Drug-induced QT prolongation is the most clinically significant form of antiarrhythmic proarrhythmia and one of the leading causes of drug withdrawal from the market. It results from blockade of the hERG-encoded rapid delayed rectifier potassium current (IKr) channel, which is unusually susceptible to drug interaction due to the unique structural features of its inner vestibule.¹

IKr blockade slows phase 3 repolarization, prolonging the action potential duration (APD) and QT interval. The resulting excessive APD creates conditions

for early afterdepolarizations (EADs): inward currents (reactivated L-type calcium current (ICaL), window INa) overcome the reduced outward repolarizing reserve during the prolonged plateau, producing oscillatory depolarizations during phase 2 or 3. EADs exceeding threshold trigger extrasystoles that, in the setting of heterogeneous APD across the ventricular wall, can initiate re-entrant torsades de pointes (TdP).^1,2

Drug-induced QT prolongation is a necessary but not sufficient condition for TdP. Clinical risk factors that amplify risk of torsades de pointes include:² Female sex: Women have an intrinsically longer baseline QTc and lower IKr reserve than men, accounting for the ~2:1 female predominance of drug-induced TdP. Hypokalemia and hypomagnesemia: Both reduce outward repolarizing currents and directly promote early afterdepolarization (EAD) formation. These are modifiable risk factors that must be corrected before and during antiarrhythmic initiation.

Bradycardia and pauses: TdP is characteristically pause-dependent (short-long-short RR sequence preceding the initiating beat). Rate-dependent APD prolongation (reverse use-dependence) amplifies this risk.

Structural heart disease and LV hypertrophy: Increase transmural dispersion of repolarization, the substrate for TdP re-entry. Congenital LQTS (even subclinical): Drug exposure can unmask a previously silent congenital LQTS. History of drug-induced TdP should prompt genetic testing. QTc ≥500 ms at baseline: The single most important quantitative threshold. Discontinue the QT-prolonging drug if QTc exceeds 500 ms (or 550 ms in the presence of bundle branch block). Multiple QT-prolonging drugs: Combinations produce additive or synergistic QT prolongation. Avoid co-prescription of Class Ia + Class III antiarrhythmics, or antiarrhythmics + fluoroquinolones + azole antifungals.

The CredibleMeds database (Arizona CERT (Center for Education and Research on Therapeutics), University of Arizona, provides a continuously updated, evidence-based classification of QT risk for thousands of drugs. It is the clinical standard for QT risk stratification:³ The Known Risk category includes drugs with substantial evidence of both QT prolongation and TdP: amiodarone, sotalol, dofetilide, ibutilide, quinidine, methadone, and haloperidol. The Conditional Risk category includes drugs whose risk of torsades de pointes emerges under specific conditions such as high dose, drug interaction, or hypokalemia: azithromycin, ciprofloxacin, ondansetron, fluconazole, and tamoxifen. The Possible Risk category includes drugs with evidence of QT prolongation but insufficient data to confirm risk of torsades de pointes: hydroxychloroquine and some antidepressants and antivirals. The Special Risk category includes drugs that pose risk of torsades de pointes specifically in patients with congenital LQTS: epinephrine and dopamine in long QT syndrome type 1 (LQT1) patients.

TdP is a polymorphic ventricular tachycardia with a characteristic twisting of the QRS axis around the isoelectric baseline (‘twisting of the points’), typically occurring in runs of 5–20 beats that may self-terminate or degenerate to VF. It is almost always preceded by a pause (short-long-short sequence) and occurs on a background of QT prolongation.²

Torsades de Pointes: Acute Management Protocol

1. WITHDRAW the offending QT-prolonging drug immediately. 2. IV MAGNESIUM SULFATE 2 g over 1–2 min, first-line regardless of serum Mg level. Suppresses EADs by ICaL blockade. Repeat 2 g if recurrent. 3. CORRECT ELECTROLYTES: Target K+ ≥4.5 mEq/L, Mg²⁺ ≥2.0 mg/dL. 4. INCREASE HEART RATE to eliminate pauses and reverse use-dependence: IV isoproterenol infusion (1–4 mcg/min, titrate to HR 90–110 bpm) OR temporary transvenous pacing at 90–110 bpm (preferred if isoproterenol contraindicated, e.g., ischemic heart disease). 5. AVOID CALCIUM in acquired TdP (unlike digoxin toxicity, calcium worsens EADs). 6. AVOID additional QT-prolonging drugs. Review all medications. 7. If degeneration to VF: immediate unsynchronized DC defibrillation.

Renal impairment affects antiarrhythmic drug management through three mechanisms: reduced drug clearance (accumulation), altered protein binding (increased free drug fraction), and electrolyte disturbances (hypokalemia, hyperkalemia in advanced CKD, hypomagnesemia) that amplify proarrhythmic risk.⁵

Sotalol is approximately 100% renally eliminated and requires mandatory dose adjustment; it is contraindicated at creatinine clearance (CrCl) below 40 mL/min and requires extended dosing intervals at CrCl 40 to 60 mL/min; accumulation markedly increases QT prolongation and risk of torsades de pointes. Dofetilide is 80% renally eliminated and requires mandatory four-tier dose adjustment by CrCl; dose changes require re-initiation with monitored QTc surveillance. Digoxin is 70 to 80% renally eliminated; dose must be reduced proportionally to CrCl, and levels are unpredictable in CKD given its narrow therapeutic index. Procainamide is 50 to 60% renally eliminated but its active metabolite NAPA (N-acetylprocainamide) is nearly 100% renally cleared; dose and frequency reduction are required and NAPA accumulation worsens QT prolongation in renal failure. Flecainide is approximately 30% renally eliminated; dose reduction is required when CrCl falls below 35 mL/min, as accumulation produces QRS widening. Amiodarone has minimal renal elimination and requires no dose adjustment in renal impairment, making it the safest antiarrhythmic in severe CKD; hepatic clearance predominates. Lidocaine has minimal renal elimination and requires no IV dose adjustment, though the active metabolite MEGX (monoethylglycinexylidide) may accumulate in prolonged infusions, increasing CNS toxicity risk. Mexiletine has approximately 10% renal elimination and requires only minor dose adjustment in severe CKD; clearance is primarily hepatic.

Arrhythmias during pregnancy range from benign ectopy to life-threatening sustained tachycardias. Pharmacologic management requires balancing maternal hemodynamic stability against fetal drug exposure. Physiologic changes of pregnancy alter drug pharmacokinetics: increased plasma volume, reduced albumin, increased GFR, and progesterone-mediated QT prolongation all modify drug behavior.⁶

Use the lowest effective dose of the drug with the most established safety record. All antiarrhythmics cross the placenta to some extent. Avoid drug initiation in the first trimester whenever possible, as organogenesis is most vulnerable to teratogenic exposure. SVT (atrioventricular nodal reentrant tachycardia (AVNRT), atrioventricular reentrant tachycardia (AVRT)) is the most common significant arrhythmia in pregnancy. Vagal maneuvers first; IV adenosine is safe (rapid metabolism prevents fetal exposure).

DC cardioversion is safe at any gestational age when hemodynamic compromise requires it; fetal monitoring should accompany the procedure.

Agent-Specific Safety

Adenosine is safe for IV use in pregnancy; its ultra-short half-life produces negligible fetal exposure and it is the first-line agent for acute SVT termination. Beta-blockers (metoprolol preferred over atenolol, which is associated with lower birth weight) are relatively safe with the most established evidence; concerns include intrauterine growth restriction (IUGR), neonatal bradycardia, and hypoglycemia; used for rate control in AF, SVT prophylaxis, LQTS, and catecholaminergic polymorphic ventricular tachycardia (CPVT). Digoxin has decades of use and is relatively safe; it crosses the placenta and fetal heart rate should be monitored; used for rate control in AF and for treating fetal SVT via maternal dosing. Flecainide has limited data but is used in fetal SVT treatment via maternal dosing; it crosses the placenta and is used for maternal SVT in the absence of structural heart disease. Sotalol has limited data with documented fetal exposure; it carries risk of neonatal QT prolongation and bradycardia and is used as second-line when flecainide fails. Amiodarone should be avoided if at all possible; it carries risk of neonatal hypothyroidism from iodine load, IUGR, premature birth, and neonatal bradycardia; it is reserved for life-threatening maternal arrhythmias refractory to all other agents. Verapamil should be used with caution; IV use carries risk of neonatal AV block, hypotension, and bradycardia; oral use is relatively safer; used for SVT rate control if beta-blockers fail or are contraindicated.