title: Risperidone prolongs cardiac repolarization by blocking the rapid component of the delayed rectifier potassium current.
abstract: Cases of QT prolongation and sudden death have been reported with risperidone, a neuroleptic agent increasingly prescribed worldwide. Although hypokalemia was present in some of these events, we hypothesized that risperidone may have unsuspected electrophysiologic effects predisposing patients to proarrhythmia. In six isolated guinea pig hearts, risperidone elicited prolongation of cardiac repolarization: action potential duration increased from a baseline value of 128 ms +/- 5 to 147 ms +/- 5 (15%) with risperidone 1 microM during pacing at 250-ms cycle length, whereas the increase was only 10%, from 101 ms +/- 2 to 111 ms +/- 4, with pacing at a cycle length of 150 ms. In human ether-a-go-go (HERG)-transfected Chinese hamster ovary cells (n = 16), risperidone caused concentration-dependent block of the rapid component (I(Kr)) of the delayed rectifier potassium current with an IC(50) for tail block of 261 nM. Risperidone did not block I(Ks). Risperidone exerts cardiac electrophysiologic effects similar to those of Class III antiarrhythmic drugs. These effects are observed at clinically relevant concentrations. Because risperidone is metabolized primarily by CYP2D6, these actions likely enhance risk for risperidone-related QT prolongation and proarrhythmia in specific patient subsets (e.g., poor metabolizers and those taking interacting drugs).
authors.affiliation: Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee, U.S.A.
authors.forename: Benoit
authors.initials: B
authors.lastname: Drolet
authors.forename: Tao
authors.initials: T
authors.lastname: Yang
authors.forename: Pascal
authors.initials: P
authors.lastname: Daleau
authors.forename: Dan M
authors.initials: DM
authors.lastname: Roden
authors.forename: Jacques
authors.initials: J
authors.lastname: Turgeon
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D016466:CHO Cells; D027682:Cation Transport Proteins; D006224:Cricetinae; D051668:Delayed Rectifier Potassium Channels; D051638:Ether-A-Go-Go Potassium Channels; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated; D018967:Risperidone / Q000494:pharmacology*; D013045:Species Specificity
chemical_list: D014150:Antipsychotic Agents; D027682:Cation Transport Proteins; D051668:Delayed Rectifier Potassium Channels; D051638:Ether-A-Go-Go Potassium Channels; C092509:KCNH6 protein, human; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D018967:Risperidone