Histamine II and Anti-Histaminics

In the preface to Part I of this volume, which appeared in 1966, we stated: " ... we had to leave the Antihistaminics for another volume of unpredictable dimensions. In 1924, eight pages inserted in a Chapter on Mutterkorn by Arthur R.Cushing were considered enough, in Vol. II, Part II, pp. 1319-1326 of the Hand­ buch. Now 922 pages did not suffice to cover all aspects of the subject ... the subject has been expanded in so many directions, that the anti histaminic part had to be excluded from the present volume. Possibly, another thousand pages will be necessary to cover what remains of the subject."* This prediction was fulfilled, and the subject of histamine has grown to such an extent that dealing with the antihistaminics only in Part II would be quite inadequate. It is imperative to include the large number of recent findings on the subject of histamine, namely the splitting of its pharmacologic receptors, and the great variety of new contributions on ,its participation in physiopathologic phenomena, metabolism and interaction with newly found mediators.

I: Recent Developments of the Histamine Problem.- Section A: Pharmacological Actions.- 1. Cardiovascular Actions of Histamine.- I. Introduction.- II. Systemic Vascular Effects of Histamine.- A. Rat.- B. Guinea-Pig.- C. Rabbit.- D. Dog.- E. Cat.- F. Calf, Horse, and Sheep.- G. Man.- III. Cardiac Actions of Histamine.- A. Intact Animals.- 1. Inotropic Action.- 2. Chronotropic Action.- 3. Dromotropic Action.- 4. Cardiac Output.- B. Isolated Heart Preparations.- 1. Inotropic Action.- 2. Chronotropic Action.- 3. Dromotropic Action.- 4. Coronary Flow.- IV. Effects of Histamine on Regional Vasculatures.- A. Coronary.- B. Pulmonary Lung.- C. Splanchnic.- D. Liver-Portal.- E. Renal.- F. Musculo-Cutaneous.- G. Cerebral.- H. Miscellaneous.- V. Microcirculatory Actions of Histamine.- A. Direct In-Vivo Microcirculatory Actions of Histamine.- B. H1 Versus H2-Receptors in Microcirculation.- C. Effects of Histamine on Vascular Permeability and Endothelial Cells.- VI. Isolated Vascular Smooth Muscle and Histamine.- VII. Conclusions.- References.- 2. Histamine and Gastric Secretion.- I. Introduction.- II. Historical Review.- III. Physiologic Evidence.- A. Histidine Decarboxylase Activation.- B. Histamine Release and Gastric Secretion.- IV. H2-Receptor Antagonists: Gastric Secretion and the Role of Histamine.- V. Conclusions.- References.- Section B: Histamine Release.- 1. On the General Problem of the Release of Histamine.- I. Introduction.- II. The Noncytotoxic Nature of Histamine Secretion.- III. Histamine Release and Complement.- IV. The IgE Receptor.- V. Control Mechanisms of Histamine Release.- Cyclic Nucleotides and Histamine Release.- VI. Enhancers and Inhibitors of Histamine Release.- A. Enhancers of Histamine Release.- 1. Phosphatidyl Serine.- 2. Deuterium Oxide (D2O).- 3. Cholinergic Stimulation.- B. Inhibitors of Histamine Release.- 1. The Role of Calcium in Histamine Release.- 2. Desensitization.- VII. Histamine Release from Tissues and Platelets.- A. Histamine Release from Isolated Tissues and Organs.- B. Histamine Release from Platelets.- VIII. Concluding Remarks.- References.- 2. The Mechanism of Histamine Release from Mast Cells.- I. Introduction.- II. The Normal Mast Cells.- A. Morphology.- B. Contents.- III. The Degranulating Mast Cell.- A. Degranulating Agents.- B. Noncytotoxic Character of the Degranulation Process.- C. Electron-Microscopic Changes.- IV. Storage Properties of Basophil Granules.- A. Role of Heparin.- B. Role of Zinc.- C. Role of the Granule Protein-Heparin Complex.- V. Relationship Between Degranulation and Histamine Release.- References.- 3. Metabolic Changes in Mast Cells Associated with Histamine Release.- I. Energy Dependence of Anaphylactic Histamine Release.- II. Energy Metabolism of Mast Cells.- III. Changes in Mast Cell Respiration in Relation to Histamine Release.- IV. Changes in Glucose Metabolism in Mast Cells Associated with Histamine Release.- V. Changes in Adenosine Triphosphate Content of Mast Cells Associated with Histamine Release.- VI. Conclusion.- References.- Section C: Metabolism and Excretion of Histamine.- 1. Biogenesis of Histamine.- I. Introduction.- II. Methods for Determination of Histidine Decarboxylase Activity of Mammalian Tissues.- III. Histamine Formation in vitro.- IV. Histamine Formation in vivo.- V. Inhibition of Histamine Formation in vitro.- VI. Inhibition of Histamine Formation in vivo.- VII. Histidine Decarboxylase Activation and Deactivation; Role of Protein and RNA Synthesis.- VIII. Effect of Hormones on Histamine Formation.- IX. Histamine Formation in Brain.- X. Histamine Formation and Antihistamines.- XL Conclusion.- References.- 2. Histamine Metabolism and Excretion.- I. Histamine Metabolism in Tissues.- II. Changes in Histamine Metabolism in Tissues.- III. Histamine Metabolism and Excretion in Animals.- A. Rat.- B. Mouse.- C. Guinea Pig.- D. Hamster.- E. Rabbit.- F. Sheep.- G. Goat.- H. Pig.- I. Cow.- J. Horse.- K. Cat.- L. Toad, Tortoise, Terrapin.- IV. Changes in Histamine Metabolism and Excretion in Animals.- V. Histamine Metabolism in Human Tissues.- VI. Histamine Metabolism and Excretion in Man.- VII. Changes in Histamine Metabolism and Excretion in Man.- VIII. Blood Diseases.- IX. Allergy.- X. Burns.- XL Miscellaneous.- XII. Comments.- References.- 3. The Enzymatic Isotonic Assay of Histamine.- I. Introduction.- A. Principle of Isotope Derivative Dilution Assays.- B. Applications of Isotope Derivative Dilution Analysis in Biological Work.- C. Enzymatic Isotope Derivative Dilution Assays.- II. Double Isotope Assay (with ?-3H-Histamine as Internal Standard).- A. Principle.- B. Chemicals.- C. Preparation of ?-3H-(side-chain label)-Histamine.- D. Preparation of Histamine-N-Methyltransferase.- E. Storage and Preparation of Samples for Analysis.- F. Reagents and Stock Solutions (in Order of Use).- G. Incubation Procedure.- H. Extraction and Measurement of Labeled Methylhistamine.- I. Calculation.- J. Comments.- III. Single Isotope Microenzymatic Assay of Histamine.- A. Introduction.- B. Chemicals.- C. Reagents.- D. Procedure.- E. Calculation.- F. Comments.- IV. General Precautions to Be Observed with Enzymatic Assays of Histamine.- A. Specificity of Assay.- B. Assay Blanks and Precision of Assay.- C. Extraction Procedure and Use of Unlabeled Methylhistamine as Carrier.- D. Interference from Drugs and Tissue Constituents.- E. Importance of Purity of Labeled SAMe.- V. Use of Enzymatic Assay in Measurement of Histamine, L-Histidine, and Histamine-Metabolizing Enzymes in Tissues.- A. Histamine.- B. Assay of Histidine.- C. Histidine Decarboxylase.- D. Assay of Histamine-N-Methyltransferase.- References.- II: Chemistry and Structure-Activity Relationships of Synthetic Anti-Histaminics.- Section A: Chemistry of Anti-H1 Histamine Antagonists.- I. Introduction.- II. Chemical Types of H1Antihistaminic Drugs.- A. Early Work.- B. Ethylenediamines.- C. Tertiary-aminoalkyl Ethers.- D. 1,2-Diaryl-4-Aminobutenes.- E. 1,1-Diaryl-3-Aminopropenes.- F. 3-Amino-1-Aryl-1-(2-Pyridyl)Propanes(Pheniramines).- G. Phenothiazine Derivatives.- H. Further Tricyclic Derivatives.- I. Miscellaneous Types.- References.- Section B: Structure-Activity Relationships of H1 -Receptor Antagonists.- I. Introduction.- II. Compilation of the Most Important Structures with Anti-H1 Activity. Classification of the Structures Considered and Review of Measured Anti-H1 Activities.- III. Physical Properties and Anti-H1 Activity.- A. Qualitative Drug Design Based on the Physical Properties of Structures.- 1. Ionization Constants.- 2. Solubilities.- 3. Surface Properties.- 4. Spectral Data.- 5. Bond Stabilities.- 6. Charge Localizations.- 7. Dipole Moments.- B. Quantitative Design. The Hansch Approach.- 1. Introduction.- 2. The Hansch Approach Applied to a Series of Ring-Substituted Diphenhydramine Derivatives.- 3. The Hansch Approach Applied to a Series of Diphenhydramines with the Nitrogen Atom Included in a Ring System.- 4. The Activities of 1,1-Diaryl-3-Aminopropenes, and Some Related Compounds.- C. Some Features of Anti-H1 Activity Connected with Stereospecificity. Conformational Preferences.- 1. Anti-H1 Activities of Structures with an Optically Active Center.- 2. Anti-H1 Activities of Cis-Trans Isometric Structures.- 3. The Inclusion of Optically Active Structures into the Hansch Approach.- D. Integrated QSAR of H1-Receptor Antagonists.- IV. Conclusion.- References.- Section C: Chemistry and Structure-Activity Relationships of H2-Receptor Antagonists.- I. Introduction.- II. Development of H2-Receptor Antagonists.- A. The Search for an Antagonist.- B. Development of Burimamide.- C. Development of Metiamide.- D. Development of Cimetidine.- III. Chemical Constitution.- A. Introduction.- B. Burimamide and Metiamide.- C. Cimetidine.- IV. Chemical Mode of Action.- V. Pharmacokinetics.- A. Absorption and Distribution.- B. Metabolism and Elimination.- VI. Chemical Differentiation Between H1- and H2-Receptor Antagonists.- VII. Synthesis of Burimamide, Metiamide, and Cimetidine.- References.- III: Mechanism of Action of Antihistaminics.- Section A: Kinetics of Antagonist Action.- I. The Charnière Theory.- II. Applications of the Theory.- III. Appendix.- References.- Section B: Competitive and Noncompetitive Antagonism.- I. Introduction.- II. Material and Methods.- A. Test Organs.- B. Affinity and Intrinsic Activity Values.- C. Test Substances.- III. Results and Discussion.- A. Closer Inspection of the Intrinsic Activity and Affinity Values in Table 1.- 1. Intrinsic Activity and Affinity Values of Partial Agonists.- 2. pA2-Values Based on a Smaller Number of Animals than the Accompanying pD’2-Values, and Vice Versa.- B. The Interaction of Agonists and Competitive Antagonists with the Histamine Receptors; the Role of Additional Receptor Areas.- C. Competitive Antagonists and Their Affinity to the Metactoid Receptor.- 1. The pA2/pD’2-Ratios in the Histaminergic System.- 2. The pA2/pD’2-Ratios in the Cholinergic System.- 3. Comparison of the pD’2-Values in the Histaminergic and the Cholinergic System.- D. Influence of Some Molecular Modifications on the Affinity Values.- 1. The Influence of the Substitution of a Methyl Group to the Secondary N-Atom. The “Rule of Pfeiffer”.- 2. The Influence of the Presence or Absence of an N-Atom in the Ring in the “Mimetic Moiety” (Pyridyl or Phenyl Ring).- 3. The Influence of Para-Substitution of a Cl-Atom at the Phenyl Ring in the N-phenyl-N-benzyl-ethylamine Group.- 4. The Influence of Para-Substitution at the Phenyl Ring of N-(N’-phenyl-N’-benzyl-?-aminoethyl)-N-methyl-{2-(?-aminoethyl)-pyridine-}.- E. Quantitative Structure-Activity Correlations of 2-(?-aminoethyl)-pyridines.- F. Pitfalls in Structure-Activity Relationship Studies.- References.- Section C: Naturally Occuring Antihistaminics in Body Tissues.- I. Introduction.- II. Methods of Extraction of Antihistamine Activity.- General Considerations.- III. Methods of Assay of Natural Antihistamine Substance(s) (NAS).- Units of Activity.- IV. Estimation of Antihistamine Activity in Mammals.- V. Modifications of Amount of NAS Present in Tissues and Fluids.- A. Elevation of NAS.- B. Diminution of NAS.- VI. Mechanism of Action of NAS.- VII. Physical and Chemical Aspects of NAS.- A. Molecular Weight.- B. Solubility.- C. Stability.- D. Chemical Structure.- VIII. Role of NAS.- References.- IV: Pharmacological Actions of Antihistaminics.- Section A: Bioassay of Antihistaminic Action.- I. Introduction.- II. In Vitro Assays for Antihistaminics.- A. Assays on the Guinea Pig Ileum and Other Smooth Muscle Structures.- B. On the Schultz-Dale Reaction of the Sensitized Strips of the Guinea Pig Ileum and Uterus.- C. Bioassay of Antihistaminics on the Isolated Mammalian Heart.- D. Interrelations Between Antihistaminics and the Histamine(H1) Receptors.- III. In Vivo Assays of Antihistaminics.- A. Protection Against the Lethal Effects of Histamine.- B. Protection Against Asthma (Bronchospasm) Produced by Inhalation of a Histamine Aerosol.- C. Protection of Sensitized Guinea Pigs Submitted to the Challenging Dose of the Antigen.- D. Atropine-like Effects of Antihistaminics.- E. Local Anesthetic Action of Antihistaminics.- F. Action on the Skin Vessels and on Vascular Permeability.- IV. Conclusions.- References.- Section B: Antianaphylactic and Antiallergic Effects.- I. Introduction.- II. General Aspects of Antianaphylactic and Antiallergic Effects of Antihistaminics.- A. Receptor Specificity.- B. Potency of Antihistaminics.- C. Effect of Antihistaminics on Endogenously Released Histamine.- D. Nonspecific Effects of Antihistaminics.- III. Effects of Antihistaminics on Guinea Pig Anaphylaxis.- A. Systemic Shock.- 1. Antilethal Effects.- 2. Effect of Antihistaminics on Bronchospasm in vivo.- B. Action of Antihistaminics in Isolated Organs.- 1. Lung and Trachea.- 2. Isolated Gut.- 3. Uterus.- 4. Striated Muscle.- C. Heart Anaphylaxis.- D. Heart-Lung Preparation (HLP).- E. Adrenals and Adrenergic System.- 1. Role of Catecholamine Release in the Antianaphylactic Action of Antihistaminics on Acute Shock.- 2. Protracted Shock and Adrenal Glands.- F. Action of Antihistaminics on Antigen Aerosols.- G. Action of Antihistaminics on Cutaneous Anaphylaxis.- H. Forssman Shock.- I. Miscellaneous.- IV. Anaphylaxis in Dogs.- V. Anaphylaxis in Rabbits.- VI. Anaphylaxis in Rats.- VII. Anaphylaxis in Mice.- VIII. Other Species.- Summary and Conclusions.- References.- Section C: Antiinflammatory Effects.- I. Recent Work Involving H2-Receptors.- II. Effect of Antiinflammatory Drugs on the Interactions of Histamine with Other Possible Mediators of Inflammation.- III. Implications of Antiinflammatory Drugs for Elucidating Possible Roles of Histamine.- A. In Anaphylactic Shock.- B. In Allergy.- C. Responses of Tracheal Muscle.- IV. Inflammations in Which Antihistaminics Have Little or No Effect 510 V. Evidence from Depletion Experiments.- References.- V: Absorption, Distribution, Metabolism, and Elimination of Antihistamines.- I. Early Studies of Antihistamine Distribution, Excretion, and Metabolism.- II. Diphenhydramine and Orphenadrine.- III. Tripelennamine Metabolism.- IV. Cyclizine, Chlorcyclizine, and Related Compounds.- V. Chlorpheniramine and Brompheniramine.- VI. Chlorphenesin, Chlorphenesin Carbamate, and Related Phenoxy Propanediols.- VII. Perazine, Prochlorperazine, Trifluperazine, and Fluphenazine.- VIII. Promethazine, Chlorpromazine, and Related Compounds.- IX. Cyproheptadine, Amitriptyline, Nortriptyline, and Protriptyline.- X. Doxepin.- XL Hepzidine.- XII. Drug Metabolism and Enzyme Induction.- XIII. H2 Histamine Antagonists.- References.- VI: Therapeutic Action of Anti-Histaminics.- Section A: Antihistaminics as Central Nervous System Depressants.- I. Introduction.- II. Laboratory Studies.- A. Behavioral Studies.- B. Drug Interaction Studies.- C. EEG Studies.- III. Clinical Studies.- A. Ethylenediamine Agents.- B. Alkylamine Agents.- C. Piperazine Agents.- D. Phenothiazine Agents.- E. Aminoalkyl Ether Agents.- IV. Mechanism of Action.- References.- Section B. Circulatory Shock, Histamine and Antihistamines: Therapeutic Aspects.- I. Introduction.- II. Vasoactive Agents: Use and Misuse in Low-Flow States.- III. Failure of Peripheral Vascular-Homeostatic Mechanisms.- IV. Vasoactive Mediators in Circulatory Shock.- V. Is Histamine the Mediator of the Shock Syndrome?.- VI. Plasma Histamine Levels in Man and Animals in Shock.- A. Hemorrhage.- B. Trauma.- C. Endotoxemia-Sepsis.- D. Burns-Scalding.- E. Anaphylactic Shock.- VII. Influence of Antihistamines on Survival after Circulatory Shock.- A. Histamine Shock.- B. Hemorrhage.- C. Trauma.- D. Endotoxemia-Sepsis.- E. Burns-Scalding.- F. Anaphylactic Shock.- VIII. Conclusions and Future Outlook for Antihistamine Therapy in Circulatory Shock and Low-Flow States.- References.- Author Index.