Galantamine (Reminyl®) delays cardiac ventricular repolarization and prolongs the QT interval by blocking the HERG current

Abstract

Galantamine is a reversible inhibitor of acetylcholinesterase and an allosteric-potentiating ligand of the nicotinic acetylcholine receptors. It is used for treating mild-to-moderate Alzheimer's disease. Interestingly, QT interval prolongation on the electrocardiogram (ECG), malignant ventricular arrhythmias and syncope have been reported with galantamine. Our objective was to evaluate the effects of galantamine on cardiac ventricular repolarization. Three sets of experiments were undertaken: 1) Whole cell patch-clamp experiments: HERG- or KCNQ1+KCNE1-transfected cells were exposed to galantamine 0.1–1000μmol/l (n=25 cells, total) to assess drug effect on HERG and KCNQ1+KCNE1 currents. 2) Langendorff perfusion experiments: Isolated hearts from male Hartley guinea pigs (n=9) were exposed to galantamine 1μmol/l to assess drug-induced prolongation of monophasic action potential duration measured at 90% repolarization (MAPD90). 3) Cardiac telemetry experiments: Guinea pigs (n=7) implanted with wireless transmitters were injected a single intraperitoneal (i.p.) dose of galantamine 3mg/kg and 24h ECG recordings were made. 1) The estimated IC50 for galantamine on HERG current was 760.2μmol/l. Moreover, galantamine 10μmol/l had a small inhibiting effect on KCNQ1+KCNE1 current (12.17±2.19% inhibition, n=10 cells). 2) While pacing at cycle lengths of 150, 200 or 250ms, galantamine 1μmol/l prolonged MAPD90 by respectively 5.1±1.6ms, 9.4±1.9ms and 12.1±2.1ms. 3) Galantamine 3mg/kgi.p. caused a maximal 11.9±2.7ms prolongation of the corrected QT (QTc). Galantamine is a weak HERG blocker. This contributes to its mild QT-prolonging effect. Patients could be at risk of cardiac proarrhythmia during drug overdosage or interactions involving cytochrome 2D6 drug-metabolizing enzyme.