Abnormal atrial and ventricular repolarisation resembling myocardial injury after tricyclic antidepressant drug intoxication

Zakynthinos, E. G.; Vassilakopoulos, T.; Roussos, Charis; Zakynthinos, S.

doi:10.1136/heart.83.3.353

Cited by 9 publications

(7 citation statements)

References 3 publications

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“…The predicted mean QTcB in the study mimicking that described by Zakynthinos et al [ 43 ] was 531 ms (520 ms observed in the clinic). In one out of ten simulated patients, arrhythmia was observed.…”

Section: Resultssupporting

confidence: 79%

“…Because of lack of clinically observed precise data on time-matched concentrations of AT and NT, presentation of other PK metrics on the goodness of model prediction was not possible. The results of the cases are described in the order defined in the Materials and Methods section: The predicted mean QTcB in the study mimicking that described by Zakynthinos et al [ 43 ] was 531 ms (520 ms observed in the clinic). In one out of ten simulated patients, arrhythmia was observed.…”

Section: Resultsmentioning

confidence: 69%

“…The found cases were divided into three groups with corresponding methodology: Cases without ingested dose reported [ 35 , 43 ]: the free cardiac AT and NT concentrations were estimated based on observed plasma AT and NT concentrations according to the (Eq. 5 ): where C free,cardiac is drug free cardiac concentration, Kp ht is heart tissue to plasma partition coefficient, and fu ht is drug unbound fraction in heart tissue.…”

Section: Methodsmentioning

confidence: 99%

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Physiologically based pharmacokinetic-quantitative systems toxicology and safety (PBPK-QSTS) modeling approach applied to predict the variability of amitriptyline pharmacokinetics and cardiac safety in populations and in individuals

Tylutki

Mendyk

Polak

2018

J Pharmacokinet Pharmacodyn

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The physiologically based pharmacokinetic (PBPK) models allow for predictive assessment of variability in population of interest. One of the future application of PBPK modeling is in the field of precision dosing and personalized medicine. The aim of the study was to develop PBPK model for amitriptyline given orally, predict the variability of cardiac concentrations of amitriptyline and its main metabolite—nortriptyline in populations as well as individuals, and simulate the influence of those xenobiotics in therapeutic and supratherapeutic concentrations on human electrophysiology. The cardiac effect with regard to QT and RR interval lengths was assessed. The Emax model to describe the relationship between amitriptyline concentration and heart rate (RR) length was proposed. The developed PBPK model was used to mimic 29 clinical trials and 19 cases of amitriptyline intoxication. Three clinical trials and 18 cases were simulated with the use of PBPK-QSTS approach, confirming lack of cardiotoxic effect of amitriptyline in therapeutic doses and the increase in heart rate along with potential for arrhythmia development in case of amitriptyline overdose. The results of our study support the validity and feasibility of the PBPK-QSTS modeling development for personalized medicine.Electronic supplementary materialThe online version of this article (10.1007/s10928-018-9597-6) contains supplementary material, which is available to authorized users.

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Section: Resultssupporting

confidence: 79%

Section: Resultsmentioning

confidence: 69%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Physiologically based pharmacokinetic-quantitative systems toxicology and safety (PBPK-QSTS) modeling approach applied to predict the variability of amitriptyline pharmacokinetics and cardiac safety in populations and in individuals

Tylutki

Mendyk

Polak

2018

J Pharmacokinet Pharmacodyn

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“…Guthrie & Lott (1986) reported elevation of serum creatine kinase and MB fraction following an amitriptyline overdose without ECG changes in a patient who subsequently had normal coronary angiogram. Zakynthinos et al (2000) reported ECG changes mimicking acute myocardial infarction associated with tricyclic antidepressant overdose. ST segment elevation was reported in leads of DI, aVL, V1 and V2 mimicking a current of anteroseptal subepicardial injury after amitriptyline overdose, which persisted for four days.…”

Section: Discussionmentioning

confidence: 99%

Acute Myocardial Infarction Associated with Amitriptyline Overdose

Kıyan

Aksay

Yanturali

et al. 2006

Basic Clin Pharma Tox

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Tricyclic antidepressant overdose is known to cause cardiopulmonary and central nervous system complications. As with other cardiovascular complications, amitriptyline toxicity may cause acute myocardial infarction. This paper reports the case of a young female with acute myocardial infarction as a novel consequence of tricyclic antidepressant overdose.Tricyclic antidepressant overdose is the one of the most common in self-poisoning. Tricyclic antidepressants account for the third largest number of deaths reported to American poison control centres. Amitriptyline is the most common single agent (Watson et al. 2005). The high rate of mortality in tricyclic antidepressant overdosing is due to central nervous system and cardiovascular system toxicity. Evidence of cardiovascular toxicity is present in the majority of tricyclic antidepressant overdoses. Cardiotoxicity is hypotension, QRS widening and ventricular arrhythmias (Smilkstein 1990). Transient electrocardiographic changes and cardiac arrhythmias are well-documented complications of tricyclic antidepressant overdose, however acute myocardial infarction has only been rarely reported. Here we report a case of tricyclic antidepressant overdose, followed by acute myocardial infarction. Materials and MethodsCase report. A 33 year old female was referred to Emergency Department after ingestion of 30 tablets (300 mg) of amitriptyline for suicidal purpose. She was admitted to state hospital 4 hr after ingestion, and because of decreased level of consciousness (Glasgow coma score 3) she had been intubated with nasogastric tube administered, 50 g of activated charcoal and the finally referred to the Emergency Departments.Her past medical history was major depression, and she had been heated with amitriptyline for five years. She had no coronary artery risk factors such as a diabetes, hypertension, hyperlipidaemia, smoking and no family history of heart disease. Her blood pressure was 110/70 mmHg, heart rate was 120 beats/min., and pulse oxymetre with artificial ventilation was 100% on admission. Her oral mucous membrane was dry, and bowel sounds werediminished. Her pupils reacted to light and no neurological signs were found. The rest of physical examination was also normal. Her initial ECG revealed sinus tachycardia, QRS widening (120 msec.) and QTc interval prolongation (521 msec.) ( fig. 1). Initial complete blood count and serum electrolytes were normal. Arterial blood gas examination Author for corresponcence: Selahattin Kiyan, Ege University Hospital, Department of Emergency Medicine, 35100, Bornova, Izmir, Turkey (fax π90 232 388 38 05, e-mail selahattin.kiyan/ege.edu.tr). revealed respiratory alkalosis (pH: 7.55, PaCO2: 24.9 mmHg, PaO2: 99.3 mmHg, BE: 1.7 mmol/l). D Dimer 0.4 mg/ml (0-0.5 mg/ml) was normal. Toxicological screen cocaine, amphetamine, opiates and heroin was negative. In our institution, amitriptyline level could not be measured. The patient was extubated 26 hr after ingestion. She denied any drug ingestion other than amitriptyline after...

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“…Rapid deterioration in mental status should be anticipated, as should abrupt onset of seizure activity [94,[100][101][102]. A prospective study of acute first-generation cyclic antidepressant ingestions showed the utility of the ECG in predicting cardiac dysrhythmias and seizures [103].…”

Section: Managementmentioning

confidence: 99%