This article has been cited by other articles in PMC. Abstract Paracetamol acetaminophen overdose remains the leading cause of death or transplantation due to acute liver toxic person in many parts of the world. Acetylcysteine has long been recognized as an effective antidote, via oral or intravenous administration, minimizing the risk and severity of acute liver injury if administered sufficiently early after a paracetamol overdose.
Despite this, its mechanisms of action remain obscure, and there is uncertainty regarding the optimal dose and duration of treatment.
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The intravenous infusion protocol was originally developed as a three-step loading regimen; it causes very high early peak plasma concentrations of acetylcysteine whereas the later maintenance infusion is associated with toxic person lower concentrations. This pharmacokinetic profile lista bolilor de helmint associated with two papillomatosis antibiotic concerns: a high rate of occurrence of adverse effects toxic person occur after the initial loading infusion, and the possibility that the maintenance phase of treatment might deliver too low a dose of acetylcysteine for optimum protection against toxic person injury.
Recently described novel administration regimens offer different rates of intravenous acetylcysteine administration in both the loading and maintenance phases. These alternative regimens toxic person to be well tolerated in small patient groups, but too few clinical data are available to evaluate their comparative efficacy in preventing paracetamol-induced liver injury.
Keywords: acute liver toxicity, overdose, paracetamol Background Paracetamol acetaminophen overdose was first recognized as a cause of acute liver failure in the s [ Davidson and Eastham, ]. It has since become the leading cause of death or transplantation due to acute liver failure in the UK, the USA, and elsewhere, and the occurrence of paracetamol liver injury continues to rise [ Gow et al. Acetylcysteine is highly effective in preventing severe liver injury if administered within 8—10 h after a significant paracetamol overdose [ Prescott et al.
However, the standard regimen of intravenous acetylcysteine is associated with a high rate of occurrence of adverse effects, toxic person treatment is normally reserved for patients who have absorbed substantial overdoses of paracetamol and who have a significant risk of acute liver injury [ Buckley and Eddleston, ; Heard, ].
The precise pharmacological basis for the antidotal properties of acetylcysteine is somewhat uncertain, and several different mechanisms have been proposed [ Jones, ].
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Moreover, there is toxic person concerning the optimal dose and duration of acetylcysteine administration and important international differences exist concerning the precise indications for antidote toxic person. The basis for the prevailing acetylcysteine administration protocols is discussed, along with the pharmacological basis to support recently proposed novel administration regimens.
Pathophysiology of aracetamol-induced liver injury Acute paracetamol administration is associated with significant depletion of glutathione GSHattributed to covalent binding of an intermediate paracetamol metabolite, N-acetyl-p-benzoquinone imine NAPQI to critical proteins and enzymes within hepatocytes.
Restoration of toxic person glutathione concentrations in animals minimized the extent of NAPQI covalent binding to hepatocytes, and lessened toxic person severity of the biochemical and histopathological changes observed after paracetamol-induced acute liver injury [ Jollow et al.
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Therefore, NAPQI has been implicated as the toxic intermediate responsible of paracetamol-induced acute liver injury. Role of glutathione GSH is toxic person tripeptide that consists of the amino acids cysteine, glycine, and glutamate.
It possesses sulfhydryl donor groups and can act as a powerful intracellular reducing agent and antioxidant whilst being converted to its oxidized form, glutathione disulfide GSSG The contribution of oxidative stress to drug-induced organ toxicity and its detection in vitro and in vivo have recently been reviewed [ Pereira et al.
The initial metabolic step in the synthesis of GSH involves cancerul ingrasa synthetase. The rate and extent of GSH synthesis depends upon the local availability of cysteine, which is normally found in comparatively low concentrations in hepatocytes compared with other tissues [ Stipanuk et al.
L-Cysteine normally does not greatly increase intrahepatic glutathione due to its rapid and extensive catabolism within the gut and circulation [ Frimpter, ].
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Nonetheless, its direct intravenous administration protects against liver damage after paracetamol toxic person in man [ Prescott, ].
However, intravenous administration of large doses is technically difficult due to its poor solubility in aqueous media.
Glutathione donors Early studies explored the efficacy of alternative sulfhydryl-containing agents. One example is cysteamine, which was shown toxic person prevent paracetamol-induced liver injury in animals [ Mitchell et al.
Prescott and colleagues reported the successful treatment of paracetamol overdose patients with cysteamine, and it was more effective than either penicillamine or methionine [ Prescott et al. However, cysteamine administration was frequently associated with very unpleasant adverse effects. Prescott and Matthew first suggested that N-acetylcysteine, which is converted into cysteine in vivo, might protect the liver against paracetamol toxicity [ Prescott and Matthew, ].
Acetylcysteine was subsequently shown to replenish hepatic GSH stores, and to be more effective than cysteamine and methionine in preventing paracetamol hepatotoxicity and death in animals [ Piperno and Berssenbruegge, ; Piperno et al.
Acetylcysteine: pharmacodynamic properties Acetylcysteine prevents GSH depletion and minimizes hepatocyte injury caused by a number of different toxins [ Dawson et al. Animal studies of paracetamol-induced liver injury suggest that a primary mechanism of acetylcysteine is the provision of cysteine to stimulate replenishment of GSH to toxic person detoxification of NAPQI [ Viña et al.
Perhaps more importantly, at a later stage it can also prevent toxicity aparat ionic cleanse reversing the oxidation and arylation of critical hepatic proteins and enzymes [ Davies et al.
This action may contribute to the finding toxic person acetylcysteine may improve liver function and lessen the severity of acute injury in patients with established paracetamol-induced liver failure, even when administered late after ingestion at a time when NAPQI concentrations would be expected to be negligible [ Keays et al. These findings suggest that the therapeutic mechanism of acetylcysteine may be more complex than restoration of glutathione alone.
The potent electron donor properties of acetylcysteine and the consequent ability to lessen oxidative stress might be another independent mechanism that protects against acute liver injury [ Toxic person and Lau-Cam, ]. Intravenous acetylcysteine regimen The early clinical toxic person of acetylcysteine in paracetamol-poisoned patients demonstrated virtually complete protection against severe liver damage if it was given within 10 h after the overdose [ Prescott et al.
Novel acetylcysteine regimens for treatment of paracetamol overdose
The intravenous infusion regimen was developed with the objective of giving the highest tolerated dose as rapidly as possible in view of the short time window of therapeutic efficacy. No pharmacokinetic data were available at that time.
Despite these observations, the original infusion regimen developed in Edinburgh has persisted with virtually no alteration for more than 30 years.
Following its original inception, a wealth of clinical experience viermi fără prescripție medicală accrued to support the efficacy of this regimen, and it remains the standard treatment for paracetamol poisoning toxic person the UK and elsewhere.
Adverse effects of acetylcysteine The reported rate of occurrence of adverse effects varies according to whether data are collected prospectively or retrospectively. Detailed evaluation of a subset of this patient population found that anaphylaxis is characterized clinically by symptoms of flushing, hypotension, and erythema [ Pakravan et al.
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Such reactions are around three times commoner in patients with asthma, although of similar severity, and wheeze and laryngeal oedema have been reported in severe cases [ Schmidt and Dalhoff, ]. The toxic person appears related to acetylcysteine concentration-dependent toxic person person release but, in contrast to true anaphylaxis, it is independent of tryptase and immunoglobulin E [ Pakravan et al. Toxic person of anaphylaxis may require that acetylcysteine administration is temporarily withheld for a sufficient time to allow plasma concentrations to decline [ Kerr et al.
In many cases, the reaction will resolve spontaneously, although antihistamine administration is effective and used in more severe cases. These reactions do not have an allergic basis, so that acetylcysteine can normally be safely reintroduced.
Other adverse effects include nausea, vomiting, generalized malaise, and abdominal pain, which appear dose dependent and consistent with the adverse effects observed after other sulphydryl-containing drugs. Gastrointestinal symptoms appear attributable to a direct local effect, and are particularly prominent after oral acetylcysteine administration, although localized histamine release may also be important.