Drugs to Treat Cardiac Arrhythmias (Dysrhythmias) PDF

Drugs to Treat Cardiac Arrhythmias (Dysrhythmias) Peter W. Abel, Ph.D. Department of Pharmacology [email protected] Antiarrhythmic Drugs – Outline Electrical properties of the heart Generation of arrhythmias (dysrhythmias) - abnormal heart beat. Too fast, too slow,...

Drugs to Treat Cardiac Arrhythmias (Dysrhythmias) Peter W. Abel, Ph.D. Department of Pharmacology [email protected] Antiarrhythmic Drugs – Outline Electrical properties of the heart Generation of arrhythmias (dysrhythmias) - abnormal heart beat. Too fast, too slow, irregular. Antiarrhythmic drug class prototypes, mechanisms of action, adverse effects, use: – class I: sodium channel blockers – class II: beta blockers – class III: potassium channel blockers – class IV: calcium channel blockers – class V: adenosine, others Cardiac Conduction Pathways 1 2 3 4 4  Lead II ECG Recording from: http://www.medicine.mcgill.ca/physio/vlab/cardio/ECGbasics.htm ECG and Cardiac Action Potential Cardiac Action Potential Refractory Period The refractory period is the time during which heart cells do not respond to stimulation.  Types of Arrhythmias Arrhythmias are abnormal heart beats caused by disturbances of automaticity or conduction. Disturbances of automaticity, initiation of action potentials, can occur in any part of the heart. Tachycardia, ectopic pacemakers. Disturbances of the conduction pathway of the action potential: – Atrioventricular block – Reentry (recirculating activation) at purkinjie fibers/ventricular muscle Vaughan Williams Classification of Antidysrhythmic Drugs Class I: sodium channel blockers – Quinidine, lidocaine Class II: beta blockers – Propranolol, metoprolol Class III: potassium channel blockers – Amiodarone Class IV: calcium channel blockers – Verapamil, diltiazem Class V: other – Adenosine Antiarrhythmics Antiarrhythmic Drug Targets  Quinidine – class Ia prototype Effects on the heart: – Blocks sodium channels – Delays repolarization (due to K+ channel block) – Blocks vagal input to the heart Slows impulse conduction: – Prolongs the QT interval Therapeutic use: – Limited use against supraventricular and ventricular arrhythmias  Quinidine – class Ia prototype Adverse effects – Diarrhea, nausea, vomiting – Cinchonism (blurred vision, tremor, tinnitus, vertigo, lightheadedness) – Cardiotoxicity (e.g., ventricular arrythmias including torsades de pointes) – Arterial embolism – α-adrenergic receptor blockade, resulting in hypotension – Hypersensitivity reactions  Class II – Beta Blockers propranolol, metoprolol, esmolol Propranolol - class II prototype Effects on the heart: – Decreased automaticity of the SA node – Decreased conduction through the AV node – Decreased myocardial contractility Therapeutic use: – Arrhythmias caused by excessive sympathetic stimulation – Supraventricular tachycardia Suppression of excessive discharge Slowing of ventricular rate  Propranolol - class II Cardiovascular adverse effects: – Heart block – Heart failure – AV block – Sinus arrest – Hypotension Propranolol and other Beta-adrenergic receptor antagonists have common use. Class III – Potassium Channel Blockers Amiodarone Effects on K+ channels in the heart – Delays repolarization by blocking K+ efflux Other effects on the heart – Reduced automaticity in the SA node – Reduced conduction velocity – Reduced contractility Prolongs the PR and QT intervals  Amiodarone - class III Adverse effects – Pulmonary toxicity: pulmonary fibrosis – Cardiotoxicity: sinus arrest, AV block, can precipitate heart failure – Corneal microdeposits (disappear after drug withdrawal) – Thyroid dysfunction: both hypo- and hyper- thyroid – Photosensitivity with grayish-blue skin deposits Long half-life of weeks complicates use  Amiodarone – class III Therapeutic use – Is the most widely used antiarrhythmic drug, in part, because of its non-class III effects. Highly effective for all types of arrhythmias. Amiodarone levels can be increased by grapefruit juice and drugs that inhibit CYP3A4 causing toxicity. The risk of severe arrhythmias is increased by diuretics that reduce K+ and by other drugs. Amiodarone with a beta blocker or verapamil, can lead to dangerous slowing of heart rate. Class IV – Calcium Channel Blockers Verapamil Effects on the heart: – Reduces SA nodal automaticity – Delays AV nodal conduction – Reduces myocardial contractility Therapeutic use: – Common use to treat arrhythmias – Slows ventricular rate in atrial fibrillation or flutter – Terminate tachycardia caused by AV nodal dysfunction  Verapamil - class IV Adverse effects: – Bradycardia – Hypotension – AV block – Heart failure – Peripheral edema – Constipation  Class V – Other: Adenosine Mechanism of action: – Activates adenosine receptors, increases K+ efflux and hyperpolarizes cardiac cells. Effects on the heart and ECG: – Decreases automaticity in the SA node – Slows conduction through the AV node – Prolongation of PR interval Class V – Other: Adenosine Therapeutic use: – Common use IV for rapid termination of paroxysmal supraventricular tachycardia Adverse effects: – Sinus bradycardia – Dyspnea – Hypotension – Facial flushing End