title: Ranolazine-induced severe bladder hypotonia.
abstract: OBJECTIVE
  To describe a case of acute urinary retention due to bladder hypotonia during ranolazine treatment.
  
  
  METHODS
  An 81-year-old male with multiple cardiovascular diseases was hospitalized for worsening angina and heart failure symptoms. Ranolazine 375 mg twice daily was started, in addition to ongoing therapy (clopidogrel 75 mg once daily, diltiazem 60 mg 3 times daily, isosorbide mononitrate 40 mg 3 times daily, carvedilol 6.25 mg twice daily, rosuvastatin 20 mg once daily, enoxaparin 5000 IU once daily, pentoxifylline 600 mg twice daily, pantoprazole 40 mg twice daily, enalapril 20 mg twice daily, furosemide 150 mg once daily, and spironolactone 37 mg once daily). Two months later, the ranolazine dose was increased to 500 mg twice daily; shortly thereafter, acute urinary retention occurred and persisted despite institution of α-lytic (alfuzosin) and antiandrogenic (dutasteride) therapy. A urodynamic study revealed that urinary retention was caused by severe hypocontractility of the detrusor muscle. Ranolazine was withdrawn and, within 2 days, the patient recovered his ability to void spontaneously; a second urodynamic study confirmed that detrusor contractility was substantially improved. Drug rechallenge was not performed due to the patient's clinical condition. Nevertheless, a phenotyping test to assess the activity of the cytochrome isoenzymes CYP3A4 and CYP2D6 (responsible for ranolazine metabolism) was performed, with dextromethorphan used as the probe drug. The urinary metabolic ratios indicated relatively low activity for CYP3A4 and intermediate activity for CYP2D6.
  
  
  CONCLUSIONS
  The causal role of ranolazine in our case of bladder hypotonia is probable according to the Naranjo criteria. The mechanism of bladder dysfunction is tentatively ascribed to blockage of late sodium current in smooth muscle cells. Although drug plasma concentrations were not measured, they were probably elevated, since the metabolic activity of CYP3A4 was at the lower end of the reference range. Enzyme inhibition produced by diltiazem may have contributed to decreasing CYP3A4 activity.
  
  
  CONCLUSIONS
  Acute urinary retention in elderly men taking ranolazine may be due to drug-induced bladder hypotonia.
authors: Cardiology Clinic, Department of Cardiac, Thoracic and Vascular Sciences, University of Padova, Padova,  Italy.
authors: Marco
authors: M
authors: Panfili
authors: Massimo
authors: M
authors: Iafrate
authors: Filippo
authors: F
authors: Marzot
authors: Silvia
authors: S
authors: Secco
authors: Giovanni
authors: G
authors: De Rosa
authors: Francesca
authors: F
authors: Groppa
authors: Roberto
authors: R
authors: Padrini
mesh_terms: D000083:Acetanilides / Q000008:administration & dosage / Q000009:adverse effects*; D000369:Aged, 80 and over; D000787:Angina Pectoris / Q000188:drug therapy; D019389:Cytochrome P-450 CYP2D6 / Q000652:urine; D051544:Cytochrome P-450 CYP3A / Q000652:urine; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D006333:Heart Failure / Q000188:drug therapy; D006801:Humans; D008297:Male; D009123:Muscle Hypotonia / Q000139:chemically induced* / Q000652:urine; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects*; D000069458:Ranolazine; D001745:Urinary Bladder Diseases / Q000139:chemically induced* / Q000652:urine; D016055:Urinary Retention / Q000139:chemically induced* / Q000652:urine
chemical_list: D000083:Acetanilides; D004791:Enzyme Inhibitors; D010879:Piperazines; D000069458:Ranolazine; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human