Forensic Toxicological Implication of an Autopsy Case of Mixed Drug Overdose Involving Clomipramine, Chlorpromazine and Flunitrazepam
A case of fatal poisoning involving clomipramine, chlorpromazine and flunitrazepam is presented. Quantitative toxicological analysis showed that the concentrations of clomipramine, chlorpromazine and 7-aminoflunitrazepam (a metabolite of flunitrazepam) in the femoral blood were 3.24 μg/ml, 0.36Ķg/ml and 0.61 μg/ml, respectively, and large amounts of drugs were also detected from the stomach contents. We concluded that the cause of death was due to the combined use of clomipramine, chlorpromazine and flunitrazepam.
Hiroshi Kinoshita 1; Minori Nishiguchi 1; Shogo Kasuda 1; Motonori Takahashi 1; Harumi Ouchi 1; Takako Minami 1; Kiyoshi Matsui 1; Takehiko Yamamura 1; Hiroyuki Motomura 2; Nao Ohtsu 1; Shie Yoshida 1; Nobuyuki Adachi 1; Takehiko Ohta 1; Motoo Komeda 1; Kiyoshi Ameno 3; Shigeru Hishida 1
Department of Legal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 66 -8501, Japan
1; Forensic Science Laboratory, Hyogo Prefectural Police Headquarters, 4-1, Shimoyamate -dori 5-chome, Chuo-ku, Kobe, 650-8510, Japan
2; Department of Forensic Medicine, Faculty of Medicine, Kagawa University, 1750-1 Miki, Kagawa, 761-0793, Japan
Vyšlo v časopise:
Soud Lék., 53, 2008, No. 3, p. 28-30
Autoři uvádějí případ smrtelné otravy clomipraminem, chlorpromazinem a flunitrazepamem. Ve femorální krvi byla kvantitativní toxikologickou analýzou stanovena koncentrace chlomipraminu 3,24 μg/ml, chlorpromazinu 0,36 μg/ml a 7–aminoflunitrazepamu (metabolitu flunitrazepamu) 0,61 μg/ml a velké množství léků bylo také zjištěno v žaludečním obsahu. Uzavřeli jsme, že příčinou smrti bylo kombinované požití clomipraminu, chlorpromazinu a flunitrazepamu.
Accidental and suicidal poisoning
cases due to multiple psychiatric drug ingestion are large problems
in the fields of psychiatric drug treatments and forensic toxicology.
Clomipramine is a chlorinated analogue of imipramine, and its
therapeutic and toxic effects are similar to those of the imipramine
[2,10]. Chlorpromazine, a phenothiazine derivative, is widely
used in the treatment of psychotic disorders . Flunitrazepam, an
analogue of nitrazepam, is used as a hypnotic agent. Here we report
a case of death involved the combined toxicity of clomipramine,
chlorpromazine and flunitrazepam.
A 22-year-old woman (height
165 cm, weight 40 kg) with a history of eating disorders, was
found dead in her house. She had been prescribed antidepressants.
A number of empty packets of prescribed drugs were found near
the corpse. The postmortem interval was approximately 2 days. Autopsy
findings indicated no evidence of external injury. The lungs were
severely congested, and pleural effusions were observed. The stomach
contained 350 ml of a green-brownish fluid. Drug screening
testing using a TriageTM
(Biosite Diagnostic Inc, San Diego, USA) panel was positive for
benzodiazepines and tricyclic antidepressants. Postmortem samples
including heart blood, femoral blood, left and right pleural
effusion, stomach contents and urine were collected for toxicological
examination and kept at -40 °C until analysis.
Toxicological analysis was
performed using a high performance liquid chromatography drug
analysis system (Class-VP system, Shimadzu, Kyoto, Japan) . The
system operation was in accordance with the manufacturer’s
specifications. Quantitation of ethanol was performed using
a head-space gas-chromatography.
Toxicological analysis identified
clomipramine, chlorpromazine and 7-aminoflunitrazepam, a metabolite
of flunitrazepam, but no ethanol was detected in the blood. Table 1
shows the quantitation of clomipramine, chlorpromazine, flunitrazepam
and its metabolite, 7-aminoflunitrazepam, in the victim’s blood,
pleural effusion and stomach contents, and also summarizes their
fatal and therapeutic levels [2, 5, 14, 16]. Although
7-aminoflunitrazepam was identified, no flunitrazepam was detected in
the blood or pleural effusion. This observation may be due to
postmortem bioconversion of flunitrazepam to 7-aminoflunitrazepam
, and, therefore, 7-aminoflunitrazepam is an important marker of
flunitrazepam usage .
The victim’s femoral blood
concentrations of clomipramine, chrolpromazine and
7-aminoflunitrazepam were 3.24, 0.36, and 0.61 μg/ml
respectively. These clomipramine and flunitrazepam concentrations
exceed fatal levels [2, 5], while the chrolpromazine is within
therapeutic levels . As shown in Table 1, the concentrations of
clomipramine and chlorpromazine in heart blood and pleural effusion
were about 1.3 and over 2 fold higher than in the femoral blood,
while 7-aminoflunitrazepam concentrations in the same were about 3
fold higher than in the femoral blood. These variations are due to
postmortem redistribution of each drug from lung or liver [7, 9, 11]
and postmortem diffusion of each drug from the stomach , because
a more than 650-fold higher concentration of clomipramine and
chlorpromazine was detected in the stomach contents than in the
femoral vein, due to large amounts of those drugs being left in the
stomach. It was possibly due to the cholinergic effects of
clomipramine on stomach emptying and peristalsis [6, 10].
In this case, it was apparent
that the victim died during the absorption phase following oral
ingestion, based on the detection of the quite high concentrations
and large amounts of drugs in the stomach. In the absorption phase,
drug concentration in the portal vein is the highest among various
site of blood, and the concentration in the hepatic vein remains
relatively high, even though the drug is metabolized in the liver as
the first pass metabolism . These concentration gradients may be
one possible reason why drug concentrations in heart blood are higher
than in femoral blood.
We have also estimated the
victim’s total amounts of ingestion of clomipramine, chlorpromazine
and flunitrazepam, using forensic toxicokinetic factors. Estimation
of the antemortem blood concentration of flunitrazepam was 0.67
calculating from 7-aminoflunitrazepam data in the femoral blood. The
calculated amounts of clomipramine, chlorpromazine and flunitrazepam,
using values of the distribution volume (Vd) for clomipramine (17
L/kg), chlorpromazine (10-35 L/kg) and flunitrazepam (3.4-5.5 L/kg)
[1–3], the victim’s body weight and femoral blood levels, were
approximately 2176 mg, 144–504 mg and 91–147 mg,
respectively. The total ingested dose of each drug is the sum of the
above value and the dose left in the stomach. We therefore estimated
that she had ingested at least 2910 mg of clomipramine, 278 mg
of chlorpromazine and 170 mg of flunitrazepam.
From the autopsy findings and the
results of the toxicological examination, we concluded that death was
mainly due to the combined toxicity of clomipramine with
flunitrazepam, while chlorpromazine may also have partially
contributed. The present case indicates that we should pay more
attention to the toxicity of combinations of multiple psychotropic
drugs. We also have to consider the postmortem diffusion or
redistribution of drugs for the evaluation of postmortem data.
correspondence concerning this paper should be addressed to:
of Legal Medicine, Hyogo College of Medicine,
Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan
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