Paracetamol
Drugs

Author: Gianpiero Pescarmona
Date: 21/12/2011

Description

DESCRIPTION

Paracetamol (acetaminophen ), is a widely used over-the-counter analgesic (pain reliever) and antipyretic (fever reducer). It is commonly used for the relief of headaches and other minor aches and pains and is a major ingredient in numerous cold and flu remedies.

CLASSIFICATION

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INDICATIONS

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PHARMACOKINETICS

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MOLECULAR MECHANISM

TRPA1 underlies a sensing mechanism for O2, 2011

Channels: A TRP in the air, 2011

PHARMACOGENOMICS

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EFFECTS

Efficacy of paracetamol for acute low-back pain: a double-blind, randomised controlled trial, 2014

  • Summary
    Background
    Regular paracetamol is the recommended first-line analgesic for acute low-back pain; however, no high-quality evidence supports this recommendation. We aimed to assess the efficacy of paracetamol taken regularly or as-needed to improve time to recovery from pain, compared with placebo, in patients with low-back pain.
    Methods
    We did a multicentre, double-dummy, randomised, placebo controlled trial across 235 primary care centres in Sydney, Australia, from Nov 11, 2009, to March 5, 2013. We randomly allocated patients with acute low-back pain in a 1:1:1 ratio to receive up to 4 weeks of regular doses of paracetamol (three times per day; equivalent to 3990 mg paracetamol per day), as-needed doses of paracetamol (taken when needed for pain relief; maximum 4000 mg paracetamol per day), or placebo. Randomisation was done according to a centralised randomisation schedule prepared by a researcher who was not involved in patient recruitment or data collection. Patients and staff at all sites were masked to treatment allocation. All participants received best-evidence advice and were followed up for 3 months. The primary outcome was time until recovery from low-back pain, with recovery defined as a pain score of 0 or 1 (on a 0—10 pain scale) sustained for 7 consecutive days. All data were analysed by intention to treat. This study is registered with the Australian and New Zealand Clinical Trial Registry, number ACTN 12609000966291.
    Findings
    550 participants were assigned to the regular group (550 analysed), 549 were assigned to the as-needed group (546 analysed), and 553 were assigned to the placebo group (547 analysed). Median time to recovery was 17 days (95% CI 14—19) in the regular group, 17 days (15—20) in the as-needed group, and 16 days (14—20) in the placebo group (regular vs placebo hazard ratio 0·99, 95% CI 0·87—1·14; as-needed vs placebo 1·05, 0·92—1·19; regular vs as-needed 1·05, 0·92—1·20). We recorded no difference between treatment groups for time to recovery (adjusted p=0·79). Adherence to regular tablets (median tablets consumed per participant per day of maximum 6; 4·0 [IQR 1·6—5·7] in the regular group, 3·9 [1·5—5·6] in the as-needed group, and 4·0 [1·5—5·7] in the placebo group), and number of participants reporting adverse events (99 [18·5%] in the regular group, 99 [18·7%] in the as-needed group, and 98 [18·5%] in the placebo group) were similar between groups.
    Interpretation
    Our findings suggest that regular or as-needed dosing with paracetamol does not affect recovery time compared with placebo in low-back pain, and question the universal endorsement of paracetamol in this patient group.

SIDE EFFECTS

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TOXICITY

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RESISTANCE

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DEPENDENCE AND WITHDRAW

Comments
2012-02-14T21:06:23 - Jessica Borrelli

DESCRIPTION

Acetaminophen (IUPAC: N(4-hydroxyphenyl)acetamide, chemical formula: C8H9NO2), also known as paracetamol, is classified as an “Aniline analgesic” and it is the only drug of this family still used nowadays. The terms "acetaminophen" and "paracetamol" both come from a chemical name of the compound, para-acetylaminophenol, and it can be also abbreviated as APAP. Even though there is evidence that paracetamol and NSAIDs (Non steroidal anti-inflammatory drugs) have a similar pharmacological activity, it is not considered part of this class because of its lack of significant anti-inflammatory activity. It is the active metabolite of phenacetin, now felt into disuse because carcinogenic in therapeutic doses.

Acetaminophen

CLASSIFICATION

  1. Analgesic, non-narcotic
  2. Antipyretic

INDICATIONS

Acetaminophen is above all an analgesic and antipyretic; it is administered to relieve pain from headaches, muscle aches, menstrual periods, colds, sore throats, toothaches, backaches, osteoarthritis and reactions to vaccinations. It can be used in combination with aspirin and caffeine to relieve the pain associated with migraine headache, and with opioid analgesics in order to treat post-surgical pain and to provide palliative cure in patients with cancer at the terminal stage.
Analgesic properties of paracetamol can be compared with those of aspirin and salicylates, but its anti-inflammatory effect is weaker (it is a weak COX inhibitor and it has no results in reducing redness and swelling unlike other common analgesics such as ibuprofen and aspirin which are NSAIDs), although patients with excessive gastric acid secretion better tolerate this drug because of its lack of gastric ulcerative effects.
At therapeutic doses acetaminophen does not irritate the lining of the stomach nor affect blood coagulation, kidney function or the fetal ductus arteriosus. Like NSAIDs and unlike opioid analgesics, it doesn’t cause euphoria or alter mood in any way; these drugs also have the benefit of being completely free of problems with addiction, dependence, tolerance and withdrawal.
Paracetamol can be administrated by oral, rectal and intravenous route; the absorption is rapid and almost complete.

PHARMACOKINETICS

To date, the mechanism of action of acetaminophen is not completely understood, although it is thought to act primarily in the CNS, increasing the pain threshold by inhibiting the isoforms of cyclooxygenase COX-1, COX-2, and COX-3 enzymes involved in prostaglandin synthesis. Because of its selectivity it does not significantly inhibit the production of thromboxanes. Unlike NSAIDs it does not inhibit cyclooxygenase in peripheral tissues and, thus, has no peripheral anti-inflammatory activity; this is due to several factors, one of which is high level of peroxides present in inflammatory lesions: while aspirin acts as an irreversible inhibitor of COX and directly blocks the enzyme’s active site, acetaminophen indirectly locks COX, and this blockade is ineffective in presence of peroxides; this explains why acetaminophen is effective in CNS and in endothelial cells but not in platelets and immune cells which have high levels of peroxides.

The COX family enzymes are involved in the metabolism of arachidonic acid to prostaglandin H2, a molecule then converted to numerous other pro-inflammatory compounds. COX enzyme is highly active only in its oxidized form; paracetamol prevents the formation of pro-inflammatory molecules by reducing the oxidized form of this enzyme. In this way a reduced amount of PGE2 reaches the thermoregulatory centre in the hypothalamus obtaining the target of lowering temperature through peripheral vasodilatation, sweating and hence heat dissipation.

Paracetamol also acts in modulating the endogenous cannabinoid system in the metabolized form of AM404 . This molecule has several actions but the most important is the inhibition of the uptake of the endogenous cannabinoid anandamide by neurons. In this way the activation of the main nociceptor of the body, TRPV1, is prevented. Moreover, AM404 blocks sodium channels, provoking an anesthetic effect.

Probably differences in activity between acetaminophen, aspirin and other NSAIDs, are due to the fact that further COX variants may exist.

MOLECULAR MECHANISM

Approximately 90 to 95% of a dose of paracetamol is metabolized in liver into non-toxic products, which are excreted in the urine after conjugation with glucuronic or sulphuric acid, while about 3% is excreted unchanged.

Three metabolic pathways are known:
- Glucuronidation (about 40% of the metabolism of the drug)
- Sulfate conjugation (20-40%)
- N-hydroxylation and rearrangement, then GSH conjugation (15%): the hepatic cytochrome P450 enzyme metabolizes the drug, forming a metabolite known as NAPQI (N-acetyl-p-benzo-quinone imine) that is irreversibly conjugated with sulphydryl group of glutathione .

All the final products of these pathways are inactive and non-toxic, and they are excreted by the kidney. However NAPQI is the responsible of the toxic effects of acetaminophen.
The production of this metabolite is due to two isoenzymes of cytochrome P450: CYP2E1 and CYP1A2. However the gene codifying for P450 is highly polymorphic and it probably exists another isoenzyme, CYP2D6; this polymorphism may contribute in individual differences in paracetamol toxicity and in the different rate of production of NAPQI. At usual doses, NAPQI is quickly detoxified by conjugation, but in case of overdose this pathway becomes saturated and NAPQI accumulates, GSH is depleted and hepatic necrosis arises.

NAPQI:
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Acetaminophen's metabolism:
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SIDE EFFECTS

In recommended doses, paracetamol is well tolerated with few side effects.
Prolonged daily use increases the risk of the onset of symptoms as rash, hives, itching, swelling, hoarseness, difficulty in breathing and also of more severe complications as stomach bleeding, kidney or liver damage, thrombocytopenia, leukopenia, anemia, agranulocytosis, epidermal necrolisys, multiform erythema, Steven-Jhonson’s syndrome.
Paracetamol is metabolized in liver and is hepatotoxic; the risk of hepatotoxicity is increased in patients with liver damage and in chronic alcoholics .
Chronic users of paracetamol undertake a higher risk of developing blood cancer.
Use of paracetamol must be also avoided by patients with severe haemolytic anemia and rare forms of fructose intolerance.

Paracetamol was believed to be safe in pregnancy and, unlike aspirin, it is not correlated with Reye’s syndrome in children with viral illnesses. However, recent studies underline that paracetamol can be linked to infertility in adult life of the unborn, and also to the increase in the incidence of rhinoconjunctivitis, eczema and asthmatic symptoms.

PARACETAMOL AND ASTHMA

Paracetamol has been widely used for the treatment of pain and fever in patients of all ages since its introduction in the mid-1950s. Although it is an extremely well-tolerated drug, there has been an emerging interest in its potential to increase the risk of a number of conditions including asthma. Several studies found an association between early administration of paracetamol and antibiotics and development of wheezing. This could be due to confounding: wheeze and asthmatic symptoms in early childhood are difficult to distinguish from respiratory tract infections that are widely treated with these drugs; in case of persistence of symptoms up to school age, this could explain the observed relationship.
The reason for this line of investigation, initiated in the late 1980s, are manifold and include early evidence, later dismissed, that paracetamol can aggravate asthma in patients with co-existent aspirin and non-steroidal anti-inflammatory sensitivity; an ecological analysis of two major international studies showing that higher paracetamol sales were associated with higher prevalence of both childhood and adult asthma acrossmultiple centres; and evidence for a plausible biological mechanism through paracetamol-induced inhibition of glutathione pathways in respiratory epithelium, resulting in increased airway inflammation. While there is evidence for and against these associations, the debate on whether paracetamol is a cause of asthma, or whether this association is confounded by other factors, remains unresolved.

Six studies analyzed this issue . The age of children studied ranged from 30 to 84 months. Features of the studies variably included an association with paracetamol use during all trimesters of pregnancy and an association with persistent asthma, severe asthma, and with atopy.
The effect of the timing of paracetamol use during pregnancy is relevant to the consideration of the potential mechanisms by which paracetamol may have an effect, if the association is causal. Glucuronidation, the main pathway for metabolism of paracetamol in adults, is markedly reduced in the foetus in the first trimester, whereas GST, which detoxifies the oxidative paracetamol metabolites, is reduced in the third trimester. The balance between these two pathways could determine whether paracetamol exposure in the first or third trimester increased the predisposition to subsequent asthma, through the build-up of toxic oxidative metabolites. This hypothesis would also invoke the concept of programming, in which an insult at a crucial stage of foetal development may predispose to an increased risk of subsequent disease in childhood or adult life.

There are several mechanisms that have been proposed to explain why paracetamol use may increase susceptibility to asthma and other allergic disorders. The main mechanism is that paracetamol may impair respiratory antioxidant defences by decreasing the amount of reduced glutathione present. Oxygen radicals may produce tissue injury, smooth muscle contraction and bronchial hyperresponsiveness, increased vascular permeability, release of pro-inflammatory mediators and impaired b-receptor function, all effects potentially relevant to the pathogenesis of asthma. Depletion of antioxidants such as glutathione has the potential to impair the protection against these injurious effects of oxygen radicals, resulting in airways’ inflammation. Glutathione is present in increased concentrations in alveolar fluid of patients with asthma, and an association exists between levels of glutathione and the degree of bronchial hyperresponsiveness. These data suggest that patients with asthma have increased antioxidant defences, which may balance an increase in oxygen radical generation, which has been observed in patients.
The continuous fetal exposure to paracetamol after 20 weeks of gestation, could result in the production of the toxic metabolite N-acetyl-p-benzoquinoneimina (NAPQI) and in the depletion of glutathione. This in turn could lead to oxidative stress, damage to the fetal epithelium of the respiratory system and increased vulnerability of the latter to severe postnatal oxidative damage, which are able to determine a bronchial hyperresponsiveness (BHR) over the years.

Paracetamol crosses the placenta and the observed increased risk may be related to the limited capacity of the foetus to metabolize paracetamol. In adults, the main detoxification pathway of paracetamol is glucuronidation to the non-toxic metabolite glucuronide, while in the foetus the main metabolic pathway initially involves sulphation.
Glucuronidation consists of transfer of the glucuronic acid component of UDP-glucuronic acid to a substrate by any of several types of UDP-glucuronosyltransferase.
Glucuronidation starts at the 18th gestational week and increases until the 23rd week-a pattern that could be related to an increased risk from exposure in the first trimester. Metabolism of paracetamol to the highly reactive oxide N-acetyl-pbenzoquinoneimine (NAPQI), depends on the activity of the cytochrome P450 system and on Glutathione S Transferase (GST). In adults, cytochrome P450 enzymes metabolize 4–5% of the paracetamol to NAPQI, and this percentage increases when glucuronidation and sulphation are saturated. NAPQI is then detoxified by GST.

The expression of GST in the lung of the foetus progressively decreases after week 15 of gestation, and this could be related to an increase in risk from use of paracetamol in the third trimester. A paracetamol dose-dependent decrease in levels of the anti-oxidant glutathione in the lung has been proposed. Recent studies suggest that glutathione’s depletion in the lung may occur in relatively low doses. This may reduce the capacity to counteract the toxic effects of NAPQI and may affect the response to oxidative stress and possibly also to impaired antigen processing. Avoiding NSAIDs may exert an effect on the lungs mediated by the lack of suppression of COX, an anti-inflammatory pathway that promotes prostaglandin E2 production in favour of T-helper type 2 response while inhibiting T-helper type I lymphocytes. This would promote an allergic tendency in the immune response to various antigenic stimuli. Yet, another possible mechanism is an immune-modulating IgE mediated effect of paracetamol as an antigenic agent,which would increase asthma provocation.

Conclusion and clinical relevance: the use of paracetamol during pregnancy is associated with an increased risk of childhood asthma. Although there are insufficient data that postnatal ingestion of paracetamol increases the risk of asthma, the available data on the effects of prenatal exposure justify further rigorous research. More research is urgently required to determine the impact of paracetamol during pregnancy on the risk of wheezing in offspring so that appropriate public health recommendations can be made.

TRPA1, PARACETAMOL AND INLFAMMATION OF AIRWAYS

TRPA1 is a member of the TRPA branch of the TRP ion channel gene family. This family includes a large and heterogeneous group of membrane channels, non-selectively permeable to cations. About the structure, this channel is characterized by a multiple N-terminal ankyrin repeats (14 in humans). Studies showed that the functions of TRPA1 are interlinked with that of TRPV1 (Transient receptor potential vanilloid 1); this is particularly clear in relation to pain and neurogenic inflammation where these two receptors are co-expressed on sensory nerves and they cooperate in a lot of noxious stimuli. Both channels are calcium-permeable and they may form a complex on the plasma membrane of sensory neurons: in this way TRPV1 can influence TRPA1 with voltage-current relationships and enhancing its open probability at negative potentials. Recently, this collaboration between TRPA1 and TRPV1, has been demonstrated also in a multitude of non-neural sites as vascular smooth muscle, keratinocytes and endothelium.
In mammals TRPA1 has both a central and a peripheral expression:
# Central expression: The location of TRPA1 and TRPV1 on small diameter Aδ and C fibres of sensory nerves is linked with its role in pain and inflammation. A TRPV1-specific antibody was used to demonstrate the presence of this receptor throughout the neuroaxis, including areas as the dopaminergic neurones of substantia nigra, hyppocampal pyramidal neurones, hypothalamic neurones and neurones in the locus coeruleus, in addiction to various layers of the cortex. This study was confirmed by RT-PCR. These channels were also identified in cerebellum, dorsal root ganglia, trigeminal and nodose vagal that give rise to afferent nerve fibre bundles that transduce different sensory signals (mechanical, chemical, thermal).
# Peripheral expression: in humans

_.SITE_.EFFECT
Corneal epitheliuminflammatory mediator secretion
Corneal endotheliumtemperature sensation
Cerebromicrovascular endotheliumregulation of blood brain barrier permeability
Blood and Mononuclear cellsnociception, role in inflammatory process (?)
Epidermal keratinocytesnoxious chemical sensor
Preadipocytes and adipose tissueadipogenesis
Synoviocytesadaptive/pathological changes in arthritic inflammation
Nasal endothelium, submucosal glandsstimulate epithelial secretion

The expression on peripheral sensory neurons implicates a specialized role in transduction; TRPA1 channels respond to a multitude of irritants with different origins and chemical structures. Because of this variety of activators, we can speculate three ways of activation:
# Chemical irritants can bind TRPA1 with a ligand-receptor activation; this receptor has the capacity of binding multiple ligands with diverse structures.
# Some reactive irritants as mustard oil can form transient or permanent covalent bonds with the channel, activating it. Isothiocyanates, allicin and unsaturated aldehydes are reactive electrophiles compounds capable of forming covalent bonds with cysteine and other proteic residues.
# Reactive irritants could interfere with signalling pathways that regulate TRPA1 as phosphorylation cascades and regulation of intracellular calcium.

The functions of TRPA1 receptor are many:
# Receptor for noxious cold and hot temperature.
# It can be bind by a lot of irritant substances as mustard oil, tetrahydrocannabinol, acreolin that activate this channel inducing effects as pain, coughing, apnea and lachrymation. The pungent and irritant properties of mustard (allyl isothiocyanate), garlic (Allicin), cinnamon (cinnamaldehyde), and other spices are due to their ability to activate the TRPA1 channel.
# It is involved in pain and neurogenic inflammation.
# The channel can signal tissue damage because is activated by numerous endogenous or exogenous inflammatory and irritating molecules, also generated by oxidative stress. The activation of the channel TRPA1, expressed at the neuronal level, causes, via the release of proinflammatory neuropeptides (substance P and calcitonin gene-related peptide), pain and neurogenic inflammation.
# It is a O2-sensing receptor; TRPA1 cation channel uses reactive disufides with different redox potential to sense oxygen. This sensing is based upon different process:
## PHD (prolyl-hydrolase) exerts an oxygen-dependent inhibition on TRPA1 activity in normoxia.
## Direct O2 action cancels the inhibition via cysteine-mediated oxidation in hyperoxia. TRPA1 may at least take two oxidized states upon the hyperoxia.
## TRPA1 is activated through relief from the same PHD-mediated inhibition in hypoxia. This relief can be made by insertion of unmodified TRPA1 proteins to the plasma membrane or by dehydroxylation.

TRPA1 and acetaminophen
TRPA1 is expressed on the central terminals of primary sensory neurons in the dorsal horn of the spinal chord. Activation of TRPA1 by electrophilic metabolites of APAP increases the influx of calcium, which causes inactivation of voltage-gated calcium channel (VGCC). Cation influx through TRPA1 also depolarizes the membrane and produces inhibition of voltage gated sodium-channel (NaV), thereby reducing neuronal excitability and action potential-dependent neurotransmitter release. The net result of these actions is inhibition of C-fibre-evoked postsynaptic excitation, although TRPA1-mediated calcium influx may initially increase spontaneous excitatory postsynaptic currents via activation of ionotropic glutamate receptors (iGluR). Similar molecular mechanisms have been advanced to explain the antinociceptive effect of spinal TRPV1 activation.
TRPA1 is a unique sensor of noxious stimuli and, as a consequence, a potential drug target for analgesics. Epidemiological evidence has associated the use of therapeutic APAP doses with the risk of chronic obstructive pulmonary disease (COPD) and asthma. Because NAPQI, like other TRPA1 activators, is an electrophilic molecule, it has been hypothesized that APAP, via NAPQI, stimulates TRPA1, thus causing airway neurogenic inflammation. Generated through a P450 cytochrome-oxidative pathway, NAPQI is normally inactivated by glutathione (GSH) conjugation, forming the 3’-glutathionyl-S-yl-APAP adduct (3’-GS-APAP). GSH consumption by NAPQI has been proposed as one possible mechanism by which APAP increases the risk of asthma, because GSH depleted lungs would no longer be protected against oxidative stress.
The TRPA1 cation channel is coexpressed by a subset of nociceptive primary sensory neurons with the "capsaicin receptor", TRPV1. TRPV1 or TRPA1 stimulation in peripheral terminals of primary sensory neurons releases the neuropeptides calcitonin gene-related peptide (CGRP) and substance P (SP), which mediate neurogenic inflammatory responses. Neurogenic inflammation encompasses hyperemia, plasma protein extravasation, mediator release, and leukocyte infiltration and has been thought to contribute to a series of inflammatory diseases, including asthma and COPD. A team of researchers oh the King’s College of London used a test with a hot plate to observe the effects of acetaminophen in mice. They measured the number of seconds required because a rat withdrew its paw from a hot surface slightly. Scientists discovered that paracetamol increased this interval of time, thus demonstrating that the drug reduces the pain induced by heat. The scientists then conducted experiments to observe what happened when the TRPA1 protein was not absolutely present in the mouse. They found that when they eliminated TRPA1 and repeated the hot plate test, paracetamol had no effect against pain. This has proved that TRPA1 is necessary because the paracetamol is an effective analgesic.
We said that this channel appears strongly correlated to the onset of diseases affecting the respiratory system, such as asthma or COPD. In particular, some irritating agents, as well as metabolites of the oxidative stress, have proved to be potent activators of the channel TRPA1 on primary sensory nerve fibers which innervate the respiratory tract. Therefore a lot of experiments suggest that the channel TRPA1 could be expressed, in the lung tissue and in particular at the level of alveolar epithelial cells. This hypothesis is further supported by the observation that in the rat lung mRNA levels for the channel TRPA1 appear to be very high. Using real time PCR technique and immunocytochemistry, it has been shown that the receptor TRPA1 is expressed in cell lines and primary cultures of cells of the terminal airways (A549, SAEC) and lung fibroblasts cells. The data also support the idea that TRPA1 may be one of the players involved in recruiting immune cells to the airways and thus may have a potential role in modulating inflammatory response in the airways. Scientists also show that administration of therapeutic doses (including 15 mg/kg, the recommended dose for children) of APAP to mice causes TRPA1-dependent neurogenic inflammatory responses in the airways. APAP-induced airway inflammation is an early phenomenon, already evident 90 min after APAP administration, at a time when, even after a 300 mg/kg dose, no inflammation or tissue damage is detectable in the liver. The abundant sensory fiber network in the airways, which is absent in the liver, may explain the differential effect. Thus, it’s evident that the transient response to therapeutic doses of APAP is observed only in highly innervated tissues, whereas non innervated tissues exhibit solely the delayed, tissue-damaging effect caused by toxic APAP doses.
Functional activation of this endogenously expressed channel induces an increase in calcium influx in both CCD19-Lu and A549 cells.
Moreover it has been demonstrated that the opening of the channel and the consequent massive entry of Ca2+ induces mainly apoptotic cell damage. The TRP channels mediate transmembrane flux of cations according to their electrochemical gradient, resulting in a increase in intracellular calcium/sodium ions and consequently cell depolarization. The calcium ion is recognized as an activator of protein mechanisms, calcium-dependent, which control cellular events such as the regulation of gene transcription and cellular proliferation and the induction of cellular and inflammatory mechanisms.

TOXICITY

Recommended dose is of 1,000 mg per single dose and up to 3,000 mg per day for adults. The maximum daily dose of acetaminophen is 4,000 mg, and liver failure has been observed as low as 6,000 mg per day. The overdose threshold may be lowered in people taking other drugs, in chronic alcoholics and in serious undernourished; if the overdose is spread over a period of time the threshold may be higher, as the initial paracetamol dose is effectively metabolized.
Often there are no symptoms in the first 24 hours following overdose, although there may be mild nausea and vomiting. Then loss of appetite, sweating, extreme tiredness, unusual bleeding and pain in the upper right part of stomach may arise, followed by jaundice, confusion and loss of consciousness due to the deterioration of liver function .
The treatment against paracetamol overdose is aimed at removing the drug from body and replacing the GSH. To reach this aim N-acetylcysteine is administered: it acts as a precursor of GSH and help the body in replacing it.
In case of severe liver damage a transplant may be requested.

JESSICA BORRELLI (735199)
SERENA MUSSO (739387)

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