dothiepin-hydrochloride and Drug-Overdose

We present the case report of a 57-year-old woman with severe monointoxication with dosulepine (Prothiaden) who developed a Brugada-like electrocardiographic pattern. In tricyclic antidepressants (TCAs) poisoning the Brugada-like pattern on electrocardiogram is a characteristic albeit rare manifestation of the frequently occurring conduction abnormalities in the myocardium and its recognition is imperative as it is associated with a higher degree of morbidity and mortality. An overview of the literature is given and recommendations concerning treatment of TCA-induced arrhythmias are provided. After successful treatment, the electrocardiogram in the patient normalized. However, 4 days after intoxication, the ajmaline test was positive (pharmacological induction of a type I Brugada-like pattern), but a subsequent one, repeated after 11 days, was reportedly normal, probably because of the slow clearance of dosulepine. This raises questions about the specificity of ajmaline testing for Brugada syndrome in patients taking dosulepine and perhaps other TCAs and neuroleptic agents.

Topics: Antidepressive Agents, Tricyclic; Brugada Syndrome; Charcoal; Dothiepin; Drug Overdose; Electrocardiography; Female; Humans; Middle Aged; Secologanin Tryptamine Alkaloids; Sedentary Behavior; Vasodilator Agents

To assess interobserver agreement when experienced clinicians measure QRS-interval duration in tricyclic antidepressant (TCA) overdose.. We studied the admission ECGs of 231 patients with ICA poisoning. Three of the authors, with experience in the management of TCA poisoning, independently measured QRS intervals manually. Each rater was blinded to patient outcome and the measurements made by the other raters. Our main outcome measure was agreement among raters, particularly as it applies to clinically used QRS cutoff points for the determination of treatment and disposition.. Agreement on the measurement of QRS intervals was good (intraclass correlation coefficient, 60; 95% confidence interval [CI], 53 to .66) for transformed data and .82 (95% CI, 7B to .85) for raw data. When assigning patients to categories of QRS interval, the raters agreed on 169 of 231 patients (73%) (weighted kappa = 83; P < .0001). However, the raters did not agree unanimously on whether the QRS interval was less than 100 milliseconds or 100 milliseconds or greater in 45 of 231 of patients (19.5%) (kappa = 69; P < .0001).. Reliance on the manually measured QRS interval to determine management in TCA poisoning is not justified because of substantial observer variation in the determination of whether the interval falls below the clinical cutoff point of 100 milliseconds. Agreement is sufficient to make the measurements useful as part of the overall assessment of toxicity.

Topics: Antidepressive Agents, Tricyclic; Dothiepin; Drug Overdose; Electrocardiography; Heart; Humans; Observer Variation

Tricyclic antidepressant (TCA) toxicity results predominantly from myocardial sodium-channel blockade. Subsequent ventricular dysrhythmias, myocardial depression, and hypotension cause cardiovascular collapse. Animal studies have demonstrated the effectiveness of intravenous lipid-emulsion in treating TCA cardiotoxicity.. We report a case of dothiepin (tricyclic antidepressant) overdose causing refractory cardiovascular collapse, which seemed to be successfully reversed with lipid-emulsion therapy (Intralipid(®); Fresenius, Cheshire, UK).. Lipid emulsions are a potentially novel therapy for reversing cardiotoxicity seen in TCA overdose. Research is required into the role of lipid emulsion in the management of poisoning by oral lipophilic agents.

Topics: Adult; Antidepressive Agents, Tricyclic; Dothiepin; Drug Overdose; Electrocardiography; Emulsions; Fat Emulsions, Intravenous; Female; Heart Arrest; Humans; Phospholipids; Soybean Oil

CONTEXT. We report a successful acute reversal of potential life threatening QRS complex widening and prolonged QT interval following dosulepin overdose using intravenous lipid emulsion 20% in an unstable patient. CASE DETAILS. A 36-year-old female following the ingestion of 5.25 g of dosulepin. On submission the QRS complex was 120 ms and the QT interval was 348 ms (BP 129/71 mmHg, HR 113 beats/min). Her level of consciousness deteriorated and the patient had episodes of seizures. The patient received bicarbonate, 200 mmol, and assisted ventilation. Ninety minutes following submission, the QRS complex was 158 ms and the QT interval was 422 ms (BP 118/55 mmHg, HR 91 beats/min), and to treat the intoxication intravenous lipid emulsion 20% was dosed as 1.5 ml/kg (100 ml) in 5 min followed by 400 ml in 20 min. Blood pressure was immediately stabilised and the monitored QRS complex narrowed and QT interval became shorter. DISCUSSION. Cyclic antidepressants affect the cardiac conduction system and the myocardium. The exact mechanism of action from intravenous lipid emulsions may not be determined from the data presented, and the obtained effect does not rule out the supposed effects of alkalinisation and supported ventilation. However, the effects of the treatment of the severe dosulepin intoxication support the theory of intravenous lipid emulsions creating an intravenous lipid sink for drugs with high lipid solubility.

Topics: Adult; Antidepressive Agents, Tricyclic; Dothiepin; Drug Overdose; Electrocardiography; Fat Emulsions, Intravenous; Female; Humans

We report a case that involves the use of intravenous lipid emulsion as an antidote for a drug overdose involving a 20-month-old girl who had ingested a potentially lethal amount of the tricyclic antidepressant (TCA) dothiepin. The patient's condition continued to deteriorate despite implementation of standard pediatric treatment recommendations for TCA toxicity. Administration of intravenous lipid emulsion in addition to standard therapy (including sodium bicarbonate) and direct-current cardioversion for ventricular arrhythmia led to a successful outcome. The case report is followed by a review of the current evidence underlying this novel therapy and the background on its use. TCA toxicity is addressed specifically.

Topics: Antidepressive Agents, Tricyclic; Dothiepin; Drug Overdose; Fat Emulsions, Intravenous; Female; Humans; Infant

This case highlights the importance of considering drug ingestion when the clinical features at presentation are unusual. To our knowledge, this is the first report of atrial flutter secondary to tricyclic antidepressant (TCA) overdose in a child.

Topics: Adenosine; Anti-Arrhythmia Agents; Antidepressive Agents, Tricyclic; Atrial Flutter; Child, Preschool; Dothiepin; Drug Overdose; Electrocardiography; Follow-Up Studies; Heart Rate; Humans; Injections, Intravenous; Male

Tricyclic antidepressants (TCAs) may have dangerous cardiac effects in overdose. ECG is useful as both a screening tool for tricyclic antidepressant exposure and as a prognostic indicator. TCA overdose may produce various ECG changes. We report a case of Dothiepin overdose resulting in Brugada like pattern including RBBB which resolved spontaneously.

Topics: Adult; Alprazolam; Antidepressive Agents, Tricyclic; Brugada Syndrome; Dothiepin; Drug Overdose; Electrocardiography; Female; Gastric Lavage; Humans; Hypnotics and Sedatives; Suicide, Attempted; Treatment Outcome

Polymer shielded liposomes were investigated as detoxifying agents for the weak bases imipramine and dosulepin and the diprotic drug opipramol. In vitro binding measurements in the presence of human serum samples revealed that the liposomes reduced the free drug concentration of the weak bases (corrected for protein binding) by 88-93%. The reduction for opipramol was around 76%. The results demonstrate that polymer shielded liposomes composed of anionic lipids are widely useful for drug overdose treatment. Polyethylene glycol chain lengths of 2000 and 5000 for the polymer coatings were also explored, and chain length showed no evidence of affecting drug uptake by liposomes. Liposomes compete favorably with other binding targets for drugs, and pharmacokinetic considerations suggest that liposomes could reduce toxicity by transporting drugs from fast-equilibrating organs such as the heart to slow-equilibrating organs such as the fat, muscle, and skin.

Topics: Antidepressive Agents, Tricyclic; Antidotes; Dothiepin; Drug Overdose; Humans; Hydrogen-Ion Concentration; Imipramine; Liposomes; Opipramol; Phosphatidylethanolamines; Phosphatidylglycerols; Phospholipids; Polyethylene Glycols; Tissue Distribution

In this article, 2 cases of intentional dothiepin intoxication are presented. Both patients survived after receiving appropriate supportive care. The dothiepin and metabolite levels were measured at different times after ingestion. The initial levels of dothiepin were 1900 microg/L in case 1 and 5500 microg/L in case 2. In case 1, a toxicokinetic model was fitted, suggesting a higher peak level, corresponding with the QRS duration and clinical symptoms. In case 2, a combined dothiepin-ethanol intoxication was seen, complicating the interpretation of clinical parameters, such as the QRS duration. In conclusion, the severity of dothiepin intoxication is poorly predicted by plasma levels alone, as time of ingestion can be critical for interpretation. However, especially in combined intoxications, interpretation of the QRS duration may also fail. Therefore, it is important to evaluate the whole range of clinical parameters, QRS duration, clinical symptoms, dothiepin concentration(s), and other possible intoxications.

Topics: Adult; Antidepressive Agents, Tricyclic; Dothiepin; Drug Overdose; Electrocardiography; Female; Humans

Topics: Antidepressive Agents, Tricyclic; Dothiepin; Drug Overdose; Electrocardiography; Humans; Male; Middle Aged; Myocardial Infarction

Topics: Adult; Antidepressive Agents, Tricyclic; Diagnosis, Differential; Dothiepin; Drug Overdose; Electrocardiography; Humans; Male; Myocardial Infarction; Ventricular Dysfunction

An ingestion of an unknown quantity of Harmomed (dothiepin and diazepam) capsules in a suicide is described. The authors report a new and fast method of analysing and determining the dothiepin concentration in postmortem specimens. Quantitation of dothiepin, and its metabolite desmethyldothiepin was performed by ethyl acetate extraction from alkalinized body fluids before GC-MS analysis. The analyses were performed without any complex sample clean-up steps and with little sample material. Postmortem concentrations of dothiepin, desmethyldothiepin, diazepam and desmethyldiazepam in body fluids are given. The proposed method is a rapid procedure for analysis in cases of deliberate poisoning with the antidepressant drug dothiepin.

Topics: Adult; Anti-Anxiety Agents; Antidepressive Agents, Tricyclic; Autopsy; Body Fluids; Diazepam; Dothiepin; Drug Combinations; Drug Overdose; Fatal Outcome; Gas Chromatography-Mass Spectrometry; Humans; Male; Postmortem Changes; Sensitivity and Specificity; Suicide; Tissue Distribution

A case of dothiepin poisoning complicated by cardiogenic shock is described. Hypotension was resistant to conventional inotropes but responded rapidly to high-dose intravenous glucagon. Glucagon should be considered as a useful therapeutic positive inotrope and a potentially antiarrhythmic agent in severe tricyclic antidepressant overdose.

Topics: Adult; Antidepressive Agents, Tricyclic; Cardiotonic Agents; Dothiepin; Drug Administration Schedule; Drug Overdose; Female; Glucagon; Humans; Injections, Intravenous; Shock, Cardiogenic

We evaluated the homogeneity of drug concentrations in muscle in 14 cadavers, comprising 11 drug overdoses and three cases of chronic therapeutic drug use. Analyses were performed on samples from twelve named muscles and femoral venous blood. Standard analytical techniques and instrumentation were used throughout. There was marked within-case variability in drug concentrations with highest:lowest concentrations ranging up to 21.7. Overall highest concentrations were found in the diaphragm and mean diaphragm:blood ratios ranged from 1.1 (temazepam, two cases) and 1.2/1.3 (paracetamol, six cases) up to 6.5/13.5 (amitriptyline, three cases) and 5.3/21.3 (propoxyphene, four cases). Excluding the diaphragm, mean muscle:blood ratios ranged from 0.4 (prothiaden), 0.5 (temazepam), and 0.7 (paracetamol) up to 3.7 (temazepam), 4.3 (propoxyphene) and 5.7 (amitriptyline). We suggest that muscle is suitable for qualitative analysis but not for quantitative corroboration of a blood sample or as a quantitative alternative to blood.

Topics: Acetaminophen; Adult; Aged; Amitriptyline; Analgesics; Analgesics, Opioid; Anti-Anxiety Agents; Antidepressive Agents, Tricyclic; Cadaver; Central Nervous System Agents; Chromatography, High Pressure Liquid; Diaphragm; Dothiepin; Drug Overdose; Female; Forensic Medicine; Gas Chromatography-Mass Spectrometry; Humans; Male; Middle Aged; Muscle, Skeletal; Suicide; Temazepam; Time Factors; Tissue Distribution; Toxicology

Topics: Antidepressive Agents, Tricyclic; Antidotes; Charcoal; Child, Preschool; Dothiepin; Drug Overdose; Gastric Lavage; Humans; Infant; Poison Control Centers; Sorption Detoxification; United Kingdom

Topics: Adult; Antidepressive Agents, Tricyclic; Anxiety; Confusion; Depressive Disorder; Dothiepin; Drug Overdose; Drug Therapy, Combination; Female; Humans; Mianserin; Mirtazapine

The homogeneity of drug concentrations in skeletal muscle was assessed in eight fatal overdoses. Ten to 30 random samples were taken from leg muscle weighing 1,650 to 7,985 g. For cases involving paracetamol the mean muscle-to-blood ratio ranged from 0.1 to 1.1 (n = 4) for amitriptyline 1.1 to 3.6 (n = 3), and for dothiepin 0.8 to 2.1 (n = 2). The coefficient of variance was large for all drugs, ranging from 10.5 (carbamazepine) to 50 (thioridazine). Skeletal muscle is not homogeneous with respect to drug concentrations in fatal overdose cases. Of 16 instances of drug detection in blood 2 (nortriptyline and promethazine) were not detected in muscle. Muscle-to-blood drug ratios varied significantly among cases, possibly influenced by survival time after drug ingestion. Quantitative interpretations of muscle drug levels present significant difficulties. However, skeletal muscle can be used for qualitative corroboration of blood analyses and is a suitable specimen for drug detection where none other is available.

Topics: Acetaminophen; Central Nervous System Agents; Dibenzocycloheptenes; Dothiepin; Drug Overdose; Gas Chromatography-Mass Spectrometry; Humans; Leg; Muscle, Skeletal; Promethazine; Reproducibility of Results; Temazepam; Tissue Distribution

Topics: Adolescent; Charcoal; Codeine; Dothiepin; Drug Overdose; Humans; Intestinal Obstruction; Jejunal Diseases; Male; Sorption Detoxification; Temazepam

To compare the fatal toxicities of antidepressant drugs in 1987-92.. Retrospective epidemiological review of prescription data of the Department of Health, Scottish Office Home and Health Department, and Welsh Health Common Services Authority (excluding data from most private general practices and most hospitals), and mortality data from the Office of Population Censuses and Surveys and General Register Office in Scotland.. General practice, England, Scotland, and Wales.. Deaths per million prescriptions and deaths per defined daily dose.. 81.6% (1310/1606) of deaths from antidepressant overdose were due to two drugs, amitriptyline and dothiepin. The overall average of deaths per million prescriptions was 30.1. The overall rate for tricyclic drugs was 34.14 (95% confidence interval 32.47 to 38.86; P < 0.001), monoamine oxidase inhibitors 13.48 (6.93 to 22.19; P < 0.001), atypical drugs 6.19 (4.04 to 8.80; P < 0.001), and selective serotonin reuptake inhibitors 2.02 (0.64 to 4.17; P < 0.001). The numbers of deaths per million prescriptions of amoxapine, dothiepin, and amitriptyline were significantly higher than expected, while nine drugs had a significantly lower number of deaths per million prescriptions than expected. Analysis of deaths per defined daily dose showed a similar pattern.. Safety in overdose should be considered in risk-benefit and cost-benefit considerations of antidepressants. A switch in prescribing, from drugs with a high number of deaths per million prescriptions to drugs with a low number, could reduce the numbers of deaths from overdose. Although this form of suicide prevention can be implemented easily and immediately, its introduction needs to be considered against the higher costs of some of the newer drugs.

Topics: Amitriptyline; Antidepressive Agents; Antidepressive Agents, Tricyclic; Dothiepin; Drug Overdose; England; Humans; Monoamine Oxidase Inhibitors; Retrospective Studies; Scotland; Selective Serotonin Reuptake Inhibitors; Wales

Epidemiological studies have implicated dothiepin in a greater number of self-poisoning deaths than would be expected from its use. We have prospectively assessed the clinical toxicity of dothiepin and other tricyclic antidepressants (TCAs) in overdose. We followed-up consecutively admitted patients with TCA poisoning managed by our department between January, 1987, and August, 1992. 75 patients had taken dothiepin, 101 amitriptyline, 83 doxepin, and 61 other TCAs. Death after TCA poisoning is rare nowadays, so we used intermediate outcome measures--general seizures, tachyarrhythmias, sedation, and QRS width on the electrocardiogram. 15 patients had seizures and 7 tachyarrhythmias. When we excluded patients who had taken more than one TCA, general seizures were more likely after dothiepin than after other TCAs (9/67 vs 5/220) as were arrhythmias (4/67 vs 3/220). Rates of other complications were similar. The dothiepin group had ingested a larger dose, attributable to the larger average tablet strength, than patients who took other TCAs. The odds ratio for seizures with dothiepin versus other TCAs was 6.7 (95% Cl 2.2-20.7) unadjusted and 7.1 (2.2-23.2) after adjustment for sex, age, and ingested dose. The corresponding odds ratios for arrhythmias were 4.6 (1.0-21.1) and 3.4 (0.7-16.3). Dothiepin in overdose seems to be proconvulsant. Patients with only minor sedation and normal limb-lead QRS width may still have major complications. Consideration should be given to the use of other antidepressants in patients at risk of seizures or suicide. Regulatory authorities should review the need for a 75 mg strength tablet of any TCA.

Topics: Adult; Antidepressive Agents, Tricyclic; Arrhythmias, Cardiac; Dothiepin; Drug Overdose; Female; Humans; Male; Poisoning; Seizures

Topics: Arrhythmias, Cardiac; Bias; Dothiepin; Drug Overdose; Humans; Poisoning; Seizures

Topics: Antidepressive Agents, Tricyclic; Dothiepin; Drug Overdose; Humans; Seizures

Data from different analyses of reported deaths from overdose with antidepressants in the U.K. reveal that amitriptyline and dothiepin are the antidepressants most likely to be associated with death from overdose. All widely used tricyclic antidepressants (TCAs) except clomipramine and lofepramine appear to be dangerous in overdose, whereas the newer antidepressants such as mianserin, trazodone, viloxazine and the TCA lofepramine appear to be relatively safe. The toxicity of amitriptyline and dothiepin appears to be greater than all antidepressants including other TCAs and it is important to try to understand why. A number of explanations will be considered: 1. Dothiepin and amitriptyline may be inherently more toxic than other TCAs. 2. Dothiepin and amitriptyline may induce suicide more than other antidepressants. It is assumed that antidepressants are neutral with regard to inducing suicide but this may not be true. There is, for example, evidence that alprazolam and other benzodiazepines induce suicidal behaviour. 3. Amitriptyline and dothiepin are often presented in subtherapeutic and ineffective doses and it is possible that increased suicides may result from inadequately treated depression. 4. There may be a selective overreporting of deaths with amitriptyline and dothiepin. 5. Amitriptyline and prothiaden may be selectively given to the suicide prone on the mistaken assumption that they are safe.

Topics: Amitriptyline; Cross-Sectional Studies; Dibenzothiepins; Dose-Response Relationship, Drug; Dothiepin; Drug Overdose; Humans; Incidence; Risk Factors; Suicide; United Kingdom