1. Introduction to Cardiac Electrophysiology Understanding antiarrhythmic drugs requires a foundational understanding of the cardiac action potential (AP) and the ion channels that govern it. Cardiac arrhythmia is defined as any abnormality in the site of origin of the cardiac impulse, its rate and regularity, or its conduction. 1.1 Types of Cardiac Cells & Action Potentials There are two main types of electrical tissues in the heart, distinguished by their action potentials: Figure 1. Comparison of Fast and Slow Response Action Potentials. The fast response AP (left) is characteristic of His-Purkinje fibers and myocytes, with a rapid Phase 0 driven by Na+ influx. The slow response AP (right) is characteristic of nodal tissue (SA, AV nodes), with a slower Phase 0 driven by Ca2+ influx and a spontaneous diastolic depolarization in Phase 4 driven by the pacemaker current (If). 1.2 The Cardiac Action Potential Phases PhaseDescriptionMajor Drug TargetsPhase 0Rapid Depolarization (Na+ influx in fast cells, Ca2+ in slow cells)Class I (Na+ blockers)Class IV (Ca2+ blockers - nodes)Phase 1Early Repolarization (transient K+ efflux)-Phase 2Plateau (balance of Ca2+ influx and K+ efflux)Class IV (minor effect)Phase 3Rapid Repolarization (massive K+ efflux)Class III (K+ blockers)Phase 4Resting Potential (stable in fast cells, unstable in pacemakers)Class II (β-blockers affect pacemaker slope) Key Concepts for Exams: 2. Mechanisms of Arrhythmogenesis Arrhythmias arise from three fundamental mechanisms: Figure 2. Mechanism of Reentry. An impulse travels down a pathway that bifurcates around an obstacle. Path A has a unidirectional block, preventing anterograde conduction. Path B has slow conduction. The impulse travels down Path B and then retrogradely up Path A, which is now no longer refractory. It then re-enters the circuit, establishing a continuous loop. Antiarrhythmic drugs work by either converting the unidirectional block to a bidirectional block or by prolonging the refractory period so the impulse finds the tissue unexcitable. 3. Classification of Antiarrhythmic Drugs The Vaughan Williams Classification is the standard system used in pharmacology, classifying drugs based on their primary effect on ion channels and the action potential. Note: This system has limitations as many drugs have multiple actions (e.g., Amiodarone spans all four classes). ClassPrimary MechanismMain Effect on APExamplesClass INa+ Channel BlockersSlow Phase 0 depolarization(Subdivided below)Class IIBeta-Adrenergic BlockersSympatholytic; slow Phase 4 in nodesMetoprolol, Propranolol, EsmololClass IIIK+ Channel BlockersProlong Phase 3 repolarization (↑ APD and ERP)Amiodarone, Sotalol, DofetilideClass IVCa2+ Channel BlockersSlow Phase 0 in nodal tissue; slow conductionVerapamil, Diltiazem (Non-DHPs) Figure 3. Effect of Antiarrhythmic Drug Classes on the Action Potential. Class I drugs decrease the slope of Phase 0 (Na+ influx). Class II drugs decrease the slope of Phase 4 depolarization in pacemakers. Class III drugs prolong Phase 3 repolarization (K+ efflux). Class IV drugs decrease the slope of Phase 0 in pacemaker cells (Ca2+ influx). 4. Class I: Sodium Channel Blockers These drugs block voltage-gated fast Na+ channels, primarily affecting non-pacemaker tissue. They are subdivided into IA, IB, and IC based on the kinetics of channel binding and their effect on Action Potential Duration (APD). 4.1 Class IA: Moderate Na+ Blockers + K+ Block 4.2 Class IB: Weak Na+ Blockers / Rapid Dissociation 4.3 Class IC: Strong Na+ Blockers / Slow Dissociation 5. Class II: Beta-Adrenergic Blockers 6. Class III: Potassium Channel Blockers 6.1 Amiodarone: The "Broad Spectrum" Antiarrhythmic Amiodarone is unique because it possesses characteristics of all four Vaughan Williams classes. It is highly effective for both supraventricular and ventricular arrhythmias and is preferred in heart failure patients. Amiodarone Toxicity Profile (High Yield for PG Exams): Because of its iodine moiety, huge volume of distribution, and extremely long half-life (weeks), it causes multi-organ toxicity that requires careful monitoring. Figure 4. Amiodarone Toxicity Profile. Amiodarone can affect multiple organ systems. The most serious is pulmonary fibrosis. Other common side effects include thyroid dysfunction (hypo- or hyperthyroidism), corneal deposits, hepatotoxicity, bradycardia, QT prolongation, and blue-gray skin discoloration. 6.2 Other Class III Agents 7. Class IV: Calcium Channel Blockers (Non-DHP) 8. Miscellaneous Antiarrhythmic Drugs 8.1 Adenosine: The "Chemical Cardioverter" 8.2 Digoxin 8.3 Magnesium Sulfate 9. The "Proarrhythmic" Effect A critical concept is that all antiarrhythmic drugs can cause arrhythmias. 10. Exam Summary Table: Clinical Applications Arrhythmia Clinical ScenarioPreferred DrugsDrugs to AVOIDAcute PSVT (termination)Adenosine (1st line), IV Verapamil/Diltiazem.Atrial Fibrillation (Rate Control)β-blockers, Ca2+ Blockers (Non-DHP).Ventricular Tachycardia (Acute, Ischemic)Lidocaine (IV), Amiodarone (IV).Class IA/IC.Torsades de Pointes (TdP)IV Magnesium (1st line).Any QT-prolonging drug (Class IA, III).Arrhythmias in Heart Failure (HFrEF)Amiodarone, β-blockers, Digoxin.Non-DHP CCBs (Verapamil, Diltiazem), Class IC. 11. References
