Cardiac action potential

Category: membrane

Overview

Ventricular AP has 5 phases. Phase 0 (rapid depolarization): voltage-gated Na+ channels (Nav1.5) — CLASS I antiarrhythmics block (Ia quinidine + procainamide; Ib lidocaine + mexiletine; Ic flecainide + propafenone). Phase 1 (early repolarization): Ito1 transient outward K+. Phase 2 (plateau): L-type Ca2+ current — CLASS IV CCBs (verapamil + diltiazem) block here. Phase 3 (repolarization): IKr (hERG, KCNH2 = Kv11.1) + IKs (KCNQ1) — CLASS III (sotalol + dofetilide + ibutilide + amiodarone) block IKr → QT prolongation. Phase 4 (resting potential): inward rectifier IK1 maintains. SA + AV node: β1-AR controls If "funny current" pacemaker — β-BLOCKERS (CLASS II) slow rate. Genetic LQTS: KCNH2 LOF (LQT2, drug-induced TdP susceptibility), KCNQ1 LOF (LQT1), SCN5A GOF (LQT3).

Organ Systems

• cardiovascular

Pathway Steps

1. phase-0-depolarization → phase-1-early-repolarization — via Nav1.5 opens; Ito1 closes; CLASS I antiarrhythmic target. Phase 0 is the fast upstroke from Nav1.5 sodium influx — the Class-I antiarrhythmic target, and where loss-of-function causes Brugada syndrome. Phase 1 is brief Ito-mediated early repolarization.
2. phase-1-early-repolarization → phase-2-plateau — via L-type Ca2+ inward + Ito1 declining; CCB target. The plateau is the cardiac AP’s signature: inward L-type Ca²⁺ current (the Class-IV calcium-channel-blocker target) balances outward K⁺, sustaining depolarization to drive excitation–contraction coupling (Ca-induced Ca release).
3. phase-2-plateau → phase-3-repolarization — via IKr (hERG) + IKs activate; CLASS III antiarrhythmic + drug-induced TdP target. Repolarization via delayed-rectifier K⁺ currents IKr (hERG) and IKs is the Class-III antiarrhythmic target — and hERG block by many non-cardiac drugs causes acquired long-QT/torsades, a leading reason drugs are withdrawn for cardiac safety.
4. phase-3-repolarization → phase-4-resting — via IK1 inward rectifier; If pacemaker in SA/AV nodes; β-BLOCKER target. IK1 sets the resting potential; in the SA/AV nodes the funny current If drives spontaneous phase-4 depolarization (automaticity) — the ivabradine target, slowed by β-blockers, the basis of heart-rate control.

Known Modulators

• quinidine (inhibitor) — Na+ channel + IKr (class IA). oldest antiarrhythmic; broad Na+/K+ block; cinchonism + QT prolongation + thrombocytopenia tail; CYP2D6 potent inhibitor (DDI authored Wave 2a v1.1: DXM 43×, propafenone, desipramine)
• mexiletine (inhibitor) — Na+ channel (class IB). oral lidocaine analog; ventricular arrhythmia + myotonic dystrophy off-label
• flecainide (inhibitor) — Na+ channel (class IC). strong Na+ blocker; CAST trial established mortality harm in post-MI structural heart disease — contraindicated; safe in lone AF + SVT
• propafenone (inhibitor) — Na+ channel (class IC) + weak β-block. CYP2D6 substrate (poor metabolizers 5-10× AUC of S-enantiomer); pill-in-pocket for AF cardioversion
• amiodarone (inhibitor) — multi-channel (K+ class III dominant; also Na+/Ca²⁺/β). broadest-spectrum antiarrhythmic; AF + VT/VF; thyroid + pulmonary + ocular + hepatic toxicity tail; very long t½ (~50 days); strong CYP3A4 inhibitor
• sotalol (inhibitor) — β + IKr (class III). racemic; D-sotalol pure IKr blocker (negative SWORD trial mortality); racemic AF/VT — initiate inpatient with QT monitoring
• dofetilide (inhibitor) — IKr-selective (class III pure). AF rhythm control; mandatory 3-day inpatient initiation with QT/CrCl titration
• ivabradine (inhibitor) — If (HCN4) — sinus pacemaker funny current. reduces heart rate without inotropy or BP effect; HFrEF (SHIFT) + chronic stable angina; phosphenes (visual side effect) from retinal HCN expression
• lidocaine (inhibitor) — Na+ channel (class IB). IV antiarrhythmic for monomorphic VT; also workhorse local anesthetic (covered in CNS-2 wave)
• digoxin (inhibitor) — Na+/K+-ATPase (myocardial). cardiac glycoside; positive inotrope + negative dromotrope; narrow therapeutic index; renally cleared; classic K+/Mg²⁺/digoxin-toxicity triad
• ranolazine (inhibitor) — late Na+ current (INaL). reduces Ca²⁺ overload via late-Na blockade; chronic stable angina; modest HbA1c effect; QT prolongation
• adenosine (activator) — A1 receptor → IKACh activation. IV bolus terminates AVNRT/AVRT via transient AV block; 10-second half-life; flushing/chest pressure + bronchoconstriction warning

References

• PMID 16183911