RARE DISEASE
Acute tricyclic antidepressant poisoning
Acute tricyclic antidepressant poisoning
Acute tricyclic antidepressant poisoning
Drug discovery
1
drug
With orphan designation
Overview
Acute tricyclic antidepressant (TCA) poisoning is a high-risk toxicity characterized by rapid-onset cardiovascular collapse, seizures, and anticholinergic effects. Symptoms typically manifest within 6 hours, with widened QRS complexes (≥100 ms) and ventricular arrhythmias on ECG indicating severe toxicity. Sodium bicarbonate remains the cornerstone treatment to correct acidosis and stabilize sodium channel blockade. Supportive care includes airway management, benzodiazepines for seizures, and vasopressors for hypotension. Despite advances in antidepressants, TCAs account for significant overdose mortality due to their narrow therapeutic index [1][4][7][10].
Population
Primarily adults with intentional overdoses (suicidal or self-harm) and accidental pediatric ingestions [1][8][10].
High-risk subgroups: Patients with preexisting cardiac conditions, desipramine/nortriptyline exposures (higher toxicity potential), and mixed overdoses with CNS depressants [5][8][16].
Burden
Mortality: Responsible for ~270 annual UK deaths and 85 U.S. fatalities in 2004 (often intentional) [1][8].
Healthcare costs: ICU admissions, prolonged monitoring (>24 hours), and complications (e.g., aspiration pneumonia, arrhythmias) [7][10].
Long-term impact: Survivors often require psychiatric follow-up due to suicidality [10][12].
Therapies
Alkalinization: Sodium bicarbonate boluses for QRS widening or arrhythmias (target pH 7.5) [1][7][10].
Supportive care: Intubation for airway protection, IV fluids, and norepinephrine for hypotension [1][4][16].
Adjuncts: Benzodiazepines for seizures, lipid emulsion therapy in refractory cases; avoid class 1 antiarrhythmics [1][10][16].
Categories: rare disorders due to toxic effects
Research Papers
217 drug discovery papers about Acute tricyclic antidepressant poisoning, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
217 drug discovery papers about Acute tricyclic antidepressant poisoning, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-03-30 | Recommendations from the Clinical Toxicology Recommendations Collaborative on the administration of activated charcoal in acute oral overdose
INTRODUCTION: The Clinical Toxicology Recommendations Collaborative was established by three international clinical toxicology societies and tasked to produce recommendations on the management of poisonings. The Activated Charcoal in Clinical Toxicology Workgroup (the Workgroup) was formed to provide recommendations on the administration of activated charcoal for gastrointestinal decontamination and enhanced elimination in poisoning. METHODS: Based on a systematic review of the literature, 43 poisons or poison categories were selected for appraisal. Voting statements were drafted using a predetermined format. Strength of consensus was measured using the Disagreement Index as defined by the RAND/University of California at Los Angeles Appropriateness Method. A two-round modified Delphi method was used to reach expert consensus. RESULTS: The Workgroup concluded that there is no role for activated charcoal in poisoning from arsenic, caesium, copper, ethanol, methanol, ethylene glycol, iron, lead, lithium, and metformin. Activated charcoal is appropriate after ingestion of antidysrhythmics (types I and III not discussed specifically), beta-adrenergic antagonists, bupropion, calcium-channel blockers, carbamazepine, cardiac glycosides, chloroquine, cocaine, colchicine, cyanide, dapsone, diphenhydramine, disopyramide, factor Xa inhibitors, ibuprofen, isoniazid, lamotrigine, methotrexate, moclobemide, opioids, organophosphorus insecticides, paracetamol (acetaminophen), paraquat, phenobarbital, phenytoin, quinidine and quinine, salicylates, selective serotonin reuptake inhibitors, sulfonylureas, thallium, theophylline, tricyclic antidepressants, valproic acid, venlafaxine, and warfarin. An additional dose of activated charcoal to complete gastrointestinal decontamination is appropriate after ingestion of carbamazepine, paracetamol, paraquat, phenobarbital, salicylates, thallium, theophylline, valproic acid and verapamil. The maximum time post-ingestion for which activated charcoal administration is recommended differs for each poison and different formulations. According to an individualized risk assessment, activated charcoal is appropriate up to 6 h post-ingestion for many poisons. If ongoing absorption is suspected, which may occur, for example, with pharmacobezoar formation, certain modified-release preparations, or when drug burden exceeds the limits of solubility, then activated charcoal can be administered beyond 6 h post-ingestion for gastrointestinal decontamination. Multiple-dose activated charcoal for enhanced elimination is appropriate in poisoning with carbamazepine, cardiac glycosides, colchicine, dapsone, phenobarbital, phenytoin, thallium and theophylline. The following good practice statement was adopted: Nasogastric or orogastric tube insertion without endotracheal intubation should not be performed solely for the purpose of administration of AC. DISCUSSION: The decision to use activated charcoal is complex and depends primarily on the nature of the poison(s), the time since ingestion, the severity of the symptoms present at the time of decision or expected based on the dose ingested or patient comorbidities, and the availability of antidotes or other treatments. Although the existing level of evidence is primarily of low or very low quality, clinical decisions are still necessary. CONCLUSIONS: The Workgroup recommends the administration of a single-dose of activated charcoal beyond the traditional 1 h post-ingestion time point in selected poisons and introduces the concept of an additional dose of activated charcoal to prevent further absorption of poisons that may remain in the gastrointestinal tract for prolonged periods of time. Multiple-dose activated charcoal is also recommended to enhance elimination in selected clinical scenarios.
2025-11-17 | Use of intravenous lipid emulsions in drug-induced toxicities: a 2025 narrative review
Intravenous lipid emulsions (ILE) were first proposed in 1998 as a treatment for bupivacaine-induced cardiac arrest. Since then, their use has expanded to include poisonings by various lipophilic drugs such as tricyclic antidepressants, calcium channel blockers, and antipsychotics. This 2025 narrative review explores the evolving pathophysiological mechanisms of ILE therapy, including the lipid sink and lipid shuttle theories, as well as non-scavenging cardiotonic effects such as membrane stabilization, mitochondrial support, and modulation of vascular tone. It summarizes recent findings from randomized controlled trials, cohort studies, animal models, and case registries. While clinical trials demonstrate potential benefits-particularly in tramadol, clozapine, and organophosphate poisonings-mortality reduction remains unproven, and evidence is limited by study heterogeneity and low methodological quality. Adverse effects, although rare, include acute pancreatitis, interference with laboratory testing, and fat overload syndrome, especially at high infusion volumes. Current guidelines recommend ILEs as a first-line treatment for local anesthetic systemic toxicity and as a second-line option in life-threatening poisonings involving other lipophilic agents. However, significant uncertainty remains regarding optimal indications, dosing strategies, and long-term safety. High-quality, multicenter studies and updated registries are needed to refine these recommendations and clarify the role of ILEs in clinical toxicology.
2025-06-10 | Acute drug toxicity as a risk factor for lethal deep venous thrombosis.
Thrombosis of the deep veins of the legs is a relatively common occurrence initiated by venous stasis, endothelial damage or hypercoagulable states. Prolonged sitting has also been associated with thrombotic events. A case is reported where immobility caused by drug overdose resulted in lethal pulmonary thromboembolism. Case report: A 50-year-old male was found sitting in the driver's seat of his car slumped forward. A suicide note was present. At autopsy finely granular tablet residue was found in the stomach. Deep venous thrombosis was present in both calves with bilateral pulmonary thromboembolism. Toxicological examination of blood revealed elevated levels of amitriptyline (0.92 mg/L), nortriptyline (0.41 mg/L) and oxycodone (0.17 mg/L). Death was due to pulmonary thromboembolism arising from bilateral deep venous thromboses complicating mixed drug toxicity. Prolonged immobility should be considered a possible mechanism for venous thrombosis in drug takers.
2023-12-01 | Impact of damiana (Turnera diffusa) against amitriptyline induced heart injury, dysfunctions and DNA damage in male rats
Amitriptyline (AMT) is a tricyclic antidepressant and an inhibitor of lysosomal acid sphingomyelinase. Amitriptyline has a bad reputation for its cardiovascular complications in psychiatric patients. However, the mechanisms implying the cardiovascular toxicity of amitriptyline are still unknown. This study aimed to clarify damiana's preventive and therapeutic role as adjuvant herbal therapy against amitriptyline-induced heart injury in rats. A total of 36 male albino rats were equally distributed into six groups (1st, control; 2nd, damiana; 3rd, Amitriptyline; 4th, co-treated amitriptyline rats with damiana; 5th, post-treated amitriptyline rats with damiana; 6th, self- healing Amitriptyline rats). A significant elevation in cardiac enzymes (CK-MB, LDH, CKP, and Myoglobin), AST, ALP, sodium ions, cholesterol, triglycerides, LDL, and cardiac DNA damage, injury, and proliferating cell nuclear antigen (PCNA) immunoreactivity in treatment rats with amitriptyline and self-treated group as compared to control and damiana groups. In contrast, potassium ions and HDL revealed a significant depletion in amitriptyline and self- healing Amitriptyline rats’ groups as compared to control and damiana groups. Co- and post-treatment of rats with damiana showed a modulation and improvement of cardiac toxicity with a better result in co-treatments than post-treatments. This study suggests using damiana, which is promising in protecting heart structure and functions.
2023-08-01 | The Benefit of Activated Charcoal in Reducing Mortality in Toxic Patient: A Meta-Analysis
The objective of the study was to estimate the effect of activated charcoal (AC) administration on the mortality of patients taking toxic materials and the effect of drug properties on drug exposure. Thirty studies were integrated in a meta-analysis. AC administered 0–5 min after administration of a drug reduced median drug exposure by 88.4% (25–75 percentile: 65.0–96.8) (P < 0.00001). The effect of AC continued to be statistically significant when administered up to 4 h after drug intake (median reduction in drug exposure 27.4% (range 21.3–31.5%, P = 0.0006). Furthermore, there were significant decrease in the mortality as long as AC is administered early. The reduction in drug exposure was correlated with the AC/drug ratio (ρ = 0.69, P < 0.0001), the volume of distribution (Vd) (ρ = 0.46, P = 0.0001), and time to peak concentration (ρ = 0.40, P = 0.02). We found that AC is most effective when given immediately after drug ingestion but has statistically significant effects even when given as long as 4 h after drug intake. AC appears to be most effective when given in a large dose. And it affects the mortality in earlier intervention better than late intervention.
small molecules
2026-03-30 | Recommendations from the Clinical Toxicology Recommendations Collaborative on the administration of activated charcoal in acute oral overdose
INTRODUCTION: The Clinical Toxicology Recommendations Collaborative was established by three international clinical toxicology societies and tasked to produce recommendations on the management of poisonings. The Activated Charcoal in Clinical Toxicology Workgroup (the Workgroup) was formed to provide recommendations on the administration of activated charcoal for gastrointestinal decontamination and enhanced elimination in poisoning. METHODS: Based on a systematic review of the literature, 43 poisons or poison categories were selected for appraisal. Voting statements were drafted using a predetermined format. Strength of consensus was measured using the Disagreement Index as defined by the RAND/University of California at Los Angeles Appropriateness Method. A two-round modified Delphi method was used to reach expert consensus. RESULTS: The Workgroup concluded that there is no role for activated charcoal in poisoning from arsenic, caesium, copper, ethanol, methanol, ethylene glycol, iron, lead, lithium, and metformin. Activated charcoal is appropriate after ingestion of antidysrhythmics (types I and III not discussed specifically), beta-adrenergic antagonists, bupropion, calcium-channel blockers, carbamazepine, cardiac glycosides, chloroquine, cocaine, colchicine, cyanide, dapsone, diphenhydramine, disopyramide, factor Xa inhibitors, ibuprofen, isoniazid, lamotrigine, methotrexate, moclobemide, opioids, organophosphorus insecticides, paracetamol (acetaminophen), paraquat, phenobarbital, phenytoin, quinidine and quinine, salicylates, selective serotonin reuptake inhibitors, sulfonylureas, thallium, theophylline, tricyclic antidepressants, valproic acid, venlafaxine, and warfarin. An additional dose of activated charcoal to complete gastrointestinal decontamination is appropriate after ingestion of carbamazepine, paracetamol, paraquat, phenobarbital, salicylates, thallium, theophylline, valproic acid and verapamil. The maximum time post-ingestion for which activated charcoal administration is recommended differs for each poison and different formulations. According to an individualized risk assessment, activated charcoal is appropriate up to 6 h post-ingestion for many poisons. If ongoing absorption is suspected, which may occur, for example, with pharmacobezoar formation, certain modified-release preparations, or when drug burden exceeds the limits of solubility, then activated charcoal can be administered beyond 6 h post-ingestion for gastrointestinal decontamination. Multiple-dose activated charcoal for enhanced elimination is appropriate in poisoning with carbamazepine, cardiac glycosides, colchicine, dapsone, phenobarbital, phenytoin, thallium and theophylline. The following good practice statement was adopted: Nasogastric or orogastric tube insertion without endotracheal intubation should not be performed solely for the purpose of administration of AC. DISCUSSION: The decision to use activated charcoal is complex and depends primarily on the nature of the poison(s), the time since ingestion, the severity of the symptoms present at the time of decision or expected based on the dose ingested or patient comorbidities, and the availability of antidotes or other treatments. Although the existing level of evidence is primarily of low or very low quality, clinical decisions are still necessary. CONCLUSIONS: The Workgroup recommends the administration of a single-dose of activated charcoal beyond the traditional 1 h post-ingestion time point in selected poisons and introduces the concept of an additional dose of activated charcoal to prevent further absorption of poisons that may remain in the gastrointestinal tract for prolonged periods of time. Multiple-dose activated charcoal is also recommended to enhance elimination in selected clinical scenarios.
2025-11-17 | Use of intravenous lipid emulsions in drug-induced toxicities: a 2025 narrative review
Intravenous lipid emulsions (ILE) were first proposed in 1998 as a treatment for bupivacaine-induced cardiac arrest. Since then, their use has expanded to include poisonings by various lipophilic drugs such as tricyclic antidepressants, calcium channel blockers, and antipsychotics. This 2025 narrative review explores the evolving pathophysiological mechanisms of ILE therapy, including the lipid sink and lipid shuttle theories, as well as non-scavenging cardiotonic effects such as membrane stabilization, mitochondrial support, and modulation of vascular tone. It summarizes recent findings from randomized controlled trials, cohort studies, animal models, and case registries. While clinical trials demonstrate potential benefits-particularly in tramadol, clozapine, and organophosphate poisonings-mortality reduction remains unproven, and evidence is limited by study heterogeneity and low methodological quality. Adverse effects, although rare, include acute pancreatitis, interference with laboratory testing, and fat overload syndrome, especially at high infusion volumes. Current guidelines recommend ILEs as a first-line treatment for local anesthetic systemic toxicity and as a second-line option in life-threatening poisonings involving other lipophilic agents. However, significant uncertainty remains regarding optimal indications, dosing strategies, and long-term safety. High-quality, multicenter studies and updated registries are needed to refine these recommendations and clarify the role of ILEs in clinical toxicology.
2025-06-10 | Acute drug toxicity as a risk factor for lethal deep venous thrombosis.
Thrombosis of the deep veins of the legs is a relatively common occurrence initiated by venous stasis, endothelial damage or hypercoagulable states. Prolonged sitting has also been associated with thrombotic events. A case is reported where immobility caused by drug overdose resulted in lethal pulmonary thromboembolism. Case report: A 50-year-old male was found sitting in the driver's seat of his car slumped forward. A suicide note was present. At autopsy finely granular tablet residue was found in the stomach. Deep venous thrombosis was present in both calves with bilateral pulmonary thromboembolism. Toxicological examination of blood revealed elevated levels of amitriptyline (0.92 mg/L), nortriptyline (0.41 mg/L) and oxycodone (0.17 mg/L). Death was due to pulmonary thromboembolism arising from bilateral deep venous thromboses complicating mixed drug toxicity. Prolonged immobility should be considered a possible mechanism for venous thrombosis in drug takers.
2023-12-01 | Impact of damiana (Turnera diffusa) against amitriptyline induced heart injury, dysfunctions and DNA damage in male rats
Amitriptyline (AMT) is a tricyclic antidepressant and an inhibitor of lysosomal acid sphingomyelinase. Amitriptyline has a bad reputation for its cardiovascular complications in psychiatric patients. However, the mechanisms implying the cardiovascular toxicity of amitriptyline are still unknown. This study aimed to clarify damiana's preventive and therapeutic role as adjuvant herbal therapy against amitriptyline-induced heart injury in rats. A total of 36 male albino rats were equally distributed into six groups (1st, control; 2nd, damiana; 3rd, Amitriptyline; 4th, co-treated amitriptyline rats with damiana; 5th, post-treated amitriptyline rats with damiana; 6th, self- healing Amitriptyline rats). A significant elevation in cardiac enzymes (CK-MB, LDH, CKP, and Myoglobin), AST, ALP, sodium ions, cholesterol, triglycerides, LDL, and cardiac DNA damage, injury, and proliferating cell nuclear antigen (PCNA) immunoreactivity in treatment rats with amitriptyline and self-treated group as compared to control and damiana groups. In contrast, potassium ions and HDL revealed a significant depletion in amitriptyline and self- healing Amitriptyline rats’ groups as compared to control and damiana groups. Co- and post-treatment of rats with damiana showed a modulation and improvement of cardiac toxicity with a better result in co-treatments than post-treatments. This study suggests using damiana, which is promising in protecting heart structure and functions.
2023-08-01 | The Benefit of Activated Charcoal in Reducing Mortality in Toxic Patient: A Meta-Analysis
The objective of the study was to estimate the effect of activated charcoal (AC) administration on the mortality of patients taking toxic materials and the effect of drug properties on drug exposure. Thirty studies were integrated in a meta-analysis. AC administered 0–5 min after administration of a drug reduced median drug exposure by 88.4% (25–75 percentile: 65.0–96.8) (P < 0.00001). The effect of AC continued to be statistically significant when administered up to 4 h after drug intake (median reduction in drug exposure 27.4% (range 21.3–31.5%, P = 0.0006). Furthermore, there were significant decrease in the mortality as long as AC is administered early. The reduction in drug exposure was correlated with the AC/drug ratio (ρ = 0.69, P < 0.0001), the volume of distribution (Vd) (ρ = 0.46, P = 0.0001), and time to peak concentration (ρ = 0.40, P = 0.02). We found that AC is most effective when given immediately after drug ingestion but has statistically significant effects even when given as long as 4 h after drug intake. AC appears to be most effective when given in a large dose. And it affects the mortality in earlier intervention better than late intervention.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
1 orphan drug designation for Acute tricyclic antidepressant poisoning.
1 orphan drug designation for Acute tricyclic antidepressant poisoning.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Alpha-1-acid glycoprotein | proteins | FDA | 2004-03-17 | — | Bio Products Laboratory |
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.