What is the mechanism by which phenothiazine derivatives, such as promethazine, Reglan (metoclopramide), and droperidol, cause an increased QT interval on an electrocardiogram (EKG)?

Mechanism of QT Prolongation by Phenothiazines and Related Antipsychotics

Phenothiazines (promethazine), metoclopramide (Reglan), and droperidol prolong the QT interval primarily through blockade of the rapid delayed rectifier potassium channel (IKr), encoded by the hERG gene, which disrupts the balance between inward and outward currents during cardiac repolarization. 1, 2

Molecular Mechanism

The fundamental mechanism involves disruption of cardiac action potential repolarization through the following pathway:

• hERG potassium channel blockade is the primary mechanism whereby these drugs prolong individual cardiac action potentials 1, 2
• Cardiac repolarization normally represents a balance between inward currents (primarily calcium and sodium channels) and outward currents (primarily through rapid and slow delayed rectifier potassium channels) 2
• When IKr (the rapid delayed rectifier current) is blocked, the outward potassium current is reduced, leading to delayed repolarization and prolonged action potential duration 1, 2
• This prolongation of individual cellular action potentials manifests on the surface electrocardiogram as QT interval prolongation 2

Drug-Specific Effects

The magnitude of QT prolongation varies significantly among these agents:

Droperidol

• Causes dose-dependent QT prolongation, with 0.1,0.175, and 0.25 mg/kg associated with median QTc prolongation of 37,44, and 59 msec respectively 3
• QT prolongation occurs within 10 minutes of administration 3
• Carries an FDA black box warning for QT prolongation, torsades de pointes, and sudden death 4, 3
• However, the actual incidence of torsades de pointes is extremely low at 0.006% (1/16,546 patients) 5

Promethazine

• Induces significant QTc prolongation when corrected using both Bazett's and Fridericia's formulas 6
• Importantly, promethazine does not significantly affect transmural dispersion of repolarization (T-peak to T-end interval), which suggests the risk of torsadogenic action is very low despite measurable QT prolongation 6

Metoclopramide (Reglan)

• While grouped with phenothiazines due to structural similarities, specific QT prolongation data is limited in the provided evidence
• Shares the dopamine antagonist properties and potential for similar hERG channel effects as other phenothiazines 4

Arrhythmogenic Consequences

The clinical significance of QT prolongation lies in its association with torsades de pointes, a polymorphic ventricular tachycardia that can degenerate into ventricular fibrillation and sudden death:

• Marked action potential prolongation is accompanied by arrhythmogenic afterdepolarizations that trigger torsades de pointes 2
• QT intervals generally exceed 500 msec before development of torsades de pointes 4
• The risk is not uniform—high-risk drugs like haloperidol and droperidol may increase risk in individuals with genetic mutations, while the absolute incidence remains very low 4

Critical Risk Factors That Amplify the Mechanism

The following conditions significantly increase the risk of progression from QT prolongation to life-threatening arrhythmias:

• Electrolyte abnormalities, particularly hypokalemia and hypomagnesemia, which further impair repolarization 4, 3
• Concomitant use of other QT-prolonging medications, which creates additive hERG blockade 4, 3
• Female gender, as women have inherently longer QT intervals and higher risk of torsades de pointes 4, 7
• Baseline QTc >500 ms or underlying long QT syndrome 4, 7
• Bradycardia (<50 bpm), which prolongs the action potential duration further 3
• Significant cardiac disease including heart failure and left ventricular hypertrophy 3

Important Clinical Caveats

Route of Administration Matters

• Intravenous haloperidol carries significantly higher risk than oral or intramuscular administration 4
• Intramuscular dosing is the preferred parenteral route for antipsychotics in emergency settings 4

QT Prolongation ≠ Torsades de Pointes Risk

• Not all QT prolongation carries equal arrhythmic risk 4, 6
• Promethazine prolongs QTc but does not affect transmural dispersion of repolarization, suggesting low torsadogenic potential despite measurable QT changes 6
• The incidence of torsades de pointes with droperidol is extraordinarily low (0.006%) despite the FDA black box warning 5

Drug Interactions via Cytochrome P450

• Many phenothiazines (including thioridazine) are metabolized by cytochrome P450 enzymes 4
• Co-administration with enzyme inhibitors (macrolide antibiotics, imidazole antifungals, fluoxetine, fluvoxamine) can cause plasma levels to rise unduly, increasing QT prolongation risk 4

Monitoring Recommendations

For patients receiving these medications, particularly droperidol:

• Obtain 12-lead ECG prior to administration to identify baseline QTc >440 ms (males) or >450 ms (females) 3
• If prolonged QT interval is present, droperidol should NOT be administered 3
• Continue ECG monitoring for 2-3 hours after treatment completion when droperidol is used 3
• Correct electrolyte abnormalities before initiating therapy, targeting potassium >4.5 mEq/L 4, 7