RARE DISEASE
Paracetamol poisoning
Paracetamol poisoning
Paracetamol poisoning
Synonyms: Acetaminophen poisoning
Synonyms: Acetaminophen poisoning
Synonyms: Acetaminophen poisoning
Drug discovery
6
drugs
With orphan designations
Overview
Paracetamol (acetaminophen) poisoning occurs when excessive doses overwhelm hepatic glutathione reserves, leading to toxic metabolite (NAPQI)-induced hepatotoxicity. Initial symptoms (nausea, vomiting, abdominal pain) may progress to liver failure, coagulopathy, and multi-organ dysfunction within 72 hours. Diagnosis relies on timed serum paracetamol levels plotted on the Rumack-Matthew nomogram [1][7]. First-line treatment with intravenous N-acetylcysteine (NAC) within 8-10 hours of ingestion prevents liver damage by replenishing glutathione [3][9][14].
Population
Common in intentional self-harm among adolescents/young adults in high-income countries [9][16], with 25,000 annual UK hospitalizations [9].
Accidental pediatric ingestions account for 6% of poisonings globally [8][13], particularly in children <7 years [10].
High-risk groups: chronic alcohol users, malnourished patients, and those taking enzyme-inducing medications (e.g., anticonvulsants) [1][5].
Burden
Leading cause of acute liver failure in the US/UK, contributing to 56% of severe hepatic injury cases [8][13].
Mortality: 0.1–0.4% in treated cases, rising to 95% in untreated patients with acidosis (pH <7.3) [4][11].
Economic impact: 492 deaths (1996–2019) and 5,666 hospitalizations in Brazil alone [2]; liver transplants cost >$500,000 USD per case [13][17].
Therapies
Immediate decontamination: Activated charcoal within 1-2 hours for ingestions >75–100 mg/kg [3][7].
Antidote: Weight-based NAC infusion (two-bag regimen: 200 mg/kg over 4h → 100 mg/kg over 16h) [7][14], reducing adverse reactions vs older protocols.
Risk stratification: NAC initiated if serum paracetamol exceeds nomogram thresholds (≥100 mg/L at 4h) or for staggered/uncertain-time overdoses [1][7][14].
Categories: rare disorders due to toxic effects
Research Papers
2,668 drug discovery papers about Paracetamol poisoning, with 16 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2,668 drug discovery papers about Paracetamol poisoning, with 16 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-17 | Subchronic Alcohol Exposure Exacerbates Acetaminophen-Induced Acute Liver Injury via Macrophage-Mediated Inflammation and Mitochondrial Dysfunction.
Alcohol use is a major coexposure in patients taking acetaminophen (APAP), yet how subchronic alcohol exposure reshapes hepatic vulnerability to APAP remains incompletely defined. In this study, we examined the effects of chronic alcohol intake on APAP-induced liver injury in mice. Our results indicated that subchronic alcohol exposure significantly increased the mortality rate in APAP-overdosed mice. Alcohol pretreatment also exacerbated APAP-induced hepatic damage, as evidenced by elevated serum ALT and AST levels, enhanced inflammatory responses, and aggravated oxidative stress. Quantitative polymerase chain reaction (qPCR) analysis revealed that alcohol consumption suppressed mitochondrial biogenesis (MB)-related genes, including Pgc-1α and transcription factor A, mitochondrial (TFAM). Notably, macrophage depletion via clodronate liposomes not only attenuated hepatocyte injury and inflammation induction but also restored the expression of MB/function-related genes, including Pgc-1α, TFAM, and Opa1. These findings suggest macrophage-involved inflammatory amplification may aggravate APAP-induced liver injury, at least in part, by impairing mitochondrial adaptive repair responses.
2026-08-11 | Clinical Characteristics and Pattern of Paracetamol-Induced Liver Injury at Hospital Shah Alam: A Three-Year Retrospective Case Series
Background: Paracetamol poisoning is the most common type of therapeutic drug poisoning seen globally. The dose of ingested paracetamol and the time of presentation to a healthcare facility are important factors in assessing the severity of poisoning. In addition, factors affecting hepatic glutathione levels further influence the risk of toxicity. Objective: This three years case series aims to analyse the characteristics of liver injury observed in patients who presented to the hospital’s ED for Shah Alam following an intentional paracetamol overdose. Additionally, it seeks to determine risk factors specific to this local population. Methodology: Patients with a history of intentional paracetamol overdose and biochemical evidence of liver injury who presented to the ED of Hospital Shah Alam between 1st January 2022 and 31st December 2024 were included in this study. Patients aged less than 18 years were excluded from this study. Results: A total of 13 patients were included in this case series. The pattern of liver injury followed an established clinical course; however, no patients developed liver failure. High doses of paracetamol ingestion and late presentation after overdose were the expected risk factors. A further risk factor identified in this case series was low body weight. Six patients in this case series weighed less than 45 kg. Underweight patients may have underlying malnutrition. Paracetamol overdose hepatotoxicity risk is linked to depleted hepatic glutathione, which is known to be due to malnutrition. Conclusion: High doses of paracetamol ingestion with late presentation to a healthcare facility are known risk factors for paracetamol-induced liver injury. This case series also revealed that underweight patients are at risk, possibly because of malnutrition. These findings suggest that clinicians may consider a lower treatment threshold, such as the 100-line threshold, in underweight or potentially malnourished patients, although larger studies are needed.
2026-08-11 | Defining risk: the case for conceptual clarity in acetaminophen poisoning
Despite the widespread availability of acetylcysteine, acetaminophen (paracetamol) poisoning remains the most common cause of acute liver failure and acute liver transplantation in the United State...
2026-08-07 | Acetaminophen Poisoning: From Molecular Mechanisms to Multidisciplinary Management - A Contemporary Clinical Overview
Acetaminophen (N-acetyl-para-aminophenol, paracetamol) remains the leading cause of acute liver failure in the United States and accounts for a substantial proportion of pharmaceutical overdoses globally. This comprehensive review examines the epidemiology, pathophysiology, clinical presentation, and evidence-based management of acetaminophen toxicity, with particular emphasis on the critical role of timely intervention. The drug's widespread availability and pervasive public perception of safety contribute to its prominence in toxicity statistics, with over 60 million Americans using acetaminophen weekly, often unknowingly through combination products. The pathophysiological cascade is initiated by the saturation of hepatic sulfation and glucuronidation pathways, leading to the formation of the highly reactive metabolite N-acetyl-p-benzoquinoneimine (NAPQI) through cytochrome P450-mediated oxidation, predominantly via CYP2E1. When hepatic glutathione stores are depleted, NAPQI binds covalently to mitochondrial proteins, triggering oxidative stress, lipid peroxidation, and ultimately centrilobular necrosis. The clinical course classically progresses through four distinct stages, with the Rumack-Matthew nomogram serving as the cornerstone for risk stratification following acute ingestion. N-acetylcysteine, the specific antidote, is most effective when administered within 8 hours of ingestion and acts through glutathione replenishment, direct conjugation with NAPQI, and anti-inflammatory mechanisms. Emerging evidence suggests a potential role for fomepizole as adjunctive therapy in high-risk patients, though this remains investigational. Prognosis is excellent with early treatment, but delays significantly increase morbidity and mortality, with approximately 1-3% of severe cases requiring liver transplantation. A multidisciplinary approach encompassing emergency medicine, toxicology, hepatology, and critical care is essential for optimal patient outcomes. This review underscores the imperative for enhanced patient education, improved labeling practices, and continued research into novel therapeutic strategies to further reduce the burden of acetaminophen-induced hepatotoxicity.
2026-07-31 | Boosting Thioredoxin-1 Protects Against Acetaminophen-Induced Cardiotoxicity
Background: Although overdose-induced acute hepatic failure following acetaminophen (APAP) administration is well documented, clinical studies have also reported myocardial infarction, cardiac dysfunction, arrhythmias, pericarditis, and cardiac myocyte necrosis in APAP poisoning. As APAP overdose is associated with excessive reactive oxygen species (ROS) production and metabolism-mediated glutathione depletion, the cytosolic thioredoxin system (Trx-1/TrxR1/NADPH) may offer an alternative mechanism for cardioprotection. Although transgenic mice overexpressing thioredoxin-1 (Trx-1) are protected against doxorubicin/Adriamycin-induced cardiotoxicity, whether pharmacological enhancement of the cytosolic Trx system can mitigate APAP-induced cardiotoxicity and improve the therapeutic efficacy of chlorpromazine (CPZ) remains unclear. Methods: Cardiotoxicity was induced in wild-type C57BL/6 mice using APAP (400 mg/kg, i.p.). Expression of the Trx system was upregulated via chronic daily administration of low-dose epinephrine (EP, 0.2 mg/kg, s.c. for 14 days), and mice were subsequently treated with a subtoxic dose of CPZ (6 mg/kg, i.p.). Results: EP significantly upregulated the expression of Trx-1, thioredoxin-like protein 1 (Trx-L1), and thioredoxin reductase 1 (TrxR1) in cardiac tissue. Furthermore, EP attenuated APAP-induced acute cardiac injury, and its combination with CPZ additively amplified these cardioprotective effects. These findings were supported by the normalization of serum cardiac biomarkers (aspartate aminotransferase [AST], lactate dehydrogenase [LDH], and cardiac troponin I [cTnI]), reduction of oxidative stress (restoration of reduced glutathione [GSH], superoxide dismutase [SOD], and nuclear factor erythroid 2-related factor 2 [Nrf2]) and inflammatory markers (tumor necrosis factor-alpha [TNF-α]) in cardiac tissue, and preservation of normal myocardial histological architecture. Mechanistically, activation of the Trx system was accompanied by upregulation of β-arrestin-1 and cAMP response element-binding protein 1 (CREB1), indicating their involvement in Trx-mediated cardioprotection. Conclusion: Pharmacological enhancement of the cytosolic thioredoxin system protects against APAP-induced acute cardiac injury, and combining EP with CPZ exerts an additive cardioprotective effect.
2026-08-17 | Subchronic Alcohol Exposure Exacerbates Acetaminophen-Induced Acute Liver Injury via Macrophage-Mediated Inflammation and Mitochondrial Dysfunction.
Alcohol use is a major coexposure in patients taking acetaminophen (APAP), yet how subchronic alcohol exposure reshapes hepatic vulnerability to APAP remains incompletely defined. In this study, we examined the effects of chronic alcohol intake on APAP-induced liver injury in mice. Our results indicated that subchronic alcohol exposure significantly increased the mortality rate in APAP-overdosed mice. Alcohol pretreatment also exacerbated APAP-induced hepatic damage, as evidenced by elevated serum ALT and AST levels, enhanced inflammatory responses, and aggravated oxidative stress. Quantitative polymerase chain reaction (qPCR) analysis revealed that alcohol consumption suppressed mitochondrial biogenesis (MB)-related genes, including Pgc-1α and transcription factor A, mitochondrial (TFAM). Notably, macrophage depletion via clodronate liposomes not only attenuated hepatocyte injury and inflammation induction but also restored the expression of MB/function-related genes, including Pgc-1α, TFAM, and Opa1. These findings suggest macrophage-involved inflammatory amplification may aggravate APAP-induced liver injury, at least in part, by impairing mitochondrial adaptive repair responses.
2026-08-11 | Clinical Characteristics and Pattern of Paracetamol-Induced Liver Injury at Hospital Shah Alam: A Three-Year Retrospective Case Series
Background: Paracetamol poisoning is the most common type of therapeutic drug poisoning seen globally. The dose of ingested paracetamol and the time of presentation to a healthcare facility are important factors in assessing the severity of poisoning. In addition, factors affecting hepatic glutathione levels further influence the risk of toxicity. Objective: This three years case series aims to analyse the characteristics of liver injury observed in patients who presented to the hospital’s ED for Shah Alam following an intentional paracetamol overdose. Additionally, it seeks to determine risk factors specific to this local population. Methodology: Patients with a history of intentional paracetamol overdose and biochemical evidence of liver injury who presented to the ED of Hospital Shah Alam between 1st January 2022 and 31st December 2024 were included in this study. Patients aged less than 18 years were excluded from this study. Results: A total of 13 patients were included in this case series. The pattern of liver injury followed an established clinical course; however, no patients developed liver failure. High doses of paracetamol ingestion and late presentation after overdose were the expected risk factors. A further risk factor identified in this case series was low body weight. Six patients in this case series weighed less than 45 kg. Underweight patients may have underlying malnutrition. Paracetamol overdose hepatotoxicity risk is linked to depleted hepatic glutathione, which is known to be due to malnutrition. Conclusion: High doses of paracetamol ingestion with late presentation to a healthcare facility are known risk factors for paracetamol-induced liver injury. This case series also revealed that underweight patients are at risk, possibly because of malnutrition. These findings suggest that clinicians may consider a lower treatment threshold, such as the 100-line threshold, in underweight or potentially malnourished patients, although larger studies are needed.
2026-08-11 | Defining risk: the case for conceptual clarity in acetaminophen poisoning
Despite the widespread availability of acetylcysteine, acetaminophen (paracetamol) poisoning remains the most common cause of acute liver failure and acute liver transplantation in the United State...
2026-08-07 | Acetaminophen Poisoning: From Molecular Mechanisms to Multidisciplinary Management - A Contemporary Clinical Overview
Acetaminophen (N-acetyl-para-aminophenol, paracetamol) remains the leading cause of acute liver failure in the United States and accounts for a substantial proportion of pharmaceutical overdoses globally. This comprehensive review examines the epidemiology, pathophysiology, clinical presentation, and evidence-based management of acetaminophen toxicity, with particular emphasis on the critical role of timely intervention. The drug's widespread availability and pervasive public perception of safety contribute to its prominence in toxicity statistics, with over 60 million Americans using acetaminophen weekly, often unknowingly through combination products. The pathophysiological cascade is initiated by the saturation of hepatic sulfation and glucuronidation pathways, leading to the formation of the highly reactive metabolite N-acetyl-p-benzoquinoneimine (NAPQI) through cytochrome P450-mediated oxidation, predominantly via CYP2E1. When hepatic glutathione stores are depleted, NAPQI binds covalently to mitochondrial proteins, triggering oxidative stress, lipid peroxidation, and ultimately centrilobular necrosis. The clinical course classically progresses through four distinct stages, with the Rumack-Matthew nomogram serving as the cornerstone for risk stratification following acute ingestion. N-acetylcysteine, the specific antidote, is most effective when administered within 8 hours of ingestion and acts through glutathione replenishment, direct conjugation with NAPQI, and anti-inflammatory mechanisms. Emerging evidence suggests a potential role for fomepizole as adjunctive therapy in high-risk patients, though this remains investigational. Prognosis is excellent with early treatment, but delays significantly increase morbidity and mortality, with approximately 1-3% of severe cases requiring liver transplantation. A multidisciplinary approach encompassing emergency medicine, toxicology, hepatology, and critical care is essential for optimal patient outcomes. This review underscores the imperative for enhanced patient education, improved labeling practices, and continued research into novel therapeutic strategies to further reduce the burden of acetaminophen-induced hepatotoxicity.
2026-07-31 | Boosting Thioredoxin-1 Protects Against Acetaminophen-Induced Cardiotoxicity
Background: Although overdose-induced acute hepatic failure following acetaminophen (APAP) administration is well documented, clinical studies have also reported myocardial infarction, cardiac dysfunction, arrhythmias, pericarditis, and cardiac myocyte necrosis in APAP poisoning. As APAP overdose is associated with excessive reactive oxygen species (ROS) production and metabolism-mediated glutathione depletion, the cytosolic thioredoxin system (Trx-1/TrxR1/NADPH) may offer an alternative mechanism for cardioprotection. Although transgenic mice overexpressing thioredoxin-1 (Trx-1) are protected against doxorubicin/Adriamycin-induced cardiotoxicity, whether pharmacological enhancement of the cytosolic Trx system can mitigate APAP-induced cardiotoxicity and improve the therapeutic efficacy of chlorpromazine (CPZ) remains unclear. Methods: Cardiotoxicity was induced in wild-type C57BL/6 mice using APAP (400 mg/kg, i.p.). Expression of the Trx system was upregulated via chronic daily administration of low-dose epinephrine (EP, 0.2 mg/kg, s.c. for 14 days), and mice were subsequently treated with a subtoxic dose of CPZ (6 mg/kg, i.p.). Results: EP significantly upregulated the expression of Trx-1, thioredoxin-like protein 1 (Trx-L1), and thioredoxin reductase 1 (TrxR1) in cardiac tissue. Furthermore, EP attenuated APAP-induced acute cardiac injury, and its combination with CPZ additively amplified these cardioprotective effects. These findings were supported by the normalization of serum cardiac biomarkers (aspartate aminotransferase [AST], lactate dehydrogenase [LDH], and cardiac troponin I [cTnI]), reduction of oxidative stress (restoration of reduced glutathione [GSH], superoxide dismutase [SOD], and nuclear factor erythroid 2-related factor 2 [Nrf2]) and inflammatory markers (tumor necrosis factor-alpha [TNF-α]) in cardiac tissue, and preservation of normal myocardial histological architecture. Mechanistically, activation of the Trx system was accompanied by upregulation of β-arrestin-1 and cAMP response element-binding protein 1 (CREB1), indicating their involvement in Trx-mediated cardioprotection. Conclusion: Pharmacological enhancement of the cytosolic thioredoxin system protects against APAP-induced acute cardiac injury, and combining EP with CPZ exerts an additive cardioprotective effect.
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Drug Discovery Landscape
6 orphan drug designations for Paracetamol poisoning, including 2 approved therapies.
6 orphan drug designations for Paracetamol poisoning, including 2 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Fomepizole | small molecules | FDA | 2021-03-02 | — | Denver Health - Rocky Mountain Poison & Drug Safety |
calmangafodipir | small molecules | FDA | 2019-03-15 | — | Egetis Therapeutics AB |
melatonin | small molecules | FDA | 2017-03-02 | — | WORPHMED Srl |
acetylcysteine effervescent tablets for oral solution [Cetylev] | small molecules | FDA | 2015-02-24 | 2016-01-29 | Arbor Pharmaceuticals, Inc. |
acetylcysteine [Acetadote] | small molecules | FDA | 2001-10-19 | 2004-01-23 | Cumberland Pharmaceuticals, Inc. |
Acetylcysteine | small molecules | FDA | 1987-08-13 | — | Bristol-Myers Squibb Company |
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