Goodman & Gilman Clinical Pharmacology will always be an invaluable guide for physicians and researchers. June 5, 2001 A.G. Gilman, J.G. Hardman, L.E. Limberd XII PREFACE TO THE FIRST EDITION When writing this book, we set ourselves three tasks: clinical use of drugs in the light of the latest scientific advances, pay special attention to the application of the principles of pharmacodynamics in drug therapy. Although pharmacology is a completely independent medical science, it borrows a lot from other theoretical and clinical disciplines and, in turn, generously shares its achievements with them. Therefore, it is so important to present the actual pharmacological data in the manuals on pharmacology in the light of the achievements of other medical sciences. Further, in modern manuals on pharmacology, it is important not only to describe new drugs, but also to constantly review the mechanisms of action and clinical application of already known drugs in terms of the latest scientific data. Sometimes this requires a departure from widespread but outdated views. Finally, as the title of the book suggests, it focuses on the clinical aspects of pharmacology. Indeed, it is important for the medical student to understand the mechanisms of action of drugs in terms of treatment and prevention of disease; the pharmacological data alone are meaningless to him if he cannot apply them in practice. This book is also written for medical practitioners and provides them with information on the latest advances in drug therapy. A few words should be said about the principles of choosing the cited literature. It would be absurd, and simply impossible, to try to cite sources for all the facts contained in the book. Therefore, we gave preference to reviews, articles on new drugs, and primary sources on the most controversial issues. In most cases, the latest articles are cited, mostly written in English. We are deeply grateful to many of our colleagues at Yale School of Medicine for their generous help and critical remarks ... A special thanks go to Professor Henry Gray Barber, whose advice and continued support has been invaluable. New Haven, pcs. Connecticut, November 20, 1940 Louis S. Goodman, Alfred Gilman XIII PART IV ANTI-INFLAMMATORY AND ANTI-ALLERGIC DRUGS J. Morrow, J. Roberts II the body's reactions to tissue damage. We will also consider drugs that inhibit the production of these substances or block their action. In ch. 25 discusses histamine and bradykinin. Another inflammatory mediator, serotonin (E-hydroxytryptamine), is described in Ch. 11. Eicosanoids (prostaglandins, thromboxanes, leukotrienes) and platelet activating factor, which are formed during hydrolysis of membrane phospholipids, are discussed in Ch. 26. Ch. 27 is devoted to NSAIDs, including those that selectively inhibit inducible cyclooxygenase (cyclooxygenase-2); the action of these drugs is based on the blockade of the synthesis of prostaglandins and thromboxanes. In ch. 28 describes the treatment of bronchial asthma, including new principles that have emerged with the awareness of its inflammatory nature. This section discusses substances that are normally present in the body or can be synthesized in it. All of them are involved in humoral regulation, but they cannot be classified as hormones or neurotransmitters. As a rule, they quickly break down and act in a par- crine manner, which is why they are often called topical hormones. Unlike true hormones that are carried to target cells through the systemic circulation, these substances often do not enter the bloodstream, for example, they act within an inflammatory focus. For these reasons, we find the term autacoid apt, from the Greek words autos (self) and akos (medicine). The allocation of autacoids into a separate group is controversial for many reasons. First, it did not include many peptides produced by specialized cells of some endocrine glands and exocrine glands of the gastrointestinal tract, which mainly act on nearby cells. They are commonly referred to as paracrine hormones; these include, in particular, somatostatin. Histamine also performs important paracrine functions, regulating the secretion of hydrochloric acid in the stomach (Chapter 37). Secondly, many autakoids act not only paracrinally, but are also transferred to some target cells through the systemic circulation, which means that they can be called hormones. Thirdly, this group did not include numerous cytokines that play an important role in humoral and cellular immunity. They are also mediators of inflammation and are involved in local humoral regulation. Ch. Is devoted to cytokines and substances affecting their production. 53. However, no matter how 502 we call autacoids and similar substances, it is important that they participate in physiological and pathological processes, which means that there are prerequisites for creating drugs that reproduce, suppress their action or affect their synthesis and metabolism ... 25 N. Brown, J. Roberts II HISTAMINE, KININS AND PREPARATIONS THAT SUPPRESS THEIR EFFECT This chapter discusses the role of histamine in health and disease, as well as the use of NG blockers (blockers of histamine NG receptors). H2-blockers, used mainly for the treatment of peptic ulcer disease and the prevention of its recurrence, are described in detail in Ch. 37. We will briefly touch on the functions of the H3 receptors and discuss the recently developed H3 blockers and H3 stimulants; none of them has yet been approved by the FDA for clinical use. The second part of the chapter is devoted to the physiology and pathophysiology of other inflammatory mediators - kinins. To date, two types of kinin receptors have been identified, named Bj and B2, and their selective blockers have been created, to which attention will also be paid. Another inflammatory mediator, serotonin (E-hydroxytryptamine), is discussed in Ch. 11. Histamine Historical background. The histories of histamine (f-aminoethylimidazole) and acetylcholine are remarkably similar. The chemists who synthesized these substances had no idea about their biological significance. Initially, both substances were considered only active components of the ergot extract that caused uterine contractions. They were later isolated from this extract, and it was shown that both histamine and acetylcholine are formed in ergot by bacteria. Studying the properties of histamine, Dale and Laidlaw (1910, 1911) found that it stimulates the contraction of many smooth muscles and at the same time has a strong vasodilator effect. They drew attention to the fact that sensitized animals immediately after the introduction of a normally inert protein developed symptoms resembling histamine poisoning. These data were explained many years later, when it was discovered that histamine is contained in the body and is released during immediate allergic reactions and tissue damage. Only in 1927 Best et al. (Best, 1927) isolated histamine from very fresh samples of the lungs and liver and thus proved that it is a natural constituent of the body. It was soon shown to be found in many other tissues, hence its name - histamine (from the Greek histos - tissue). Meanwhile, Lewis et al. have accumulated a lot of data that a substance with the same properties as histamine ("substance H") is released from skin cells when damaged, including during the antigen-antibody reaction (Lewis, 1927). By that time, the presence of histamine in the body was confirmed chemical methods, and it was no longer difficult to prove that the "substance H" discovered by Lewis is histamine. Today it is generally known that histamine is involved in immediate allergic reactions and regulates the secretion of hydrochloric acid in the stomach. More recently, it has been found that it regulates the release of mediators in the central nervous system and peripheral nervous system ... The old assumptions that the action of histamine is mediated by various receptors was also confirmed; it is obvious that there are at least three types of them - H, (Ash and Schild, 1966), H2 (Black et al., 1972) and H3 (Arrangetal., 1983). The first drugs with anti-histamine activity (for example, mepiramine), created in the 1940s, selectively blocked H] -receptors. In the early 1970s. H2-blockers appeared, and the interest of biologists and doctors in histamine increased again (Chapter 37). Then it was discovered that H3 receptors are located at the presynaptic ends of histaminergic neurons and provide negative feedback, suppressing the synthesis and secretion of histamine itself. The significance of these receptors in histaminergic neurons in vivo was better understood after the development of H3-stimulators and H3-blockers; none of them is used in the clinic yet. Over the past 15 years, second-generation H, blockers have appeared, which do not have a sedative effect and immediately found wide clinical use. Histamine and kinins 503 Chemical properties. Histamine is a hydrophilic molecule that consists of an imidazole ring and an amino group linked by two methylene groups. The active form of the stimulant of all histamine receptors is the monocationic tautomer with a hydrogen atom at N-1 (the charged form of the molecule shown in Figure 25.1), but the interaction with Ng and H2 receptors has its own peculiarities (Ganellin, in Ganellin and Parsons , 1982). Each of the three types of receptors is activated by different histamine analogs (Figure 25.1). Thus, 2-methylhistamine binds predominantly to Hj-receptors, 4E) -methylhistamine - to H2-receptors (Black et al., 1972), and the chiral analog of histamine with a limited conformational mobility (K) -a-methylhistamine - to H3 -receptors (Arrang et al., 1987). Histamine metabolism Content in tissues. Histamine is present in the body of most animals and is part of many poisons of animal origin, bacteria, and plants. Almost all mammalian tissues contain histamine in different concentrations: from 1 μg / g or less to 100 μg / g or more. So, a person has a lot of histamine in the CSF, and very little in the plasma and extracellular fluid. In almost all tissues, mast cells serve as the main histamine depot (see below); its concentration is especially high in tissues rich in these cells: skin, bronchial mucosa and intestines. In some tissues, histamine is rapidly synthesized, but is destroyed almost immediately, and its level may be low. Synthesis and accumulation. In the quantities that usually come from food or are synthesized in the digestive tract by bacteria, histamine CH2CH2NH2 Histamine li-stimulants „CH2CH2NH2 CH3 2-methylhistamine H2-stimulants CH3ss CH2CH2NH2 4E) -methylhistamine CH2CH2NH2 CH2CH2NH2 2-pyridylethyl-CH2 / HN Dimaprit ^ CH2CH2NH2 2-thiazolylethylamine CH3 CH2SCH2CH2HNCNHCH2CH2CH2 Impromidine H3-stimulants R-cx-methylhistamine Figure 25.1. Structure of histamine and some H, -, H2- and H3-stimulants. histamine is formed by histidine decarboxylase.The main histamine depot in most tissues is mast cells, and in the blood - basophils; here it is formed and deposited in secretory granules.At a pH in the granules of about 5.5, histamine molecules have a positive charge and bind negatively charged acid groups that are part of other components of secretory granules, mainly proteases, heparin and chondroitin sulfates (Serafin and Austen, 1987). The rate of synthesis of histamine in the granules is low, so when the tissue rich in mast cells is deprived of histamine stores, it may take several weeks to replenish them. Histamine can also be synthesized in cells of the epidermis, gastric mucosa, neurons of the central nervous system, and rapidly renewing cell populations. In these cells, the rate of its metabolism is high (histamine is almost not deposited and is constantly released), and therefore they make a significant contribution to the daily urinary excretion of histamine and its metabolites. Since histidine decarboxylase is an inducible enzyme, histamine synthesis depends on various physiological and pathological factors. Catabolism. There are two main pathways for histamine catabolism in humans (Figure 25.2). The most important is the methylation of the imidazole ring under the action of histamine-N-methyltransferase contained in many tissues to form N-methyl-histamine. After that, most of it under the action of MAO is converted into N-methyl imidazoleacetic acid; the reaction is suppressed by MAO inhibitors (Chapter 19). The second way is oxidative deamination, catalyzed by the nonspecific enzyme diamine oxidase (histaminase), which results in the formation of imidazoleacetic acid, and then its riboside. These metabolites are almost inactive and are excreted in the urine. It is important that the concentration of N-methylhistamine in the urine is more reliably indicative of the production of histamine in the body, and not the concentration of histamine itself. The fact is that the level of the latter can increase if there are some bacteria in the genitourinary system that can decarboxylate histidine. In addition, histamine metabolism appears to be impaired in mastocytosis (Roberts and Oates, 1991). In this case, the level of its metabolites serves as a more sensitive indicator (Keyzeretal., 1983). Histamine Histamine-M-methyltransferase, CH2CH2NH2 I N-methyl histamine MAO CH2COOH CH2CH2NH2 Diamine oxidase H CH2soon Imidazoleacetic acid Ribosyl transferase yC NN H CH2COOH N-methylimidazoleacetic acid Histamine metabolism (see text). Physiology and pathophysiology of histamine The role of histamine in the body is extremely important. It is contained in the granules of mast cells and is released when the antigen interacts with IgE on the surface of these cells, playing a leading role in immediate allergic reactions. Many allergy symptoms are associated with the action of histamine on the smooth muscles of the bronchi and blood vessels. A number of drugs directly stimulate mast cell degranulation, which explains some of the side effects of their use. Histamine is the main regulator of the secretion of hydrochloric acid in the stomach, and recently it became known that it regulates the release of neurotransmitters in the nervous system. Allergic reactions. The main target cells for immediate allergic reactions are mast cells and basophils (Galli, 1993; Schwartz, 1994). After contact with the antigen, IgE are formed, which are attached to the surface of mast cells and basophils using high-affinity Fc-receptors (FceRI). Each such receptor consists of one a-, one p-, and two y-chains; their molecular structure is known (Ravetch and Kinet, 1991). Upon repeated contact, the antigen binds to the IgE molecules, and intracellular signaling is triggered through the IgE Fc receptors in the sensitized cells. In atopic diseases, IgE is formed, as a rule, to airborne allergens. Atopy is based on a hereditary predisposition (Cookson et al., 1992; Shirakawa et al., 1994). It is possible that the gene encoding the p-chain of the IgE Fc receptor is responsible for its development; therefore, it is of particular interest to study the mechanisms of intracellular signal transmission in mast cells and basophils. The antigen binds to IgE, the tyrosine kinases Lyn (part of the Src family of kinases) and Syk are activated, after which various proteins are phosphorylated; all this occurs within 5-15 seconds after exposure to the antigen (Scharenberg and Kinet in Symposium, 1994). Of the phosphorylated proteins, the most important are the p- and y-subunits of the IgE Fc receptor, as well as the phospholipases Cyl and Cy2. Under the action of phospholipases, IF3 is formed from phospholipids, which causes the release of Ca2 + from intracellular stores, increasing its concentration in the cytoplasm (Chapter 2). As a result, the contents of the secretory granules are excreted by exocytosis. In general, the degranulation of mast cells and basophils occurs in the same way as secretion in various endocrine and exocrine glands: an external stimulus causes an increase in the intracellular concentration of Ca2 +, which triggers exocytosis. The mechanism by which an increase in the concentration of Ca2 + leads to the fusion of granules with the cell membrane is not fully known, but it may be associated with the activation of Ca2 + -calmodulin-dependent protein kinases and protein kinase C. Stimulation of IgE Fc receptors, in addition to activating phospholipase C, also leads to activation phospholipase A2, as a result of which a number of inflammatory mediators are formed, including the platelet activating factor and metabolites of arachidonic acid. One of them - leukotriene D4 - causes severe bronchospasm (Ch. 26,28). In some allergic reactions, kinins are formed (see below). Thus, not only histamine is released from mast cells, but also other inflammatory mediators, each of which contributes to the development of typical allergy symptoms: bronchospasm, arterial hypotension, increased capillary permeability, edema (see below). Medicinal effects on mast cell degranulation. In allergic reactions, many inflammatory mediators are released, so drugs that block the action of only one of them are ineffective. Considerable efforts have been directed towards elucidating the regulatory mechanisms of mast cell and basophil degranulation. These cells do indeed have receptors that, through appropriate intracellular signaling systems, are able to enhance or suppress the release of inflammatory mediators caused by the interaction of antigen with IgE. Drugs acting on M-cholinergic receptors or a-adrenergic receptors increase the release of inflammatory mediators, but this effect is of little clinical significance. Epinephrine (in small doses) and other drugs acting on P2-adrenergic receptors successfully suppress degranulation (cAMP serves as the second mediator). Nevertheless, the effect of C-adrenostimulants in allergic diseases (for example, bronchial asthma) is mainly due to relaxation of the smooth muscles of the bronchi (Ch. 10, 28). Cromoline inhibits the degranulation of mast and other cells in the lungs (Chapter 28). Stimulants of histamine release: drugs, peptides, ada and other substances. Many substances, including drugs, directly release histamine from mast cells without prior sensitization. This often happens with the on / in the introduction of certain substances, especially organic bases: amides, amidines, quaternary ammonium salts, piperidines, alkaloids and antibiotics, pyridine derivatives. The same property is possessed by tubocurarine, suxamethonium chloride, morphine, radiopaque substances, and some blood substitutes based on dextran. It is important to remember that all of these drugs can cause sudden anaphylactoid reactions. Thus, the reddening of the upper torso and face, as well as arterial hypotension that occurs after taking vancomycin, is at least in part due to the release of histamine (Levy et al., 1987). Some of the substances used in the experiments are specifically designed to stimulate the release of histamine. Their ancestor is the 48/80 substance - a polymer base, which is a mixture of low molecular weight polymers of parametoxy-N-methylphenethylamine, the most active of which is hexamer (Lagunoff et al., 1983). Polypeptides with base properties often cause degranulation of mast cells, and their activity, within certain limits, increases in proportion to the number of basic groups. Of these substances, the most active is polymyxin Viv, to a lesser degree - bradykinin and substance R. Similar polypeptides are released during tissue damage and are contained in poisons of animal origin. Anaphylatoxins, fragments of the complement components C3a and C5a, which are structurally low molecular weight peptides, can act in the same way. A few seconds after the intravenous injection of a substance that stimulates the release of histamine, burning and itching occur, especially in the palms, face, scalp and ears, but soon there is a feeling of strong warmth. The skin in these areas turns red, and redness quickly spreads throughout the body. Blood pressure decreases, heart rate increases, and, as a rule, a headache occurs. After a few minutes, blood pressure returns to normal, and hives usually appear on the skin. Intestinal colic, nausea, hyperchlorhydria, and moderate bronchospasm often develop. With repeated injections of the same substance, the effect weakens, since the stores of histamine in mast cells are depleted. Mast cell degranulation stimulants do not free tissues from histamine synthesized by other cells. Mechanism. The listed substances increase the intracellular concentration of Ca2 + in mast cells and basophils. Some are calcium ionophores and carry Ca2 + into the cell; others (for example, anaphylatoxins) may act as specific antigens, increasing the membrane permeability for Ca2 +. Still others (for example, the peptide mastoparan from wasp venom) can bypass membrane receptors directly stimulate G-proteins, causing the activation of phospholipase C (Higashijima et al., 1988). Stimulants of mast cell degranulation with base properties (for example, substance 48/80 and polymyxin B) cause the release of Ca2 + from intracellular stores (Lagunoff et al., 1983). Physical factors that stimulate the release of histamine. With cold, solar and cholinergic urticaria, histamine and kinins 505 min are released under the influence of physical factors. Perhaps, in some cases, this is due to the specific response of mast cells, mediated by IgE attached to their surface. The release of histamine also occurs with any nonspecific damage. Typical example - erythema and urticaria with mechanical irritation of the skin. Mastocytosis, myeloid leukemia, gastric carcinoids. In case of urticaria pigmentosa (a form of generalized cutaneous mastocytosis), the upper layers of the dermis are infiltrated with mast cells, which is why hyperpigmented rashes appear on the skin, with mechanical irritation of which blisters are formed. With systemic mastocytosis, increased proliferation of mast cells is also noted in the internal organs. Symptoms of systemic mastocytosis - urticaria, urticaria dermographism, itching, headache, weakness, arterial hypotension, hot flashes, gastrointestinal tract damage, including peptic ulcer - are associated with excessive release of histamine. In such patients, mast cell degranulation is provoked by various factors, including physical activity, excitement, fever, taking drugs that directly activate mast cells or to which the patient is sensitized. With myeloid leukemia, the level of basophils in the blood is increased, and therefore the content of histamine increases sharply, which can lead to constant itching. Gastric carcinoids produce histamine on their own, which periodically causes vasodilation and hot flashes, accompanied by the appearance of spots with clear boundaries throughout the body (Roberts et al., 1979). Secretion of hydrochloric acid in the stomach. Histamine stimulates the secretion of hydrochloric acid in the stomach by acting on the H2 receptors of the parietal cells. At the same time, the production of pepsin and Castle's intrinsic factor is enhanced. The secretion of hydrochloric acid also increases with irritation of the vagus nerve, as well as under the action of the gastrointestinal hormone gastrin. It is believed that the gastric mucosa contains cells containing somatostatin, which can inhibit the secretion of hydrochloric acid, and the release of somatostatin, in turn, is blocked by acetylcholine. The interaction between these regulators is not fully understood. Nevertheless, it is obvious that histamine is the main physiological stimulant of the secretion of hydrochloric acid in the stomach, since H2 blockers suppress the secretion of hydrochloric acid, caused not only by the action of histamine, but also by gastrin, as well as by irritation of the vagus nerve (for more details, see Chapter 37) ... Central nervous system. There is strong evidence that histamine is one of the mediators of the central nervous system. The content of histamine, histidine decarboxylase, and enzymes that destroy histamine is not the same in different parts of the central nervous system. It is especially high in the synptosomal fractions of brain homogenates. H, -receptors are found in all parts of the central nervous system, most of them in the hypothalamus. Acting on central H, -receptors, histamine maintains the state of wakefulness (Monti, 1993), which explains the mechanism of the sedative effect of H-blockers. Through the same receptors, histamine reduces appetite (Ookuma et al., 1993). Histaminergic neurons can be involved in the regulation of water metabolism (feelings of thirst and secretion of ADH), body temperature, as well as blood pressure and pain threshold; apparently, both Hg and H2 receptors are involved in this (Hough, 1988). Effects of Histamine: Ng and H2 Receptors Histamine can act locally or systemically on smooth muscle and glands. It causes contraction of some smooth muscles (for example, muscles of the bronchi and intestines) and a pronounced relaxation of others (for example, muscles of small vessels). As already mentioned, histamine stimulates the secretion of hydrochloric acid in the stomach. In addition, it causes swelling and irritation of the sensitive nerves. Some effects, such as bronchospasm and intestinal muscle contraction, are mediated by H, -pe- 506 Chapter 25 receptors (Ash and Schild, 1966). Others, in particular the secretion of hydrochloric acid, are due to the activation of H2 receptors, and therefore are suppressed by H2 blockers (Black et al., 1972). Thirdly (for example, in vasodilation, which leads to a decrease in blood pressure), both types of receptors are involved. Histamine poisoning. It has been established that the symptoms of poisoning that occurs after eating stale fish of the mackerel and coriphene families (for example, tuna) are associated with the action of histamine (Morrow et al., 1991). The bacteria found in fish that are rich in histidine decarboxylate it, which produces a lot of histamine. After eating such fish, severe nausea, vomiting, headache, hot flashes and profuse sweating occur. Histamine poisoning (with headache and other symptoms) sometimes develops after drinking red wine, apparently in individuals with delayed histamine breakdown (Wantke et al., 1994). In case of histamine poisoning, H, -blockers are effective. The cardiovascular system. Histamine causes the expansion of small vessels, which leads to hot flashes, a decrease in TPR and blood pressure. In addition, it increases capillary permeability. Expansion of blood vessels. This is the characteristic vascular effect of histamine and is associated with many of its most important effects. It is mediated by H, - and H2 receptors, which are present in almost all arterioles. Nevertheless, the arterioles of different vascular basins under the action of histamine expand into varying degrees ... Activation of any of the two types of receptors can lead to maximum vasodilation, but the affinity of H, - and H2 receptors for histamine is not the same, and the reaction is different in mechanism and duration. H, -receptors have a higher affinity for histamine; their activation leads to rapid and short-term vasodilation. On the contrary, when H2 receptors are activated, the effect develops more slowly, but also lasts longer. As a consequence, H, -blockers effectively suppress slight vasodilation at low concentrations of histamine, but at higher concentrations of this substance, they only weaken the initial phase of the reaction. H2 receptors are located on smooth muscle cells, and vasodilatation when activated is mediated by cAMP. H, -receptors are located on endothelial cells, and their activation leads to the formation of substances with a local vasodilating effect (see below). Increased vascular permeability of the microvasculature. This classic effect of histamine leads to the release of proteins and fluid from the vascular bed through the wall of small vessels, which is accompanied by edema, an increase in lymph volume and protein content in it. An important role in increasing vascular permeability belongs to H, -receptors; the involvement of H2 receptors is not yet known. The increase in permeability is associated primarily with the effect of histamine on postcapillary venules. Endothelial cells contract, intercellular contacts are weakened, and the distance between cells increases, due to which the basement membrane is exposed, which is freely permeable to fluid and plasma proteins. Through the resulting gaps, blood cells can come out, migrating into the tissues when mast cells are activated. The migration of leukocytes is associated with an increase in their adhesion. Acting through H, -receptors, histamine causes the appearance of adhesion molecules, P-selectin, on endothelial cells (Gaboury et al., 1995). Lewis Triad. With the intradermal administration of histamine, the Lewis triad occurs (Lewis, 1927): 1) a red spot several millimeters in diameter, which can be seen within a few seconds; in about a minute, its brightness reaches a maximum, 2) a bright red rim, which appears later and extends beyond the spot by about 1 cm, 3) a blister that appears after 1-2 minutes in the same place where the spot was. The appearance of a red spot is due to the direct vasodilating effect of histamine, the rim is an axon reflex, which leads to vasodilation indirectly, and the blister is due to an increase in capillary permeability. Constriction of large vessels, Histamine causes constriction of large vessels, the degree of which is not the same in animals different types... So, in rabbits, not only large vessels are narrowed, but even arterioles, which can level the expansion of smaller vessels, causing an increase in OPSS and blood pressure. Direct action on the heart, histamine alters contractility as well as electrical processes in the myocardium. It increases the contractility of the atria and ventricles, enhancing the entry of Ca2 + into cardiomyocytes, and increases the heart rate, accelerating diastolic depolarization in the cells of the sinus node. In addition, histamine inhibits AV conduction, increases automatism, and can cause arrhythmias, especially at high concentrations. The slowing down of AV conduction is due to the activation of H, receptors, and other effects on the heart are due to the activation of H2 receptors. With intravenous administration of histamine, its direct effect on the heart is hardly noticeable, since due to a decrease in blood pressure, sympathetic tone rises baroreflexively. Histamine shock. The introduction of large doses of histamine or its release during anaphylactic reactions leads to a rapid and significant decrease in blood pressure. Small vessels expand, capturing a significant part of the blood, their permeability increases, as a result, the plasma leaves the vascular bed. Hemodynamic disorders resemble shock during surgery or after trauma: effective BCC decreases, venous return, cardiac output drops sharply. Smooth muscles of internal organs. As a rule, histamine, due to its effect on H, -receptors, causes smooth muscle contraction. Much less often, it causes their relaxation, which is mediated mainly by H2 receptors. The response of smooth muscle to histamine varies widely, even in one individual (Parsons, in Ganellin and Parsons, 1982). The smooth muscles of the bronchi of guinea pigs are especially sensitive to histamine. In bronchial asthma and some other lung diseases, histamine causes severe bronchospasm even in small doses, while in healthy people sensitivity to histamine is much less. In the human bronchi, histamine acts mainly on H, receptors, causing bronchospasm, but there are also H2 receptors, the activation of which leads to the expansion of the bronchi. For this reason, in vitro H2 blockers somewhat increase histamine-induced bronchospasm. In bronchial asthma, an additional cause of bronchospasm may be irritation of the afferent endings of the vagus nerve (Eyre and Chand, in Ganellin and Parsons, 1982; Nadel and Barnes, 1984). In some animals, histamine causes contraction of the uterus, and in women, including pregnant women, almost none. The smooth muscles of the intestine usually contract in response to histamine, but different parts of the intestine may respond differently; the effect is different for different species of animals. Histamine has almost no effect on the bladder and gallbladder, ureter, iris, and smooth muscles of many other organs. Exocrine glands. As already mentioned, histamine regulates the secretion of hydrochloric acid in the stomach by stimulating H2-receptors (Chapter 37). Nerve endings. Histamine irritates sensitive nerve endings, and its secretion in the epidermis causes itching, and in the dermis pain, sometimes along with itching. With the action of histamine on nerve endings, including autonomic nerves (afferent and efferent), hyperemia is associated with its intracutaneous administration (see above) and an indirect effect on the bronchi and other organs. The action of histamine on nerve endings is mediated mainly by H receptors (Rocha and Silva, 1978; Ganellin and Parsons, 1982). Mechanism of action. H, - and H2 receptors belong to the superfamily of G-protein coupled receptors. When H, -receptors are stimulated, phospholipase C is activated, which hydrolyzes phospholipids cell membrane with the formation of DAG and IF3; the latter causes a rapid release of Ca2 + from the sarcoplasmic reticulum. DAG (and Ca2 +) activates protein kinase C, and Ca2 + activates Ca2 + -calmodulin-dependent protein kinases and phospholipase A2 in target cells, which leads to a typical reaction. Stimulation of H2 receptors is accompanied by activation of adenylate cyclase and, as a consequence, protein kinase A. In different animal species, adenosine receptors can interact differently with H, receptors. Thus, in the central nervous system of a person, upon activation of Aβ receptors, the formation of second mediators caused by the action of histamine on H1receptors is inhibited. A possible mechanism is the interaction at the level of G-proteins with which A, - and H, -receptors are coupled (Dickenson and Hill, 1993). In the smooth muscles of large vessels, bronchi and intestines, stimulation of H] -receptors causes the formation of IF3, followed by an increase in the concentration of Ca2 + in the cytoplasm, which activates the Ca2 + -calmodulin-dependent kinase of myosin light chains. Phosphorylation of myosin light chains with a molecular weight of 20,000 leads to the formation of actomyosin bridges and contraction. The action of histamine on sensitive nerve endings is also mediated by H, -receptors. As already mentioned, the vasodilating effect of histamine is associated with the activation of H, receptors of endothelial cells and H2 receptors of smooth muscle cells. When H, -receptors are stimulated, the concentration of Ca2 + in the cytoplasm increases, phospholipase A2 is activated and NO is formed (Palmer et al., 1987). The latter diffuses into smooth muscle cells, activates soluble guanylate cyclase there and causes the accumulation of cGMP. It is believed that vasodilatation mediated by cGMP is associated with the stimulation of protein kinase G and a decrease in the level of Ca2 + in the cytoplasm. In addition, the activation of phospholipase A2 in endothelial cells leads to the production of prostaglandins, mainly prostacyclin (prostaglandin 12), which, acting on smooth muscle cells, makes an important contribution to the vasodilating effect of histamine in some types of vessels. The mechanism of smooth muscle relaxation mediated by cAMP is not clear, but it is believed that this decreases the concentration of Ca2 + in the cytoplasm (Taylor et al., 1989). The effects mediated by cAMP on cardiomyocytes, mast cells, basophils and other cells are poorly understood, but in any case, the consequences of stimulation of H2 receptors should be the same as when stimulating other receptors that activate adenylate cyclase (for example, p- adrenergic receptors). Application In the clinic, histamine is used only for diagnostic purposes. It is used to assess the reactivity of the bronchi in patients with bronchial asthma and as a positive control in allergic skin tests. ^ -blockers For each of the three types of histamine receptors, selective blockers have been created. Here we will consider the properties and applications of H, -blockers. H2 blockers (eg, cimetidine, ranitidine) are widely used in the treatment of gastric ulcer and are discussed in detail in Ch. 37.0 drugs acting on H3 receptors will be discussed below; they are not yet used in the clinic. Historical reference. In 1937, Bove and Staub first established that one of the amines, a phenol ester, 2-isopropyl-5-methylphenoxyethyl diethylamine, blocks the action of histamine. In guinea pigs, this substance im suppressed smooth muscle contractions, reduced the symptoms of a 11 i phylactic shock, and they survived even after the introduction of 11 stamines at a dose several times higher than the lethal dose.However, this substance was too toxic for clinical use, and in 1944 Beauvais et al. proposed mepiramine, which still remains one of the most selective and effective H, blockers. The highly effective diphenhydramine and tripelenamine were soon developed (Bovet, 1950; Ganellin, in Ganellin and Parsons, 1982). Finally, in the 1980s. managed to create H, -blockers of the second generation, which do not have a sedative effect. Many drugs with antihistaminic activity were used in the clinic as early as the early 1950s, but all of them did not interfere with some of the effects of histamine, in particular its action on gastric secretion. Black et al. created drugs that suppress the secretion of hydrochloric acid in the stomach, which made it possible to better understand the functions of histamine in the body. Thus, a new large class of drugs was created - H2-blockers (cimetidine, famotidine, nizatidine and ranitidine; ch. 37). Chemical properties. All H, -blockers competitively and reversibly inhibit the interaction of histamine with H, -receptors. Like histamine, many H, -blockers are substituted ethylamines, -C-C-NII \ However, if in a histamine molecule the primary ethylamine is directly linked to a single aromatic ring, then in the molecules of most H, -blockers, tertiary ethylamine is linked to two aromatic radicals through a carbon atom, nitrogen or ether bond; the general formula looks like this: Ar, I I \ where Ar is an aromatic radical, X is a nitrogen, carbon atom or an ether bond (-C-O-) with ethylamine. Sometimes two aromatic radicals are connected by a bridge (as in tricyclic derivatives), or ethylamine is part of a cyclic structure (Fig. 25.3) (Ganellin, in Ganellin and Parsons, 1982). Pharmacological properties Almost all H, -blockers have similar pharmacological properties and indications for use. Their action is easy to predict, knowing that they suppress the effects of histamine mediated by H, -receptors. Smooth muscles. As a rule, H, -blockers suppress the reaction of smooth muscles to histamine. Prevention of bronchospasm 508 Chapter 25 is easily demonstrated in vivo and in vitro. For example, after administration of even relatively small doses of histamine, guinea pigs die from asphyxia, but with the use of an H, blocker, they can survive after administration of a dose of histamine 100 times higher than the lethal dose. In these animals, H, -blockers completely eliminate bronchospasm and in case of anaphylactic reactions. However, in humans, in addition to histamine, other inflammatory mediators, such as leukotrienes and platelet activating factor, are involved in the development of bronchospasm, and therefore H blockers are not so effective (Chapter 26). H, -blockers suppress the constricting effect of histamine on large vessels and, equally, a faster expanding effect on small vessels, mediated by H, -receptors of endothelial cells. Residual vasodilation is associated with the participation of H2-receptors of smooth muscle cells and is eliminated by H2-blockers. In accordance with changes in vascular tone, blood pressure also changes. Capillary permeability. H, -blockers prevent an increase in capillary permeability, the development of edema and blisters. Hyperemia and itching. The appearance of a hyperemic rim (one of the components of the Lewis triad) and itching after intradermal administration of histamine are two manifestations of its effect on nerve endings; both are eliminated by H, -blockers. Exocrine glands. Ng blockers do not affect gastric secretion, but inhibit histamine-induced secretion of the salivary, lacrimal and other exocrine glands. Many H, -blockers also have an atropine-like effect, and therefore can suppress the secretion of glands with cholinergic innervation and reduce the production of mucus in the airways. Allergic reactions of immediate type. Histamine is one of the most active inflammatory mediators released during allergic reactions (see above). However, its contribution to the development of symptoms is very different in different tissues and in animals of different species, which is why the effect of H, -blockers is not the same. For example, in humans, these drugs completely eliminate edema and itching, and to a lesser extent - arterial hypotension. Perhaps this is due to the release from mast cells and other substances, especially prostaglandin D2, which causes vasodilation (Roberts et al. , 1980). Pribronchospasm H, -blockers are almost ineffective (Dahlen et al., 1983). Central nervous system. H, -blockers of the first generation can have both exciting and depressing effects on the central nervous system. Sometimes patients who take them in normal doses become restless, nervous, and suffer from insomnia. Excitation is a characteristic sign of poisoning with H, -blockers; it is often accompanied by seizures, especially in infants. However, much more often H, -blockers in usual doses have a depressing effect on the central nervous system, which is manifested by depression of consciousness, lethargy, and drowsiness. The degree of this effect differs from drug to drug, and even the response to the same drug is individual. Ethanolamines such as diphenhydramine are particularly sedating (Figure 25.3). H, -blockers of the second generation (for example, loratadine, cetirizine, fexofenadine) in therapeutic doses almost do not penetrate the blood-brain barrier. When they are taken, the objective indicators of the depressive effect on the central nervous system (falling asleep time, EEG and psychophysiological data) change no more than when taking a placebo (Simons and Simons, 1994). Because of the sedative effect of first-generation H, -blockers, they are often poorly tolerated and unsafe. The creation of second-generation drugs, devoid of this effect, has become an important stage on the way to the widespread use of H, -blockers. Some H-blockers can prevent motion sickness. This valuable property was first noted when taking dimensionhydrinate, and then diphenhydramine (an active metabolite of dimensionhydrinate), piperazine and promethazine derivatives. The most effective drug for the prevention of motion sickness is scopolamine (Chapter 7), and therefore a similar property of H, -blockers, is most likely due to the M-anticholinergic action. This effect is most pronounced with promethazine (see below). ; co-ci: H2-CH2-N c-CH2-CH2-n n Diphenhydramine (ethanolamine), CH3 Chlorpheniramine 6 (alkylamine) N-CH3 Mepiramine (ethylenediamine) Chlorcyclizing (piperazine) RS2H5, CH3 S N-CH CH2-CH -N Promethazine (phenothiazine) Figure 25.3. Typical representatives of different groups of H, -blockers. a Dimenhydrinate is a combination of equal molar amounts of diphenhydramine and 8-chlorotheophylline. 6 Pheniramine - the same structure, but without C1. c Tripelenamine - the same structure, but without Н3СО. d Cyclizine - the same structure, but without C1. Loratadine (tricyclic piperidine) M-anticholinergic action. Many first-generation Hb blockers inhibit M-cholinergic receptor responses to acetylcholine. In some drugs, this effect is so pronounced that it is clearly manifested when used in the clinic (see below). Second-generation drugs do not act on M-cholinergic receptors. Local anesthetic action. A number of Hb blockers have a local anesthetic effect, and some of them (especially promethazine) are more effective than procaine. However, this effect is observed at concentrations in non-histamine and kinins 509 how many times higher than those required for antihistamine activity. Pharmacokinetics. Ng blockers are well absorbed from the gastrointestinal tract. The maximum serum concentration after oral administration is reached after 2-3 hours, the effect usually lasts 4-6 hours, and for some drugs much longer (Table 25.1). Table 25.1. H, -blockers Drugs Duration of action, h Dosage forms Single dose (for adults) First generation drugs Tricyclic antidepressants - dibenzoxepines Doxepin Ethanolamines Carbinoxamine Clemastine Diphenhydramine Dimenhydrinate Ethylenediamines Mepiramine Tripeleniphenylamine) pamoate) Cyclizine (hydrochloride) Cyclizine (lactate) Meclosine Phenothiazines Promethazine Piperidines Cyproheptadine6 Phenindamine Second-generation drugs Alkylamines Acrivastin8 Piperazines Cetirizine Phthalazinones Azelastinab 8-24 Piperidinadine 4-6- 6-6 6 4-6 4-6 6-24 6-24 4-6 4-6 12-24 4-6 4-6 4-6 4-6 12-24 12-24 6 24 12 F, T, M f, t, t, t, m, and w, t, and f, t, m t, t, t, and f, t, and f, t, and w, t t and t, t, and, s w, t t t t m m w, t t 10-150 mg 4-8 mg 1.34-2.68 mg 25-50 mg 50-100 mg 25-50 mg 25-50 mg, 100 mg (long-term action) 37.5-75 mg 4 mg, 8-12 mg (duration action), 5-20 mg (injection 4 mg, 8-12 mg (long-acting), 5-20 mg (injection 25-100 mg 25-100 mg 50 mg 50 mg 12.5-50 mg 12.5- 50 mg 4 mg 25 mg 8 mg 5-10 mg 2 aerosol doses in each nostril One drop of 10 mg 60 mg F - liquid dosage forms for oral administration, I - preparations for injections, solid dosage forms for oral administration. a For more information on phenothiazines, see Ch. 20. 6 The drug also has antiserotonergic activity. a The drug has a mild sedative effect. M - dosage forms used topically, C - suppositories, T - 510 Chapter 25 There have been few large studies in the pharmacokinetics of Hj-blockers. The maximum serum concentration of diphenhydramine after oral administration is reached after about 2 hours, then for about 2 hours the concentration remains almost at the same level, and then rapidly decreases; T1 / 2 is 4-8 hours. The drug is distributed to all organs, including the central nervous system, and is excreted in the urine mainly in the form of metabolites. Other first-generation Hb blockers are believed to be cleared in the same way (Paton and Webster, 1985). It is not yet known whether Hj blockers accumulate in the skin and mucous membranes. Nevertheless, after taking some long-acting drugs, the local reaction to the intradermal administration of histamine or allergen is suppressed within 36 hours or more even at a very low serum concentration of the drug. Therefore, the recommended doses must be approached individually (Table 25.1) and, in some cases, the frequency of administration must be reduced. One of the most potent histamine receptor blockers, the tricyclic antidepressant dosepin (Chapter 19), is nearly 800 times more active than diphenhydramine (Sullivan 1982; Richelson, 1979). Perhaps that is why doxepin often helps patients with chronic urticaria with the ineffectiveness of other H, -blockers; it is used internally or topically. Like many other drugs with a high metabolic rate of H, β-blockers are eliminated faster in children than in adults, and especially slowly in people with severe liver disease. H, -blockers are one of many drugs that increase the activity of liver microsomal enzymes, and therefore can enhance their own metabolism (Paton and Webster, 1985; Simons and Simons, 1988). The second-generation ng blocker loratadine is rapidly absorbed from the gastrointestinal tract and, under the action of microsomal liver enzymes, is converted into an active metabolite (Simons and Simons, 1994). This process can be disrupted while taking other drugs that are also metabolized by these enzymes. The other two second-generation H, blockers that have already been discontinued, astemizole and terfenadine, are converted to active metabolites by the same enzymes. It was found that with liver diseases or taking drugs that suppress isoenzymes of the IIIA subfamily of cytochrome P450, both drugs occasionally cause life-threatening arrhythmias - pirouette tachycardia. For this reason, terfenadine was discontinued in 1998 and astemizole was discontinued in 1999. Loratadine, cetirizine (an active metabolite of hydroxyzine), fexofenadine (an active metabolite of terfenadine), and azelastine do not prolong repolarization and do not induce tachycardia tachycardia (DuBuske, 1999). Cetirizine, loratadine and fexofenadine are well absorbed from the gastrointestinal tract and are mainly excreted unchanged: the first two drugs in the urine, and the last in the feces (Brogden and McTavish, 1991; Spencer et al. , 1993; Barnes et al., 1993; Russell et al., 1998). Side effects. The most common side effect of first generation H] blockers is sedation. Sometimes it can be useful, but much more often it is undesirable, as it reduces performance. With the simultaneous use of other drugs that depress the central nervous system, or alcohol consumption, this effect is enhanced, leading to impaired motor skills (Roehrs et al., 1993). Other side effects associated with the effect on the central nervous system are lightheadedness, tinnitus, lethargy, lack of coordination, fatigue, blurred vision, diplopia, euphoria, irritability, insomnia, tremors. The next most common side effect of H, -blockers is gastrointestinal disturbances: decreased appetite, nausea, vomiting, epigastric discomfort, constipation or diarrhea. To prevent them, you should take the drug with meals. In rare cases, H, -blockers increase appetite and cause weight gain. Side effects of some first-generation Hi-blockers, possibly related to M-choline blocking action, include dry mouth and airways (sometimes causing coughing), urinary retention, or increased and painful urination. H, -blockers of the second generation are free of the listed side effects. Carcinogenicity. According to the results of one short-term study carried out on a non-standard experimental model, in mice, against the background of some H, -blockers, the proliferation of melanoma and fibrosarcoma cells injected into them increased (Brandes et al., 1994). However, experimental studies on standard models and clinical observations do not confirm the carcinogenicity of these drugs (Food and Drug Administration, 1994). Other side effects. Drug allergy is possible when taking H, -blockers inside, but much more often it is observed when applied topically. So, allergic contact dermatitis often occurs, fever and photosensitivity occur. Hematological complications (leukopenia, agranulocytosis, hemolytic anemia) are very rare. The teratogenic effects of piperazine derivatives have been reported, but extensive clinical studies have not found any association between their intake and fetal malformation. Since H, -blockers affect the results of allergic skin tests, before carrying out the latter, it is necessary to stop taking such drugs in advance. In acute poisoning with H, -blockers, the greatest danger is their excitatory effect on the central nervous system. There are hallucinations, agitation, ataxia, impaired coordination, athetosis, convulsions. The clinical picture - wide, non-responsive pupils, facial flushing, sinus tachycardia, urinary retention, dry mouth and fever - strongly resembles atropine poisoning. In severe cases, a deep coma develops and death occurs within 2-18 hours as a result of cardiovascular failure and respiratory depression. Treatment is reduced to eliminating symptoms and maintaining the functions of vital organs. Hj blocker groups. The features of the groups of Hj-blockers differing in chemical structure are described below. Representatives of each group of drugs are shown in table. 25.1. Dibenzoxepine derivatives. The only representative of this group - doxepin - formally refers to tricyclic antidepressants (Chapter 19), but also has a powerful H] -blocking effect. Doxepin can cause drowsiness and has an M-anticholinergic effect. It is better tolerated by patients suffering from depression. Others sometimes do not tolerate this drug well, since even at very low doses (for example, 20 mg) it can cause disorientation and confusion. Ethanolamines. A typical representative is diphenhydramine. Ethanolamines have a pronounced M-anticholinergic effect and more often than others have a sedative effect. Drowsiness is noted in about half of patients receiving them in normal doses. Gastrointestinal disturbances are rare. Ethylenedi amines. A typical representative is pyrilamine. Some of the most selective Ngblokators belong to this group. Although they have a rather weak effect on the central nervous system, many people note drowsiness when taking them. Gastrointestinal disturbances are common. Alkylamines. Chlorphenamine is a typical representative. These are some of the most powerful Ng blockers. They rarely cause drowsiness, and therefore are better than others for daytime use. Nevertheless, many patients still note a sedative effect. Compared with drugs from other groups, alkylamines more often have an exciting effect on the central nervous system. First generation piperazines. The very first representative of this group - chlorcyclizine - acts longer than others and rarely causes drowsiness. Hydroxyzin is a long-acting drug widely used for allergic skin reactions; its pronounced antipruritic effect may be associated with a strong inhibitory effect on the central nervous system. Cyclizine and meclozine are used mainly for the prevention of motion sickness, although there are more effective drugs - promethazine, diphenhydramine, dimensionhydrinate, and also scopolamine (see. below). Second generation piperazines. The only representative of this group - cetirizine - has a weak M-anticholinergic effect. It almost does not penetrate the central nervous system, but causes drowsiness a little more often than other second-generation H-blockers. Phenothiazines. A typical representative is promethazine. Almost all drugs in this group block not only H, -receptors, but also M-cholinergic receptors. Currently, promethazine, which has a pronounced sedative effect, and many of its derivatives are prescribed mainly as antiemetics (Chapter 38). First generation piperidines. These include cyproheptadine and phenindamine. The peculiarity of cyproheptadine is that it has not only antihistamine, but also antiserotoninergic activity. Cyproheptadine and phenindamine induce drowsiness and have a strong M-anticholinergic effect. Second generation piperidines. A typical representative is terfenadine. As mentioned above, terfenadine and astemizole were discontinued because they occasionally caused life-threatening arrhythmias - pirouette tachycardia. This is not typical of modern piperidines - loratadine and fexofenadine. They have a very high selectivity for H, -receptors and have almost no M-anticholinergic action. Drugs in this group poorly penetrate the central nervous system. All this explains the low risk of side effects with the appointment of second-generation piperidines. The use of H, -blockers plays an important role in the symptomatic treatment of immediate allergic reactions. In addition, some of them have a depressing effect on the central nervous system, so they are used as sleeping pills and to prevent motion sickness. Allergic diseases. H1 blockers are especially effective for immediate allergic reactions, manifested by rhinitis, urticaria and conjunctivitis. However, they only eliminate the symptoms caused by the secretion of histamine during the reaction of antibodies with antigens. In bronchial asthma, Ng blockers are ineffective, and in the form of monotherapy they are useless (Chapter 28). In anaphylactic reactions, in which the main role is played not by histamine, but by other mediators of inflammation, adrenaline serves as the basis of treatment, while Ngblokato-Histamine and kinins 511 ry are only an auxiliary agent. This also applies to severe Quincke's edema, which is accompanied by life threatening asphyxiation. H, -blockers successfully treat many allergic diseases of the respiratory tract. With seasonal allergic rhinitis and conjunctivitis (hay fever), they eliminate sneezing, runny nose, itchy eyes and nose, sore throat. They help almost all patients well, especially at the beginning of the flowering period, when there is still little pollen in the air. However, H, -blockers are less effective with a high concentration of allergens, prolonged contact with them, pronounced swelling of the nasal mucosa. Topical H, blockers such as levocabastine have been shown to be effective in allergic conjunctivitis and rhinitis (Janssens and Vanden Bussche, 1991). In the United States, this drug is available in the form of eye drops (Chapter 66) and an aerosol for intranasal administration. H, -blockers help well with some allergic skin diseases, especially with acute urticaria; however, they are likely to relieve itching better than edema and erythema. With chronic urticaria, the effect is less, but still noticeable in many patients. In its absence, it is useful to use a combination of Hg and H2 blockers. As already mentioned, for chronic urticaria, refractory to many histamine receptor blockers, doxepin sometimes helps. Quincke's edema is treatable with Hj-blockers, but in severe cases, especially with life-threatening asphyxia, adrenaline is the drug of choice (Chapter 10). Additionally, you can assign H, -blockers in / in. They are also used to treat itching. They often relieve symptoms of diffuse neurodermatitis or contact dermatitis (although topical glucocorticoids are more effective) and help with insect bites and allergic contact dermatitis caused by sumac plants. Itching of a non-allergic nature is sometimes also amenable to treatment with H, -blockers, which are best applied topically and less often inside. It is important to remember that topical application of H, -blockers can be complicated by allergic contact dermatitis. Doxepin is more effective than other Ng blockers in suppressing skin symptoms caused by the secretion of histamine, in particular itching. H, -blockers should be canceled long before allergic skin tests are performed, otherwise the results of these tests will be unreliable. In serum sickness, H, β-blockers eliminate urticaria and edema, but fever and arthralgia, as a rule, do not. H, -blockers help well with many medicinal allergic reactions, especially those with itching, urticaria, Quincke's edema; with intensive treatment, the symptoms of immunocomplex allergic reactions also decrease. As already mentioned, with a powerful release of histamine, adrenaline is the main drug, and H, blockers are only an auxiliary agent. Sometimes, before taking a drug that stimulates mast cell degranulation, it is enough to prescribe H] -blockers in advance so that the symptoms are much weaker. Acute respiratory diseases. Contrary to popular belief, H, blockers are useless for these diseases. Although H, -blockers of the first generation, due to the weak M-cholinoblocking action, reduce the common cold, but drying the nasal mucosa can do more harm than good; moreover, they cause drowsiness. Motion sickness, vestibular dizziness and sedation. Scopolamine (by mouth, cutaneous or parenteral) prevents and relieves motion sickness better than other drugs, but in mild cases, some Hj-blockers also help; their advantage is the lower risk of side effects. Dimenhydrinate and piperazines (eg, cyclizine, meclosine) are used. Promethazine (from the phenothiazine group) is more effective and has an antiemetic effect, but causes severe drowsiness. Ideally, any drug should be prescribed 512 Chapter 25 about an hour before the anticipated motion sickness. Reception after the onset of nausea and vomiting, as a rule, is useless. Some Hp blockers (especially dimensionhydrinate and meklozine) are often used for Meniere's syndrome and other types of vestibular vertigo. For the treatment of nausea and vomiting caused by anticancer chemotherapy or radiation therapy, only promethazine is used of the Nr blockers; besides it, there are other effective antiemetics (Chapter 38). Diphenhydramine is used for extrapyramidal disorders that have arisen while taking phenothiazines. Due to the M-anticholinergic action, this drug can be prescribed in the early stages of the treatment of Parkinson's disease (Chapter 22), although there are more active M-anticholinergics, for example, trihexyphenidil. Some Ng blockers cause drowsiness, which is why they are used as sleeping pills. They (mainly diphenhydramine) are often found in various over-the-counter over-the-counter drugs for insomnia. These drugs are usually ineffective at the recommended doses, although drowsiness still occurs in some patients. Hydroxysine and diphenhydramine have a sedative and mild anxiolytic effect, therefore they are used as mild tranquilizers. Stimulants and blockers of H3 receptors Originally, H3 receptors were described as presynaptic receptors located on histaminergic nerve endings in the central nervous system and providing feedback regulation of histamine formation and release (Arrang et al. , 1983). Subsequently, it was found that they are contained in many tissues and regulate the secretion of not only histamine, but also other mediators, including acetylcholine, dopamine, norepinephrine, and serotonin (Leurs et al., 1998). H3 receptors, like other types of histamine receptors, are coupled with G proteins; stimulation of H3 receptors leads to a decrease in calcium entry into the cell. The H3-stimulator R-a-methyl-histamine has an affinity for H3 receptors almost 1500 times higher than for H2 receptors and 3000 times higher than for Hj receptors (Timmerman, 1990). The development of such highly selective and potent H3 stimulants was an important advance in the study of the functions of H3 receptors. In 1999, the structure of the H3 receptors was determined (Lovenberg et al., 1999). This will allow in the near future to create lines of genetically modified animals for further study of the physiological role of these receptors. Recently, another isoform of H3 receptors was found in the brain of guinea pigs (Tardivel-Lacome et al., 2000). It is not yet known whether humans have it, and whether the functions of the two H3 receptor isoforms in guinea pigs differ. Many of the first H3 blockers (for example, impromidine and burimamide) also interacted with H2 receptors. The first selective H3 blocker used in experiments was thioperamide (Timmerman, 1990). This powerful H3 blocker is still widely used today. Other drugs have also been created: clobenpropite binds to H3 receptors reversibly, and N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) - irreversibly. It is known that regulatory suppression of the function of many organs is carried out through H3 receptors. H3 stimulants induce drowsiness by inhibiting the activation of CNS H1 receptors, which are responsible for maintaining wakefulness (Monti, 1993). Stimulation of H3 receptors attenuates ileal motility caused by Hj stimulants, and also decreases the level of histamine (and therefore gastrin) in the gastric mucosa (Hollande et al., 1993). H3-stimulants also prevent bronchospasm caused by the activation of H -receptors. In 1987, H3 receptors were discovered in the cardiovascular system, and H3 stimulants were shown to inhibit the transmission of excitation at the endings of vasoconstrictor sympathetic fibers and cause mesenteric artery dilation in guinea pigs (Ishikawa and Sperelakis, 1987). Later, H3 receptors were found on sympathetic nerve endings in the human saphenous vein, where H3 stimulants blocked the release of norepinephrine (Molderrings et al. , 1992). In addition, H3 receptors have a negative chronotropic effect. Apparently, in normal conditions, their effect on the release of norepinephrine is almost not manifested, but with an increase in sympathetic tone (for example, with ischemia), they suppress this release (Imamura et al., 1994). Currently, researchers are paying more and more attention to the creation of H3 receptor ligands. Perhaps, H3-stimulants will find application as agents protecting the gastric mucosa, as well as anti-inflammatory, anticonvulsants, and will help in the treatment of septic shock, heart failure, and myocardial infarction. H3 blockers are proposed for use in obesity, cognitive impairment, and attention deficit hyperactivity disorder in children (Leurs et al., 2000). Many powerful and selective H3-stimulants and H3-blockers have already been created, but none have yet been approved for use in Kinins.When tissue damage, allergies, viral infections and other inflammatory processes are triggered, a cascade of proteolytic reactions is triggered, leading to the formation of kinins in tissues - bradykinin and kallidine (Wachtfogel et al., 1993). They act locally, causing pain, increased permeability and vasodilation, enhancing the synthesis of prostaglandins. Thus, kinins are among the mediators of inflammation. Interesting discoveries have been made in this area over the past few years. The kinin metabolites, once thought to be inactive wastes, are now considered potent inflammatory mediators that cause pain. These peptides interact with special receptors that appear when tissue is damaged. Perhaps these discoveries will help create new drugs for the treatment of chronic inflammatory processes. Historical reference. In the 1920s-1930s. Frey and his collaborators Kraut and Werle found a substance with a hypotensive effect in urine and showed that it is also found in saliva, plasma and in many tissues. The pancreas is especially rich in them, so the substance was named kallikrein from the ancient Greek name for the gland - kallikreas. In 1937, Werle, Goetze and Keppler established that under the action of kallikreins a certain active substance is formed from the inactive plasma precursor. In 1948, Werle and Berek named this active substance kallidin and showed that it is a polypeptide that is cleaved from a plasma globulin, which they called kallidinogen (Werle, 1970). Interest in these discoveries increased after Rosha-e-Silva et al. in 1949, it was reported that under the action of trypsin or some snake venoms, a substance is formed from plasma globulin that lowers blood pressure and causes a slow contraction of the intestine. Because of the low speed of this reaction, they called the substance bradykinj (from the Greek bradys - slowly and kinein - to move). In the 1960s. Elliott et al. isolated bradykinin, and Boissonne et al. synthesized this substance. It was soon established that kallidin is a bradykinin de-capeptide with an additional lysine residue at the N-terminus. These substances, widespread in living nature, form a group of polypeptides that are similar in chemical structure and pharmacological properties. The whole group is usually called kshshny, and kallidin and bradykinin are called plasma kinins. In 1970 Ferreira et al. isolated a substance that enhances the action of bradykinin from the venom of the Brazilian ghararaca snake (Bothrops jararaca) (Ferreira et al., 1970). A year later, substances, ACE inhibitors, were isolated from the same poison (Ondetti et al., 1971). Later it was shown that ACE and kininase II are the same enzyme (Erdos, 1977). Today, ACE inhibitors (Chapter 31) are widely used in arterial hypertension, diabetic nephropathy, heart failure, as well as in the treatment of patients who have had myocardial infarction. In 1980, based on differences in affinity for kinin analogs, two types of kinin receptors were identified - B! and B2 (Regoli and Barabe, 1980). The structure of both types of receptors has now been elucidated. In the mid-1980s. first generation kinin receptor blockers have been synthesized (Vavrek and Stewart, 1985). Second-generation drugs that selectively block both types of receptors appeared in the early 1990s; their application helped to better understand the functions of kinins. Breeding a line of mice with an inactivated gene for B2 receptors (Borkowski et al., 1995) allowed a deeper study of the role of bradykinin in the cardiovascular system. Histamine and kinins 513 Kallikrein-kinin system Synthesis and metabolism of kinins. Bradykinin is a nonapeptide. Callidine has an additional N-terminal lysine residue, which is why it is sometimes called lysylbradykinin (Table 25.2). Both peptides are cleaved from a2-globulins called kininogens. There are two kininogens - high and low molecular weight. Numerous serine proteases are involved in kinin formation; those of them, with the help of which bradykinin and kallidin are synthesized from kininogens, are called kallikreins (Fig. 25.4). Kallikreins. Plasma kallikrein cleaves bradykinin from high molecular weight kininogen, and tissue kallikrein can act on both high molecular weight and low molecular weight kininogens, and bradykinin or kallidin are formed, respectively. Plasma and tissue kallikreins are different enzymes that differ in their activation mechanism (Bhoola et al., 1992). The precursor of plasma kallikrein, precallikrein, is an inactive protein weighing about 88,000, which forms a complex (in a 1: 1 ratio) with its future substrate, high molecular weight kininogen. The cascade of subsequent reactions is monitored in Table 25.2. Chemical structure (starting from the C-terminus) of stimulants and blockers of kinin receptors Name Structure Function Bradykinin Callidin Des-Arg9-bradykinin Des-Arg10-kallidin RMP-7 Des-Arg9- [Leu8] - bradykinin NOE 140 CP-0127
Year of issue: 2006
Genre: Pharmacology
Format: DjVu
Quality: Scanned pages
Description: The tenth edition of the book "Clinical Pharmacology by Goodman and Gilman" is published in the year of the sixtieth anniversary of this book. The goals that L. Goodman and A. Gilman set themselves when writing the first edition continue to serve as a guide to action for the authors of all subsequent editions of the book. These goals, clearly outlined in the foreword to the first edition below, are: to link pharmacological data with data from related sciences, constantly review the mechanisms of action and clinical use of drugs in the light of the latest scientific advances, and pay special attention to the application of principles of pharmacodynamics in drug therapy.
We are extremely grateful to both regular and new authors of this publication for their painstaking work in revising and updating the material of the relevant chapters in the light of the rapidly changing data of modern pharmacology. We are also grateful to the consultants, whose valuable comments helped to significantly improve the presented material. We would also like to note the selfless work of three gifted women, without whom the publication of this publication would be, if not impossible, then at least very difficult. Lorelei Edward, Ph.D., thoroughly reviewed all pharmaceutical data and was also instrumental in the early preparation of the book. Tracy Shields has shown rare scrupulousness in finalizing chapters and in checking literary references. Lynn Hutchinson took over the administration of this publication. Thanks to her extraordinary organizational skills, amazing ability to establish contacts with authors and publishers, high erudition and inexhaustible enthusiasm, the individual parts of this book were carefully put together and on time. We are also grateful to the staff of McGraw Hill Publishing House John Morris and Kathleen McCullough.
The very time of the publication of the tenth edition of Clinical Pharmacology, the first edition in the new millennium, is symbolic. We live in an era of revolution in biology and medicine, inevitably associated with the inability to process the avalanche-like flow of information. We see how the contradiction between knowledge and thinking is growing. We try to combine them, but this is not always possible, especially when we are trying to write something or teach something. How can we transfer all the accumulated knowledge in the future, while maintaining conceptuality and practical applicability? What will the textbooks on theoretical and practical medicine be like in a few years? We can only say with confidence that they will not be replaced by databases - the printed word will retain its meaning as a means of analysis and thinking.
The history of this book itself provides answers to many of these questions. It is often said that the publication of its first edition marked the emergence of clinical pharmacology as an independent discipline. The book owes such high praise not to a systematic presentation of individual facts, but to an attempt to summarize pharmacological knowledge and apply scientific concepts in clinical practice. The early authors of Clinical Pharmacology, Louis S. Goodman and Alfred Gilman, were outstanding scientists, brilliant educators and wise mentors, yet many consider this book to be their greatest achievement. The truth of this opinion is supported by the very fact that Clinical Pharmacology has already gone through 10 editions. The seventh edition (1985) was dedicated to Alfred Gilman, who died shortly before the book was published. The eighth edition (1990) was dedicated to Louis Goodman, who had by then ceased his work as principal editor of the book. Louis Goodman passed away in November 2000. We will forever remember his brilliant mind, the highest erudition, sharp humor, impeccable taste and ability to captivate and lead.
We again dedicate the next edition of Clinical Pharmacology to Louis Goodman and Alfred Gilman - with gratitude for their wise mentoring and with the hope that the goals set for the first edition of the book will be achieved in this and subsequent editions. If the successors of these two eminent scientists abide by their foundations, Goodman & Gilman Clinical Pharmacology will always be an invaluable guide for physicians and researchers.
"Clinical Pharmacology according to Goodman and Gilman"
ANTI-INFLAMMATORY AND ANTI-ALLERGIC DRUGS
Histamine, kinins and drugs that suppress their action
Eicosanoids and platelet activating factor
Non-steroidal anti-inflammatory drugs and drugs used for gout
Drugs used for bronchial asthma
DRUGS AFFECTING THE SEPARATORY AND CARDIOVASCULAR SYSTEM
Diuretics
ADH and drugs that affect the reabsorption of water in the kidneys
Agents acting on the renin-angiotensin system
Antianginal drugs
Antihypertensive drugs
Medicines used for heart failure
Antiarrhythmic drugs
Lipid-lowering drugs
Means acting on the digestive system
Means used for increased acidity of gastric contents, reflux esophagitis and peptic ulcer
Prokinetic and antiemetic drugs. Irritable Bowel Syndrome Drugs
Antidiarrheals and laxatives. Drugs used in chronic inflammatory bowel diseases. Pancreatic enzymes and bile acids
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