Pyretics and Antipyretics

1 Body Heat.- 2 Fever and its Role in Disease: Rationale for Antipyretics.- A. Fever.- B. The Role of Fever in Disease.- C. Antipyretic Drugs.- D. Effects of Antipyresis on Survival.- E. Clinical Indications and Contraindications for Antipyretic Therapy.- References.- 3 Thermoregulation: Its Change During Infection with Endotoxin-Producing Micro-organisms.- A. Introduction.- B. The Elevated Set-Point Concept of Fever.- C. The Pyrogens.- I. Bacterial Endotoxins.- II. Endogenous (Leucocyte) Pyrogens.- III. The Prostaglandins.- D. Pyrogen Action.- I. Points of Action in the Central Nervous System.- II. Effects on the Electrical Activities of Hypothalamic Neurones.- E. Areas of Current Concern and Doubt.- I. More than One Central Point of Action of Pyrogens?.- II. The Biphasic Pattern of Experimentally Induced Fever: Two Causative Factors?.- III. The Pyrogenic Metabolites of Arachidonic Acid.- IV. Are Pyrogens Only Pyrogens?.- V. Is Fever of Physiological Benefit?.- F. Mechanisms of Thermoregulation.- I. The Set-Point Machinery: Theory.- II. The Antiquity of Homeostasis and of Pyrogen Responsiveness.- III. The Pattern of Neural Connections.- G. Models for Thermoregulation.- I. Point (or Points) of Action of Pyrogens.- II. Neuronal Model of Central Thermoregulatory Connections in Sheep.- III. Point of Action of Bacterial Endotoxin in Sheep.- IV. Neuronal Theory of Fever Induction.- H. Thermoregulatory Agents.- I. Central Nervous 5HT.- II. Central Nervous Norepinephrine.- III. The Central Thermoregulatory Effects of ACh.- J. Other Set-Point Theories.- I. The Monoamine Balance Set-Point Theory.- II. The Ionic Balance Set-Point Theory.- K. Concluding Comments.- I. The Independence of Fever from the Influence of Ambient Temperature.- II. The Upper Limit to the Febrile Response.- III. More than One Pathway from Infection to Fever?.- References.- 4 Exogenous Pyrogens.- A. Introduction.- I. General Considerations.- B. Viruses.- I. Experimental Fevers with Viruses.- II. Interferon.- C. Gram-Positive Organisms.- I. Intact Organisms.- II. Extracellular Products.- III. Cell Wall Components.- D. Gram-Negative Bacteria.- I. Cell Wall Structure.- II. Pyrogenicity of LPS.- III. LPS Fever and EP Production.- IV. LPS Structure and Ability to Produce Fever.- V. Lipid A and Pyrogenicity.- VI. Pyrogenic Tolerance to LPS.- E. Mycobacteria.- I. Febrile Reactions of BCG-Sensitized Animals.- II. Release of EP from Cells Incubated with Tuberculin.- F. Fungi.- I. Pyrogenicity of Fungal Cells.- II. Fever from Fungal Products.- G. Non-Microbial Antigens.- I. Antibody-Mediated Fever.- II. Cell-Mediated Immune Fever.- H. Pyrogenic Steroids.- I. Fever in Humans.- II. Pyrogenic Steroid-Induced EP.- J. Miscellaneous Exogenous Pyrogens.- I. Polynucleotides.- II. Colchicine and Vinblastine.- III. Bleomycin.- IV. Synthetic Adjuvants.- References.- 5 Endogenous Pyrogens.- A. Introduction.- B. Nomenclature.- C. Assay of Endogenous Pyrogen.- D. Sources of LP.- I. Cells Capable of Pyrogen Release.- II. Animal Species Releasing EP.- E. Cellular Events.- F. Isolation and Characterization of EP.- I. Methods for Purification.- II. Heterogeneity of EP.- References.- 6 Role of Central Neurotransmitters in Fever.- A. Introduction.- B. Noradrenaline.- I. Depleting Agents.- II. Sympathomimetic Agents and Monoamine Oxidase Inhibitors.- III. Adrenoceptor Antagonists.- IV. Brain Catecholamine Levels.- V. Conclusion.- C. 5-Hydroxytryptamine.- I. Depleting Agents.- II. 5-Hydroxytryptamine Agonists and Uptake Inhibitors.- III. Indoleamine Antagonists.- IV. Brain 5-Hydroxytryptamine Levels and Turnover.- V. Conclusion.- D. Acetylcholine.- I. Cholinergic Antagonists.- II. Cholinomimetics and Anticholinesterases.- III. Conclusion.- E. Other Amines.- I. Dopamine.- II. ?-Aminobutyric Acid.- III. Histamine and Taurine.- F. Peptides.- I. Kinins.- II. Thyroid-Releasing Hormone.- III. Opioids.- G. Conclusion.- References.- 7 The Role of Ions in Thermoregulation and Fever.- A. Introduction.- B. Systemic Effects of Altered Ion Levels.- C. Action of Cations in the Cerebral Ventricles.- D. Action of Cations on the Hypothalamus.- I. Anatomical Localization of Ion-Induced Temperature Changes.- II. Specificity of Cation Actions.- E. Exercise, Cations, and Temperature Set-Point.- I. Hypothalamic Na+:Ca2+Ratio and Exercise.- F. Fever, Na+:Ca2+ Ratio, and Set-Point Shift.- I. In Vivo Cation Activity in the Diencephalon.- II. Antipyresis and Na+:Ca2+Efflux.- G. Critique of the Ionic Set-Point Mechanism for Body Temperature.- I. Experimental Evidence for the Ionic Set-Point Theory.- II. Primate Model of Temperature Control.- References.- 8 Electrophysiology of the Anterior Hypothalamus: Thermoregulation and Fever.- A. Introduction.- B. Microelectrode Recording Techniques.- I. Single-Unit Recordings.- II. Functional Characterization of Neurones.- 1. Physiological Stimuli.- 2. Electrical Stimuli.- 3. Pharmacological Stimuli.- III. In Vitro Recording.- IV. Data Analysis.- 1. Mean Firing Frequency and Thermosensitivity.- 2. Patterns of Neuronal Discharge.- V. Critique of Microelectrophysiology.- 1. Non-Random Selection of Neuronal Population.- 2. Lack of Positive Functional Characterization.- C. Thermosensitivity of PO/AH Neurones.- I. Thermoresponsiveness.- 1. Proportions of Thermosensitive Cells.- 2. Ratio of Warm-to Cool-Sensitive Cells.- II. Detectors Versus Interneurones.- 1. Thermal Response Form.- 2. Extrahypothalamic Inputs.- 3. Firing Pattern Analysis.- III. In Vitro Recording of PO/AH Activity.- D. Pyrogenic and Antipyretic Actions.- I. Pyrogens and Antipyretics.- 1. Pyrogenic Agents.- 2. Antipyretics.- II. Electrophysiology of Pyrogen Action.- 1. Bacterial and Leucocyte Pyrogens.- 2. Prostaglandins.- 3. Pyrogen Action on Peripheral Receptors.- III. Electrophysiology of Antipyretic Action.- E. Summary.- References.- 9 Cyclic Nucleotides and Fever.- A. Introduction.- B. Temperature Responses to Cyclic AMP in Different Species.- I. Mice.- II. Rats.- III. Rabbits.- IV. Cats.- V. Dogs.- VI. Primates.- VII. Birds.- C. Enzymes Related to Cyclic AMP.- I. Adenylate Cyclase.- 1. Activators of Adenylate Cyclase.- 2. Inhibitors of Adenylate Cyclase.- II. Cyclic Nucleotide Phosphodiesterase.- 1. Activators of Cyclic Nucleotide Phosphodiesterase.- 2. Inhibitors of Cyclic Nucleotide Phosphodiesterase.- D. Endogenous Cyclic AMP in Fever.- I. Cyclic AMP in Brain Tissue.- II. Cyclic AMP in Cerebrospinal Fluid.- E. Cyclic GMP in Fever.- F. Summary.- References.- 10 Prostaglandins in Fever and the Mode of Action of Antipyretic Drugs.- A. Introduction.- B. Temperature Responses to Prostaglandins.- I. Cats.- 1. Prostaglandins E1 and E2.- 2. Prostaglandins Fl? and F2?.- 3. Prostaglandin A1.- 4. Prostaglandin D2.- 5. Environmental Temperature and PGE1 Response.- II. Rabbits.- III. Sheep.- 1. Adult Sheep.- 2. New-born Lambs.- IV. Rats.- V. Mice.- VI. Guinea-pigs.- VII. Monkeys.- VIII. Man.- IX. Monotremes.- X. Birds.- 1. Adult Chickens.- 2. Chicks.- XI. Miscellaneous Species.- C. Prostacyclin.- D. Prostaglandin Endoperoxide Analogues.- E. Brain Trauma and Prostaglandin Synthesis.- F. Endogenous Pyrogen and Prostaglandin Synthesis In Vitro.- G. Release of Prostaglandins by Pyrogens.- I. Release of Prostaglandin in the CNS by Bacterial Pyrogen.- 1. Prostaglandins in Cat Cerebrospinal Fluid.- 2. Prostaglandins in Rabbit Cerebrospinal Fluid.- 3. Prostaglandins in Human Cerebrospinal Fluid.- II. Release of Prostaglandins by Endogeneous Pyrogen.- 1. Cats.- 2. Rabbits.- III. Peripheral Actions of Antipyretics.- H. Antipyretics and Prostaglandin Synthesis.- I. Action on Prostaglandin Fever.- II. Action on Prostaglandin Release During Endotoxin and Endogenous Pyrogen Fever.- III. Antagonism of Sodium Arachidonate Hyperthermia by Antipyretics.- J. Interactions Between Prostaglandins and Endotoxins.- I. Hypothalamic Destruction.- II. Inhibition of Prostaglandin Breakdown.- K. Effects of Prostaglandins on Neuronal Activity in the PO/AH.- L. Prostaglandin Antagonists.- M. Prostaglandins and Thermoregulation.- N. Prostaglandins and Cyclic Nucleotides.- I. Cyclic GMP.- II. Cyclic AMP.- 1. Mice.- 2. Rats.- 3. Monkeys.- 4. Cats.- 5. Rabbits.- O. Non-specific Febrile Response.- P. Sodium Fever.- Q. Discussion.- References.- 11 Protein Synthesis and Fever.- A. Introduction.- B. Experimental Evidence.- C. Conclusions.- References.- 12 The Chemistry of the Non-Steroidal Antipyretic Agents: Structure-Activity Relationships.- A. Introduction.- B. Receptor Models for Antipyretic and Anti-Inflammatory Actions.- C. Antipyretic Assay Methods.- D. Structure-Activity Relationships.- I. Enolic Acids.- II. Salicylic Acid and Related Compounds.- III. N-Arylanthranilic Acids.- IV. Aryl- and Heteroarylalkanoic Acids and Related Compounds.- 1. Substituted Arylalkanoic Acids.- 2. Alkyl- or Aryloxyarylalkanoic Acids and Related Compounds.- 3. Indanecarboxylic Acids and Related Compounds.- 4. Aroylarylalkanoic Acids and Related Compounds.- 5. Indoleacetic Acids and Analogues.- 6. Polycycloaromatic Alkanoic Acids.- V. Non-Acidic Compounds.- VI. Derivatives of Aniline and Aminophenol.- VII. Compounds of Natural Origin.- E. Conclusions.- References.- 13 Therapeutic Agents Affecting Body Temperature.- A. Introduction.- B. Effects of General Anaesthetics, Barbiturates, Narcotic Analgesics and Phenothiazines on Thermoregulation in Mammalian Species Other than Humans.- I. Effects on Body Temperature.- 1. General Anaesthetics and Barbiturates.- 2. Narcotic Analgesics.- 3. Phenothiazines.- II. Sites of Action.- 1. General Anaesthetics and Barbiturates.- 2. Morphine.- 3. Chlorpromazine.- III. Effects on Heat Gain and Heat Loss Mechanisms.- 1. General Anaesthetics and Barbiturates.- 2. Morphine.- 3. Phenothiazines.- IV. Neuropharmacology.- 1. General Anaesthetics and Barbiturates.- 2. Narcotic Analgesics.- 3. Phenothiazines.- V. Effects of Repeated Administration.- 1. Barbiturates and Ethanol.- 2. Narcotic Analgesics.- 3. Phenothiazines.- VI. Drug Interactions Producing Hyperthermia.- 1. Narcotic Analgesics.- 2. Chlorpromazine.- VII. Effects of Methionine Enkephalin and ?-Endorphin on Thermoregulation.- C. Effects of General Anaesthetics, Barbiturates, Narcotic Analgesics and Phenothiazines on Human Thermoregulation.- I. General Anaesthetics and Barbiturates.- II. Narcotic Analgesics.- 1. Single and Repeated Administration.- 2. Drug Interactions.- III. Phenothiazines.- D. Concluding Summary.- References.- 14 Capsaicin Type Pungent Agents Producing Pyrexia.- A. Introduction.- B. Historical Background.- C. Chemical Structure.- I. Natural Pungent Substances.- 1. Capsaicin.- 2. Piperine and Chavicine.- 3. Zingerone and Other Natural Pungent Agents.- II. Synthetic Congeners.- D. Heat Loss Responses Produced by Pungent Agents.- I. Effects on the Mouse.- II. Effects on the Rat.- III. Effects on the Guinea-pig.- IV. Effects on Other Animal Species.- V. Effects on Human Subjects.- E. Long-Term Thermoregulatory Changes Induced by Pungent Agents.- I. Desensitization to Pungent Agents by Capsaicin.- 1. Desensitization of the Rat.- 2. Desensitization of Other Animal Species.- II. Impairment in Thermoregulation After Capsaicin Desensitization.- 1. Thermoregulation in Cool, Cold, and Thermoneutral Environments.- 2. Thermoregulation at High Ambient Temperatures.- III. Structure-Activity Relationship.- F. Interaction with Fever, Drugs, and Neurotransmitters.- I. Interaction with the Effects of Pyrogens and Antipyretics.- II. Interactions with Neurotransmitters and Drugs.- G. Action of Capsaicin on Hypothalamic Warm-Sensors.- I. Effect of Intrahypothalamic Injection of Capsaicin.- II. Action on Hypothalamic Thermosensitive Neural Responses.- III. Ultrastructural and Biochemical Changes in the PO/AH Induced by Capsaicin.- H. Action of Pungent Agents on Sensory Receptors.- I. Capsaicin Desensitization and Sensation.- II. Electrophysiological Recordings from Exteroceptive Nerves.- III. Effects on Interoceptors.- 1. Vagal Interoceptors.- 2. Non-Vagal Pressor Chemoreflexes.- IV. Local Efferent Function of Capsaicin-Sensitive Sensory Nerve Endings.- 1. Skin and Exteroceptive Mucous Membranes.- 2. Internal Organs.- V. Concept of Sensory Neurone Blocking Effect of Pungent Acylamides.- 1. Neurone-Selective Site of Action.- 2. Mode of Action at the Neural Level.- 3. Structure-Activity Relationship.- J. Concluding Remarks.- References.- 15 The Pathophysiology of Fever in the Neonate.- A. Introduction.- B. Characteristics of Temperature Regulation in the Newborn.- I. Heat Production.- II. Heat Loss.- III. “Normal” Body Temperature.- IV. Immaturity and Malnutrition.- C. Central Mechanisms of Body Temperature Control.- I. Central Thermosensitivity.- II. Thermoregulatory Effects Evoked by Centrally Applied Monoamines.- D. Fever in the Human Neonate.- I. Definition.- II. Occurrence of Fever and/or Changes in Body Temperature During Infections.- E. Experimental Fever in Newborn Animals.- I. Characteristics of Experimental Neonatal Fever.- II. Differences Between Adult and Neonatal Febrile Responses.- F. Reasons for Differences Between Neonatal and Adult Febrile Responses.- I. Surface/Weight Ratio of the Body.- II. Ability to Produce Endogenous Pyrogen.- III. Role of Central Mediatory/Modulatory Substances.- 1. Prostaglandins.- 2. Serotonin.- 3. Noradrenaline.- 4. Other Factors.- 5. Similarities of Fever Mediation in Newborn and Adult Animals.- IV. Fever as an Abnormal Drive.- V. Relation Between Responsiveness to Thermal and Pyrogenic Stimuli.- VI. Relationship of Factors Influencing Neonatal Febrile Response.- G. Concluding Remarks.- I. Human Applications.- II. Definition of Fever.- III. Set-Point Change in Fever.- References.- 16 The Treatment of Fever from a Clinical Viewpoint.- A. Introduction.- B. The Treatment of Uncomplicated Fever.- C. The Treatment of Hyperpyrexia.- D. The Treatment of Prolonged Fevers.- E. The Treatment of Fever in High-Risk Patients.- I. Children with Febrile Seizures.- II. Patients with Head Injury.- III. Patients with Severe Mental Disorder.- IV. Patients with a Compromised Cardiovascular System.- V. Pregnant Women.- F. The Treatment of Hyperthermias.- I. Overinsulation.- II. Metabolic Disorders.- III. Drug-Induced Hyperthermia.- IV. Drug Hypersensitivity.- V. Heat Stroke Syndromes.- References.- 17 Malignant Hyperthermia: A Review.- A. Introduction.- B. History.- C. Epidemiology.- I. Previous Anaesthetics.- II. Incidence.- III. Sex and Age.- IV. Geographical Distribution and Racial Incidence.- V. Species.- VI. Heredity.- VII. Triggering Factors.- 1. Drugs.- 2. Stress.- 3. Diet.- 4. Climate.- 5. Elevated Serum Calcium.- D. The Acute Reactions.- I. Clinical Appearance.- II. Laboratory Changes.- III. Late Complications.- IV. Post Mortem Examination.- V. Prognosis.- VI. Differential Diagnosis.- E. Aetiology and Pathophysiology of Rigid MH.- I. Aetiology.- 1. Defective Calcium Uptake into, Binding by and/or Release from the Sarcoplasmic Reticulum.- 2. Defective Calcium Uptake into, Binding by and/or Release from the Mitochondria.- 3. Passive Diffusion of Extracellular Fluid Calcium Across a Defective Sarcolemma into the Myoplasm or Release of Bound Calcium from the Sarcolemma to the Myoplasm.- 4. Exaggerated Catecholamine Innervation.- II. Pathophysiology.- III. Malignant Hyperthermia — Widespread Membrane Defect.- IV. Miscellaneous Observations on the Aetiology of MH.- F. Preanaesthetic Diagnosis of MH.- I. Skeletal Muscle Studies.- 1. Signs and Symptoms of Musculoskeletal System.- 2. Electromyography.- 3. Serum Creatine Kinase Elevations.- 4. Serum Pyrophosphate.- 5. Skeletal Muscle Biopsy.- 6. Caffeine and Halothane Contracture Tests.- 7. Skinned Fibre Test.- 8. Halothane-Induced Contracture of Thin Muscle Sections.- 9. ATP Depletion Test.- II. Microscopy.- III. Heart Muscle Studies.- 1. Clinical Features.- 2. Electrocardiograms.- 3. Echocardiogram s.- 4. Myocardial Scanning with Thallium-201 (Rest and Exercise).- 5. Cardiac Catheterization and Angiography.- 6. Heart Muscle Biopsy.- IV. Extramuscular Nerves.- V. Platelets.- VI. Red Blood Cells.- VII. Endocrines.- VIII. Bone and Appendages.- IX. Miscellaneous.- G. Management of Inadvertent Fulminant Malignant Hyperthermia Reactions.- I. Stop Triggering Agents.- II. Lower Body Temperature.- III. Correct Blood Gases.- 1. Oxygen and Carbon Dioxide Tensions.- 2. Base Deficit.- IV. Lower Myoplasmic Calcium.- 1. Dantrolene.- 2. Procaine HC1 and Procaine Amide.- 3. Verapamil.- 4. Diltiazem.- V. Correct Abnormal Serum Potassium Levels.- VI. Control Arrhythmias.- VII. Stabilize Membranes.- VIII. Administer Drugs Which Exert Osmotic Force.- IX. Use Drugs of Supportive Value in the Therapy of MH Reactions: Narcotics, Barbiturates and Antipyretics.- X. Treat Acute Consumption Coagulopathy.- XI. Avoid Drugs Contraindicated During MH Reactions.- 1. Lidocaine.- 2. Cardiac Glycosides.- 3. Calcium Salts.- 4. Sympathomimetics.- 5. Parasympatholytics.- XII. Prevent Endogenous Catecholamine Release.- XIII. Monitoring.- H. Summary.- References.- 18 Febrile Convulsions.- A. Introduction.- B. Definitions: Tautology and Bogus Dichotomy.- C. Difficulties in Definition.- D. Cerebral Pathology.- I. Acute.- II. Chronic.- E. Mechanisms of Febrile Convulsions.- I. Epileptic Seizure Mechanism.- II. Anoxic Seizure Mechanism.- III. Combined Anoxic and Epileptic Mechanism.- F. Ocular Compression Study of Febrile Convulsion Phenotypes and Genotypes.- I. Syncope: Relation to Previous Febrile Convulsions.- II. Febrile Convulsion Trial.- III. Pertussis Immunization Convulsions.- IV. Genetic Analysis: Febrile Convulsions and/or Reflex Anoxic Seizures.- V. Clinical Example: Genetic Anoxic Seizures, Syncope, and Febrile Convulsions.- VI. Summary of Results from Ocular Compression Studies.- G. Genetics.- H. Brain Damage from Febrile Convulsions.- J. Prophylactic Drug Therapy of Febrile Convulsions.- K. Special Cases: Familial Dysautonomia and Down’s Syndrome.- L. New Pharmacological Aspects of Febrile Convulsions.- M. Hypotheses.- References.- 19 The Pyrogenic Responses of Non-mammalian Vertebrates.- A. Thermoregulation in Non-mammalian Vertebrates.- B. Febrile Responses of Birds.- C. Febrile Responses of Reptiles.- D. Febrile Responses of Amphibians.- E. Febrile Responses of Fishes.- F. Pyretic and Antipyretic Agents.- I. Bacterial Pyrogens.- II. Endogenous Leucocytic Pyrogen.- III. Prostaglandins.- IV. Antipyretics.- V. Parietalectomy.- VI. Hormones.- VII. Pesticides.- 1. Organochlorines.- 2. Organophosphates.- 3. Other Pesticides.- VIII. Heavy Metals and Their Salts.- IX. Inorganic Ions (Salinity).- X. Nutritive Substances.- XI. Other Substances Affecting Thermoregulation.- G. Survival Value of Fever in Non-mammalian Vertebrates.- H. Summary of Agents Found to Induce Fever in Non-mammalian Vertebrates.- J. Summary of Antipyretics Found to Block Fever in Non-mammalian Vertebrates.- References.- 20 The Pyrogenic Responses of Invertebrates.- A. Thermoregulatory Responses of Invertebrates.- B. Febrile Responses of Invertebrates.- C. Doses and Routes of Administration.- D. Similarities of Febrile Responses of Vertebrates and Invertebrates.