Ibrahim et al.

, Emergency Med 2013, 3:6

Emergency Medicine: http://dx.doi.org/10.4172/2165-7548.1000158

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Mini Review Open Access

Paracetamol Toxicity- An Overview

Tasneem Ibrahim1*, Smriti Agnihotri2 and Arun Kumar Agnihotri3
1
Lecturer, Department of Pharmacology, SSR Medical College, Mauritius
2
Professor, Department of Pathology, SSR Medical College, Mauritius
3
Department of Forensic Medicine & Toxicology, SSR Medical College, Mauritius

Introduction indicated for the symptomatic relief of fever, mild musculoskeletal

pain, headache, migraine. The most common route of administration is
Paracetamol (acetaminophen) is a safe, effective, well-tolerated the oral route (in the form of tablets, effervescent tablets & suspension);
and cheap analgesic and anti-pyretic drug with relatively few adverse other routes are the rectal route as suppository and in hospital settings,
effects when used at the recommended therapeutic dosage. It was it can be given via intravenous infusion.
first introduced in the year 1955 for its clinical application and since
then, it is widely used almost throughout the world. In many countries Following an oral dose, the drug is well absorbed from the gastro-
the drug is readily available over-the-counter without the need of intestinal tract, reaching a peak plasma concentration within 30-60
prescription. It’s easy availability and no need for prescription made minutes. The drug is metabolized in the liver, 80% of an administered
it one of the commonest drugs used for suicidal or self harm purposes. dose (therapeutic dose), undergoes glucoronide conjugation and
Its toxicity was noticed in the 1960s [1]. Since then number of cases sulphate conjugation; the remaining drug undergoes hydroxylation to
coming to the emergency department kept on increasing, especially form a highly reactive oxidative product, N-Acetyl P Benzo-quineime
in UK [2,3]. It is also a frequent cause of poisoning in many other (NAPQI), which in turn conjugates with glutathione, GSH to form
countries, including North America, Australia and New Zealand and mercapturic acid and is eliminated in urine [22].
several other countries in Europe [4-9]. Increasing number of the cases Hepato toxicity generally occurs when the glutathione stores fall to
brought the idea of legalization of drug from over the counter policy less than 30% of the normal [23]. The supply of hepatic GSH is limited
to prescription only status. Following legislation in 1998 to limit pack and in case of overdose of paracetamol, the amount of NAPQI formed
sizes, beneficial effects on paracetamol- related mortality and morbidity is greater than the GSH available such that NAPQI is not conjugated
were reported in England. Although following legislations to limit pack and being an active product, it exerts hepato-toxic effects and also
sizes, morbidity and mortality reduced, however strict measures are causes renal tubular necrosis by reacting with the nucleophilic aspects
required to reduce breaches of sales guidelines [10,11]. Role of media of the cells. Paracetamol in the dose of 10-15 g can potentially lead to
and internet should be more emphasized in awareness about hepatic fatal hepato- toxicity [24]. Severe hepato cellular damage and renal
failure due to paracetamol toxicity. tubular necrosis can result from taking 150 mg/kg (about 5-10 g) in a
With this background we review the clinical features, pharmacology, single dose [25].
management and preventive measures to reduce the load to intentional The risk of hepato cellular injury is increased by any condition that
toxicity. leads to an increase in the production of NAPQI (patients on some
Epidemiology drugs like Rifampicin, Phenobarbitone, Phenytoin, Carbamazepine,
etc.) or conditions with low GSH reserves such as fasting, malnutrition,
Paracetamol is easily available in market, and lay people alcoholic related or other types of liver diseases, HIV positive patients,
commonly underestimate its toxicity. Paracetamol toxicity is one cystic fibrosis and genetic variation.
of the most common causes of poisoning worldwide [12]. Currently
paracetamol is the most common cause of ALF in both United States Effects on Internal Organs
and United Kingdom, with a trend to increasing incidence in the Pathologic evaluation of various organs shows that the liver is a
United States [13]. A national network was established to track cases primary target for toxicity after paracetamol overdose because the
of acute liver failure in the United States, found that nearly half the hepatocytes elaborate NAPQI. As NAPQI has a short life span, it can
cases were attributable to paracetamol, and intentional (suicidal) and damage only cells that elaborate it. Overdose of paracetamol may
unintentional (chronic) poisonings accounted equally for the cases of produce severe liver injury with hepato cellular necrosis. The important
paracetamol- associated hepatic failure [14]. Pediatric paracetamol mechanisms of cell injury are metabolic activation of paracetamol,
exposures account for approximately 30,000 reports to the National glutathione depletion, alkylation of proteins, especially mitochondrial
Poison Data System annually in United States [15]. In Oxford, UK, proteins, and formation of reactive oxygen/nitrogen species [25].
the proportion of overdoses with paracetamol increased from 14.3%
in 1976 to 42% in 1990, and in 1993, 47.8% of all overdoses involved Grossly liver is usually of normal size with mottled external
paracetamol or paracetamol- containing drugs [16]. It has also become surface. On light microscopy liver shows large areas of coagulative
increasingly common in countries like Denmark and Australia [17,18].
In Scotland, the rate of paracetamol overdose increased almost 400%
between 1981–83 and 1991–93 [19].
*Corresponding author: Arun Kumar Agnihotri, Department of Forensic Medicine
Pharmacology & Toxicology, SSR Medical College, Mauritius, E-mail: [email protected]

Paracetamol has excellent anti-pyretic activity, moderate analgesic Received October 07, 2013; Accepted October 10, 2013; Published October 13,
2013
and almost no anti-inflammatory property. It acts by inhibiting
prostaglandin synthesis by its action on cyclo-oxygenase-3 enzyme, (an Citation: Ibrahim T, Agnihotri S, Agnihotri AK (2013) Paracetamol Toxicity- An
Overview. Emergency Med 3: 158. doi:10.4172/2165-7548.1000158
alternate splice product of cox-1 enzyme) [20].
Copyright: © 2013 Ibrahim T, et al. This is an open-access article distributed
The therapeutic dose of paracetamol is 0.5-1 g in adult (maximum under the terms of the Creative Commons Attribution License, which permits
of 4 g/day) and 10-15 mg/kg every 4-6 hours in children [21]. It is unrestricted use, distribution, and reproduction in any medium, provided the
original author and source are credited.

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Citation: Ibrahim T, Agnihotri S, Agnihotri AK (2013) Paracetamol Toxicity- An Overview. Emergency Med 3: 158. doi:10.4172/2165-7548.1000158

Page 2 of 3

necrosis; with some typical geographic or zonal pattern, necrosis is graph which is obtained by joining the points between 1.32 mmol/L at
typically perivenular/centrilobular/acinar Zone 3 i.e. around central 4 hours after ingestion to 0.33 mmol/L at 12 hours, then prognosis is
vein, however it spares periportal areas (around portal triad) [25,26]. poor and serious hepatic damage is likely to occur [35].
This zonal distribution is characteristically a feature of liver injury
associated with paracetamol overdose and can well be explained by Treatment
the fact that perivenular areas have more drug metabolizing enzymes The aim of the management of paracetamol toxicity focuses on the
than elsewhere; so more toxic metabolites are formed in these cells prevention of hepatotoxicity by appropriate line of treatment which is
making them susceptible to injury. Sparse inflammatory infiltrate by achieved by limiting the absorption of the drug and by decreasing the
lymphocytes and macrophages is also seen. toxic impact of NAPQI through replenishment of glutathione store.
Various studies in human and animal models have shown that The general principle for limiting the drug absorption applies
paracetamol overdose may lead to renal dysfunction [27-30]. Overall, only if the patient is seen within the first hour of acute ingestion of
renal insufficiency occurs in approximately 1-2% of patients with paracetamol. Gastric lavage with small amounts of tap water at ambient
paracetamol overdose [31]. Effects on the kidney are seen more in temperature followed by drinking of the activated charcoal solution
children and adolescents as compare to adults. The mechanism of immediately after the removal of tube decreases the absorption of
paracetamol toxicity is not well understood in the kidney. Possible paracetamol by 50-90%. The combination treatment comprising gastric
mechanisms, based on human and animal data, show the role of lavage followed by activated charcoal may be replaced by charcoal
cytochrome P-450 pathway, as well as prostaglandin synthetase, alone, even in patients presenting with larger overdoses who arrive
and Ndeacetylase enzymes [27]. The renal damage is usually in form within 1 h of drug ingestion [36].
of acute tubular necrosis both clinically and histologically. Light
microscopy shows normal glomeruli and vessels with tubular epithelial Specific treatment is carried out with N-Acetyl Cysteine (NAC).
cell necrosis [32]. Tubular swelling with loss of the tubular brush The treatment of paracetamol toxicity with NAC is originated in UK in
border and distortion of mitochondrial organization are often seen on the year 1970. The World Health Organization Model List of Essential
electron microscopy [33]. Medicines and Model Formulary of 2006 lists Acetyl Cysteine (NAC) as
an antidote for use in the treatment of paracetamol overdose [37]. NAC
Clinical Presentation is best given within the first 8 hours following an acute overdose for
maximum hepato- protective effects. A study published in 1988 found
The clinical signs usually do not become apparent for the first 24-
that NAC is uniformly effective if given within eight hours of a single
48 hours after an acute overdose of paracetamol [20]. Liver failure may
overdose, but subsequently its efficacy falls [38]. A controlled trial
occur between 2-7 days following the ingestion. The clinical course of
provided evidence that NAC can improve outcome even in patients
paracetamol toxicity is generally divided into 4 phases [34].
with encephalopathy, so those who present more than eight hours after
Phase 1 (0-24 hrs) overdose are still treated with this antidote [39].
The patient is usually asymptomatic or may present with features The Medicines and Healthcare products Regulatory Agency
like anorexia, nausea, vomiting and malaise. The liver Function Tests, (MHRA) has simplified the guidelines on the management of
shows a mild increase in the serum transaminase level (begins to rise paracetamol overdose in 2012. All patients who have a timed plasma
approximately 12 hours after an acute ingestion). paracetamol level plotted on or above the line drawn between 100 mg/L
at 4 hours and 15 mg/L at 15 hours after ingestion should receive NAC
Phase 2 (18-72 hrs) regardless of any risk factors they may have for hepato toxicity [40].
The patient usually experience nausea, vomiting, abdominal pain The treatment is continued until the patient is clinically stable and the
(right upper quadrant). On examination, tenderness is present on the liver transaminase level has fallen to less than 1000 IU/L along with
right upper quadrant; tachycardia and hypotension are usually present. normalization of the clotting screen or till the patient receives a liver
Serum transaminase level continues to rise. transplantation [40].
NAC can be administered by oral and intravenous route. The
Phase 3 (72-96 hrs) Hapatic phase
intravenous route is preferred in the presence of fulminant hepatic
This is the most critical phase. The patient is severely ill. Jaundice, failure or if there is intolerance to oral therapy such as the patient is
coagulopathy with bleeding tendencies, hypoglycemia, hepatic flap vomiting. Otherwise, the oral route of administration remains the stay
and hepatic encephalopathy occur as a result of hepatic necrosis and of treatment. NAC oral dosing schedule is as loading dose of 140 mg/
dysfunction. Metabolic acidosis with acute renal failure (due to hepato kg followed by 70 mg/kg every 4 hours, to be continued for 72 hours.
renal syndrome) may develop. Death usually occurs as a consequence If vomiting occurs within 1 hour of ingestion of the drug, the dose has
of multi-organ failure. to be repeated. NAC intravenous dosage schedule is a total dose of 300
mg/kg approximately over a period of 20 hours is given in a phasic
Phase 4 (4 days-3 weeks) Recovery phase regimen via intravenous infusion as 150 mg/kg in 200 ml of 5% glucose
Patients who survive the critical illness of phase 3, are more likely over 15 minutes, 50 mg/kg in 500 ml of 5% glucose over 4 hours and
to improve with with resolution of the symptoms and organ failure. 100 mg/kg in 1000 ml of 5% glucose over 16 hours [41].
Intravenous NAC is associated with higher incidence of adverse
Investigation
effects such as rashes, pruritus (decreased by giving anti-histaminic
The invesitgations include the timed serum paracetamol like Chlorpheniramine), nausea, vomiting, hyponatremia and
concentration, liver function tests (including prothrombin time or anaphylactoid reaction [42]. The anaphylactoid reaction is mediated
international normalised ratio) and kidney function tests. These tests are by histamine and depends on the blood level of NAC. In the event of
needed to assess risk and monitor progress. The plasma concentration development of an anaphylactoid reaction, the NAC therapy has to be
of paracetamol has predictive value, if it lies above a semi-logarithmic discontinued and treatment with adrenaline, corticosteroid and anti-

Emergency Med Volume 3 • Issue 6 • 1000158

ISSN: 2165-7548 EGM, an open access journal
Citation: Ibrahim T, Agnihotri S, Agnihotri AK (2013) Paracetamol Toxicity- An Overview. Emergency Med 3: 158. doi:10.4172/2165-7548.1000158

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histaminic has to be started immediately along with other supportive transplantation centre: an 8-year experience. J Gastroenterol Hepatol 14: 817-
821.
measures [35].
19. McLoone P, Crombie IK (1996) Hospitalisation for deliberate self-poisoning in
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fluid replacement, symptomatic treatment of vomiting with drugs like Psychiatry 169: 81-85.
metopimazine, vitamin K injection- 10 mg intravenously for bleeding 20. Rang HP, Dale MM, Ritter JM, Flower RJ (2008) Pharmacology. (6th edn),
diasthesis, correction of acidosis with sodium bicarbonate and liver Churchill Livingstone, UK.
transplantation in cases of fulminant hepatic failure. 21. Royal Pharmaceutical Society (2003) British National Formulary. BNF
publication, London.
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Citation: Ibrahim T, Agnihotri S, Agnihotri AK (2013) Paracetamol Toxicity- An

Overview. Emergency Med 3: 158. doi:10.4172/2165-7548.1000158

Emergency Med Volume 3 • Issue 6 • 1000158

ISSN: 2165-7548 EGM, an open access journal