Antiarrhythmic Drugs

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.