title: Low safety index of domperidone: mechanism for increased odds ratio for sudden cardiac death.
abstract: OBJECTIVE
  Domperidone is a dopamine antagonist with anti-nausea and anti-emetic activity. There have been several reports of sudden cardiac death (SCD) associated with the compound. Recently it was estimated to increase SCD nearly fourfold. I therefore tested domperidone for liability of cardiac repolarization disturbances (triangulation, reverse use dependence, instability and dispersion or TRIaD) and induction of arrhythmias.
  
  
  RESULTS
  In Langendorff perfused rabbit hearts, domperidone significantly prolonged the action potential duration starting at 30 nM. It induced proarrhythmic TRIaD from 100 nM on. Since therapeutic free drug concentrations extend to 19 nM, the safety ratio for domperidone equals 100/19 = 5.25, i.e., far below the minimum safety ratio of 30. Hence, widespread use of domperidone cannot be without danger; especially since it is frequently used as an over the counter medication.
  
  
  CONCLUSIONS
  In light of these new preclinical and of recent clinical warnings, domperidone should best be restricted to patients in whom its benefit is proven to justify the risks. Availability without prescription and advertising as an 'innocent' relief is incorrect and unsafe, and needs to be reconsidered.
authors: Dept. of Pharmacology, K.U.Leuven, Leuven, Belgium. Luc.Hondeghem@ScreenQT.com
authors: Luc M
authors: LM
authors: Hondeghem
mesh_terms: D000200:Action Potentials; D000818:Animals; D016757:Death, Sudden, Cardiac / Q000209:etiology*; D004294:Domperidone / Q000009:adverse effects* / Q000627:therapeutic use; D018492:Dopamine Antagonists / Q000009:adverse effects* / Q000627:therapeutic use; D006329:Heart Conduction System / Q000187:drug effects*; D066298:In Vitro Techniques; D016017:Odds Ratio; D011817:Rabbits; D016171:Torsades de Pointes / Q000139:chemically induced; D014693:Ventricular Fibrillation / Q000139:chemically induced
chemical_list: D018492:Dopamine Antagonists; D004294:Domperidone