title: 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 0.1-1000 μmol/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 1 μmol/l to assess drug-induced prolongation of monophasic action potential duration measured at 90% repolarization (MAPD(90)). 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 IC(50) for galantamine on HERG current was 760.2 μmol/l. Moreover, galantamine 10 μmol/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 250 ms, galantamine 1 μmol/l prolonged MAPD(90) by respectively 5.1 ± 1.6 ms, 9.4 ± 1.9 ms and 12.1 ± 2.1 ms. 3) Galantamine 3 mg/kgi.p. caused a maximal 11.9 ± 2.7 ms 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.
authors.affiliation: Faculté de Pharmacie, Université Laval, Pavillon Ferdinand-Vandry, 1050 Avenue de la médecine, Québec QC, Canada G1V 0A6. patrick.vigneault@criucpq.ulaval.ca
authors.forename: Patrick
authors.initials: P
authors.lastname: Vigneault
authors.forename: Sarah
authors.initials: S
authors.lastname: Bourgault
authors.forename: Nisrin
authors.initials: N
authors.lastname: Kaddar
authors.forename: Bertrand
authors.initials: B
authors.lastname: Caillier
authors.forename: Sylvie
authors.initials: S
authors.lastname: Pilote
authors.forename: Dany
authors.initials: D
authors.lastname: Patoine
authors.forename: Chantale
authors.initials: C
authors.lastname: Simard
authors.forename: Benoit
authors.initials: B
authors.lastname: Drolet
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors*; D005702:Galantamine / Q000008:administration & dosage / Q000633:toxicity*; D006168:Guinea Pigs; D020128:Inhibitory Concentration 50; D007274:Injections, Intraperitoneal; D051657:KCNQ1 Potassium Channel / Q000037:antagonists & inhibitors; D008133:Long QT Syndrome / Q000139:chemically induced*; D008297:Male; D018408:Patch-Clamp Techniques; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors
chemical_list: D002800:Cholinesterase Inhibitors; D051638:Ether-A-Go-Go Potassium Channels; D051657:KCNQ1 Potassium Channel; D024642:Potassium Channels, Voltage-Gated; D005702:Galantamine