Treatment Of Paracetamol Overdose Research Articles

Assessing the impact of a new medical toxicology service on the treatment of paracetamol overdose at a large tertiary care hospital

Background Paracetamol overdose is the most common cause of acute liver failure in the United States. Administration of acetylcysteine is the standard of care for this intoxication. Laboratory values and clinical criteria are used to guide treatment duration, but decision-making is nuanced and often complex and difficult. The purpose of this study was to evaluate the effect of the introduction of a medical toxicology service on the rate of errors in the management of paracetamol overdose. Methods This was a single center, retrospective, cohort evaluation. Patients with suspected paracetamol overdose were divided into two groups: those attending in the 1 year period before and those in the 1 year after the introduction of the medical toxicology service. The primary outcome was the frequency of deviations from the established management of paracetamol intoxication, using international guidelines as a reference. Results Fifty-four patients were eligible for the study (20 pre-toxicology-service, 34 post-toxicology-service). The frequency of incorrect therapeutic decisions was significantly lower in the post-toxicology service implementation versus the pre-implementation group (P = 0.005). Discussion Our study suggests that a medical toxicology service reduces the incidence of management errors, including the number of missed acetylcysteine doses in patients with paracetamol overdose. The limitations include the retrospective study design and that the study was conducted at a single center, which may limit generalizability. Conclusions The implementation of a medical toxicology service was associated with a decrease in the number of errors in the management of paracetamol overdose.

AN EXPERIMENTAL STUDY ON ALBINO RATS TO COMPARE THE HEPATOPROTECTIVE EFFECT OF ORALLY ADMINISTERED DL-METHIONINE AND N-ACETYLCYSTEINE ON THE LIVER INJURY CAUSED BY POSITIVE CONTROL DRUG DICLOFENAC SODIUM

Introduction: Liver, main organ for biotransformation of drugs, during which most of the drugs which are lipophilic in nature are made hydrophilic by the biochemical processes in the liver cells resulting into water-soluble products which get excreted in urine or bile. Adverse drug reactions (ADRs) pertaining to liver, can be of mainly two types, predictable or dose dependent and idiosyncratic. To counter the oxidative stress and cellular damage, several antioxidant enzymes have been developed including superoxide dismutase (SOD), Glutathione peroxidase and catalase, that detoxify the reactive oxygen species and the cells contained endogenous antioxidants that scavenge the free radicals and reduces the cellular damage of which glutathione plays a major role. Synthesis of glutathione is regulated at the substrate level by cysteine, which is synthesized from homocysteine via the trans-sulfuration pathway N-Acetylcysteine used as a specific drug in the treatment of Paracetamol overdose, serves as a prodrug to L-Cysteine, which is a precursor to the antioxidant Glutathione. L-methionine, a precursor of L-cysteine, which is considered to have antioxidant activity, is found to be a precursor to glutathione as well. Methionine is particularly important in opposing the toxicity of free radicals generated by various toxins. Hence, supplementation of the same has been proposed to have a greater role in reducing the toxic effect on liver. The aim was to study the comparative hepatoprotective effect of orally administered DL-Methionine and N-Acetylcysteine on the liver injury induced by positive control Diclofenac Sodium. Materials and Methods: The healthy albino rats were grouped for the experimental study, in various groups (n=6). After overnight fasting, rats belonging to Group I Vehicle treated Group (n=6) were administered Distilled Water 10 ml/kg orally Group II to V were administered single oral dose concomitantly with Diclofenac sodium (96 mg/kg & 240 mg/kg p.o.) and DL-Methionine (700 mg/kg p.o. & 1400 mg/kg p.o.) respectively. Group VI and VII were administered single oral dose concomitantly with Diclofenac sodium (96 mg/kg & 240 mg/kg p.o.) and N-Acetylcysteine 450 mg/kg p.o., respectively. Serum samples from each rats were collected after 24-hours of post-treatment, to study the comparative effects of DL-Methionine and N-Acetylcysteine on the liver injury induced by positive control Diclofenac Sodium through Haemato-biochemical changes. Results: The vehicle-treated group showed no significant alteration in the level of liver function tests and liver morphology. On concomitant administration of DL-Methionine 700 mg/kg with Diclofenac sodium 96 mg/kg and 240 mg/kg it was observed that there occurred significant reduction (p < 0.001) in the serum SGOT and SGPT levels as compared to control and positive control group. The hepatoprotective effect of DL-Methionine 700 mg/kg and N-Acetylcysteine 450 mg/kg on concomitant administration with positive control drug Diclofenac sodium 96 mg/kg were compared for their effect on serum SGPT levels and was observed that there was no statistically significant decrease in the levels of SGPT when compared between the two groups of hepatoprotective agents. The hepatoprotective effect of DL-Methionine 700 mg/kg and N-Acetylcysteine 450 mg/kg on concomitant administration with positive control drug Diclofenac sodium 240 mg/kg, were compared for their effect on serum SGPT levels. It was observed that there was a significant reduction (p <0.05) in SGPT levels, with DL-Methionine 700 mg/kg and N-Acetylcysteine 450 mg/kg. However, in both the doses of DL-Methionine, there were no statistically significant changes in the Total Serum Bilirubin, serum Alkaline Phosphatase & serum Gamma-Glutamyl Transpeptidase (GGTP) levels. Conclusion: We have compared for the effectiveness of DL-Methionine and N-Acetylcysteine for their hepatoprotective effect against Diclofenac-induced hepatotoxicity, where we have observed, both DL-Methionine and N-Acetylcysteine reduces the serum transaminases levels, that were elevated due to the hepatotoxic effect of diclofenac sodium. However, there was no much of a difference of hepatoprotective effect of both DL-Methionine and N-Acetylcysteine. In summary, our present study reinforced the concept that hepatotoxicity induced by drug can be protected by administering NAC even in cases of non-paracetamol induced liver injury.

A two-bag acetylcysteine regimen is associated with shorter delays and interruptions in the treatment of paracetamol overdose

Background The three-bag intravenous (IV) acetylcysteine regimen for paracetamol overdose is associated with frequent and long delays during treatment. This has not been previously studied in regard to the two-bag regimen. Aims Our primary aim was to compare the cumulative duration of delays during IV acetylcysteine infusion between the three-bag and two-bag regimens. Secondary aims were to compare the frequency of delays and to identify causes for delay. Methods This was a retrospective cohort study of patients receiving IV acetylcysteine for the treatment of paracetamol overdose, conducted at three Australian emergency departments. A cohort of patients treated with the three-bag regimen from October 2009 to October 2013 was compared to patients treated with the two-bag regimen from February 2014 to May 2020. Start times of each infusion were sourced from medical records and delays were calculated by comparing actual infusion time against prescribed time. Evidence of adverse drug reactions – gastrointestinal reactions and cutaneous and systemic non-allergic anaphylactoid reactions (NAARs) – were also recorded. Results The three-bag cohort included 271 cases and the two-bag cohort included 598 cases. Delays were significantly shorter in the two-bag cohort, compared to the three-bag cohort: median delay 35 min (IQR: 15, 70) vs 65 min (IQR: 40, 105), p < 0.01. Delays longer than 1 h were less frequent in the two-bag cohort: 31% vs 51%, p < 0.01. NAARs were associated with significantly longer delays in both cohorts and were more frequent in the three-bag cohort. Conclusions The two-bag regimen was associated with significantly fewer and shorter delays. NAARs, which were more frequent in the three-bag cohort, were associated with significantly longer delays.

An insight into paracetamol and its metabolites using molecular docking and molecular dynamics simulation.

Paracetamol is a relatively safe analgesia/antipyretic drug without the risks of addiction, dependence, tolerance, and withdrawal when used alone. However, when administrated in an opioid/paracetamol combination product, which often contains a large quantity of paracetamol, it can be potentially dangerous due to the risk of hepatotoxicity. Paracetamol is known to be metabolized into N-(4-hydroxyphenyl)-arachidonamide (AM404) via fatty acid amide hydrolase (FAAH) and into N-acetyl-p-benzoquinone imine (NAPQI) via cytochrome P450 (CYP) enzymes. However, the underlying mechanism of paracetamol is still unclear. In addition, paracetamol has the potential to interact with other drugs that are also involved with CYP family enzymes (inducer/inhibitor/substrate), an example being illicit drugs. In our present work, we looked into the relationship between paracetamol and its metabolites (AM404 and NAPQI) using molecular docking and molecular dynamics (MD) simulations. We first carried out a series of molecular docking studies between paracetamol/AM404/NAQPI and their reported targets, including CYP 2E1, FAAH, TRPA1, CB1, and TRPV1. Subsequently, we performed MD simulations and energy decomposition for CB1-AM404, TRPV1-AM404, and TRPV1-NAPQI for further investigation of the dynamics interactions. Finally, we summarized and discussed the reported drug-drug interactions between paracetamol and central nervous system drugs, especially illicit drugs. Overall, we are able to provide new insights into the structural and functional roles of paracetamol and its metabolites that can inform the potential prevention and treatment of paracetamol overdose. Graphical abstract Paracetamol and its metabolites.

Antioxidant therapy in patients with severe aluminum phosphide poisoning: A pilot study

Background:N-acetyl cysteine (NAC) is a powerful antioxidant and has been used extensively in the treatment of paracetamol overdose with great success. Aluminum phosphide (ALP) ingestion results in significant oxidative stress. In this study, we evaluated the effects of NAC on mortality in patients with severe ALP poisoning.Subjects and Methods:This prospective intervention study was carried out in the emergency medical unit attached to the Nehru Hospital at PGIMER, Chandigarh, over a period of 1 year. All the patients presenting with severe ALP poisoning were randomized into two group. The treatment group received NAC in the dose of 150 mg/kg intravenous over 1 h, followed by 50 mg/kg over 4 h, followed by 100 mg/kg 16 h in 5% dextrose. The placebo group received 5% dextrose. The primary end point was mortality.Results:A total of 50 patients were recruited. The baseline parameters were comparable in both groups. The survivors in the treatment group received 19 g of NAC, but the nonsurvivors received only 12.15 g of NAC. The overall mortality in the study group was 88% with 87.5% mortality in the treatment group and 88.5% in the placebo group.Conclusions:Antioxidant therapy in the form of NAC in severe ALP poisoning did not confer any survival benefit.

Treatment of paracetamol overdose: room for improvement?

Treatment of paracetamol overdose: room for improvement?

Identification of Patients at Risk of Anaphylactoid Reactions to N-acetylcysteine in the Treatment of Paracetamol Overdose: Schmidt LE. Clin Toxicol 2013;51:467–72.

Paracetamol (acetaminophen) is a frequent cause of accidental and intentional poisoning worldwide. N-acetylcysteine (NAC) is an effective antidote if administered expeditiously, but can lead to anaphylactoid reactions in some patients. This observational case series looked at a group of patients receiving NAC for acetaminophen overdose and aimed to identify patients at greater risk for reactions. Patient records from a hospital in Denmark identified 1218 cases of acetaminophen poisoning in 950 patients.

Impact of Amending the Acetylcysteine Marketing Authorisation on Treatment of Paracetamol Overdose

In September 2012, the Medicines and Healthcare products Regulatory Agency (MHRA) substantially amended the Marketing Authorisation for acetylcysteine following an extensive review. The present study examined the impact of this license change on patterns of acetylcysteine use in patients presenting to hospital after paracetamol (acetaminophen) overdose. Between September 2011 and April 2013, 785 consecutive patients presented to York Hospital due to paracetamol overdose, and a before-after analysis was used to compare outcomes. There were 483 patients before and 302 patients after the license amendment, and age, gender, acute or staggered overdose pattern, and dose were similar in both groups. In the patients with paracetamol concentrations between the “100-line” and “200-line,” a significantly higher proportion received acetylcysteine treatment (51% before versus 98% after, P = 0.0029), as expected. A modest increase was also observed in relation to late or staggered overdose or cases where the time of ingestion was uncertain (53% versus 74%, P = 0.0430). The median duration of hospital stay increased across the entire study population, from 15 to 24 hours (P = 0.0159) due to the increased proportion of patients requiring acetylcysteine treatment. The findings indicate that the MHRA amendment is a financially costly intervention, and further studies are needed to examine clinical outcomes so that its cost effectiveness might be addressed.

Identification of patients at risk of anaphylactoid reactions to N-acetylcysteine in the treatment of paracetamol overdose

Context. N-acetylcysteine (NAC) is acknowledged as an effective antidote for paracetamol overdose. However, adverse effects to NAC are common and may be a point of concern for the patient and the treating physician. Objective. The aim of the present study was to further analyse possible risk factors of anaphylactoid adverse effects to intravenous NAC in order to identify individual patients or groups of patients at particular risk. Methods. This study is an observational case series of adverse effects to NAC administered according to the standard guidelines in patients who presented with paracetamol overdose between March 1999 and September 2011. Results. A total of 1218 admissions for paracetamol overdose receiving intravenous NAC were recorded in 950 patients. Anaphylactoid adverse effects occurred in 18.6%. The proportion of cases with adverse effects gradually declined from 25.9% in cases with undetectable p-paracetamol to 6.3% in cases with p-paracetamol above 1.5 mmol/L (226 μg/mL) (Spearman Rank R-test: p < 0.00001). The proportion of cases with adverse effects was significantly higher in cases of non-Danish origin than that of Danish origin (28.5% vs. 15.1%; Chi-square: p < 0.00001). In patients with repeated exposure to NAC, the rate of adverse effects on re-exposure was significantly higher in patients with a previous reaction to NAC compared to those without a previous reaction (Rate Ratio 6.2; 95% CI 2.9–17.1). Conclusion. The development of anaphylactoid adverse effects to intravenous NAC was strongly associated with a low p-paracetamol, non-Danish origin and a history of previous reaction to NAC. These adverse effects are common, but usually mild and easily manageable. The incidence of adverse effects may be reduced by pre-treating selected patients with antihistamines, in particular those with a previous reaction to NAC.

Cimetidine enhances the hepatoprotective action of N-acetylcysteine in mice treated with toxic doses of paracetamol

Paracetamol, in toxic doses, is associated with extensive liver damage. This represents one of the common causes of morbidity and mortality in drug poisoning cases. This study was undertaken to investigate the possible potentiation of the hepatoprotective action of N-acetylcysteine (NAC) by cimetidine (CMD), an inhibitor of hepatic microsomal oxidative enzymes. The effects of NAC, cimetidine and the two in combination, administered 2 h post-paracetamol dose, on mortality, plasma glutamic oxaloacetic (GOT) and glutamic pyruvic (GPT) transaminase activities and hepatic reduced glutathione (GSH) levels were investigated in mice 24 h after treatment with a single oral dose of paracetamol (400 mg/kg). Both NAC and cimetidine caused a partial improvement of survival rate, plasma GOT and GPT activities. In addition, they prevented the depletion of hepatic GSH contents. However, concomitant administration of NAC and cimetidine produced a 100% survival rate and a marked reduction in plasma GOT and GPT activities to within the normal range, while significantly raising hepatic GSH concentrations to values close to those measured in saline-treated control animals. It is therefore concluded that cimetidine and N-acetylcysteine may have an additive hepatoprotective action in the treatment of paracetamol overdose.