Nefazodone poisoning: toxicokinetics and toxicodynamics using continuous data collection.
Nefazodone overdose has been reported infrequently. The commonest effects reported are drowsiness, nausea, dizziness, and vomiting, less commonly hypotension and bradycardia. We report a case of single-agent nefazodone poisoning. Serial drug concentrations were taken for quantification of parent drug and metabolites. Clinical findings were documented every 1 to 2 hours. We modeled both the toxicokinetics of nefazodone and correlated this with clinical effects and electrocardiograph (ECG) abnormalities. A 16-year-old female took 2.4 g of nefazodone. She had significant drowsiness in the first 6 hours, associated with hypotension (systolic BP < 90 mmHg; lowest BP 70/30 mmHg) for 18 hours, and mild bradycardia (slowest rate of 56 bpm). She had a prolonged QT/QTc which normalized over 24 hours. She was given charcoal and intravenous fluids and was observed carefully, recovering with no problems. The terminal elimination half-life for nefazodone was 8.3 hours, and its metabolite hydroxy(OH)-nefazodone was 14.6 hours. BP-time curves demonstrated an 18-hour period of hypotension. There was a significant correlation between systolic BPand OH-nefazodone (R2 = 0.602). HR remained between 56 and 66 bpm for 30 hours despite hypotension. QT was significantly correlated with nefazodone (R2 = 0.911) and OH-nefazodone (R2 = 0.797), but no significant relationship between QTc and drug concentrations. The case demonstrates that nefazodone may potentially cause cardiac toxicity, which appears to be concentration-dependent. Although QT was concentration-dependent, this would need confirmation with other cases. Bradycardia, hypotension, and drowsiness are the most significant effects and are maximal in the first 12 hours when parent and metabolite concentrations are high.
University of Newcastle, Newcastle, Australia. gsbite@bigpond.com
Geoffrey K
GK
Isbister
L Peter
LP
Hackett
D000293:Adolescent; D018687:Antidepressive Agents, Second-Generation / Q000493:pharmacokinetics* / Q000506:poisoning*; D000931:Antidotes / Q000627:therapeutic use; D001711:Biotransformation; D001794:Blood Pressure / Q000187:drug effects; D002606:Charcoal / Q000627:therapeutic use; D003866:Depressive Disorder / Q000188:drug therapy / Q000523:psychology; D062787:Drug Overdose; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D005440:Fluid Therapy; D006207:Half-Life; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced / Q000503:physiopathology; D010879:Piperazines; D014230:Triazoles / Q000493:pharmacokinetics* / Q000506:poisoning*
D018687:Antidepressive Agents, Second-Generation; D000931:Antidotes; D010879:Piperazines; D014230:Triazoles; D002606:Charcoal; C051752:nefazodone