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The Annals of Pharmacotherapy Sep 2008To report a case of erratic absorption, double peak serum concentrations, and hepatotoxicity following premature cessation of intravenous N-acetylcysteine (NAC)...
OBJECTIVE
To report a case of erratic absorption, double peak serum concentrations, and hepatotoxicity following premature cessation of intravenous N-acetylcysteine (NAC) treatment in the setting of a massive acetaminophen overdose.
CASE SUMMARY
A 78-year-old man reportedly ingested approximately 96 immediate-release acetaminophen 500-mg tablets (48 g) over a one-hour period in an apparent suicide attempt. The acetaminophen concentration at 2.25 hours was 264 microg/mL. Intravenous NAC was initiated 5 hours postingestion. At 6.25 hours postingestion, the acetaminophen concentration was 281 microg/mL. Following administration of intravenous NAC for 21 hours, therapy was discontinued despite a residual acetaminophen concentration of 116 microg/mL. The patient experienced hepatotoxicity, coagulopathy, and renal injury. Pharmacokinetic analysis revealed significantly prolonged acetaminophen absorption and a second peak acetaminophen concentration of 228 microg/mL approximately 48 hours postingestion. Direct in-hospital monitoring of the patient made a second ingestion unlikely.
DISCUSSION
Acetaminophen overdose is usually effectively managed with NAC. Patients with massive ingestions may have altered absorption kinetics due to acetaminophen's solubility being exceeded, physiologically or chemically altered gastrointestinal emptying or motility, or other factors. These patients may benefit from gastrointestinal decontamination and prolonged NAC therapy.
CONCLUSIONS
In patients with massive acetaminophen ingestion, erratic absorption may occur, and toxic serum concentrations may persist beyond a standard 21-hour course of intravenous NAC therapy. Acetaminophen concentrations and aminotransferase levels should be evaluated at the completion of the intravenous NAC infusion to ensure complete elimination of acetaminophen and absence of hepatotoxicity and to exclude the need for prolonged treatment.
Topics: Acetaminophen; Acetylcysteine; Aged; Chemical and Drug Induced Liver Injury; Drug Overdose; Free Radical Scavengers; Half-Life; Humans; Male; Time Factors
PubMed: 18628444
DOI: 10.1345/aph.1K680 -
British Medical Journal Mar 1975
Topics: Acetaminophen; Animals; Antidotes; Chemical and Drug Induced Liver Injury; Humans; Inactivation, Metabolic
PubMed: 1139142
DOI: 10.1136/bmj.1.5957.536 -
British Journal of Nursing (Mark Allen...It is easier than we may think to overdose inadvertently on paracetamol. With another winter upon us, many cold remedy products now carry a manufacturer's warning;...
It is easier than we may think to overdose inadvertently on paracetamol. With another winter upon us, many cold remedy products now carry a manufacturer's warning; however, do nurses themselves fully understand why paracetamol can be so fatal?
Topics: Acetaminophen; Humans; Intestinal Absorption; Metabolic Clearance Rate; Patient Education as Topic; Tissue Distribution
PubMed: 8260799
DOI: 10.12968/bjon.1993.2.20.1027 -
Professional Nurse (London, England) Sep 1993
Topics: Acetaminophen; Humans; Metabolic Clearance Rate
PubMed: 8367509
DOI: No ID Found -
Critical Care and Resuscitation :... Mar 2012Paracetamol is one of the commonest medications used worldwide. This review was conceived as a consequence of evaluating the literature in the protocol development of... (Review)
Review
BACKGROUND
Paracetamol is one of the commonest medications used worldwide. This review was conceived as a consequence of evaluating the literature in the protocol development of two randomised, controlled clinical trials investigating the safety and efficacy of paracetamol in ICU patients (the HEAT [Permissive HyperthErmiA Through Avoidance of Paracetamol in Known or Suspected Infection in the Intensive Care Unit] study; the Paracetamol After traumatic Brain Injury [PARITY] Study).
OBJECTIVE
To provide a historical perspective on the introduction of paracetamol into clinical practice, to present the pharmacology of paracetamol in critical illness, and evaluate the current evidence for its use as an antipyretic and analgesic in intensive care.
DESIGN
Literature searches were performed using keywords: "paracetamol", "acetaminophen", "critical illness", "intensive care", "history", "pharmacology", "antipyre*", "analgesi*", "adverse effect*", "administration and dosage", "toxicity", "animals" and "humans".
DATA SOURCES
Embase, MEDLINE, PubMed (1947/1950 to July 2011).
REVIEW METHODS
The authors examined each article's title and abstract, fully reviewing relevant articles, with searching of reference lists and additional hand-searching. The most recent and highest quality available evidence was included.
RESULTS
Limited data are available on the pharmacology of paracetamol in the critically ill. Among patients with sepsis, paracetamol may inhibit the immunological response. Among patients with neurological injury paracetamol can reduce temperature but appears not to improve outcome. When administered with opioids after major surgery, paracetamol does not reduce the incidence of pain or opioid related side-effects.
CONCLUSION
Despite the widespread use of paracetamol in critical illness, there is a paucity of data supporting its utility in this setting. Further research is required to determine how paracetamol should be used in the critically ill.
Topics: Acetaminophen; Analgesics; Antipyretics; Critical Illness; Drug-Related Side Effects and Adverse Reactions; Humans
PubMed: 22404066
DOI: No ID Found -
European Journal of Clinical... Apr 1977Plasma paracetamol concentrations were measured in 6 volunteers after single intravenous (1000 mg) and oral (500 mg, 1000 mg and 2000 mg) doses of the drug. Paracetamol...
Plasma paracetamol concentrations were measured in 6 volunteers after single intravenous (1000 mg) and oral (500 mg, 1000 mg and 2000 mg) doses of the drug. Paracetamol levels declined multiphasically with a mean clearance after intravenous administration of 352 +/- 40 ml/min. A two-compartment open model appeared to describe the decline adequately. Comparison of the areas under the plasma concentration-time curves (AUC) indicated that oral bioavailability increased from 0.63 +/- 0.02 after 500 mg, to 0.89 +/- 0.04 and 0.87 +/- 0.08 after 1000 mg and 2000 mg, respectively. As a consequence of the incomplete bioavailability of paracetamol, as well as its multicompartmental distribution, accurate estimates of its distribution volume and clearance cannot be obtained if the drug is given orally. However, an estimate of its total plasma clearance may be derived from the AUC after a 500 mg oral dose.
Topics: Acetaminophen; Administration, Oral; Biological Availability; Half-Life; Humans; Injections, Intravenous; Kinetics; Male; Models, Biological
PubMed: 862649
DOI: 10.1007/BF00607678 -
Acta Neurobiologiae Experimentalis 2010Acetaminophen use in children has been associated with increased autism risk. Recent evidence suggests that acetaminophen's analgesic actions result from activation of...
Acetaminophen use in children has been associated with increased autism risk. Recent evidence suggests that acetaminophen's analgesic actions result from activation of the endocannabinoid system, and activation of this system can have neuromodulatory consequences during development. This investigation was performed to determine if there is evidence to support the hypothesis that acetaminophen use can trigger autism by activation of the endocannabinoid system.
Topics: Acetaminophen; Autistic Disorder; Cannabinoid Receptor Modulators; Child; Child, Preschool; Endocannabinoids; Fever; Humans; Monocytes; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2
PubMed: 20628445
DOI: 10.55782/ane-2010-1793 -
Acta Anaesthesiologica Scandinavica Jan 2001Paracetamol (N-acetyl-p-amino-phenol) or acetaminophen has become the most widely used analgesic and antipyretic in children. However, there is a wide discrepancy... (Review)
Review
BACKGROUND
Paracetamol (N-acetyl-p-amino-phenol) or acetaminophen has become the most widely used analgesic and antipyretic in children. However, there is a wide discrepancy between the extent to which paracetamol is used and the limited available pharmacological data in small infants. The purpose of this article is to present a review of the current literature regarding the use of paracetamol in neonates and infants with a particular emphasis on pharmacological issues.
METHODS
A MEDLINE search (up to March 2000) was conducted to identify relevant English-language publications using paracetamol, children, infants and neonates as search terms. Additional studies were identified from bibliographies of the reviewed literature.
RESULTS
Pharmacological studies on paracetamol in infants are few. Most studies have focused on the administration of one single paracetamol dose, and the problem of cumulative toxicity with repeated dosing has not been addressed. Plasma paracetamol concentration should be 10-20 mg ml(-1) to achieve antipyretic and analgesic effects. The bioavailability of the different formulations and routes of administration vary with age. Rectal absorption is slower and more erratic than the oral; however, in the very young, rectal bioavailability is higher than in older patients. Volume of distribution seems to be age-independent, whereas clearance is reduced in neonates and particularly in preterm babies. Neonates and infants are capable of forming the reactive intermediate metabolite that causes hepatocellular damage, particularly after multiple doses. They have an immature glucuronide conjugation system, but the rate constant for the sulphation metabolic pathway is larger than in older children, and this is the most important route of metabolism.
CONCLUSIONS
The pharmacokinetics and pharmacodynamics of paracetamol differ substantially in neonates and infants from those in older children and adults; hence, dosing should be adjusted accordingly.
Topics: Acetaminophen; Analgesics, Non-Narcotic; Humans; Infant; Infant, Newborn
PubMed: 11152028
DOI: 10.1034/j.1399-6576.2001.450104.x -
Effect of acetaminophen (paracetamol) and its antagonists on glutathione (GSH) content in rat liver.Biochemical Pharmacology Jul 1980
Topics: Acetaminophen; Acetylcysteine; Animals; Glutathione; In Vitro Techniques; Liver; Methionine; Rats; Time Factors
PubMed: 7397003
DOI: 10.1016/0006-2952(80)90113-6 -
Environmental Science and Pollution... Mar 2009Pharmaceuticals and their metabolites are detected in the aquatic environment and our drinking water supplies. The need for high quality drinking water is one of the...
BACKGROUND, AIM, AND SCOPE
Pharmaceuticals and their metabolites are detected in the aquatic environment and our drinking water supplies. The need for high quality drinking water is one of the most challenging problems of our times, but still only little knowledge exists on the impact of these compounds on ecosystems, animals, and man. Biological waste water treatment in constructed wetlands is an effective and low-cost alternative, especially for the treatment of non-industrial, municipal waste water. In this situation, plants get in contact with pharmaceutical compounds and have to tackle their detoxification. The mechanisms for the detoxification of xenobiotics in plants are closely related to the mammalian system. An activation reaction (phase I) is followed by a conjugation (phase II) with hydrophilic molecules like glutathione or glucose. Phase III reactions can be summarized as storage, degradation, and transport of the xenobiotic conjugate. Until now, there is no information available on the fate of pharmaceuticals in plants. In this study, we want to investigate the fate and metabolism of N-acetyl-4-aminophenol (paracetamol) in plant tissues using the cell culture of Armoracia rusticana L. as a model system.
MATERIALS AND METHODS
A hairy root culture of A. rusticana was treated with acetaminophen in a liquid culture. The formation and identification of metabolites over time were analyzed using HPLC-DAD and LC-MSn techniques.
RESULTS
With LC-MS technique, we were able to detect paracetamol and identify three of its metabolites in root cells of A. rusticana. Six hours after incubation with 1 mM of acetaminophen, the distribution of acetaminophen and related metabolites in the cells resulted in 18% paracetamol, 64% paracetamol-glucoside, 17% paracetamol glutathione, and 1% of the corresponding cysteine conjugate.
DISCUSSION
The formation of two independently formed metabolites in plant root cells again revealed strong similarities between plant and mammalian detoxification systems. The detoxification mechanism of glucuronization in mammals is mirrored by glucosidation of xenobiotics in plants. Furthermore, in both systems, a glutathione conjugate is formed. Due to the existence of P450 enzymes in plants, the formation of the highly reactive NAPQI intermediate is possible.
CONCLUSIONS
In this study, we introduce the hairy root cell culture of A. rusticana L. as a suitable model system to study the fate of acetaminophen in plant tissues. Our first results point to the direction of plants being able to take up and detoxify the model substrate paracetamol. These first findings underline the great potential of using plants for waste water treatments in constructed wetlands.
RECOMMENDATIONS AND PERSPECTIVES
This very first study on the detoxification of a widely used antipyretic agent in plant tissues again shows the flexibility of plant detoxification systems and their potential in waste water treatment facilities. This study covers only the very first steps of acetaminophen detoxification in plants; still, there is no data on long-term exposure as well as the possible impact of pharmaceuticals on the plant health and stress defense. Long-term experiments need to be performed to follow the fate of acetaminophen in root and leaf cells in a whole plant system, and to evaluate possible usage of plants for the remediation of acetaminophen from waste water.
Topics: Acetaminophen; Anti-Inflammatory Agents, Non-Steroidal; Armoracia; Cells, Cultured; Glucose; Glutathione; Kinetics; Molecular Structure; Plant Roots
PubMed: 19145453
DOI: 10.1007/s11356-008-0095-z