Antiarrhythmic Agents · Mechanism & Clinical Use

• Cardiac myocytes and conduction system generate rhythmic electrical impulses via ion channel flux
• Two major fiber categories based on depolarization mechanism
  • Fast‑response fibers: atrial muscle, ventricular muscle, His‑Purkinje system
  • Slow‑response fibers: sinoatrial (SA) node, atrioventricular (AV) node
• Resting membrane potential (RMP) determines channel availability and response velocity
• Antiarrhythmic drugs target specific ion channels to modify conduction, automaticity, or refractoriness

• Slow fibers lack functional Na⁺ channels for phase 0 – depolarization relies entirely on Ca²⁺ influx
• Pacemaker activity originates in tissues with steepest phase 4 slope (normally SA node)
• Class II and IV agents preferentially slow phase 4 in nodal tissues

• Phase 0 – rapid depolarization
  • Fast Na⁺ channels open → massive Na⁺ influx
  • Rate of depolarization (V_max) depends on RMP and channel availability
  • Class I drugs reduce V_max by blocking Na⁺ channels
• Phase 1 – early repolarization (notch)
  • Transient outward K⁺ current (I_to) and inward Cl⁻ current
  • Minimal drug effect on these transient currents
• Phase 2 – plateau
  • Balanced Ca²⁺ influx (I_Ca‑L) and delayed rectifier K⁺ efflux (I_K)
  • Drug effects on plateau currents are generally limited
• Phase 3 – repolarization
  • Delayed rectifier K⁺ current increases; Ca²⁺ current inactivates
  • Class III agents block I_K → prolong repolarization → ↑ AP duration (APD) and ERP
• Phase 4 – diastolic interval
  • RMP restored by Na⁺/K⁺‑ATPase
  • In pacemaker cells: slow inward currents (I_f, I_Ca‑T) create spontaneous depolarization
  • Class II (β‑blockers) and Class IV (Ca²⁺ blockers) reduce phase 4 slope

• Automaticity
  • Ability to generate spontaneous action potentials
  • Determined by phase 4 slope steepness
  • Fastest pacemaker suppresses slower foci (overdrive suppression)
• Effective Refractory Period (ERP)
  • No stimulus can elicit a response – extends into late phase 3
  • Na⁺ channels are inactivated and not yet recoverable
  • K⁺ channel blockers prolong ERP (Class III effect)
• Relative Refractory Period (RRP)
  • Strong stimulus can elicit a response, but conduction is delayed / abnormal
  • Premature impulses may arise → re‑entry arrhythmias
• ERP / APD ratio
  • Lower ratio → increased vulnerability to premature beats
  • Higher ratio → protection against re‑entry

• Voltage‑gated Na⁺ channel has three conformations
  • Resting (ready) – closed, capable of opening
  • Open (active) – conducting Na⁺
  • Inactivated (refractory) – closed, cannot reopen until recovery
• Two gates: activation (M) gate opens quickly; inactivation (h) gate closes more slowly
• Recovery from inactivation
  • Rate depends on RMP – faster at normal resting potentials
  • Ischemic tissue with partial depolarization → slower recovery → reduced conduction velocity
  • Na⁺ channel blockers further slow recovery, especially in depolarized tissues
• Class I agents bind preferentially to open or inactivated states (use‑dependent blockade)

• SA node receives rich parasympathetic (M₂) and sympathetic (β₁) innervation
• β₁ activation → ↑ cAMP
  • ↑ I_Ca‑L → faster upstroke in pacemakers
  • ↑ I_K → shorter AP duration
  • ↑ I_f → steeper phase 4 slope → ↑ heart rate
• M₂ activation → ↓ cAMP
  • Opposite effects: slower phase 4, ↓ heart rate
  • Also activates I_K/ACh → additional hyperpolarization
• β‑blockers (Class II) prevent cAMP formation → primary effect on SA and AV nodes

• Class IA – moderate Na⁺ blockade + K⁺ blockade
  • ↑ APD and ERP (K⁺ block prolongs repolarization)
  • Use‑dependent blockade of open Na⁺ channels

• Class IB – fast Na⁺ blockade with preference for inactivated channels
  • ↓ APD (block window current) → ↑ diastolic recovery time
  • Selective for depolarized / ischemic tissues → ↑ threshold in hypoxic zones

• Class IC – potent Na⁺ blockade, primarily in His‑Purkinje tissue
  • No effect on APD
  • No autonomic effects
• Flecainide
  • Limited use due to proarrhythmic risk
  • ↑ sudden death post‑MI and when used prophylactically for ventricular tachycardia

• Mechanism
  • Competitive antagonism of β₁‑adrenergic receptors
  • ↓ cAMP production → ↓ I_Ca‑L and ↓ I_f → ↓ phase 4 slope
  • Primary effect on SA node (↓ HR) and AV node (↓ conduction)
• Representative agents
  • Propranolol – non‑selective (β₁ + β₂)
  • Atenolol, Metoprolol, Esmolol – cardioselective (β₁)
• Clinical uses
  • Post‑MI prophylaxis (reduces mortality)
  • Supraventricular tachyarrhythmias (rate control)
  • Esmolol – IV, ultrashort half‑life, used in acute SVTs

• Block delayed rectifier K⁺ current (I_K) → slow phase 3 repolarization
• ↑ APD and ERP in Purkinje and ventricular fibers → anti‑re‑entrant effect
• Amiodarone
  • Multiclass activity: I, II, III, IV effects
  • ↑ APD and ERP in all cardiac tissues
  • Half‑life > 80 days; extensive tissue binding (large V_d)
  • Uses: broad spectrum – any arrhythmia
  • Adverse effects: pulmonary fibrosis, interstitial pneumonitis, phototoxicity, corneal deposits, hepatic necrosis, blue‑gray skin pigmentation, thyroid dysfunction (hypo‑ or hyper‑)
• Dronedarone
  • Similar multi‑channel effects to amiodarone
  • Shorter half‑life; fewer iodine‑related side effects (no thyroid or pulmonary toxicity)
  • Contraindicated in decompensated heart failure
• Sotalol
  • Class III + non‑selective β‑blockade (β₁ + β₂)
  • Use: life‑threatening ventricular arrhythmias
  • Significant risk of torsade de pointes – requires QT monitoring

• Block L‑type Ca²⁺ channels in slow‑response fibers
• ↓ phase 0 upstroke velocity and ↓ phase 4 slope → ↓ SA rate, ↓ AV conduction
• Prototype agents: Verapamil and Diltiazem (non‑dihydropyridines)
• Clinical uses
  • Supraventricular tachycardia (rate control in atrial fibrillation / flutter)
  • AV nodal re‑entrant tachycardia
• Adverse effects
  • Verapamil: constipation, dizziness, flushing, hypotension, AV block
  • Diltiazem: similar but less constipating
• Drug interactions
  • Additive AV block with β‑blockers and digoxin
  • Verapamil displaces digoxin from tissue binding → ↑ digoxin toxicity

• Adenosine
  • Activates A₁ receptors (G_i‑coupled) → ↓ cAMP → ↓ SA and AV nodal activity
  • Drug of choice for paroxysmal supraventricular tachycardia (PSVT) and AV nodal re‑entry
  • IV administration; half‑life < 10 seconds
  • Adverse effects: flushing, sedation, dyspnea (transient)
  • Antagonized by methylxanthines (theophylline, caffeine)
• Magnesium
  • Use: torsade de pointes (especially in acquired long QT)
  • Mechanism: stabilizes membrane, reduces early after‑depolarizations

• Long QT syndrome
  • Familial or acquired; risk of torsade de pointes
  • Class IA and III drugs increase risk in these patients
  • Other drugs that prolong QT: antipsychotics (thioridazine), tricyclic antidepressants
  • Management: correct hypokalemia, correct hypomagnesemia, discontinue offending drugs
• Potassium balance
  • Both hyperkalemia and hypokalemia are arrhythmogenic
  • Hypokalemia potentiates the proarrhythmic effects of Class I and III agents
• Atrial fibrillation – two pillars of management
  • Rate control: β‑blockers, non‑dihydropyridine CCBs, digoxin
  • Anticoagulation: risk‑stratified (CHA₂DS₂‑VASc) to prevent thromboembolism
• Drug interactions to remember
  • Quinidine + digoxin: displacement → ↑ digoxin toxicity
  • Verapamil + digoxin: displacement → ↑ digoxin toxicity
  • Verapamil + β‑blockers: additive AV block
  • Adenosine + methylxanthines: antagonism