Which drugs are associated with cardiac potassium‑channel (hERG/IKr) blockade and which are associated with sodium‑channel (Nav1.5) blockade?

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Drugs Associated with Cardiac Potassium-Channel (hERG/IKr) vs Sodium-Channel (Nav1.5) Blockade

Drug-induced QT prolongation is primarily caused by blockade of cardiac potassium channels (hERG/IKr), not sodium channels; sodium-channel (Nav1.5) blockade actually serves as a protective modulator that can reduce QTc prolongation and arrhythmia risk. 1, 2

Potassium Channel (hERG/IKr) Blockers

Antiarrhythmic Drugs

  • Class IA antiarrhythmics: quinidine, procainamide, disopyramide 3
  • Class III antiarrhythmics: sotalol, dofetilide, ibutilide 3
  • Amiodarone: causes marked QT prolongation (though lower torsades risk due to uniform repolarization delay across myocardial layers) 3, 4

Antipsychotic Medications

  • Highest risk: thioridazine (25-30 ms QTc increase), pimozide (13 ms increase), haloperidol (7 ms increase, dramatically higher with IV route) 3, 5
  • Moderate risk: ziprasidone, quetiapine, clozapine, chlorpromazine, risperidone, olanzapine (5-10 ms increases) 3, 5, 6
  • All antipsychotics prolong QT by blocking the IKr current through hERG-encoded channels 1, 7

Antidepressants

  • Tricyclic antidepressants (amitriptyline, imipramine, doxepin): cause more QT prolongation than SSRIs (mean 24 ms increase) 3, 8
  • SSRIs: citalopram and escitalopram can prolong QT, particularly in patients with pre-existing cardiovascular disease 3

Antibiotics

  • Macrolides: erythromycin (highest risk, especially IV), clarithromycin, azithromycin 1, 3
  • Fluoroquinolones: moxifloxacin > levofloxacin > ciprofloxacin (in descending order of QT risk) 3
  • Trimethoprim-sulfamethoxazole: blocks potassium channels 3

Antifungals

  • Azole antifungals: ketoconazole and other imidazole antimycotics 3

Antimalarials

  • Chloroquine, hydroxychloroquine, halofantrine, mefloquine, quinine 3

Antiemetics

  • Ondansetron, dolasetron, domperidone, droperidol (all carry FDA warnings) 3

Other Medications

  • Methadone: significant QT prolongation risk 3
  • Pentamidine: used for Pneumocystis pneumonia 3
  • Cisapride: withdrawn from US market 3

Sodium Channel (Nav1.5) Blockers

Critical Distinction

Sodium-channel blockade does NOT cause QT prolongation in therapeutic use; instead, it acts as a compensatory mechanism that offsets hERG-mediated QT prolongation. 4, 2

Mechanism of Sodium-Channel Effects

  • Inhibition of the late sodium current (late INa) can partially offset repolarization delay caused by hERG blockade 4, 2
  • The hERG/Nav1.5 ratio explains 57% of overall QTc variability with antipsychotics—drugs with dual blockade show less net QT prolongation 2
  • Agents blocking both hERG and late INa (e.g., ranolazine) produce only modest QTc prolongation despite strong IKr inhibition 4

Sodium-Channel Blockers in Overdose Context

  • Tricyclic antidepressants in overdose: cause wide QRS complexes, sinusoidal ventricular tachycardia, and other arrhythmias through dominant sodium-channel toxicity (distinct from therapeutic hERG-mediated effects) 1, 4
  • Class IA antiarrhythmics can cause conduction disturbances through sodium-channel effects 1
  • Cocaine: produces toxicity partly through sodium-channel blockade 1

Management of Sodium-Channel Toxicity

  • Administer sodium chloride or sodium bicarbonate boluses to reverse conduction slowing or cardioversion-resistant VT 1
  • Beta blockers have been used successfully for sodium-channel blocker toxicity 1

Key Clinical Implications

Genetic Determinants

  • Genetic polymorphisms in the hERG channel (not sodium channels) are the principal determinants of individual susceptibility to drug-induced QTc prolongation and torsades de pointes 4
  • Loss-of-function mutations in KCNH2 (encoding hERG α-subunit) produce congenital long-QT syndrome type 2 4

Predictive Value

  • The ratio of total plasma drug concentration to hERG IC₅₀ is the most reliable predictor of clinical QTc prolongation, outperforming sodium-channel affinity measures 2, 5

Route of Administration

  • IV administration of hERG blockers (especially haloperidol, erythromycin) carries dramatically higher torsades risk than oral or IM routes 3

References

1
Guideline

Guideline Directed Topic Overview

Dr.Oracle Medical Advisory Board & Editors, 2025

3
Guideline

Medications That Can Lengthen QT Interval

Praxis Medical Insights: Practical Summaries of Clinical Guidelines, 2026

4
Guideline

Mechanisms Underlying Antipsychotic‑Induced QTc Prolongation

Praxis Medical Insights: Practical Summaries of Clinical Guidelines, 2026

7
Research

Antipsychotic drugs and QT interval prolongation.

The Psychiatric quarterly, 2003

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This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

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