Ballicules.com

QT prolongation

What a long QT means

Slow repolarization, and the arrhythmia it invites

• The QT interval is ventricular depolarization plus repolarization; corrected for rate it is QTc, and the common ceilings are about 450 ms in men and 460 ms in women¹²
• A QTc above 500 ms, or a rise of more than 60 ms after a drug is started, is the threshold at which a drug is usually stopped¹²
• Prolonged repolarization allows early afterdepolarizations; a pause then a beat can trigger torsades de pointes — a twisting polymorphic VT that is usually self-limited and sometimes is not²³
• Torsades needs a substrate as well as a drug: the same dose does nothing in most patients and kills one in a very few³

Why hERG catches so many drugs

The channel with a promiscuous pore

• Phase-3 repolarization runs on two potassium currents, IKr (the hERG/KCNH2 channel) and IKs (KCNQ1); losing either shrinks the "repolarization reserve"³⁴
• The hERG pore is unusually wide and lined with aromatic residues (Tyr652, Phe656) that stack against the rings of many unrelated drugs — antiarrhythmics, antipsychotics, antihistamines, macrolides, antifungals, antiemetics⁴
• This is the mechanism the hERG peg marks, sized by the expected QTc change; CredibleMeds sorts the same drugs into known, possible and conditional risk of torsades⁵

Route 2 — hERG trafficking, not the pore

The channel never reaches the membrane

• Pentamidine does not block the open hERG pore; it stops newly made channels from reaching the cell surface, so the current falls over days rather than minutes⁶
• Arsenic trioxide and probucol act the same way; the QT lengthens late and stays long after the drug is gone⁶
• Because the peg means pore block, these carry no hERG peg — they live on the interaction list instead

Route 3 — gene expression: the HDAC inhibitors

A different lever on the same currents

• Histone deacetylase inhibition changes transcription of ion-channel genes; repolarization slows without any direct channel block⁷
• Romidepsin, vorinostat, panobinostat and givinostat all carry the warning; the HDAC card, not the hERG card, owns it⁷

Route 4 — hormones: androgen deprivation

Testosterone shortens the QT; taking it away lengthens it

• Men have shorter QT intervals than women from puberty on, and androgen deprivation removes that protection: GnRH agonists and antiandrogens lengthen QTc as a class⁸¹¹
• The effect is modest in most men and matters when it stacks with a hERG blocker or low potassium⁸

Route 5 — heart rate

Slow the heart and the QT lengthens with it

• The QT lengthens at slower rates, and torsades is pause-dependent, so drugs that slow the sinus node raise the risk without touching a potassium channel²¹⁰
• Ivabradine (HCN4 block), fingolimod (first-dose bradycardia and AV block) and the cholinesterase inhibitors are the drug examples; beta blockers and digoxin amplify other drugs the same way¹⁰

Route 6 — ischemia and vasospasm

The fluoropyrimidines

• Fluorouracil and its prodrug capecitabine cause coronary vasospasm and endothelial injury; chest pain, ST change and QT prolongation follow during the infusion⁹
• Not a channel effect: it resolves with the infusion and recurs on rechallenge⁹

Route 7 — QRS widening lengthens QT

Conduction slowing, mislabeled

• The QT is measured from the start of the QRS, so anything that widens the QRS lengthens the QT even when repolarization is normal — flecainide, propafenone and the tricyclics in overdose²
• The danger there is wide-complex ventricular arrhythmia, not torsades; the Nav1.5 card owns it

The amplifiers

What turns a modest QT drug into torsades

• Low potassium and low magnesium — diuretics, vomiting, laxative misuse — reduce repolarization reserve; the AHA targets are potassium ≥ 4.0 and magnesium ≥ 2.0 mmol/L in patients at risk¹²
• CYP3A4 inhibitors raise the level of a hERG blocker that depends on 3A4 — the terfenadine and cisapride story that took both drugs off the market³
• Female sex, older age, bradycardia, structural heart disease, congenital long-QT, renal or hepatic impairment, IV or high doses, and any second QT-prolonging drug¹²

What to do

Before, during, and if torsades happens

• Baseline ECG and electrolytes before a high-risk drug; repeat at steady state or after a dose change; correct potassium and magnesium first¹²
• Stop or reduce the drug at QTc > 500 ms or a rise > 60 ms; look for the second drug, the inhibitor and the diuretic¹²
• Torsades: IV magnesium sulfate 2 g, even with a normal magnesium; temporary pacing or isoproterenol to raise the rate; defibrillate if unstable; never a class IA or III antiarrhythmic²
• CredibleMeds lists known, possible and conditional risk⁵

References

Numbered as cited on the slides

• [1] Drew BJ, et al. Prevention of torsade de pointes in hospital settings: a scientific statement from the AHA and the ACC Foundation. Circulation 2010;121:1047–1060
• [2] Tisdale JE, et al. Drug-induced arrhythmias: a scientific statement from the American Heart Association. Circulation 2020;142:e214–e233
• [3] Roden DM. Drug-induced prolongation of the QT interval. N Engl J Med 2004;350:1013–1022
• [4] Sanguinetti MC, Tristani-Firouzi M. hERG potassium channels and cardiac arrhythmia. Nature 2006;440:463–469
• [5] Woosley RL, Heise CW, Romero KA. QTdrugs list, CredibleMeds (AZCERT), crediblemeds.org
• [6] Kuryshev YA, et al. Pentamidine-induced long QT syndrome and block of hERG trafficking. J Pharmacol Exp Ther 2005;312:316–323
• [7] Shah MH, et al. Cardiotoxicity of histone deacetylase inhibitor depsipeptide in patients with metastatic neuroendocrine tumors. Clin Cancer Res 2006;12:3997–4003
• [8] Gagliano-Jucá T, et al. Androgen deprivation therapy is associated with prolongation of QTc interval in men with prostate cancer. J Endocr Soc 2018;2:485–496
• [9] Sara JD, et al. 5-fluorouracil and cardiotoxicity: a review. Ther Adv Med Oncol 2018;10:1758835918780140
• [10] Ivabradine (CORLANOR) and fingolimod (GILENYA) prescribing information: bradycardia and QT prolongation warnings
• [11] Leuprolide, bicalutamide and apalutamide prescribing information: QT prolongation with androgen deprivation therapy

Topic, not a peg: hERG blocker cards mark pore blockade. This presentation and the INTERACTIONS list “QTc prolongation” cover that route and six others.

Self-check

• How does pentamidine lower hERG current without blocking the pore?
  Prevents new channels reaching the cell surface.
• Can QRS widening lengthen QT despite normal repolarization?
  Yes; QT includes the QRS.

All mechanisms · Open the interactive console ↗
Open the interactive console in slides ↗