Refractory Arrhythmias in a Young Patient Poisoned by Imipramine.

Tricyclic antidepressants are used to treat a variety of mental disorders, and are considered a common cause of fatal drug poisoning. This study reports a young woman with no history of cardiac diseases who presented to the emergency department with heart palpitation, weakness, and lethargy. After a short period of time, she became unconscious and experienced hypotension and refractory arrhythmia, finally being diagnosed with imipramine poisoning. Accurate history taking and the possible causes of these complications including cardio-toxic drug poisoning should be considered in such patients.

Case Report: Hemodynamic Instability Following Severe Metoprolol and Imipramine Intoxication Successfully Treated With Intravenous Fat Emulsion.

We present the case of a 22-year-old patient who was successfully treated with intravenous fat emulsion for severe and refractory cardiac depression after an overdose with a tricyclic antidepressant and beta-blocker.

Neurologic and Cardiovascular Complications in Pediatric Life Threatening Imipramine Poisoning.

We present an 18-month boy with imipramine poisoning to illustrate the neuro-cardiac toxic effects of this potentially deadly poison in children. The toddler ingested an unknown amount of imipramine from a non-childproof bottle which clearly labelled that the drug must be kept out of reach from children. He developed neurologic and cardiac symptoms. Electrocardiography (ECG) showed tachycardia and widened QRS. He was immediately treated with bicarbonate infusion and made an uneventful recovery. This is the youngest and only reported case of symptomatic imipramine ingestion in our locality. Imipramine has been surpassed by newer antidepressants for the treatment of depression in the past decade. Literature is searched to review the mortality rate in young children. Intensive care neuro-cardiac support contributes to the favorable outcome. Despite clear labelling of the bottle, carelessness on the part of the adult and the use of non-childproof bottle are definite preventable factor to such potentially fatal ingestion.

Clinical psychopharmacology and medical malpractice: the four Ds.

The four Ds of medical malpractice are duty, dereliction (negligence or deviation from the standard of care), damages, and direct cause. Each of these four elements must be proved to have been present, based on a preponderance of the evidence, for malpractice to be found. The principles of psychopharmacology and the information in the package insert for a drug often play a central role in deciding whether dereliction and direct cause for damages were or were not applicable in a particular case. The author uses data from two cases in which patients were inadvertently fatally poisoned by medication to illustrate two ways in which such information can affect the outcome. In one case, the clinician should have known that he was giving a toxic dose to the patient, whereas that was not true in the other case.

Inadvertent fatal imipramine poisoning of a child: what happened to Tommy?

This column illustrates the importance of considering interindividual variance when prescribing medications. In this tragic case, the failure to consider age and body weight when prescribing a drug, imipramine, with a narrow therapeutic index caused the death of an otherwise physically healthy 6-year-old child. This death could also have been avoided by using therapeutic drug monitoring to properly adjust the dose. This case illustrates the importance of the second (pharmacokinetics) and third (biological variance) variables in the equation frequently cited in this column: clinical response=affinity for and intrinsic activity at site of action x drug concentration at site of action x underlying biology of the patient.

Temporary cardiac pacemaker in the treatment of junctional rhythm and hypotension due to imipramine intoxication.

Tricyclic antidepressants (TCAs) account for approximately 3% of all pediatric hospitalizations due to poisoning. TCAs remain a common cause of fatal drug poisoning because of their cardiovascular toxicity as manifested by electrocardiogram (ECG) abnormalities, arrhythmias, and hypotension. We report a 15-year-old girl with junctional escape rhythm and resistant hypotension caused by severe imipramine intoxication. Initial ECG showed junctional escape rhythm (46 bpm) with no atrial activity, low QRS voltage, widening of the QRS complex (160 ms) with a right bundle branch-like pattern, R wave > 3 mm in aVR (6 mm), and prolongation of the QT interval (QTc 550 ms). Despite intravenous fluids and inotropic support, she had resistant hypotension and acute renal failure. Junctional rhythm was successfully terminated by using temporary cardiac pacemaker. Hemodialysis and hemoperfusion were also performed. She was discharged on the day 5 without any complications. During follow-up, no ECG abnormalities were noted. We reported successful use of temporary cardiac pacemaker for treatment of junctional rhythm and resistant hypotension in imipramine intoxication. The conventional methods of activated charcoal, alkalinization, and symptomatic treatment of complications are usually enough for nonlethal doses of TCA intoxication. However, in imipramine intoxication with serious arrythmias and hypotension, using temporary cardiac pacemaker, hemodialysis, and hemoperfusion can be a life-saving therapeutic approach.

A physiologically based pharmacokinetic (PBPK) model for predicting the efficacy of drug overdose treatment with liposomes in man.

Physiologically based pharmacokinetic (PBPK) models were developed for design and optimization of liposome therapy for treatment of overdoses of tricyclic antidepressants and local anesthetics. In vitro drug-binding data for pegylated, anionic liposomes and published mechanistic equations for partition coefficients were used to develop the models. The models were proven reliable through comparisons to intravenous data. The liposomes were predicted to be highly effective at treating amitriptyline overdoses, with reductions in the area under the concentration versus time curves (AUC) of 64% for the heart and brain. Peak heart and brain drug concentrations were predicted to drop by 20%. Bupivacaine AUC and peak concentration reductions were lower at 15.4% and 17.3%, respectively, for the heart and brain. The predicted pharmacokinetic profiles following liposome administration agreed well with data from clinical studies where protein fragments were administered to patients for overdose treatment. Published data on local cardiac function were used to relate the predicted concentrations in the body to local pharmacodynamic effects in the heart. While the results offer encouragement for future liposome therapies geared toward overdose, it is imperative to point out that animal experiments and phase I clinical trials are the next steps to ensuring the efficacy of the treatment.

Binding of imipramine, dosulepin, and opipramol to liposomes for overdose treatment.

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.

An autopsy case of imipramine poisoning.

We present a fatal imipramine poisoning. Quantitative analysis of imipramine and its metabolite, desipramine, was performed by high-performance liquid chromatography. The concentrations of imipramine and desipramine were 18.67 microg/mL and 6.21 microg/mL in heart blood and 6.90 microg/mL and 1.77 microg/mL in the femoral venous blood, respectively. We concluded that the cause of death was due to imipramine poisoning.

Excess fatality from desipramine and dosage recommendations.

Higher case fatality rates (CFR) were previously reported from desipramine than for 3 other tricyclic antidepressants (TCAs): amitriptyline, nortriptyline, and imipramine. The database of the American Association of Poison Control Centers (AAPCC) Toxic Exposure Surveillance System (TESS) for the 20 years 1983-2002 was used to evaluate the CFR of desipramine and the other TCAs. The CFR of desipramine was 2.25-, 2.31-, and 2.62-fold the CFR for amitriptyline, nortriptyline, and imipramine, respectively (P < 0.001). Mechanisms of desipramine toxicity and its dosage recommendations are discussed. Desipramine and nortriptyline have higher distribution volumes and erythrocyte/plasma ratios than their parent compounds imipramine and amitriptyline. This implies lower therapeutic plasma levels and reduced doses for desipramine and nortriptyline compared with their parent compounds. Such adjustments have been done for nortriptyline, but not for desipramine. The authors suggest that the high CFR of desipramine might be reduced by lowering its dose, therapeutic plasma level, and maximal pill content.

Cardiotoxicity in imipramine intoxication: report of one case.

Imipramine is the most commonly prescribed tricyclic antidepressant of acute life threatening self-poisoning. We report a 15-month-old boy of accidental poisoning with imipramine, who developed generalized tonic-clonic convulsions and drug-related cardiac conduction abnormalities with PR prolongation, QRS widening, and QTc lengthening. The patient's imipramine level was 1389 ng/ml. The rapid resolution of intraventricular conduction delay and normalization of the QRS-T complexes after gastric lavage, installation of activated charcoal and alkalinization of the blood strongly implicates imipramine intoxication in the etiology of the cardiotoxicity. The patient made a full recovery without neurological sequelae.

Imipramine overdose complicated by toxic megacolon.

Tricyclic antidepressants are a class of drugs commonly used for the treatment of depression. Tricyclic antidepressants account for approximately 20 to 25 per cent of drug overdoses that require acute medical admission. The most common cause of mortality is cardiovascular toxicity (e.g., arrhythmia, heart block, or hypotension). Other morbidities include conditions secondary to anticholinergic effects (central and peripheral) and respiratory complications. Ileus, constipation and urinary retention are common peripheral anticholinergic sequelae, whereas unusual complications include pancreatitis, intestinal pseudo-obstruction with cecal perforation, and sigmoid colon gangrene. We report a case of imipramine overdose that was complicated by toxic megacolon with an associated perforation.

Tricyclic poisoning--successful management of ventricular fibrillation following massive overdose of imipramine.

Serious complications from tricyclic antidepressant (TCA) overdose are uncommon. We present a case of massive imipramine overdose complicated by ventricular fibrillation and a prolonged period of cardiovascular collapse. A total of 400 mmol of sodium bicarbonate, 5 mg of adrenaline and 80 mg of sotalol were given during 50 minutes of cardiac arrest. The patient made a full recovery with no apparent neurological sequelae. The highest TCA plasma level we could find in the published literature was 4873 ng/ml4; our patient's peak TCA level was 6000 ng/ml. Tricyclic antidepressant overdose is a common cause of intensive care unit admission. It has a low mortality rate.

Response to glucagon in imipramine overdose.

A 25-year-old woman, severely hypotensive following a massive imipramine overdose, had an immediate and sustained rise in blood pressure following intravenous glucagon (10 mg bolus followed by an infusion of 10 mg over 6 h). The QRS interval on the electrocardiogram shortened from 129 to 89 msec. Glucagon should be considered in hypotension following tricyclic antidepressant overdose; it may also be antiarrhythmic.

Extracorporeal circulation in the management of severe tricyclic antidepressant overdose.

Extracorporeal circulation is a technique that provides precise control of circulation, oxygenation, temperature, and blood composition in patients suffering from cardiopulmonary failure. The investigators present the case of a near fatal tricyclic antidepressant overdose that failed to respond to standard therapy but was resuscitated using extracorporeal circulation.

Multiple drug overdose in a kidney transplant patient.

Development of depression in patients with organ transplants is accompanied by an increased incidence of suicide attempts. A 60-year-old man with chronic polycystic renal disease underwent a kidney transplant 2 years previously. Six months prior to admission, the patient had been medicated for depression. This course was complicated by noncompliance and worsening family problems. One morning, the patient was found unconscious, along with a suicide note and empty bottles of cyclosporine (CsA), imipramine (IP), meticorten, azathioprine, oxazepam, alprazolam, and fluoxetin, approximately 24 h after the presumed intake of these agents. Initial plasma IP level was 2260 ng/ml, whole blood total cyclosporine (T-CsA) concentration was 1,800 ng/ml and that of specific cyclosporine (Sp-CsA), 714 ng/ml. Urine toxic screening was positive also for benzodiazepines metabolites. IP and CsA blood levels were measured daily. Five days after overdose, the IP concentration was 232 ng/ml, that of T-CsA 401 ng/ml, and that of Sp-CsA 96 ng/ml. Compared to subjects on therapeutic doses, a significant prolongation of the half-life, t 1/2, was observed for both IP (t1/2, 43.4 h) and Sp-CsA (t1/2, 70.1 h). In the present case, prolonged elevated IP plasma levels were not associated with cardiovascular complications. On the 5th hospital day, after the patient had apparently recovered from the intoxication, he jumped from the 8th floor to his death.

The study of tricyclic antidepressants in formalin-fixed human liver and formalin solutions.

The stability of amitriptyline, nortriptyline, desipramine and imipramine in formalin-fixed human liver tissue and formalin solutions was investigated. The levels of the tricyclic and its primary demethylated metabolite in the frozen liver were determined and compared with levels obtained in the formalin-fixed liver and formalin solutions in which the liver was stored. It was obvious that some methylation of the secondary amine, nortriptyline, to the corresponding tertiary amine, amitriptyline, and of desipramine to imipramine took place in the formalin environment. Nortriptyline was not detected in most cases, suggesting that it may degrade more rapidly than desipramine. There was no consistent ratio between the concentration of the drug in the frozen liver tissue versus formalin-preserved tissue or versus formalin solution. The methylation rates of the secondary amines could not be quantitated. Storage of the liver tissue in formalin at room temperature resulted in leaching of the drugs into the formalin solution. The drugs tested may be detected for up to 22 months in the formalin-fixed liver and in the formalin medium.