CARDIOLOGY · DRUG SAFETY · ARRHYTHMIA

Drug-induced QT prolongation

Drug-induced QT prolongation is caused by off-target hERG potassium channel blockade and is the leading reason for drug withdrawal since the 1990s. This guide covers the molecular mechanism, QTc correction formulas, risk stratification, high-risk drug classes, electrolyte management, and torsades de pointes management.

Mechanism

hERG (IKr) channel block

Threshold (action)

QTc >500 ms or ↑≥60 ms

Correction formula

Bazett (clinical) or Fridericia (trials)

TdP first-line Rx

IV MgSO₄ 2 g + K+ correction

Mechanism: hERG channel block

The hERG (KCNH2/Kv11.1) channel encodes the rapidly activating delayed rectifier potassium current (IKr) — the dominant repolarising current in phase 3 of the cardiac action potential. Blocking IKr delays repolarisation, extending the QT interval and creating an arrhythmogenic substrate.

hERG is uniquely vulnerable to pharmacological block because its central vestibule contains two aromatic residues (Tyr652 and Phe656) that physically trap hydrophobic, aromatic molecules. This structural feature explains why drugs from completely unrelated therapeutic classes (antibiotics, antipsychotics, antihistamines, antifungals, antiemetics) all block hERG as an off-target effect. Under ICH S7B, all new NCEs must be assessed for hERG affinity in vitro (IC50 measurement); ICH E14 requires QTc assessment in dedicated thorough QT/QTc studies in Phase I.

QTc correction formulas

Bazett formula

QTc = QT / √RR

Most widely used in clinical practice. Overcorrects at HR >100 bpm (artefactually elevated QTc) and undercorrects at HR <60 bpm.

Fridericia formula

QTc = QT / RR^1/3

Preferred in clinical trials (ICH E14 guidance). More accurate across the full heart rate range. Use for drug development QTc assessments.

Normal QTc: Males ≤440 ms (some guidelines ≤450 ms); Females ≤460 ms. Action thresholds: QTc >500 ms — review all QT-prolonging drugs, consider withdrawal; QTc increase ≥60 ms from baseline — significant; QTc increase ≥30 ms — monitor closely.

High-risk drugs by class

Class	Examples	Risk level
Class III antiarrhythmics	Sotalol, dofetilide, ibutilide, amiodarone	Known (highest)
Class Ia antiarrhythmics	Quinidine, disopyramide, procainamide	Known
Antipsychotics	Haloperidol IV, thioridazine, ziprasidone, sertindole	Known/Conditional
Antibiotics	Clarithromycin, azithromycin, moxifloxacin, levofloxacin	Conditional/Known
Antifungals	Fluconazole, voriconazole, posaconazole, ketoconazole	Conditional
Antiemetics	Ondansetron IV (esp. >32 mg), domperidone	Conditional
Opioids	Methadone (dose-dependent) — ECG monitoring required	Known
Antimalarials	Chloroquine, hydroxychloroquine	Conditional
Oncology	Many TKIs (sorafenib, vandetanib, ribociclib), tamoxifen	Conditional/Possible

Patient risk factors amplifying QT risk

Female sex

Women have inherently longer QTc (additional ~6–10 ms) and 2–3× higher TdP risk

Hypokalaemia

K+ <3.5 mmol/L significantly reduces repolarisation reserve — most modifiable risk factor

Hypomagnesaemia

Mg2+ <0.7 mmol/L — common with loop diuretics and critical illness

Bradycardia

Slow heart rate lengthens baseline QT — TdP is "pause-dependent"

Structural heart disease

HF, LVH, post-MI — reduced repolarisation reserve

Congenital LQTS

Baseline QT >470 ms — additive drug effect dramatically increases TdP risk

Torsades de pointes management

1. Stop the offending drug

Immediately withdraw QT-prolonging drug(s). If multiple drugs involved, stop all where clinically feasible.

2. IV magnesium sulphate

MgSO₄ 2 g (8 mmol) IV over 10–15 min — first-line regardless of serum Mg²⁺ level. Stabilises cardiomyocyte membrane. Repeat if TdP recurs.

3. Correct electrolytes

Target K+ 4.5–5 mmol/L (IV replacement as needed); correct Mg²⁺ >0.8 mmol/L; correct Ca²⁺.

4. Increase heart rate

Overdrive pacing (transvenous 90–110 bpm) or isoprenaline IV infusion to 90–110 bpm — eliminates pause-dependent TdP. Most effective intervention for recurrent TdP.

5. DC cardioversion

For sustained TdP with haemodynamic compromise — synchronised if possible, unsynchronised for VF.

FAQ

What causes drug-induced QT prolongation?

Off-target blockade of the hERG (KCNH2/Kv11.1) potassium channel, which carries the IKr current responsible for phase 3 cardiac action potential repolarisation. hERG is uniquely susceptible because its central cavity physically traps hydrophobic aromatic molecules. All new drugs must be assessed for hERG affinity (ICH S7B) and QTc effect (ICH E14).

What are the Bazett and Fridericia QTc correction formulas?

Bazett: QTc = QT / √RR — widely used clinically but overcorrects at high HR. Fridericia: QTc = QT / RR^(1/3) — more accurate across heart rates, preferred in drug trials. Normal QTc: males ≤440 ms, females ≤460 ms. Act at QTc >500 ms or ≥60 ms increase from baseline.

Which drug classes most commonly cause QT prolongation?

Antiarrhythmics (sotalol, dofetilide, quinidine — known risk), antipsychotics (haloperidol IV, thioridazine), antibiotics (clarithromycin, azithromycin, moxifloxacin), antifungals (fluconazole, voriconazole), antiemetics (ondansetron IV), methadone, and antimalarials. Risk is additive with combinations and amplified by hypokalaemia, female sex, bradycardia, and structural heart disease.

How is torsades de pointes managed?

Stop the offending drug; IV MgSO₄ 2 g regardless of serum Mg²⁺ (first-line); correct K+ to 4.5–5 mmol/L; increase heart rate via overdrive pacing (90–110 bpm) or isoprenaline infusion; DC cardioversion for sustained haemodynamically unstable TdP.

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