PharmacologyTier 1Medical Sciences concept

Drug-induced long QT syndrome - ion channel mechanism

Core concept

The QT interval is ventricular repolarisation, driven mainly by IKr - the rapid delayed rectifier K current, carried by the hERG (KCNH2) channel
hERG has an unusually large, flexible inner vestibule with aromatic residues -> promiscuous drug binding
- This is why so many structurally unrelated drugs block it
IKr blockade -> dec K efflux -> prolonged phase 3 repolarisation -> long QT
- Prolonged action potential -> reactivation of L-type Ca channels -> early afterdepolarisations (EADs)
- EADs in the setting of transmural dispersion of repolarisation -> R-on-T -> torsades de pointes
Reverse use-dependence - blockade is greatest at slow heart rates
- Bradycardia and pauses are pro-arrhythmic; this is why TdP follows a short-long-short sequence

Hypokalaemia paradoxically reduces IKr conductance - low extracellular K destabilises the channel and increases inactivation
- So hypokalaemia both prolongs QT itself and amplifies any drug effect
- dec K, dec Mg, dec Ca all prolong QT
QTc thresholds
- Prolonged: >450 ms men, >470 ms women
- >500 ms, or an increase of >60 ms from baseline -> high TdP risk, stop the drug
Correction formulae: Bazett overcorrects at high rates - use Fridericia or Hodges above 100 bpm
QT is measured in lead II or V5, longest interval, tangent method, excluding U waves

Drug classes

Antiarrhythmics - sotalol, amiodarone (low TdP risk despite marked QT prolongation), quinidine, procainamide, flecainide
Antibiotics - macrolides > fluoroquinolones; erythromycin and clarithromycin worst; azithromycin lower
Antifungals - fluconazole, voriconazole
Antipsychotics - haloperidol (especially IV), droperidol, quetiapine, ziprasidone
Antidepressants - citalopram (dose-capped 20 mg over 65), escitalopram, TCAs
Antiemetics - ondansetron (especially IV), domperidone, droperidol
Others - methadone, hydroxychloroquine, arsenic trioxide, ranolazine, tacrolimus
Risk multiplies when a QT drug is combined with a CYP3A4 inhibitor that raises its level - erythromycin + a CYP3A4 inhibitor is a classic

Risk factors

Female sex, age, structural heart disease, bradycardia, electrolyte disturbance, hepatic/renal impairment, congenital LQTS (subclinical KCNH2/KCNQ1 variants unmasked)

Torsades management
- Magnesium sulfate 2 g IV regardless of the serum magnesium - stabilises the membrane, suppresses EADs
- Correct K to the high-normal range (4.5-5.0)
- Stop every offending drug
- Increase the heart rate - isoprenaline infusion or overdrive pacing at 90-110 bpm (shortens repolarisation, abolishes pauses)
- Unstable -> DC cardioversion
- Amiodarone and other class III agents are contraindicated
Screening ECG before and after starting a high-risk agent (methadone, sotalol, antipsychotics), and after any dose increase
Check the cumulative burden - the patient on citalopram plus ondansetron plus clarithromycin is the one who arrests
Sotalol initiation requires inpatient ECG monitoring and renal dose adjustment

3 more sections, plus exam facts

Premium unlocks every note across every specialty, and the full exam fact library behind it.