How does ziprasidone (Geodon) prolong the QT interval?

Mechanism of Ziprasidone (Geodon) QT Interval Prolongation

Ziprasidone prolongs the QT interval by blocking the hERG (human ether-a-go-go-related gene) potassium channel, which slows potassium ion entry into cardiac myocytes and thereby delays ventricular repolarization. 1

Molecular Mechanism

• Ziprasidone preferentially binds to and blocks open hERG potassium channels in a voltage- and concentration-dependent manner, with an IC50 of 120 nM at 37°C in cardiac cells. 1

• Two critical amino acid residues—Tyr-652 and Phe-656—located in the S6 domain of the hERG channel serve as the primary binding sites for ziprasidone. When these aromatic residues are mutated, the potency of ziprasidone's channel blockade is dramatically reduced (IC50 >400 μM and 1 mM for Y652A and F656A mutations, respectively). 1

• The drug blocks the delayed rectifier potassium current (IKr), which is responsible for phase 3 repolarization of the cardiac action potential. By interfering with this current, ziprasidone slows potassium efflux from myocytes and prolongs the action potential duration, manifesting as QT interval prolongation on the ECG. 2, 1

Biophysical Properties of the Block

• The onset of hERG channel blockade by ziprasidone is rapid but not voltage-dependent, with a time constant of approximately 114 ms at +30 mV. 1

• Ziprasidone shows minimal "tonic" block (block at resting membrane potentials) but exhibits significant use-dependent block during depolarization, meaning the drug preferentially blocks channels in their open or activated state. 1

• The drug significantly slows the deactivation of hERG channels, increasing the time constant of the slow component of current deactivation from 1008 ms to 1776 ms at -50 mV, which contributes to prolonged repolarization. 1

• Ziprasidone also slows the time course of channel inactivation in a voltage-dependent manner, though it does not significantly alter the voltage dependence of steady-state activation or inactivation. 1

Clinical Magnitude of QT Prolongation

• The FDA label and clinical guidelines report that ziprasidone causes a mean QTc prolongation of 5-22 ms, which is greater than quetiapine (6 ms), risperidone (0-5 ms), olanzapine (2 ms), and haloperidol (7 ms), but less than thioridazine (25-30 ms). 3, 4, 5

• In a direct comparative study, ziprasidone produced dose-related QTc prolongation, with the effect being concentration-dependent and occurring at the time of maximum plasma concentration. 4

• High-dose intramuscular ziprasidone (20 mg followed by 30 mg four hours later) produced mean QTc changes of 4.6 ms after the first injection and 12.8 ms after the second injection. 6

Risk Factors That Amplify QT Prolongation

• Female gender and age >65 years significantly increase the risk of QTc prolongation and torsades de pointes with ziprasidone. 3

• Electrolyte abnormalities—particularly hypokalemia (K+ <4.5 mEq/L) and hypomagnesemia—exponentially increase the risk because low potassium further impairs repolarization reserve. 2, 3

• Concomitant use of other QTc-prolonging medications creates additive effects, and the FDA label explicitly contraindicates ziprasidone with Class Ia and III antiarrhythmics, mesoridazine, thioridazine, chlorpromazine, droperidol, pimozide, and multiple other agents. 4

• Baseline QTc >500 ms or a history of congenital long QT syndrome are absolute contraindications to ziprasidone use. 3, 4

• Recent acute myocardial infarction and uncompensated heart failure are contraindications due to increased arrhythmia risk. 4

Clinical Implications and Monitoring

• The FDA label mandates avoiding ziprasidone in patients with known QT prolongation, recent MI, or uncompensated heart failure, and prohibits co-administration with other QT-prolonging drugs. 4

• Baseline ECG is obligatory before initiating ziprasidone, with follow-up ECG after dose titration to document QTc changes. 3

• Treatment must be discontinued immediately if QTc exceeds 500 ms or increases >60 ms from baseline, as these thresholds are associated with increased risk of torsades de pointes. 3

• Electrolytes—particularly potassium and magnesium—must be corrected before starting ziprasidone and monitored throughout treatment, with potassium maintained >4.5 mEq/L. 2, 3

Safer Alternatives When QT Prolongation Is a Concern

• Aripiprazole (0 ms mean QTc prolongation) or brexpiprazole are first-line alternatives when cardiac risk is a concern. 3

• Olanzapine (2 ms mean QTc prolongation) represents a second-line option with minimal cardiac effects. 3

• Ziprasidone should be avoided if possible in high-risk patients, given its 5-22 ms QTc prolongation and the availability of safer alternatives. 3

Common Pitfalls

• Failing to obtain a baseline ECG before initiating ziprasidone is a critical error, as it prevents assessment of QTc changes during treatment. 3, 4

• Combining ziprasidone with other QTc-prolonging medications exponentially increases torsades risk, yet this combination is frequently overlooked in clinical practice. 3, 4

• Attributing QTc changes to ziprasidone without first correcting electrolyte abnormalities can lead to inappropriate medication discontinuation when the true culprit is hypokalemia or hypomagnesemia. 3

• Using ziprasidone in cancer patients is particularly hazardous, as nausea, vomiting, and diarrhea from chemotherapy cause electrolyte losses that amplify QT prolongation risk. 2