Main description:

The development of a new antiarrhythmic drug involves many people with disparate skills. The organic chemist who makes it is guided not only by the structure-action relations of previous compounds, but by anticipation of a requirement for a particular type of action. In fact several of the best-known antiarrhythmics, including lidocaine, mexiletine, amiodarone and verapamil, were originally synthesized for other purposes. Physicians have to determine whether the new drug works, and pharma cologists how it works. For some years I have believed that there was room for a work which could be understood by all these groups and which could enlighten each about the point of view of the others. Thus when I was invited by Springer-Verlag to prepare a volume in their series Handbook of Experimental Pharmacology, I already had a firm conception of what its form should be. In any multi-author work there are two objectives which cannot always readily be reconciled. The first is to select topics which would relate to each other in a coherent manner. to give a logical and orderly shape to the volume as a whole. The second is to offer authors the greatest possible freedom to express themselves as they wish. When the general design was complete, prospective contributors were invited to write specific chapters, being provided with a complete list of their coauthors and chosen topics, so that they could avoid overlap.

Contents:

1 Cardiac Electrophysiology.- A. The Heart as an Electrical Network.- I. Conduction.- II. The Electrocardiogram.- III. Surface Leads.- IV. Vectorcardiography.- V. Intracardiac Recording.- VI. The T Wave.- B. Cellular Electrophysiology.- I. Electromotive Force.- II. Voltage Clamp.- C. Currents in Cardiac Cells.- I. Fast Inward Sodium Current.- II. Residual or Plateau Sodium Current.- III. Inward Rectification.- IV. Second Inward Current.- V. Excitation-Contraction Coupling.- VI. Destinations of Intracellular Calcium.- VII. Repolarizing Current.- D. Currents of Uncertain Physiological Significance.- I. Transient Outward Current (Dynamic Current, Igr).- II. Calcium-Activated Potassium Current.- III. ATP-Regulated Potassium Current.- IV. Calcium-Activated Inward Current.- E. Initiation of the Heartbeat.- I. Normal Beats. The Sinoatrial Node.- II. Ionic Currents in Nodal Cells.- III. Ik.- IV. Ik2.- V. Ih (If).- VI. Sinus Node Recovery Time.- VII. Abnormal Heartbeats.- VIII. Transient Inward Current (Ti).- IX. Conclusion.- References.- 2 Classification of Antiarrhythmic Actions.- A. Functions of Selective Ionic Currents.- B. Class I Antiarrhythmic Action.- I. Subdivision of Class I Antiarrhythmic Agents.- II. Site of Attachment to Sodium Channels.- C. Class II Antiarrhythmic Action.- I. Acute Antisympathetic Effects.- II. Long-term Antisympathetic Effects.- III. Beta-Blockade After Myocardial Infarction.- D. Class III Antiarrhythmic Action.- E. Class IV Antiarrhythmic Action.- F. Class V Antiarrhythmic Action.- G. Digitalis.- H. Conclusion.- References.- 3 Acute and Chronic Animal Models of Cardiac Arrhythmias.- A. Introduction.- B. Cellular Electrophysiological Models.- C. Monophasic Action Potential Technique.- D. Atrioventricular Conduction.- E. Ventricular Fibrillation Threshold Techniques.- F. Drug Models.- G. Neural Models.- H. Acute Coronary Ligation-Reperfusion Models.- J. Subacute Coronary Artery Ligation Models.- K. Chronic Myocardial Canine Infarct Models.- L. Supraventricular Models.- M. Noncanine Models.- N. Summary.- References.- 4 Classification of Human Arrhythmias.- A. Classification of Arrhythmias According to Their Origin.- I. Atrial Arrhythmias.- 1. Extrasystoles and Tachyarrhythmias.- 2. Atrial Bradycardias.- II. Junctional Arrhythmias.- 1. Junctional Tachycardias.- 2. Atrioventricular Block.- III. Ventricular Arrhythmias.- 1. Ventricular Extrasystoles.- 2. Ventricular Tachyarrhythmias.- B. Other Current Classifications of Arrhythmias.- I. Invasive Electrophysiology and the Mechanisms of Arrhythmias.- II. Classification of Arrhythmias and Holter Monitoring Technique.- C. Arrhythmias Environment: Other Possible Classifications.- I. Arrhythmias and the Autonomic Nervous System.- II. Rate-Dependence of Arrhythmias.- D. Conclusion.- References.- 5 Successes and Limitations of Antiarrhythmic Drug Therapy.- A. Introduction.- B. Haemodynamic Effect of Arrhythmias.- I. High Rate.- II. Loss of Atrial Transport Function.- III. Abnormal Sequence of Ventricular Activation.- C. Symptoms and Complications of Arrhythmias.- I. Palpitation.- II. Dyspnoea.- III. Dizziness and Syncope.- IV. Chest Pain.- V. Pulmonary and Systemic Embolism.- D. Arrhythmias in the Normal Population.- E. Indications for Antiarrhythmic Therapy.- I. Symptoms as an Indication for Treatment.- II. Termination of Tachycardias.- III. Prevention of Tachycardias.- F. Side Effects of Antiarrhythmic Therapy.- I. Non-cardiac Side Effects.- II. Adverse Haemodynamic Effects.- III. Arrhythmogenic Effects.- G. Risk-Benefit Ratio of Antiarrhythmic Therapy.- H. Evaluation of the Success of Antiarrhythmic Therapy.- J. Alternatives to Antiarrhythmic Drug Therapy.- K. Role of Antiarrhythmic Drugs in the Treatment of Specific Arrhythmias.- I. Supraventricular Ectopic Beats.- II. Acute Atrial Fibrillation.- III. Chronic or Relapsing Atrial Fibrillation.- IV. Bradycardia-Tachycardia Syndrome.- V. Paroxysmal AV Nodal Re-entrant Tachycardias.- VI. Supraventricular Tachycardias in the Wolff-Parkinson-White Syndrome.- VII. Ventricular Ectopic Beats.- VIII. Ventricular Tachycardia.- IX. Ventricular Fibrillation.- L. Sudden Death.- M. Antiarrhythmic Therapy in Acute Myocardial Infarction.- N. Antiarrhythmic Therapy in the Late Phase of Myocardial Infarction.- O. Conclusions.- References.- 6 Distinguishing Potentially Lethal from Benign Arrhythmias.- A. Introduction.- B. Arrhythmias Which can be Directly Fatal.- I. Sustained Tachyarrhythmias.- 1. Ventricular Fibrillation.- 2. Ventricular Tachycardia.- 3. Torsade de Pointes.- II. Severe Brady arrhythmias.- C. Arrhythmias Associated with an Adverse Prognosis.- I. Ventricular Ectopic Beats.- II. Ventricular Fibrillation.- III. Second-Degree AV Block.- IV. Arrhythmias Associated with the Pre-excitation Syndromes.- D. Arrhythmias Which are Benign.- E. Situations of High Risk for Fatal Arrhythmias.- I. Myocardial Ischaemia.- 1. Acute.- 2. Chronic.- II. Resuscitated Survivors of Out-of-Hospital Sudden Death.- III. Long QT Syndromes.- IV. Cardiac Failure.- V. Antiarrhythmic Therapy.- F. Identifying Latent High-Risk Arrhythmias.- I. Standard ECG Features.- II. Exercise Stress Testing.- III. Signal Averaging.- IV. Programmed Stimulation.- G. Management.- I. Ventricular Ectopic Beats Postinfarction.- II. Ventricular Ectopic Beats in Non-ischaemic Cardiovascular Disease.- III. Long QT Syndromes.- H. Conclusions.- References.- Antiarrhythmic Therapy.- Class I Agents.- 7 Subclassification of Class I Antiarrhythmic Drugs.- A. Introduction.- B. Outline of Differences Between Subgroups.- C. Fundamental Bases for Subclassification.- I. Interaction with Sodium Channel..- 1. Rate-Dependent Block.- 2. Kinetics of Onset and Offset of Rate-Dependent Block - A Basis for Subclassification.- 3. Possible Mechanism of Rate-Dependent Block.- 4. Experimental Evidence for Prolongation of Reactivation Time by Class I Drugs.- 5. The Sodium Channel in Nerve: Local Anaesthetic Action.- 6. Model for the Sodium Channel and Its Interaction with Antiarrhythmic Drugs.- II. Effects on Action Potential Duration.- 1. Ionic Bases for the Differences.- III. Effects on Sinus Node.- D. Clinical Implications of Subclassification.- I. Relevance of Differing Onset and Offset Kinetics.- 1. Selectivity for Ischaemic Myocardium.- 2. Selectivity for Ventricular Cells.- 3. Differing Effects on Refractory Periods.- 4. Differential Depression of Premature Beats.- II. Relevance of Effects on Action Potential Duration.- 1. Action Potential Prolongation as a Proarrhythmic Effect.- 2. Action Potential Shortening - Proarrhythmic or Antiarrhythmic?.- E. Conclusions.- References.- 8 Interaction of Class I Drugs with the Cardiac Sodium Channel.- A. Introduction.- B. Historical Background.- C. Classifications of Antiarrhythmic Agents.- D. Models of Sodium Channel Block.- I. Strichartz-Courtney Model.- II. Modulated Receptor Model.- 1. Experimental Basis.- 2. Formulation.- 3. Implementation.- 4. Application of the Modulated Receptor Hypothesis.- a. Class Ia.- b. Class Ib.- c. Class Ic.- d. Class Id: Drugs That Lack Use-Dependent Block.- III. Simplified Versions of the Modulated Receptor Model.- 1. Kappa-Repriming Model.- 2. Guarded Receptor Model.- 3. Analytical Solution of Modulated Receptor Model.- E. Multiple Drug Interactions with the Cardiac Sodium Channel Receptor.- I. Charged and Neutral Drug Form.- II. Two Different Drugs Interacting with the Sodium Channel Receptor.- 1. Synergistic Interactions.- 2. Antagonistic Interactions.- 3. Parent-Metabolite Interaction.- F. Summary.- References.- 9 Clinical Use of Class Ia Antiarrhythmic Drugs.- A. Historical.- B. Clinical Pharmacology.- I. Quinidine.- II. Procainamide.- III. Disopyramide.- C. Cardiac Electrophysiological Effects.- D. Efficacy.- I. Supraventricular Arrhythmias.- 1. Quinidine.- 2. Procainamide.- 3. Disopyramide.- II. Ventricular Ectopy and/or Non-sustained Ventricular Tachycardia.- 1. Quinidine.- 2. Procainamide.- 3. Disopyramide.- III. Sustained Ventricular Tachyarrhythmias.- 1. Quinidine.- 2. Procainamide.- 3. Disopyramide.- IV. Postinfarction Prophylaxis.- E. Proarrhythmic Effects of Antiarrhythmic Drugs.- I. Torsade de Pointes.- F. Concordance Among Class Ia Drugs.- G. Combinations of Ia with Other Class I Agents.- H. Conclusions.- References.- 10 Clinical Use of Class Ib Antiarrhythmic Drugs.- A. Introduction.- B. Electrophysiology.- C. Haemodynamic Effects.- D. Pharmacokinetics.- I. Lignocaine.- II. Factors Affecting the Pharmacokinetics of Lignocaine.- III. Mexiletine.- IV. Factors Affecting the Pharmacokinetics of Mexiletine.- V. Tocainide.- VI. Factors Affecting the Pharmacokinetics of Tocainide.- E. Therapeutic Use.- I. Lignocaine.- II. Mexiletine-Ventricular Arrhythmias in Patients with Acute Myocardial Infarction.- III. Drug Refractory Ventricular Arrhythmias.- IV. Digitalis Arrhythmias.- V. Comparisons with Other Antiarrhythmic Drugs.- VI. Tocainide-Ventricular Arrhythmias in Patients with Acute Myocardial Infarction.- VII. Drug Refractory Ventricular Arrhythmias and Programmed Electrical Stimulation.- VIII. Comparisons with Other Antiarrhythmic Drugs.- F. Side Effects and Interactions.- I. Lignocaine.- II. Mexiletine.- III. Tocainide.- G. Dosage and Administration.- I. Lignocaine.- II. Mexiletine.- III. Tocainide.- H. Place in Therapy.- References.- 11 Clinical Use of Class Ic Antiarrhythmic Drugs.- A. Introduction.- B. Flecainide.- I. Cellular Electrophysiology.- II. Preclinical Studies.- III. Clinical Electrophysiology.- IV. Pharmacokinetics.- V. Clinical Efficacy.- VI. Supraventricular Tachycardia.- VII. Programmed Stimulation Studies.- VIII. Arrhythmogenicity.- IX. Hemodynamic Effects.- X. Clinical Use.- C. Lorcainide.- I. Preclinical Studies.- II. Cellular Electrophysiology.- III. Clinical Electrophysiology.- IV. Pharmacokinetics.- V. Clinical Efficacy Intravenously.- VI. Clinical Efficacy: Oral Therapy.- VII. Programmed Electrical Stimulation Studies.- VIII. Arrhythmogenicity.- IX. Hemodynamic Effects.- X. Clinical Recommendations.- XI. Lorcainide and Supraventricular Tachycardia.- D. Encainide.- I. Cellular Electrophysiology.- II. Preclinical Studies.- III. Clinical Electrophysiology.- IV. Pharmacokinetics.- V. Clinical Efficacy.- VI. Programmed Stimulation Studies.- VII. Treatment of Supraventricular Tachycardia (SVT).- VIII. Arrhythmogenicity.- IX. Hemodynamic Effects and Adverse Side Effects.- X. Adverse Profile.- XI. Clinical Use Recommendations.- E. Propafenone.- I. Cellular Electrophysiology.- II. Preclinical Studies.- III. Pharmacokinetics.- IV. Clinical Efficacy.- V. Programmed Electrical Stimulation Studies.- VI. Arrhythmogenicity and Side Effects.- VII. Hemodynamic Effects.- VIII. Supraventricular Tachycardia.- IX. Clinical Recommendations.- F. Indecainide.- I. Electrophysiology.- II. Preclinical Studies.- III. Hemodynamic Studies.- IV. Clinical Studies.- V. Final Thoughts.- References.- Class II Agents.- 12a Arrhythmias in the Normal Human Heart.- A. Introduction.- B. Incidence of Arrhythmia in Normal Subjects.- I. Resting 12-Lead Electrocardiogram.- II. Ambulatory ECG Monitoring.- III. Exercise.- C. Emotionally Induced Arrhythmia.- I. ECG Evidence.- II. Emotion and Sympathetic Activity.- III. Arrhythmogenic Action of Catecholamines and Enhanced Sympathetic Activity.- IV. Emotion and Parasympathetic Activity.- V. Individual Susceptibility and Variation.- D. Prognosis of Ectopy and Arrhythmia in Apparently Healthy People.- I. Historical Note.- II. Ectopy and Arrhythmia in Normal People.- III. Sport.- 1. Athletes.- 2. Non-athletes.- E. Emotion and Sudden Death.- F. Clinical Considerations.- References.- 12b Adrenergic Arrhythmogenicity.- A. Sympathetic Excitation and Arrhythmias.- B. Adrenoceptors in the Heart.- C. Effects of Stimulation of Individual Receptor Types.- D. Distribution of Sympathetic Innervation.- E. Reperfusion Arrhythmias.- References.- 13 Antiarrhythmic Properties of Beta-Adrenoceptor Blockade During and After Myocardial Infarction.- A. Introduction.- B. Mechanisms of Arrhythmia in Acute Myocardial Infarction.- C. Use of Beta-Blockade in the Acute Phase of Myocardial Infarction.- I. Supraventricular Arrhythmia.- II. Ventricular Arrhythmia.- III. Ventricular Fibrillation.- D. Postinfarction Beta-Blockade.- I. Prevention of Arrhythmia in Patients Who Have Survived a Myocardial Infarction.- 1. Ancillary Properties.- a. Membrane-Stabilising Activity.- b. Intrinsic Sympathetic Activity.- c. Cardioselectivity.- E. Adverse Effects of Beta-Blockade.- I. Acute Phase of Myocardial Infarction.- II. Post Myocardial Infarction Use of Beta-Blockade: Long-term Adverse Effects.- F. Conclusions.- References.- Class III Agents.- 14 Class III Antiarrhythmic Action.- A. Introduction.- B. Ionic Fluxes Affecting Repolarization.- C. Evaluation of Myocardial Repolarization in Humans.- D. Class III Antiarrhythmic Action In Vitro.- E. Class III Antiarrhythmic Action In Man.- F. Class III Antiarrhythmic Action Related to Arrhythmia Mechanism.- References.- 15 Amiodarone: Electropharmacologic Properties.- A. Development of Amiodarone.- B. Amiodarone and Antiadrenergic Antagonism.- C. Pharmacokinetic and Hemodynamic Effects.- D. Electrophysiologic Effects of Amiodarone.- I. Early Electrophysiologic Observations.- II. Amiodarone and Slow-Channel Potentials.- III. Amiodarone Effects on Fast-Channel Potentials.- IV. Effects on Fast-Sodium Channel Kinetics and Use Dependency.- V. Ionic Correlates of the Electrophysiologic Effects of Amiodarone.- VI. Electrophysiologic Effects of Amiodarone Following Chronic Administration.- VII. Significance of the Acitivity of Desethylamiodarone.- VIII. Significance of Myocardial and Sarcolemmal Amiodarone Concentrations.- IX. Amiodarone Action and Metabolism of Thyroid Hormones.- X. Amiodarone-Membrane Lipid Interactions and Effects on Membrane Fluidity.- E. In Vivo Electrophysiologic Effects on Amiodarone.- I. Experimental Observations.- II. Clinical Electrophysiologic Effects.- F. Effects of Amiodarone in Experimental Arrhythmias.- G. Clinical Antiarrhythmic Effects of Amiodarone.- H. Conclusions on the Antiarrhythmic Mechanisms of Actions of Amiodarone.- References.- 16 Sotalol.- A. Basic Pharmacology.- I. Structure.- II. Beta-Receptor Antagonism.- III. Effects on Action Potential Duration.- IV. Differential Effects of Optical Isomers of Sotalol.- V. Subsidiary Class III Actions of Other Beta-Blockers.- B. Antiarrhythmic Activity of Sotalol in Experimental Models.- I. Simple Arrhythmic Models.- II. Effects of Changes in Experimental Conditions.- III. Acute Ischaemia.- IV. Comparison of Effects of Sotalol and Amiodarone in Ischaemic Myocardium.- V. Postinfarction.- C. Clinical Pharmacology.- I. Beta-Blocking Acitivity.- II. Clinical Evidence of Acute Class III Activity.- III. Clinical Evidence of Chronic Class III Activity.- IV. Clinical Pharmacokinetics.- V. Metabolic Effects.- D. Antiarrhythmic Efficacy in Clinical Practice.- I. Supraventricular Arrhythmias.- II. Ventricular Arrhythmias.- E. Adverse Effects.- F. Conclusions.- References.- 17 Clofilium and Other Class III Agents.- A. Introduction.- B. Clofilium.- I. Specificity.- II. Effects on Refractoriness in Conscious and Anesthetized Dogs.- III. Autonomic Nerve Stimulation.- IV. Arrhythmogenicity.- V. Programmed Electrical Stimulation in Patients.- C. LY190147, a Tertiary Amine Class III Agent.- I. Basic Electrophysiology.- II. Ventricular Fibrillation Threshold.- D. Other Class III Agents.- I. Bretylium and Congeners.- II. Agents with Mixed Electrophysiological Activity.- E. Summary and Conclusions.- References.- Class IV Agents.- 18 Class IV Antiarrhythmic Agents: Utility in Supraventricular Arrhythmias and Their Proarrhythmic Potential.- A. Introduction.- B. Therapeutic Basis.- C. Effect on the Ventricle.- D. Indications.- E. Atrial Fibrillation.- F. Paroxysmal Supraventricular Tachyarrhythmias.- G. Pharmacology and Adverse Clinical Effects.- H. Calcium Blockers: Effect on Ventricular Arrhythmias.- J. A Definition for Proarrhythmia.- K. Ventricular Proarrhythmia From Calcium Channel Blockers.- L. Conclusion.- References.- Class V Agents.- 19 Specific Bradycardic Agents.- A. Introduction and Definition.- B. Alinidine.- I. Pharmacology.- 1. Isolated Cardiac Preparations.- 2. Mode of Action.- 3. Experiments in Intact Animals.- 4. Investigations in Experimental Myocardial Ischaemia.- 5. Antiarrhythmic Properties.- II. Pharmacokinetics.- III. Clinical Pharmacology.- IV. Clinical Results.- V. Adverse Effects of Alinidine.- C. Substances Chemically Related to Alinidine.- D. Falipamil (AQ-A39) and Congeners (AQ-AH208, UL-FS49).- I. Pharmacology.- 1. Isolated Preparations.- 2. Mode of Action.- 3. Experiments in Intact Animals.- 4. Investigations in Experimental Myocardial Ischaemia.- II. Investigations with Falipamil and UL-FS 49 in Healthy Humans and Patients.- E. Conclusion.- References.- Other Therapies.- 20 Use of Adenosine as an Antiarrhythmic Agent.- A. Introduction.- B. Metabolism.- C. Electrophysiological Properties and Mechanism of Antiarrhythmic Action of Adenosine.- D. Drug Regimen.- E. Indications.- I. Therapeutic Use.- II. Diagnostic Use.- F. Tolerance and Side Effects.- G. Drug Interaction.- H. Contraindications.- References.- 21 Physical and Surgical Treatment of Cardiac Arrhythmias.- A. Introduction.- B. Implantable Electronic Devices.- C. Ablation of Arrhythmia Substrates.- I. Basic Concepts.- II. Mapping Techniques..- III. Ablation Techniques.- 1. Catheter Ablation.- 2. Direct Surgical Ablation.- D. Conclusions.- References.- Factors Involved in Arrhythmogenesis.- 22 Alpha-Adrenoceptors in Arrhythmogenesis.- A. Introduction.- B. Multiple Sites of Action for Catecholamines.- I. Separation of Alpha- and Bet a-Adrenoceptors.- II. Alpha-Adrenoceptor Subtypes.- 1. Definition.- 2. Antagonists Used.- 3. Agonists Used.- 4. Postulated Alternative Criteria for Distinguishing Between Subtypes.- 5. Special Factors Relevant to the Heart.- a. Electrophysiology.- b. Transduction Processes, Second Messengers and Receptor Regulation: Comparison of Alpha and Beta.- 6. Relevance of Alpha-Adrenoceptors Outside the Heart.- a. Central Nervous System.- b. Blood Vessels - Haemodynamics.- c. Hormones and Metabolism.- 7. Consequences of Diversity of Alpha-Adrenoceptor Subtypes.- III. Separate Sites of Action for Alpha-Adrenoceptors Within the Heart.- 1. Cardiac Muscle.- 2. Coronary Vascular Smooth Muscle.- 3. Coronary Vascular Endothelium.- 4. Nerves.- a. Sympathetic Nerves in the Myocardium.- b. Sympathetic Nerves in Coronary Blood Vessels.- c. Parasympathetic Nerves in the Myocardium.- 5. Platelet Aggregation.- 6. Differences Between Circulating and Local Neurotransmitter Cathecholamines.- C. Experimental Approaches to the Role of Alpha-Adrenoceptors in Arrhythmia.- D. Summary and Rationales for Utilising Alpha-Adrenoceptor Blockade in Arrhythmia.- E. Future Directions.- References.- 23 Adrenergic Arrhythmogenesis and the Long Q-T Syndrome.- A. Introduction.- B. Acute Myocardial Ischaemia.- I. Pathophysiology.- 1. Sympathetic Activity and Cardiac Electrophysiology.- 2. Sympathetic Activity and Coronary Circulation.- 3. Sympathetic Activity and Heart Rate.- II. From Pathophysiology to Antiarrhythmic Interventions.- III. Animal Models for Adrenergic Arrhythmias.- 1. Myocardial Ischaemia and Left Stellate Ganglion Stimulation.- 2. Myocardial Ischaemia, Exercise and Healed Myocardial Infarction.- 3. Behavioural Stress and Life Threatening Arrhythmias.- C. Idiopathic Long Q-T Syndrome.- References.- 24a Effects of Cardiac Glycosides at the Cellular Level.- A. Introduction.- B. Effects of Cardiac Glycosides on Cellular Electrolytes.- I. Effects of Cardiac Glycosides on Cytosolic Sodium.- II. Effects of Cardiac Glycosides on Cellular Potassium.- III. Effects of Cardiac Glycosides on Cellular Calcium Transients.- IV. Toxic Effects of Cardiac Glycosides on Cellular Electrolyte Contents.- C. Direct Effects of Cardiac Glycosides on Cardiac Electrical Properties.- I. Contribution of the Electrogenic Sodium Pump to Cardiac Electrophysiological Properties.- II. Effects of Cardiac Glycosides on Resting Membrane Potential, Diastolic Depolarization and Action Potential Configuration.- III. Possible Mechanisms of Ectopic Activity Elicited by Cardiac Glycosides.- IV. Possible Mechanisms of Direct Antiarrhythmic Effects of Cardiac Glycosides.- D. Neurally Mediated Effects of Cardiac Glycosides.- I. Cardiac Glycoside Effects on Neurotransmitter Release.- II. Cardiac Glycoside Effects on the Sensitivity to Neurotransmitters.- E. Concluding Remarks.- References.- 24b Clinical Efficacy of Cardiac Glycosides for Arrhythmias.- A. Introduction.- B. Specific Arrhythmias.- I. Atrial Ectopic Beats.- II. Atrial Fibrillation and Flutter.- III. Supraventricular Tachycardia.- IV. Ventricular Arrhythmias.- C. Conclusions.- References.- 25 Eicosanoids and Arrhythmogenesis.- A. Introduction.- B. Activation and Modulation of the Arachidonic Acid Cascade in Myocardial Ischaemia and in Reperfusion and Their Relation to Arrhythmias.- C. Evidence for the Arrhythmogenic Effect of Thromboxane A2.- I. The Thromboxanemimetic U46619 Induces Arrhythmias When Given During Myocardial Ischaemia.- II. Effects of Selective Inhibition of Thromboxane Synthesis.- III. Effects of Thromboxane Receptor Blocking Drugs.- D. Evidence for an Antiarrhythmic Effect of Prostacyclin.- I. Myocardial Prostacyclin Generation and Early Ischaemia and Reperfusion-Induced Ventricular Arrhythmias.- 1. Antiarrhythmic Effects of Prostacyclin (and Related Stable Derivatives) During Myocardial Ischaemia and Reperfusion.- 2. Promotion of Prostacyclin Generation as an Antiarrhythmic Procedure in Acute Myocardial Ischaemia and in Reperfusion.- E. Antiarrhythmic Effects of Cyclooxygenase Inhibitors.- I. Studies with Aspirin.- II. Studies with Other Cyclooxygenase Inhibitors.- References.- 26 Possible Role of Lipids and of Free Radicals in Arrhythmogenesis.- A. Free Fatty Acids and Arrhythmias.- B. Lysophosphoglycerides and Arrhythmias.- C. Free Radicals and Arrhythmias.- References.- 27 Clinical and Pharmacological Characterization and Treatment of Potentially Malignant Arrhythmias of Chronic Chagasic Cardiomyopathy.- A. Introduction.- B. Clinical Context and Characterization.- I. Electrocardiographic Features.- II. Clinical Context.- III. Role of the Autonomic Nervous System and Cardiac Rate.- IV. Spontaneous Variability. "The Chagasic Model".- C. Pharmacologic Responses. An Approach to the Arrhythmogenic Mechanisms Underlying Chagasic Ventricular Arrhythmias.- I. Unresponsiveness to Calcium Blocking Agents.- II. Partial Response to Sodium Channel Blocking Agents.- III. Beta-Blockers. Useful Agents for Very Selected Cases.- IV. Singular Efficacy of Amiodarone.- D. Long-term Control of Chagasic Ventricular Arrhythmias with Amiodarone.- I. Long-term Antiarrhythmic Effects of Amiodarone.- II. Dose Response Relations, "Abeyance Period" and Persistence of Antiarrhythmic Protection.- III. Does Control of Potentially Malignant Ventricular Arrhythmias with Amiodarone Prevent Sudden Death in Chagasic Patients?.- IV. Side Effects.- E. Potential Usefulness of Combined Antiarrhythmic Therapy.- F. Surgical Treatment.- G. Final Remarks.- References.- 28 Autonomic Mechanisms in Cardiac Rhythm and Arrhythmias.- A. Introduction.- B. Autonomic Effects at the Cellular Level.- I. Sympathetic Effects.- 1. Beta-Adrenergic Stimulation.- 2. Alpha-Adrenergic Stimulation.- II. Parasympathetic Effects.- C. Developmental Changes in Cardiac-Autonomic Interactions.- D. Relationship of Autonomic Stimulation to the Cellular Mechanisms of Arrhythmias.- I. Abnormal Impulse Initiation.- 1. Automaticity.- 2. Afterdepolarizations.- II. Abnormal Impulse Propagation.- E. Conclusions.- References.- Epilogue.- Epilogue.