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70 Clinical Pharmacology of Antiarrhythmic Drugs
Authors:
Ayan Alam Khan
Murzaeva Mariia
(1, Student, International Medical Faculty, Osh State University, Osh, Kyrgyzstan
2, Teacher, International Medical Faculty, Osh State University, Osh, Kyrgyzstan)
Introduction
Cardiac arrhythmias are disorders of cardiac rhythm due to abnormalities in impulse generation or conduction within the heart. These disturbances range from benign premature beats to life-threatening ventricular fibrillation. Antiarrhythmic therapy aims to restore normal rhythm and conduction or to prevent more serious arrhythmias from developing.
The mechanism of antiarrhythmic drugs generally includes modification of the electrophysiological properties of cardiac cells: ion channel conductance, refractory periods, and automaticity. Clinical pharmacology related to antiarrhythmic drugs involves a deep understanding of cardiac electrophysiology, pharmacokinetics, pharmacodynamics, and their potential to cause proarrhythmic effects.
Electrophysiological Basis of Antiarrhythmic Drug Action
The cardiac action potential is divided into five phases:
Phase 0: Rapid depolarization due to an influx of sodium via fast sodium channels.
Phase 1: Early repolarization by the transient outward potassium current.
Phase 2: Plateau phase, maintained by the balance between calcium influx and potassium efflux.
Phase 3: Final repolarization occurring because of potassium efflux.
Phase 4: Resting membrane potential and diastolic depolarization.
Antiarrhythmic drugs work by altering one or more of these ionic currents. The Vaughan Williams classification remains the most commonly used system to classify antiarrhythmic drugs according to their predominant electrophysiological effect.
Antiarrhythmic Drugs Classification: Vaughan Williams System
Class I: Sodium Channel Blockers
These drugs block the fast sodium channels responsible for phase 0 depolarization in non-nodal tissues, such as atrial and ventricular myocardium and the His-Purkinje system.
Class IA (Moderate Na⁺ Channel Blockers)
Examples: Quinidine, Procainamide, Disopyramide
Mechanism: Moderate blockade of Na⁺ channels → decreased phase 0 upstroke velocity; prolong repolarization by blocking K⁺ channels → increased APD and ERP.
Clinical Uses: Atrial fibrillation, atrial flutter, supraventricular and ventricular tachycardia.
Adverse Effects: QT prolongation/torsades de pointes, anticholinergic effects, hypotension, lupus-like syndrome (procainamide).
Class IB (Weak Na⁺ Channel Blockers)
Examples: Lidocaine, Mexiletine, Phenytoin
Mechanism: Weak Na⁺ blockade; preferentially bind to inactivated Na⁺ channels → more effective in ischemic or depolarized tissue; shorten APD and ERP.
Clinical Uses: Acute ventricular arrhythmias, especially post–myocardial infarction.
Adverse Effects: CNS toxicity (tremor, seizures), hypotension, nausea.
Class IC (Strong Na⁺ Channel Blockers)
Examples: Flecainide, Propafenone
Mechanism: Strong blockade of Na⁺ channels → marked depression of phase 0 upstroke, minimal effect on APD.
Clinical Uses: Supraventricular tachycardia, atrial fibrillation in patients without structural heart disease.
Adverse Effects: Proarrhythmic effects (especially in patients with myocardial infarction or LV dysfunction), blurred vision, dizziness.
Class II: Beta-Adrenergic Blockers
Examples: Propranolol, Metoprolol, Esmolol, Atenolol
Mechanism: Decrease SA node automaticity; slow AV nodal conduction and prolong AV nodal refractoriness; indirectly reduce calcium influx.
Clinical Uses: Rate control in atrial fibrillation/flutter, prevention of recurrent MI, supraventricular tachyarrhythmias, catecholamine-induced arrhythmias.
Adverse Effects: Bradycardia, AV block, hypotension, bronchospasm (non-selective β-blockers), fatigue.
Pharmacokinetics: Lipid-soluble agents (e.g., propranolol) undergo hepatic metabolism; hydrophilic ones (e.g., atenolol) are renally excreted.
Class III: Potassium Channel Blockers
Examples: Amiodarone, Dronedarone, Sotalol, Dofetilide, Ibutilide
Mechanism: Block K⁺ channels → prolonged APD and ERP → reduced re-entry tendency. Amiodarone also exerts class I, II, and IV effects.
Clinical Uses: Atrial fibrillation and flutter, ventricular tachycardia and fibrillation, supraventricular tachycardia refractory to other drugs.
Adverse Effects: Amiodarone – pulmonary fibrosis, thyroid dysfunction, hepatotoxicity, corneal deposits, photosensitivity, QT prolongation.
Sotalol – QT prolongation, torsades de pointes, fatigue.
Pharmacokinetics: Amiodarone has a long half-life (weeks), extensive tissue binding, hepatic metabolism, and multiple drug interactions.
Class IV: Calcium Channel Blockers
Examples: Verapamil, Diltiazem
Mechanism: Inhibit slow inward Ca²⁺ current → reduced SA node automaticity and slowed AV nodal conduction; decrease myocardial contractility and oxygen demand.
Clinical Uses: Supraventricular tachycardia, atrial fibrillation/flutter rate control, angina, hypertension.
Adverse Effects: Bradycardia, AV block, hypotension, constipation, edema.
Pharmacokinetics: High first-pass metabolism; hepatic elimination; duration of action 6–8 hours.
Class V: Miscellaneous Agents
Adenosine – activates K⁺ channels, inhibits Ca²⁺ influx → transient AV block. Used for PSVT.
Digoxin – increases vagal tone → reduced AV conduction; positive inotropy via Na⁺/K⁺-ATPase inhibition. Used for AF with HF.
Magnesium sulfate – modulates Na⁺/K⁺-ATPase and Ca²⁺ channels. Used for torsades de pointes and digoxin-induced arrhythmias.
Clinical Pharmacokinetics and Pharmacodynamics
Pharmacokinetic factors including absorption, metabolism, protein binding, and excretion are critical in antiarrhythmic drug choice and dosing.
Lidocaine: IV administration; hepatic metabolism; short half-life.
Amiodarone: Oral/IV; bioavailability 30–50%; half-life 40–60 days.
Flecainide/Propafenone: Oral; hepatic metabolism; narrow therapeutic index.
Sotalol: Renal excretion; dose adjustment required in renal impairment.
Therapeutic drug monitoring is important for agents like digoxin and quinidine to prevent toxicity.
Proarrhythmic and Toxic Effects
A major limitation of antiarrhythmic drugs is their proarrhythmic potential — they may induce new or worsen existing arrhythmias.
Class I and III: QT prolongation → torsades de pointes.
Class IC: Ventricular arrhythmias in structural heart disease.
Amiodarone: Multiorgan toxicity.
These risks can be minimized by careful selection, ECG monitoring, and dose titration.
Therapeutic Strategies and Clinical Use
Atrial fibrillation: β-blockers, calcium channel blockers, amiodarone, or flecainide.
Ventricular tachycardia: Amiodarone, lidocaine, or sotalol.
Supraventricular tachycardia: Adenosine, verapamil, or β-blockers.
Prevention of sudden cardiac death: Amiodarone or implantable cardioverter-defibrillator (ICD).
Non-pharmacological therapies (ICDs, ablation) are often superior in refractory or high-risk patients.
Conclusion
The clinical pharmacology of antiarrhythmic drugs requires a precise understanding of cardiac electrophysiology and careful therapeutic monitoring. Although these agents can restore and maintain sinus rhythm, their use must balance efficacy with the risk of adverse and proarrhythmic effects. Personalized therapy guided by patient comorbidities and ECG monitoring remains the cornerstone in managing arrhythmias. Advances in molecular cardiology and the development of safer agents continue to refine antiarrhythmic therapy, reducing toxicity and improving rhythm control.
References
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Katzung, B. G., Vanderah, T. W., & Trevor, A. J. (2023). Basic and Clinical Pharmacology (16th ed.). McGraw-Hill Education.
Rang, H. P., Dale, M. M., Ritter, J. M., Flower, R. J., & Henderson, G. (2021). Rang and Dale’s Pharmacology (9th ed.). Elsevier.
Hoffman, B. F., & Rosen, M. R. (2019). Electrophysiology of the Heart (5th ed.). Oxford University Press.
Vaughan Williams, E. M. (1970). Classification of antiarrhythmic actions reassessed after a decade of new drugs. Journal of Clinical Pharmacology, 10(5), 130–147.
Zipes, D. P., & Jalife, J. (2018). Cardiac Electrophysiology: From Cell to Bedside (7th ed.). Elsevier.
