Pharmacology of Asthma

1 The Pathology of Asthma: An Overview.- A. Introduction.- B. Methods to Investigate the Pathology of Human Asthma.- C. Bronchial Epithelium and Inflammatory Cells in Asthmatic Patients Between Attacks.- I. Mast Cells.- II. Eosinophils.- III. Neutrophils.- D. Bronchial Epithelial Inflammation During an Asthma Attack.- E. Epithelial Regeneration.- F. Airway Smooth Muscle.- G. Bronchial Glands.- H. Neural Pathways.- I. Epithelium.- II. Neuroepithelial Bodies and Neuroendocrine-Like (Granule-Containing) Cells.- I. Nerves and Other Airway Structures.- J. Bronchial Circulation.- K. Leakage of the Bronchial Vascular Bed in Patients with Asthma.- L. Conclusion.- References.- 2 The Contribution of Inflammatory Cells to the Pathogenesis of Asthma.- A. Inflammation and Inflammatory Cells.- B. Pathological Evidence for Inflammation in Asthma.- C. Microvascular Leakage.- D. Neutrophils.- E. Eosinophils.- F. Mast Cells and Basophils.- G. Monocytes and Macrophages (Mononuclear Phagocytes).- H. Platelets.- I. Lymphocytes.- J. Concluding Comments.- References.- 3 Inflammatory Mediators.- A. Introduction.- I. Cellular Origin of Mediators.- II. Mediator Effects.- III. Mediator Receptors.- IV. Mediator Interactions.- V. Mediator Antagonists.- B. Histamine.- I. Synthesis and Metabolism.- II. Histamine Receptors.- III. Airway Effects.- IV. Role in Asthma.- C. Cyclooxygenase Products.- I. Synthesis and Metabolism.- II. Receptors.- III. Airway Effects.- 1. Airway Smooth Muscle.- 2. Secretion.- 3. Inflammatory Effects.- IV. Role in Asthma.- D. Lipoxygenase Products.- I. Synthesis and Metabolism.- II. Receptors.- III. Airway Effects.- 1. Airway Smooth Muscle.- 2. Secretion.- 3. Vascular Effects.- 4. Cellular Activation.- 5. Effects on Bronchial Responsiveness.- IV. Role in Asthma.- E. PAF.- I. Origin.- 1. Synthesis.- 2. Cellular Origin.- 3. Metabolism.- II. Receptors.- III. Airway Effects.- 1. Airway Smooth Muscle.- 2. Airway Secretions.- 3. Vascular Effects.- 4. Inflammatory Cell Activation.- 5. Bronchial Hyperresponsiveness.- IV. Role in Asthma.- 1. Release of PAF in Asthma.- 2. PAF Antagonists.- F. Kinins.- I. Formation and Metabolism.- II. Receptors.- III. Airway Effects.- IV. Role in Asthma.- G. Adenosine.- I. Origin.- II. Receptors.- III. Actions.- IV. Role in Asthma.- H. Complement.- I. Origin and Metabolism.- II. Receptors.- III. Airway Effects.- 1. Smooth Muscle Contraction.- 2. Vascular Effects.- 3. Mucus Secretion.- 4. Chemotaxis and Cell Activation.- 5. Bronchial Hyperresponsiveness:.- IV. Role in Asthma.- I. Serotonin.- I. Origin.- II. Receptors.- III. Airway Effects.- J. Chemotactic Factors.- K. Oxygen Radicals.- L. Conclusions.- References.- 4 Pharmacology of Airway Smooth Muscle.- A. Introduction.- B. E/C Coupling Mechanisms.- I. The Airway Smooth Muscle Cell.- II. Activator Calcium Ions and E/C Coupling.- 1. Coupling Mechanisms.- 2. Extracellular Activator Ca2+.- 3. Intracellular Activator Ca2+.- III. Biochemical Basis of Airway Smooth Muscle Contraction.- C. E/C Uncoupling Mechamisms.- I. ?-Adrenoceptor Agonists.- 1. ?-Agonist-Induced Relaxation In Vitro: General Properties.- 2. Role of Cyclic Adenosine Monophosphate (cAMP) Accumulation in the Relaxant Actions of ?-Adrenoceptor Agonists.- 3. ?-Agonists and the Ca2+ Sensitivity (or Responsiveness) of the Contractile Machinery.- 4. ?-Agonists and Inhibition of Ca2+ Influx.- 5. ?-Agonists and Inhibition of Ca2+ Release from Intracellular Stores.- 6. ?-Agonists and Promotion of Ca2+ Sequestration by Intracellular Stores.- 7. ?-Agonists and Ca2+ Extrusion.- II. Alkylxanthines.- 1. Alkylxanthine-Induced Relaxation In Vitro: General Properties.- 2. Role of cAMP Accumulation in the Relaxant Actions of Alkylxanthines..- 3. Alkyxanthines and Reduction in the Ca2+ Sensitivity (or Responsiveness) of the Contractile Machinery.- 4. Alkylxanthines and Inhibition of Ca2+ Influx.- 5. Alkylxanthines and Inhibition of Ca2+ Release from Intracellular Stores.- 6. Alkylxanthines and Promotion of Ca2+ Sequestration by Intracellular Stores.- 7. Alkylxanthines and Ca2+ Extrusion.- D. Future Trends in the Development of Bronchodilator Drugs.- References.- 5 Neural Mechanisms in Asthma.- A. Introduction.- B. Cholinergic Mechanisms.- I. Increased Vagal Tone.- II. Reflex Bronchoconstriction.- III. Increased Acetylcholine Release.- IV. Muscarinic Receptors.- V. Cholinergic Mechanisms in Asthma.- VI. Cholinergic Mechanisms in COAD.- VII. Muscarinic Receptor Subtypes.- C. Adrenergic Mechanisms.- I. Adrenergic Innervation.- II. Circulating Catecholamines.- III. ?-Adrenoceptors.- IV. ?-Adrenoceptors.- D. NANC Nerves and Neuropeptides.- I. NANC Inhibitory Nerves.- II. Increased NANC Excitatory Nerves.- III. Tachykinins.- IV. Calcitonin Gene-Related Peptide.- V. Axon Reflex Mechanisms.- VI. Modulation of NANC Bronchoconstriction.- E. Conclusions.- References.- 6 Pharmacology and Therapeutics of ?-Adrenoceptor Agonists.- A. Introduction.- B. The Molecular Nature of the ?-Adrenoceptor and Its Relationship to Adenylate Cyclase.- I. The ?-Adrenoceptor.- II. Regulatory Proteins.- III. Adenylate Cyclase.- IV. ?-Adrenoceptor Desensitization.- C. Density and Distribution of ?-Adrenoceptors in the Lung.- I. Radioligand Binding Studies.- II. Autoradiography.- 1. Trachea.- 2. Parenchyma.- D. Therapeutic Sites of Action.- I. Airway Smooth Muscle.- II. Secretory Cells and Cilia.- III. Tracheobronchial Microvessels.- IV. Cholinergic Nerves.- V. Mast Cells.- VI. Inflammatory Cells.- 1. Eosinophils.- 2. Lymphocytes.- 3. Polymorphonuclear Leukocytes.- 4. Macrophages.- 5. Platelets.- 6. Anti-Inflammatory Action in Asthmatic Airways.- E. The Status of ?-Adrenoceptor Function in Asthma.- I. In Vivo Studies.- II. In Vitro Studies.- 1. Isolated Human Leukocytes.- 2. Isolated Human Bronchi.- 3. Radioligand Binding Studies and Autoradiography in Lung.- F. The Importance of ?2-Adrenoceptor Selectivity and Efficacy.- I. ?2 Selectivity.- II. Efficacy.- G. Adverse Reactions to ?-Adrenoceptor Agonists.- I. Skeletal Muscle Tremor.- II. Cardiac Effects.- III. Changes in Plasma Constituents.- 1. Potassium.- 2. Glucose.- 3. Lipids.- IV. PaO2.- V. Neuropharmacological Effects.- VI. Hypersensitivity.- H. Therapeutic Actions of ?-Agonists.- I. Adrenaline.- II. Ephedrine.- III. Isoprenaline.- IV. Selective ?2-Agonists.- V. Prodrugs.- VI. Clinical Application.- I. Concluding Remarks.- References.- 7 Pharmacology of Anti-Asthma Xanthines.- A. Introduction.- I. Developmental Aspects.- II. Chemistry and Subdivision of Xanthines.- B. Clinical Use.- I. Acute Severe Asthma.- II. Chronic Asthma.- III. Chronic Obstructive Pulmonary Disorders.- C. Mode of Action of Xanthines.- I. Smooth Muscle Relaxation or Inhibition?.- II. Airway Anti-Inflammatory Actions.- III. Anti-Asthma Actions Outside the Airways?.- IV. Subcellular Mechanisms of Action.- V. Role of Endogenous Adenosine.- D. Conclusion.- References.- 8 Glucocotricosteroids in Asthma.- A. Mechanism of Action of Glucocorticosteroids.- I. Induction of Protein Synthesis.- 1. Lipocortins.- 2. Other Proteins Modulated by Glucocorticosteroids.- II. Effects on Cell Activation and Recruitment.- III. Other Effects.- 1. Vascular Permeability and Effects on Vascular Endothelium.- 2. Effects on ?-Adrenoceptors.- 3. Effects on Airway Function.- B. Clinical Use.- I. Pharmacokinetics of Steroids.- II. Routes of Administration.- 1. Oral.- 2. Intravenous.- 3. Inhaled.- III. Side Effects.- 1. Adrenal Suppression.- 2. Systemic Side Effects.- 3. Local Side Effects.- IV. Use in Clinical Practice.- 1. Acute Asthma.- 2. Chronic Asthma.- C. Future Developments.- References.- 9 Pharmacology of Prophylactic Anti-Asthma Drugs.- A. Cromoglycate and Nedocromil.- I. Cellular Pharmacology.- 1. Mast Cells and Basophils.- 2. Neutrophils, Eosinophils, Monocytes, and Platelets.- II. Biochemical Pharmacology.- III. Animal Pharmacology.- 1. Anaphylactic Bronchospasm.- 2. Sensory Reflexes.- IV. Human Pharmacology.- B. Ketotifen.- I. Pharmacology In Vitro.- II. Animal Pharmacology.- 1. Antihistamine, Antiallergic Properties.- 2. Inhibition of PAF-Induced Airway Hyperreactivity.- III. Human Pharmacology.- 1. Blockade of Responses to Spasmogens and Allergens.- 2. Reversal of ?-Adrenergic Receptor Tachyphylaxis.- 3. Double-Blind Placebo-Controlled Clinical Trials.- C. Pharmacological Analysis.- I. Cromoglycate and Nedocromil.- II. Ketotifen.- References.- 10 Pathophysiology and Pharmacology of Aspirin-Induced Asthma.- A. Introduction.- B. Definition and Main Clinical Features.- I. Major Offenders and Safe Alternatives.- II. Salicylates.- III. Paracetamol.- IV. Pyrazolones.- V. Tartrazine.- VI. Glucocorticosteroids.- C. Pathogenesis.- I. Allergic Mechanisms.- II. Abnormal Reactivity of Bradykinin Receptors.- III. Acetylation of Proteins.- IV. Complement Involvement.- V. The Cyclooxygenase Theory.- 1. Formulation of the Theory.- 2. Early Explanations.- 3. Participation of LTs.- 4. Platelet Involvement.- 5. Compartmentalization of Eicosanoids in the Lungs.- 6. Viral Infection.- D. Diagnosis.- E. Prevention and Therapy.- References.