China
Africa
Explore chapters and articles related to this topic
Drug Overdoses during Pregnancy
Published in “Bert” Bertis Britt Little, Drugs and Pregnancy, 2022
Importantly, acetaminophen per se is not the toxic agent in overdoses, it a proximate metabolite that is toxic, and preventing the drug’s metabolism is key to antidote treatment, and the reason for urgency in NAC administration. In acetaminophen overdose, metabolic pathways (sulfation and glucuronidation) become saturated, causing an increased metabolic demand on cytochrome P-450 oxidases. The P-450 system oxidizes the drug and produces a highly reactive intracellular metabolite (N-acetyl-p-benzoquinone imine, or NAPBQI) that complexes with hepatic glutathione. The P-450 metabolite NAPBQI binds to hepatocellular macromolecules when glutathione is depleted and hepatotoxicity ensues (Andrews et al., 1976; Davis et al., 1976). Normally, NAPBQI is produced in small amounts and degraded by the liver almost immediately. Fetal P-450 has <10 percent of adult activity, resulting in negligible production of the toxic metabolite. Some authorities speculate that the increased risk of maternal hepatotoxicity compared to fetal hepatotoxicity may be related to the largely inactive fetal enzyme complement, i.e., fetal liver has a much lower capacity to metabolize the drug to NAPBQI. As the fetal liver matures, it is likely fetuses of more advanced gestational age are at greater risk for acetaminophen toxicity than less mature fetuses. In the largest series published, this relationship was not readily apparent (Table 14.6). Maternal-fetal outcomes are generally better with expedient NAC administration following acetaminophen overdose.
Paediatric clinical pharmacology
Published in Evelyne Jacqz-Aigrain, Imti Choonara, Paediatric Clinical Pharmacology, 2021
Evelyne Jacqz-Aigrain, Imti Choonara
Paracetamol is metabolised in the liver to a variety of products, the majority of which are not toxic. N-acetyl-p-benzoquinone imine (NAPQI) is a highly reactive product, produced by paracetamol oxidation, which is normally rendered inert within the liver by combination with glutathione. In paracetamol overdose, NAPQI production overwhelms cellular reserves of glutathione and toxic levels result in severe liver damage. Paracetamol hepatotoxicity is common in adolescents, but rare in pre-pubertal children who have greater reserves of glutathione and enhanced sulphation.
Xenobiotic Biotransformation
Published in Robert G. Meeks, Steadman D. Harrison, Richard J. Bull, Hepatotoxicology, 2020
Acetanilides, such as acetaminophen and phenacetin, are nonprescription analgesics that cause hepatic necrosis in overdosage. For acetaminophen, sulfation and glucuronidation are the major pathways for biotransformation [reviewed by Jollow and Smith (1977) and Nelson (1982)]. Minor bioactivation pathways for acetaminophen include direct oxidation by P450, peroxidases, or prostaglandin synthetase to the electrophile N-acetyl-p-benzoquinoneimine (NAPQI). Massive doses are required for toxicity, because glutathione transferase efficiently detoxifies this electrophile until glutathione is depleted to 15% of normal levels. NAPQI can also undergo hydrolysis to acetamide or be reduced by P450 back to acetaminophen. The P450 most active for bioactivation of acetaminophen is CYP2A. CYP2B and CYP2A1 produce the electrophilic metabolite to a lesser extent. Clinical toxicity is believed to require activation of the minor pathway by prior or concurrent exposure to P450 inducers; for example, the use of PB for anticonvulsant therapy. Induction of PB-inducible P450, however, can modify toxicity by coordinate induction of acetaminophen glucuronidation and reduction of NAPQI back to acetaminophen.
Liver protective effect of chloroform extract of Bauhinia purpurea leaves is attributed partly to its antioxidant action and the presence of flavonoids
Published in Pharmaceutical Biology, 2023
Zainul Amiruddin Zakaria, Adibah Sahmat, Azfar Hizami Azmi, Amal Syahirah Nur Zainol, Maizatul Hasyima Omar, Tavamani Balan, Arifah Abdul Kadir, Syahriel Abdullah, Roro Azizah, Lilis Sulistyorini
NAPQI toxicity was the trigger for the search and development of the currently used antidote, N-acetylcysteine (NAC), which has been the only drug of choice for the treatment of PCM-induced hepatotoxicity for several decades. This antidote acts as a precursor or to replenish hepatic GSH, the major endogenous nucleophilic peptide that contributes to the neutralization of NAPQI (Aldini et al. 2018). Other potentials of NAC are also described elsewhere (Zhang et al. 2018; Šalamon et al. 2019). In parallel with the reports of NAC efficacy in the treatment of PCM-induced hepatotoxicity as described above, there are predictions that the global market for NAC will increase over the next five years (Šalamon et al. 2019). Despite the tremendous progress in the field of drug discovery, the increase in the global market for NAC is hampered by the fact that none of the modern hepatoprotective drugs on the market are able to completely avert or treat drug-induced liver injury (Mondal et al. 2020).
Genetic variants associated with ALT elevation from therapeutic acetaminophen
Published in Clinical Toxicology, 2022
Andrew A. Monte, Ian Arriaga Mackenzie, Jack Pattee, Sasha Kaiser, Emileigh Willems, Barry Rumack, Kate M. Reynolds, Richard C. Dart, Kennon J. Heard
Acetaminophen is the leading cause of acute liver failure in the United States, and while the majority of this liver failure is due to overdose, it is known that some patients developed transiently elevated transaminases even at therapeutic doses. Acetaminophen is the prototypical hepatocellular toxin resulting from through production of N-acetyl-p-benzoquinone imine (NAPQI) predominantly through CYP2E1 metabolism of the parent compound. When glutathione detoxification is overwhelmed, NAPQI leads to hepatocyte damage and death. However, there is evidence that immune factors may also contribute to the elevation of transaminases in the setting of therapeutic dosing [6]. This reaction is likely polygenic, given the complexity of acetaminophen metabolism (Figure 1) [7] and the range of clinical responses observed in patients taking the drug. Expanded cohorts are necessary to capture the relatively uncommon clinical outcome of transaminase elevation from therapeutic dosing, given that it is frequently asymptomatic and transient. The primary objective of this study was to examine genetic variants in metabolic enzymes and immune genes associated with acetaminophen-induced liver injury in a large, well-controlled cohort of patients taking therapeutic acetaminophen.
The nuclear receptor REV-ERBα regulates CYP2E1 expression and acetaminophen hepatotoxicity
Published in Xenobiotica, 2022
Li Zhang, Fugui Zhang, Yifei Xiao, Jianhao Du, Xingwang Zhang, Min Chen, Baojian Wu
APAP is a common analgesic and antipyretic drug used to relieve pain and fever (Lee 2017). This drug is generally safe at a therapeutic dose. However, an acute or cumulative overdose of APAP can lead to severe liver injury and even fatal centrilobular hepatic necrosis (Yoon et al. 2016). Because APAP is widely used, APAP-induced hepatotoxicity has become a major cause of acute liver failure in the US and other Western countries (Larson et al. 2005; Bernal and Wendon 2013). APAP hepatotoxicity contributes to ∼70,000 hospitalisations each year in the US (Budnitz et al. 2011), and is regarded as a significant public health problem (Ramachandran and Jaeschke 2018). After administration, the majority of APAP is conjugated in the liver with glucuronic acid or sulphate and excreted out of body through the kidney. A small proportion of APAP is catalysed by CYP2E1 to the reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI) that is responsible for the hepatotoxicity (Ramachandran and Jaeschke 2018). NAPQI is unstable and rapidly conjugated with glutathione, and further transformed to non-toxic APAP-cysteine (APAP-Cys) and APAP-N-acetylcysteine (APAP-NAC) (Zhang et al. 2018). Of note, CYP1A2 and CYP3A11 may also have a contribution to the metabolism of APAP to the toxic intermediate (Cheung et al. 2005; Jiang et al. 2015).