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A fatal case due to combined toxicity of psychotropic drugs
Forensic Science International 181 (2008) e7–e8
Contents lists available at ScienceDirect
Forensic Science International journal homepage: www.elsevier.com/locate/forsciint
Letter to the Editor A fatal case due to combined toxicity of psychotropic drugs
A R T I C L E I N F O
Keywords: Fatal poisoning Trazodone Paroxetine Pathophysiology Pharmacokinetics
To the Editor, In the unconscious victim, blood is the best samples for inferring the amount of drugs and poisons. Forensic toxicologists should consider cases of fatal poisonings who survive for a relative long intervals may have lower blood concentrations of drugs and poisons due to metabolism while undergoing intensive medical treatment. Here we report a case of drug overdose who received intensive medical treatment for 1 day. A Japanese female in her twenties (162 cm, 42.5 kg) was found unconscious in her bed. She presented with cardiopulmonary arrest on arrival at the nearest hospital. Cardiopulmonary resuscitation was initially successful, but she died approximately 22 h after admission, without recovering consciousness. The subsequent investigation by the authorities revealed that the deceased had been receiving therapy for depression. A medico-legal autopsy revealed no evidence of external injury, nor findings of natural disease. Both lungs showed severe edema and congestion. Cerebral edema was also observed. There were approximately 350 ml of stomach contents containing granules. Toxicological analysis showed that concentrations of trazodone, paroxetine and 7-aminoflunitrazepam (7-AF), a metabolite of flunitrazepam and an important marker of flunitrazepam intake [1], in the femoral blood were 5.85 mg/ml, 0.30 mg/ml and 0.13 mg/ ml, respectively. The total amounts of trazodone and paroxetine in stomach contents were approximately 65 mg and 35 mg, respectively. Blood concentrations following therapeutic dose of trazodone and paroxetine ingestion range up to 2.3 mg/ml and 0.075 mg/ ml, while fatal levels are those over 9 mg/ml and 0.4 mg/ml, respectively [2–5]. In the present case, the postmortem concentrations of trazodone and paroxetine in the femoral venous blood were at toxic levels, but below the fatal ranges. Blood concentration of 7-AF in this case was about one-third of fatal levels previously reported [6]. Since drug metabolism in a state of shock seems to be slower with a longer elimination half-life [7], forensic estimation of trazodone and paroxetine levels in the blood 0379-0738/$ – see front matter ß 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.forsciint.2008.08.005
of the deceased when she was found unconscious, was quite difficult using pharmacokinetic parameters. As relatively high doses of trazodone and paroxetine remained in her stomach, the victim was still in the drug absorption phase at the time of cardiac arrest. Taking these factors into consideration, blood concentrations of the drugs at the time of hospital admission may have been higher than those of the postmortem samples. Moreover, as the trazodone is metabolized by cytochrome P450 2D6 (CYP2D6) [5], which is strongly inhibited by paroxetine [4], estimation of antemortem blood concentration is difficult to determine. From the autopsy findings, the results of the toxicological examination and evaluation of the drug concentrations in the blood and stomach contents, we concluded that the cause of death was due to the central nervous system depression by the combined effects of trazodone, paroxetine and flunitrazepam. The present case indicates that we should pay close attention to the time course of drug metabolism and its pharmacokinetics under unusual pathophysiological conditions such as a state of shock and hypothermia. References [1] O.H. Drummer, M.L. Syrjanen, S.M. Cordner, Deaths involving the benzodiazepine flunitrazepam, Am. J. Forensic Med. Pathol. 14 (1993) 238–243. [2] Paroxetine, A.C. Moffat, M.D. Osselton, B. Widdop (Eds.), Clarke’s Analysis of Drugs and Poisons, 3rd ed., The Pharmaceutical Press, London, 2004, pp. 1398–1399. [3] Trazodone, A.C. Moffat, M.D. Osselton, B. Widdop (Eds.), Clarke’s Analysis of Drugs and Poisons, 3rd ed., The Pharmaceutical Press, London, 2004, pp. 1658–1659. [4] K.E. Goeringer, L. Raymon, G.D. Christian, B.K. Logan, Postmortem forensic toxicology of selective serotonin reuptake inhibitors: a review of pharmacology and report of 168 cases, J. Forensic Sci. 45 (2000) 633–648. [5] K.E. Goeringer, L. Raymon, B.K. Logan, Postmortem forensic toxicology of trazodone, J. Forensic Sci. 45 (2000) 850–856. [6] U. Balmaceda-Harmelink, H. Andresen, M. Tsokos, Suicidal monointoxication with flunitrazepam. Further comment on coloration phenomena of the upper gastrointestinal tract, Arch. Kriminol. 214 (2004) 93–98. [7] O.H. Drummer, M. Odell, The Forensic Pharmacology of Drugs of Abuse, Arnold, London, 2001.
Hiroshi Kinoshita* Minori Nishiguchi Department of Legal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan Shogo Kasuda Department of Legal Medicine, Nara Medical University, 840 Shijocho, Kashihara, Nara 634-8521, Japan Motonori Takahashi Harumi Ouchi Takako Minami Kiyoshi Matsui Nao Ohtsu
e8
Letter to the Editor / Forensic Science International 181 (2008) e7–e8
Shie Yoshida Nobuyuki Adachi Department of Legal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan Kiyoshi Ameno Department of Forensic Medicine, Faculty of Medicine, Kagawa University, 1750-1 Miki, Kagawa 761-0793, Japan
Shigeru Hishida Department of Legal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan *Corresponding author. Tel.: +81 798 45 6578; fax: +81 798 49 3279 E-mail address: [email protected] (H. Kinoshita) 26 June 2008 Available online 24 September 2008
Contents lists available at ScienceDirect
Forensic Science International journal homepage: www.elsevier.com/locate/forsciint
Letter to the Editor A fatal case due to combined toxicity of psychotropic drugs
A R T I C L E I N F O
Keywords: Fatal poisoning Trazodone Paroxetine Pathophysiology Pharmacokinetics
To the Editor, In the unconscious victim, blood is the best samples for inferring the amount of drugs and poisons. Forensic toxicologists should consider cases of fatal poisonings who survive for a relative long intervals may have lower blood concentrations of drugs and poisons due to metabolism while undergoing intensive medical treatment. Here we report a case of drug overdose who received intensive medical treatment for 1 day. A Japanese female in her twenties (162 cm, 42.5 kg) was found unconscious in her bed. She presented with cardiopulmonary arrest on arrival at the nearest hospital. Cardiopulmonary resuscitation was initially successful, but she died approximately 22 h after admission, without recovering consciousness. The subsequent investigation by the authorities revealed that the deceased had been receiving therapy for depression. A medico-legal autopsy revealed no evidence of external injury, nor findings of natural disease. Both lungs showed severe edema and congestion. Cerebral edema was also observed. There were approximately 350 ml of stomach contents containing granules. Toxicological analysis showed that concentrations of trazodone, paroxetine and 7-aminoflunitrazepam (7-AF), a metabolite of flunitrazepam and an important marker of flunitrazepam intake [1], in the femoral blood were 5.85 mg/ml, 0.30 mg/ml and 0.13 mg/ ml, respectively. The total amounts of trazodone and paroxetine in stomach contents were approximately 65 mg and 35 mg, respectively. Blood concentrations following therapeutic dose of trazodone and paroxetine ingestion range up to 2.3 mg/ml and 0.075 mg/ ml, while fatal levels are those over 9 mg/ml and 0.4 mg/ml, respectively [2–5]. In the present case, the postmortem concentrations of trazodone and paroxetine in the femoral venous blood were at toxic levels, but below the fatal ranges. Blood concentration of 7-AF in this case was about one-third of fatal levels previously reported [6]. Since drug metabolism in a state of shock seems to be slower with a longer elimination half-life [7], forensic estimation of trazodone and paroxetine levels in the blood 0379-0738/$ – see front matter ß 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.forsciint.2008.08.005
of the deceased when she was found unconscious, was quite difficult using pharmacokinetic parameters. As relatively high doses of trazodone and paroxetine remained in her stomach, the victim was still in the drug absorption phase at the time of cardiac arrest. Taking these factors into consideration, blood concentrations of the drugs at the time of hospital admission may have been higher than those of the postmortem samples. Moreover, as the trazodone is metabolized by cytochrome P450 2D6 (CYP2D6) [5], which is strongly inhibited by paroxetine [4], estimation of antemortem blood concentration is difficult to determine. From the autopsy findings, the results of the toxicological examination and evaluation of the drug concentrations in the blood and stomach contents, we concluded that the cause of death was due to the central nervous system depression by the combined effects of trazodone, paroxetine and flunitrazepam. The present case indicates that we should pay close attention to the time course of drug metabolism and its pharmacokinetics under unusual pathophysiological conditions such as a state of shock and hypothermia. References [1] O.H. Drummer, M.L. Syrjanen, S.M. Cordner, Deaths involving the benzodiazepine flunitrazepam, Am. J. Forensic Med. Pathol. 14 (1993) 238–243. [2] Paroxetine, A.C. Moffat, M.D. Osselton, B. Widdop (Eds.), Clarke’s Analysis of Drugs and Poisons, 3rd ed., The Pharmaceutical Press, London, 2004, pp. 1398–1399. [3] Trazodone, A.C. Moffat, M.D. Osselton, B. Widdop (Eds.), Clarke’s Analysis of Drugs and Poisons, 3rd ed., The Pharmaceutical Press, London, 2004, pp. 1658–1659. [4] K.E. Goeringer, L. Raymon, G.D. Christian, B.K. Logan, Postmortem forensic toxicology of selective serotonin reuptake inhibitors: a review of pharmacology and report of 168 cases, J. Forensic Sci. 45 (2000) 633–648. [5] K.E. Goeringer, L. Raymon, B.K. Logan, Postmortem forensic toxicology of trazodone, J. Forensic Sci. 45 (2000) 850–856. [6] U. Balmaceda-Harmelink, H. Andresen, M. Tsokos, Suicidal monointoxication with flunitrazepam. Further comment on coloration phenomena of the upper gastrointestinal tract, Arch. Kriminol. 214 (2004) 93–98. [7] O.H. Drummer, M. Odell, The Forensic Pharmacology of Drugs of Abuse, Arnold, London, 2001.
Hiroshi Kinoshita* Minori Nishiguchi Department of Legal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan Shogo Kasuda Department of Legal Medicine, Nara Medical University, 840 Shijocho, Kashihara, Nara 634-8521, Japan Motonori Takahashi Harumi Ouchi Takako Minami Kiyoshi Matsui Nao Ohtsu
e8
Letter to the Editor / Forensic Science International 181 (2008) e7–e8
Shie Yoshida Nobuyuki Adachi Department of Legal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan Kiyoshi Ameno Department of Forensic Medicine, Faculty of Medicine, Kagawa University, 1750-1 Miki, Kagawa 761-0793, Japan
Shigeru Hishida Department of Legal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan *Corresponding author. Tel.: +81 798 45 6578; fax: +81 798 49 3279 E-mail address: [email protected] (H. Kinoshita) 26 June 2008 Available online 24 September 2008