Paracetamol detoxification

Children under six years of age seem to be less susceptible to paracetamol toxicity, possibly owing to a more efficient detoxification pathway or greater glutathione content, or simply a greater liver size in relation to body mass [8]. 

Because this patient has taken a paracetamol overdose, further administration of paracetamol must be avoided. Glutathione stores will be severely depleted, hence detoxification of the toxic metabolite will be reduced, leading to even greater hepatocyte damage. 

Biotransformation, especially phase I metabolic reactions, cannot be assumed to be synonymous with detoxification because some drugs (although a minority) and xenobiotics are converted to potentially toxic metabolites (e.g. parathion, fluorine-containing volatile anaesthetics) or chemically reactive intermediates that produce toxicity (e.g. paracetamol in cats). The term lethal synthesis refers to the biochemical process whereby a non-toxic substance is metabolically converted to a toxic form. The poisonous plant Dichapetalum cymosum contains monofluoroacetate which, following gastrointestinal absorption, enters the tricarboxylic acid (Krebs) cycle in which it becomes converted to monofluorocitrate. The latter compound causes toxicity in animals due to irreversible inhibition of the enzyme aconitase. The selective toxicity of flucytosine for susceptible yeasts (Cryptococcus neoformans, Candida spp.) is attributable to its conversion (deamination) to 5-fluorouracil, which is incorporated into messenger RNA. 

Paracetamol is metabolised in the liver, where it is converted to a highly toxic intermediate that is normally detoxified by conjugation with glutathione. In overdose, this detoxification mechanism is overwhelmed and the free toxic metabolite causes hepatitis and necrosis, which can prove fatal. 

Paracetamol (known as acetaminophen in the USA) is N-acetyl-para-aminophenol (Figure 25.11). It has the same detoxification pathways as phenol and also carries the risk of inducing methemoglobinemia. To be on the safe side, it should not be used as an intravenous analgesic during a full-face phenol peel, so as not to saturate the detoxification pathways. Paracetamol is also an intermediate in the pathway for detoxification of aniline derivatives, before hepatic glucuronide and sulfate conjugation allow them to... 

The presence of prilocaine is a (relative) contraindication to combining EMLA with products with a potential to cause methemoglobinemia. Combined use with paracetamol (acetaminophen), for example, is to be avoided. Paracetamol is a derivative of phenol (N-acetyl-para-aminophenol) and is subject to the same detoxification pathways as phenol. Paracetamol inherits its properties of causing methemoglobinemia from phenol. Large doses of EMLA (>600 mg of prilocaine, or four 5 g tubes) should therefore not be applied prior to phenol. 

Paracetamol must not he injected intravenously during the peel, however, to avoid any competition among the enzymes responsible for liver detoxification. 

A combination of paracetamol (acetaminophen) plus codeine is especially well suited to post-peel pain, but should not be used in the hours following a phenol peel, as paracetamol (a phenol derivative) goes through the same detoxification pathways as phenol, which could create metabolic competition and the risks of toxicity associated with phenol might be increased. Preventive administration of benzodiazepines (lorazepam 2.5 mg before the peel and on the night of the peel before going to bed) relieves the anxiety caused by these unpleasant sensations and reduces the need for analgesics after the peel. In case of very severe, localized pain (extremely rare), a nerve block could be used. 

Lohmann, W. and Karst, U., Simulation of the detoxification of paracetamol using online electrochemistry/liquid chromatography/mass spectrometry, Anal. Bioanal. Chem., 386, 1701, 2006. 

In a randomised, placebo-controlled study, there was no difference in measures of hepatotoxicity (mean AST levels, mean INR) between 102 alcoholic patients who received paracetamol 1 g four times daily for 2 days, and 99 alcoholic patients who received placebo. In this study, patients had entered an alcohol detoxification centre, and were given paracetamol im-... 

Paracetamol is extremely toxic for cats, because they lackthe glucuronyltrans-ferase important for detoxification. Also for snakes the compound possesses high toxicity, so that it has been considered as a means to exterminate especially the brown tree snake Boiga irregularis) in Guam. [173]... 

Figure 5.57 Detoxification of reactive quinone imine metabolite of paracetamol.

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