Suicidal overdose with relapsing clomipramine concentrations due to a large gastric pharmacobezoar.

The paper presents a case of fatal intoxication after massive sustained-release clomipramine overdosage with prolonged toxicity related to a large gastric pharmacobezoar. 42-year-old female was admitted to the toxicology unit 14 h after drugs ingestion. At admission patient was deeply unconscious, required controlled mechanical ventilation. Serum total level of TCAs was 1955 ng/mL. Gastric lavage revealed no pills. Within the next 12h the patient's clinical condition improved. TCAs level decreased to 999 ng/mL. However, after another 10h the clinical condition started deteriorating again and the patient went into a deep coma requiring controlled mechanical ventilation. TCAs level increased to 2011 ng/mL. X-ray and computed tomography revealed large pharmacobezoar consisted from radio-opaque pills. In the 28th h of hospitalization gastrotomy was performed, confirming presence of pharmacobezoar formed from Anafranil SR tablets. After surgery TCAs level was gradually decreasing. However, the patient's condition did not improve, she died 32 h after gastrotomy. Post-mortem analyses revealed drug and its metabolite toxic levels in blood (clomipramine - 1729 ng/mL, norclomipramine - 431 ng/mL) and toxic levels in internal organs: myocardium (clomipramine - 14,420 ng/g, norclomipramine - 35,930 ng/g), vitreous humor (clomipramine - 1000 ng/mL, norclomipramine - 3110 ng/mL). Described case report indicates that sustained release clomipramine tablets may form pharmacobezoar. X-ray and computed tomography examinations should be considered in cases of massive abuse of sustained release clomipramine, particularly if symptoms of intoxication are recurrent or persistent.

Fatal doxepin intoxication--suicide or slow gradual intoxication?

The differentiation of intoxication courses is one of the most difficult challenges for forensic pathologists and toxicologists. The case of a 52-year-old female inpatient of a psychiatric clinic with multiple medications who died from doxepin intoxication is reported. Concentrations of doxepin metabolites and isomers, pharmacokinetic modelling and genotyping of the doxepin-metabolizing cytochrome P450 (CYP) enzymes led to the following conclusion: the lethal doxepin concentration of 2100 ng/mL was more likely to have been reached due to drug interactions and genetic peculiarities leading to a reduction of the metabolic capacity and not by an acute (suicidal) overdose.

[Prolonged toxic coma and anisocoria secondary to doxepin, lorazepam and phenobarbital poisoning--case study]. / Przedluzona spiaczka toksyczna i anizokoria w przebiegu zatrucia doksepina, lorazepamem i fenobarbitalem--opis przypadku.

Doxepin is a tricyclic antidepressant from the group of dibenzoxepines. Apart from the antidepressant effect, it has also the sedative and anxiolytic effect, so it is used in the treatment of anxiety disorder in the course of psychosis, organic diseases and alcoholism. Doxepin increases concentration of norepinephrine and serotonin in the brain by preventing inactivation and blocking their reuptake. In addition, the drug has an antagonistic effect on receptors in CNS (muscarinic M1, histamine H1, alpha-1adrenergic, serotonergic 5-HT2) and also blocks sodium and potassium channels in cardiomyocytes. In this paper we present a case of severe poisoning by various drugs, including doxepin. The dominating symptom was prolonged toxic coma. Slow return of consciousness was observed from the fifth day after intoxication, logical verbal contact with the patient was possible on the seventh day. It seems that this symptom results from the pharmacokinetic properties of doxepin as well as the high drug dose and a synergistic effect of lorazepam and phenobarbital. Transient anisokoria was an unusual symptom that appeared in the course of intoxication. The patient was examined by a neurologist and underwent CT of the head twice - no organic causes were revealed. This phenomenon can be explained by physiological anisokoria, caused by asymmetry in the sympathetic innervation of pupil rectractor muscle, exacerbated by a complete parasympathetic conduction block as a result of anticholinergic action of doxepin. Tricyclic antidepressants are often used by patients for the purpose of suicide. Because of the serious cardiological and neurological symptoms the course of doxepin intoxication may be severe.

[Determination of doxepin in whole blood by SPE-LC-MS/MS].

OBJECTIVE: To develop a method of SPE-LC-MS/MS for the determination of doxepin in whole blood. METHODS: After solid phase extraction, the samples were identified by LC-MS/MS. Positive ion electrospray ionization mode and multiple reaction monitoring (MRM) mode was selected. Amitriptyline was used as internal standard. The m/z of doxepin: 280-->107, 280-->235 and 280-->220. The m/z of amitriptyline: 278-->233. The retaining time of doxepin and amitriptyline were 15.15 and 16.94 min, respectively. RESULTS: The calibration curve was linear among the concentration of doxepin range from 0.005 to 1.00 microg/mL. The linear correlation equation was y = 3.2047x + 0.0339, the correlation coefficient was 0.9996. The detection limit of doxepin was 0.001 microg/mL and average recovery rate was 78.0%-82.9%. The relative standard precision for within-day and between-day were less than 2.55% and 5.90%, respectively. CONCLUSION: The method is effective, simple, reliable and can be used in the determination of doxepin in whole blood.

Determination of doxepin in whole blood by SPE-LC-MS/MS / 法医学杂志

OBJECTIVE@#To develop a method of SPE-LC-MS/MS for the determination of doxepin in whole blood.@*METHODS@#After solid phase extraction, the samples were identified by LC-MS/MS. Positive ion electrospray ionization mode and multiple reaction monitoring (MRM) mode was selected. Amitriptyline was used as internal standard. The m/z of doxepin: 280-->107, 280-->235 and 280-->220. The m/z of amitriptyline: 278-->233. The retaining time of doxepin and amitriptyline were 15.15 and 16.94 min, respectively.@*RESULTS@#The calibration curve was linear among the concentration of doxepin range from 0.005 to 1.00 microg/mL. The linear correlation equation was y = 3.2047x + 0.0339, the correlation coefficient was 0.9996. The detection limit of doxepin was 0.001 microg/mL and average recovery rate was 78.0%-82.9%. The relative standard precision for within-day and between-day were less than 2.55% and 5.90%, respectively.@*CONCLUSION@#The method is effective, simple, reliable and can be used in the determination of doxepin in whole blood.

Doxepin and nordoxepin concentrations in body fluids and tissues in doxepin associated deaths.

Body fluids and tissues in eight doxepin (Dox)-related deaths were investigated in order to prove whether the individual concentration of Dox, the concentration sum of parent drug and its active metabolite N-desmethyldoxepin (NDox) or the concentration ratio Dox/Ndox valuably contribute to making a cause of death determination. Individual case histories were shortly described. Dox and NDox concentrations were determined by LC-MS/MS. Dox concentration measured from two cases was well within a concentration range considered therapeutic, whereas subtherapeutic dosing may have occurred in another two cases. There were two cases of fatal Dox ingestion, as well as a case of high dosage and advanced putrefaction, respectively. The liver concentration sum may be more useful if a fatal ingestion cannot be clearly separated from a person's medication usage. High concentrations could be observed in lung tissue, and combined concentrations of Dox and NDox may also be helpful in making a cause of death determination. There was a trend to a higher concentration sum in the brain with increasing combined levels in blood. Overall, the sum of the absolute figures allows a more accurate interpretation in Dox-related deaths as compared to the molar concentration ratio which may be helpful in acute ingestion. Determination of the N-desmethyl metabolite along with its parent is recommended and analysis should include more than a single specimen.

Alleged breaches of "standards of medical care" in a patient overdose death possibly related to chronic opioid analgesic therapy, application of the controlled substances model guidelines: case report.

OBJECTIVES: The objectives of this medicolegal case report are the following: 1) to present details of a chronic pain patient (CPP) who was placed on chronic opioid analgesic therapy (COAT), and subsequently overdosed on multiple drugs, some of which were not prescribed by his COAT physician; 2) to present both the plaintiff's and defendant's (the COAT prescriber) expert witnesses' opinions as to the allegation that COAT prescribing was the cause of death; and 3) based on these opinions, to develop some recommendations on how pain physicians can utilize the use of Controlled Substances Model Guidelines in order to protect the patient and themselves from such an occurrence. METHODS: This is a case report of a CPP treated by a pain physician. RESULTS: Differences between the plaintiff's and defendant's expert's opinions are explained utilizing the Controlled Substances Model Guidelines. CONCLUSIONS: Some CPPs may withhold information critical to their COAT treatment. Application of the Controlled Substances Model Guidelines and the newer Federation of State Medical Boards' policy on opioid prescribing can be helpful in improving patient care and may be helpful in protecting the physician medicolegally.

A fatal doxepin poisoning associated with a defective CYP2D6 genotype.

It has been suggested that the polymorphism of the CYP2D6 gene can contribute to occurrence of fatal adverse effects. We therefore investigated postmortem toxicology cases of fatal drug poisonings related to CYP2D6 substrates, with the manner of death denoted as accidental or undetermined. CYP2D6 genotypes were determined in 11 consecutive cases with samples available for DNA analysis. A case of fatal doxepin poisoning with an undetermined manner of death was found to coincide with a completely nonfunctional CYP2D6 genotype (*3/*4), indicating a total absence of CYP2D6 enzyme and suggesting a poor metabolizer phenotype. The doxepin concentration was 2.4 mg/L, the concentration of nordoxepin 2.9 mg/L, and the doxepin/nordoxepin ratio 0.83, the lowest found among the 35 nordoxepin-positive postmortem cases analyzed during the same year. No alcohols or other drugs were detected in the case. The CYP2C19 genotype was determined as that of an extensive metabolizer. The high N-desmethylmetabolite concentration is not consistent with acute intoxication. It is therefore probable that the defective genotype has contributed to the death, possibly involving repeated high dosage of doxepin. Our case strongly emphasizes that a pharmacogenetic analysis in postmortem forensic setting may reveal new insight to the cause or manner of death.

[Intoxication with a tricyclic antidepressant]. / Intoxikation mit einem trizyklischen Antidepressivum.

A 48-year-old woman with a major depression and treatment with doxepin was found comatose in her flat. Her son last saw her 48 h prior to being found. On arrival of the emergency physician, she presented a generalized seizure. The patient underwent endotracheal intubation and mechanical ventilation due to respiratory insufficiency and severe cyanosis. Empty packages of tablets (doxepin ca. 4000 mg and zolpidem 100 mg) were found in the flat. On hospital admission the doxepin blood concentration was 1.2 microg/ml. No life-threatening arrhythmia occurred at any time. On the advice of the poison information center, hemoperfusion was performed for extracorporeal elimination. Within several hours the doxepin blood concentration could be lowered to 0.8 microg/ml and although still above the therapeutic range the patient was extubated. However, the patient developed a generalized seizure which required re-intubation. As a consequence of the high distribution volume and re-distribution phenomena, the doxepin blood concentration had increased again to 1.2 microg/ml. Approximately 72 h later she was extubated again while the doxepin blood concentration was 0.9 microg/ml and 3 days later, the doxepin blood concentration was lowered to 0.3 microg/ml and the patient was transferred to the psychiatric ward the following day. This case report questions the efficacy of hemoperfusion during acute doxepin intoxication in the given constellation of a non-life-threatening arrhythmia.

Is there a role for hemoperfusion/hemodialysis as a treatment option in severe tricyclic antidepressant intoxication?

OBJECTIVE: Suicidal self-poisoning with tricyclic antidepressants like doxepin is a major therapeutic problem in emergency medicine with a high fatality rate. Deaths are mainly caused by cardiotoxicity with arrhythmias, intraventricular conduction disturbances and myocardial depression. For treatment, alkalinization and hypertonic saline are recommended. The role of extracorporeal, treatment procedures is not clear. The possible benefit of hemoperfusion/hemodialysis is discussed in a case report with respect to the published literature. CASE REPORT: After ingestion of an amount of at least 5000 mg doxepin a 37-year-old man with endogenous depression developed cardiac arrest. After preclinical resuscitation with prolonged external cardiac massage, he was admitted to the intensive care unit with persistently severe hypotension and wide QRS complexes (230-260 ms). Despite fluid load, alkalinization, hypertonic saline and high-dose vasoactive substances the patient's condition did not improve. Hemoperfusion over hemoresin combined with hemodialysis led to an impressive clinical improvement with shortening of QRS duration (from 230 to 120 ms) and hemodynamic stabilization. The patient fully recovered without neurologic deficits. CONCLUSION: We report a successful treatment with hemoperfusion over hemoresin and hemodialysis in a patient with life-threatening doxepin poisoning intractable with the generally recommended treatment. In such acute TCA intoxication with severe cardiotoxicity, hemoperfusion/hemodialysis should be considered a potential treatment option, as the "toxicokinetics" of drugs may totally differ from their usual pharmacokinetic behaviour. Experimental and clinical studies are needed to clarify the toxicokinetics of TCA in order to improve the therapeutic approach.

[Toxicologic findings in suicide with doxepin and paroxetine]. / Toxikologische Befunde bei einem Suicid mit Doxepin und Paroxetin.

A young nurse was found dead in her flat. In chemical-toxicological analysis the following femoral blood drug concentrations were determined: paroxetine 0.176 mg/l, doxepine 82.12 mg/l, desmethyldoxepine 0.34 mg/l. Additionally the drug concentrations were determined in various body fluids and organs. The results of the described fatality are discussed. For interpretation of toxicologic results in antidepressant fatalities ratios of parent drug to metabolite and postmortem drug redistribution should be taken into account.

ECG abnormalities in tricyclic antidepressant ingestion.

The tricyclic antidepressant (TCA) agents are recognized for their potentially lethal cardiovascular and neurological effects in poisoned patients. The 12-lead electrocardiogram (ECG) has emerged as a popular bedside tool in the evaluation of TCA toxicity. Although the history and physical examination play a key role in the assessment of the patient with potential TCA poisoning, the presence or absence of features of the TCA toxidrome are not sufficient to detect or exclude toxicity from this class of drugs. A variety of ECG findings occur with TCA toxicity. Aside from the sinus tachycardia due principally to anticholinergic effects, TCA-toxic changes seen on the ECG are attributable primarily to the sodium channel blockade caused by these agents. The majority of patients at significant risk for developing cardiac or neurological toxicity will have a QRS complex greater than 0.10 seconds or a rightward shift of the terminal 40 ms of the frontal plane QRS complex vector. The majority of these patients will also display these changes early in their emergency department stay. However, the appearance of these findings, either alone or in combination, does not mean the patient will develop significant cardiac or neurological toxicity. The ECG can neither unequivocally rule in nor rule out impending toxicity; recognizing these limitations, the emergency physician can use this bedside tool in combination with other clinical data during the assessment of the poisoned patient.

Combined intoxication with a tricyclic antidepressive agent and a neuroleptic.

We report the case of a patient who co-ingested a tricyclic antidepressant (2500 mg of doxepin) and a neuroleptic drug (3500 mg of prothipendyl). Following overdose either agent can affect the central nervous and cardiovascular systems, inducing arrhythmias, conduction disturbances and hypotension. The presented case illustrates that a combined overdose of tricyclic antidepressants and neuroleptics enhances the possible toxic effects of each drug and especially the risk for adverse cardiac events. The clinical features and management of this combined intoxication are discussed. Treatment with sodium bicarbonate readily corrected a potentially life-threatening cardiac arrhythmia and is therefore suggested to be imperative in the treatment of these cases.

Decreased R-R variation: a criterium for overdosage of tricyclic psychotropic drugs.

OBJECTIVE: Since intoxication with tricyclic antidepressants is common, a supplementary screening method for differentiation between therapeutic and supratherapeutic ranges would be a valuable diagnostic tool, particularly in delirious and unconscious patients. SETTING: 108 patients treated with amitriptyline, 8 patients treated with doxepin, 10 patients treated with clozapine, and 72 normal control subjects matched for age and sex were tested for heart rate variability while resting. RESULTS: Considering time and frequency derived measures, which are rather independent of heart rate, the patients showed significantly decreased heart rate variability parameters (p < 0.0001), as compared with the normal subjects. Of the patients presenting delirious symptoms 6 showed coefficients of variation more than 4 standard deviations below the mean control value. CONCLUSIONS: As heart rate variability can be easily calculated, this measurement is suggested as a useful tool to quickly exclude or support the diagnosis of chronic intoxication with tricyclic antidepressants or clozapine.

A report of a suicide involving digoxin and doxepin.

In this report we give details on an overdose fatality involving both digoxin and doxepin. There have been numerous reported fatalities, both accidental and suicidal, involving digoxin and many more reports of fatalities involving doxepin. We believe that this is the first time a fatality from this drug combination has been reported in the literature.