Antiarrhythmics – A quick summary

I. Introduction and Electrophysiological Basis

Cardiac arrhythmias are disorders of the heart rate or rhythm caused by abnormalities in electrical impulse formation or conduction. Antiarrhythmic drugs (AADs) aim to restore normal sinus rhythm (NSR) or control ventricular rate, though they are characterized by a narrow therapeutic index and a paradoxical potential to induce lethal arrhythmias (proarrhythmia).

To understand the pharmacodynamics of these agents, one must first master the cardiac action potential (AP).

A. The Cardiac Action Potential

Cardiac cells are broadly categorized into two electrical types:

1. Fast-Response Fibers: (Atria, Ventricles, His-Purkinje system). Dependent on voltage-gated \(Na^+\) channels.
2. Slow-Response Fibers: (Sinoatrial [SA] node, Atrioventricular [AV] node). Dependent on \(Ca^{2+}\) channels; exhibit automaticity.

Fast-Response Phases

• Phase 0 (Rapid Depolarization): Triggered when membrane potential (\(V_m\)) reaches threshold (-70 mV). Massive influx of \(Na^+\) via voltage-gated channels (\(I_{Na}\)). The maximum upstroke velocity (\(dV/dt_{max}\)) determines conduction velocity.
• Phase 1 (Early Repolarization): Rapid inactivation of \(Na^+\) channels and transient efflux of \(K^+\) via \(I_{to}\) (transient outward current).
• Phase 2 (Plateau): A balance between inward depolarizing \(Ca^{2+}\) currents (\(I_{Ca-L}\)) via L-type calcium channels and outward repolarizing \(K^+\) currents. This phase prolongs the refractory period, preventing tetany.
• Phase 3 (Repolarization): \(Ca^{2+}\) channels close. \(K^+\) efflux dominates via delayed rectifier currents: rapid (\(I_{Kr}\)) and slow (\(I_{Ks}\)). This returns \(V_m\) to resting levels.
• Phase 4 (Resting Potential): Maintained by the \(Na^+/K^+\)-ATPase pump and the inward rectifier current (\(I_{K1}\)), stabilizing \(V_m\) at approximately -85 to -90 mV.

Slow-Response Phases (Pacemaker Cells)

These cells lack a stable Phase 4.

• Phase 0: Slower upstroke mediated by \(Ca^{2+}\) entry (\(I_{Ca-L}\)), not \(Na^+\).
• Phase 3: Repolarization via \(K^+\) efflux.
• Phase 4 (Pacemaker Potential): Spontaneous diastolic depolarization caused by the “funny current” (\(I_f\)), a mixed \(Na^+/K^+\) inward current activated by hyperpolarization.

II. Mechanisms of Arrhythmia

Arrhythmias arise from three primary mechanisms. AADs work by targeting these specific anomalies.

1. Abnormal Automaticity

• Enhanced Normal Automaticity: Accelerated firing of the SA node or latent pacemakers due to sympathetic stimulation (\(\beta\)-adrenergic) or hypokalemia.
• Abnormal Automaticity: Cells that do not normally pace (e.g., ventricular myocytes) spontaneously depolarize due to ischemia or injury currents.

2. Triggered Activity

Oscillations in membrane potential that occur during or immediately after an AP.

• Early Afterdepolarizations (EADs): Occur during Phase 2 or 3. Associated with prolonged Action Potential Duration (APD). Clinical correlate: Torsades de Pointes (TdP).
• Delayed Afterdepolarizations (DADs): Occur during Phase 4. Caused by intracellular \(Ca^{2+}\) overload (e.g., Digoxin toxicity, catecholamine excess).

3. Re-entry

The most common mechanism for clinically significant arrhythmias (e.g., Atrial Fibrillation, VT). It requires:

1. Two distinct pathways for impulse conduction.
2. Unidirectional block in one pathway (often due to heterogeneity in refractoriness).
3. Slowed conduction in the other pathway, allowing the blocked path to recover.

III. Classification of Antiarrhythmic Drugs

The Vaughan Williams (VW) classification, though imperfect, remains the clinical standard. It categorizes drugs based on their primary channel-blocking effect.

IV. Class I: Sodium Channel Blockers

Class I agents block the fast inward sodium current (\(I_{Na}\)). Their binding is state-dependent, meaning they bind more avidly to open or inactivated channels than to resting channels. This leads to Use-Dependence: the drug effect is more pronounced at faster heart rates.

Class Ia: Intermediate Kinetics

• Drugs: Quinidine, Procainamide, Disopyramide.
• Mechanism: Moderate blockade of \(I_{Na}\) and blockade of \(I_K\).
• Effects: Slows Phase 0; Prolongs APD and ERP (due to \(I_K\) block). ECG shows widened QRS and prolonged QT.
• Clinical Pearls:
  • Quinidine: “Cinchonism” (tinnitus, headache), GI distress. Potent CYP2D6/P-gp inhibitor.
  • Procainamide: Chronic use causes Drug-Induced Lupus Erythematosus (DILE).
  • Disopyramide: Strong anticholinergic effects; negative inotrope (avoid in HF).

Class Ib: Fast Kinetics

• Drugs: Lidocaine, Mexiletine.
• Mechanism: Weak blockade of \(I_{Na}\); binds preferentially to inactivated channels.
• Effects: Minimal effect on Phase 0 in normal tissue; shortens APD. Selective for ischemic tissue.
• Clinical Pearls:
  • Indications: Ventricular arrhythmias only (post-MI). Ineffective for atrial arrhythmias.
  • Lidocaine: CNS toxicity is dose-limiting (confusion, seizures). High first-pass metabolism.

Class Ic: Slow Kinetics

• Drugs: Flecainide, Propafenone.
• Mechanism: Potent blockade of \(I_{Na}\). Extremely slow dissociation.
• Effects: Marked slowing of Phase 0; No effect on APD. Marked QRS widening.
• Clinical Pearls:
  • Pill-in-the-Pocket: For paroxysmal AFib in structurally normal hearts.
  • CAST Trial Warning: Increased mortality in post-MI patients. Contraindicated in structural heart disease.

V. Class II: Beta-Adrenergic Antagonists

Drugs: Metoprolol, Atenolol, Propranolol, Esmolol.

Mechanism: Competitive blockade of \(\beta_1\) receptors. Decreases cAMP and PKA activity, reducing phosphorylation of L-type \(Ca^{2+}\) and \(I_f\) channels.

Effects: Decreases Phase 4 slope in SA node (\(\downarrow\) HR); Decreases conduction velocity in AV node (\(\uparrow\) PR interval).

VI. Class III: Potassium Channel Blockers

These agents prolong the Action Potential Duration (APD) and Effective Refractory Period (ERP) by blocking potassium repolarizing currents (primarily \(I_{Kr}\)).

Amiodarone

The dominant antiarrhythmic in clinical practice.

• Mechanism: “Broad Spectrum” (Classes I, II, III, and IV activity).
• Pharmacokinetics: Huge Volume of Distribution (\(V_d \approx 60 L/kg\)). Half-life 26–100 days.
• Adverse Effects: Pulmonary fibrosis (monitor CXR), Thyroid dysfunction (contains iodine), Hepatic toxicity, Corneal microdeposits, Blue-gray skin.
• Interactions: Inhibits CYP3A4, CYP2C9, P-gp. Increases Warfarin/Digoxin levels.

Sotalol

Racemic mixture. L-isomer is a \(\beta\)-blocker; both D- and L-isomers block \(I_{Kr}\). Exhibits Reverse Use-Dependence (more effective at slow heart rates), increasing TdP risk during bradycardia.

VII. Class IV: Calcium Channel Blockers (Non-DHPs)

Drugs: Verapamil, Diltiazem.

Mechanism: Block \(L\)-type \(Ca^{2+}\) channels in Slow Response tissues (SA/AV nodes).

Indications: PSVT termination, Rate control in AFib.

VIII. Miscellaneous Agents

Adenosine

Mechanism: Activates \(A_1\) receptors in AV node \(\to\) activates \(I_{K-Ado}\) \(\to\) hyperpolarization.

Clinical Use: The “Chemical Reset Button” for PSVT. Very short half-life (<10s).

Digoxin

Mechanism: Inhibits \(Na^+/K^+\)-ATPase \(\to\) \(\uparrow\) intracellular \(Ca^{2+}\) (inotropy). Indirectly increases vagal tone to slow AV conduction.

Magnesium Sulfate

Use: Drug of choice for Torsades de Pointes, regardless of serum Mg levels.

IX. Summary: Channel Effects