Acetaminophen liver toxicity

Therapeutic exposure Total daily dose of acetaminophen should not exceed 4g. Dosages of acetaminophen over 4-8 g day over long periods of time may be associated with higher risk of liver toxicity. Acetaminophen should not be administered for... 

The answer is c. (Hardman, pp 632-633.) Nausea, vomiting, abdominal pain, and diarrhea are early signs of the severe liver toxicity caused by high levels of acetaminophen other symptoms of acetaminophen toxicity include dizziness, excitement, and disorientation. N-acetyl-L-cysteine is the appropriate treatment for acetaminophen overdose. 

Because 1,4-dichlorobenzene is a liver toxin, it probably can interact with other chemicals that are liver toxicants. These toxicants are many, and include ethanol, halogenated hydrocarbons (chloroform, carbon tetrachloride, etc ), benzene, and other haloalkanes and haloalkenes. In addition, 1,4-dichlorobenzene toxicity may also be exacerbated by concurrent exposure with acetaminophen, heavy metals (copper, iron, arsenic), aflatoxins, pyrrolizidine alkaloids (from some types of plants), high levels of vitamin A, and hepatitis viruses. Such interactions could either be additive or S5mergistic effects. 

Reilly, T.P, Bourdi, M., Brady, J.N., Pise-Madison, C.A., Radonovich, M.R, George, J.W., and Pohl, L.R., Expression profiling of acetaminophen liver toxicity in mice using microarray technology, Biochem. Biophys. Res. Commun., 282, 321-328, 2001. 

Studies of liver toxicity caused by bromobenzene, acetaminophen, and other compounds have led to some important observations concerning tissue damage ... 

Used in mild-to-moderate pain May use in conjunction with opioid agents to decrease doses ot each Regular alcohol use and high doses of acetaminophen may result in liver toxicity Care must be exercised to avoid overdose when combination products containing these agents ate used Drug ot choice in severe pain Use immediate-release product with SR product to control breakthrough pain in cancer patents... 

A special mention of interaction of acetaminophen with alcohol consumption is warranted. Large numbers of reports in scientific literature and public media suggest that a potentially high risk of liver toxicity due to acetaminophen exists when consumed following alcohol intake. In a recent review, however. Dr. Barry Rumack suggests that only chronic heavy drinkers may be at greater risk following an overdose of acetaminophen and that no potentiation of toxicity occurs at therapeutic doses. 

Acute overdose with acetaminophen (>300 mg kg ) results in hepatotoxicity and/or nephrotoxicity. Although hepatotoxicity is frequently the predominant toxicity, acetaminophen nephrotoxicity can occur in the absence of marked hepatic toxicity. In these cases, liver function returns to normal or near normal levels before the onset of nephrotoxicity. Acute acetaminophen nephrotoxicity is generally characterized as oliguric acute renal failure with acute tubular necrosis. Acetaminophen can also induce acute nephrotoxicity in therapeutic doses, but chronic alcohol intake usually accompanies renal toxicity in these patients. 

Acetaminophen (APAP) is a widely used analgesic. Pretreatment with APAP followed by ethanol intake increases the metabolism of APAP and thereby its toxicity. Binge drinking of ethanol increases the hepatotoxicity of APAP. Caffeine also activates the metabolism of APAP and it, too, increases the hepatotoxicity of APAP. The combination of ethanol and caffeine significantly increases the liver toxicity of APAP. ... 

The antioxidant and hepatoprotective actions of M. anka against acetaminophen (AAP)-induced liver toxicity have been investigated (Aniya et al., 1998). Their results show that M. anka prevents AAP-induced liver toxicity by both antioxidant action and the inhibition of AAP metabolism. Further antioxidant action of M. anka was studied in vitro and in vivo... 

Aniya, Y., Yokomakura, T., Yonamine, M., Nagamine, T., and Nakanishi, H. 1998. Protective effect of the mold Monascus anka against acetaminophen-induced liver toxicity in rats. Jpn. J. Pharmacol. 78(1), 79-82. 

The routine administration of acetylcysteine more than 24 hours after acetaminophen overdose has been proposed. Case reports and animal studies indicate that it is relatively safe and that its use may minimize hepatotoxicity. Although accepted criteria for its use are lacking, it may be considered for patients with fulminant hepatoxicity, when acetaminophen is still measurable in the serum, or when the ingestion was not recognized within 24 hours and liver toxicity is apparent. 

Understand that acetaminophen overdose can lead to liver toxicity. 

Acetaminophen is metabolized mainly by liver glucuronyl transferase to form the inactive conjugate. A minor pathway (via P450) results in formation of a reactive metabolite (N-acetylbenzoquinoneimine) that is inactivated by glutathione (GSH). In overdose situations, the finite stores of GSH are depleted. Once this happens, the metabolite reacts with hepatocytes, causing nausea and vomiting, abdominal pain, and ultimately liver failure due to centrilobular necrosis. Chronic use of ethanol enhances liver toxicity via induction of P450. 

In the UK, warning labels on paracetamol (acetaminophen) state that the patient should not exceed 4 g in any one 24-hour period but an acute dose of paracetamol (acetaminophen) greater than 7.5 g or 150 mg/kg body weight will result in acute toxicity. Once the dose reaches 10 g a dose-dependent liver toxicity will be seen. In the UK,... 

Another issue is drug metabolism and toxicity. Acetaminophen overdose remains a major cause of liver failure in the United States. Several P450s are involved in the oxidation to the reactive imi-noquinone . Studies with P450 2E1 knockout mice indicate that P450 2E1 is a major determinant of acetaminophen toxicity, because the toxicity was considerably attenuated in null animals ... 

These data supported the hypothesis that acetaminophen-induced liver toxicity is mediated by covalent binding to critical proteins. In an attempt to further understand the mechanism of hepatotoxicity of acetaminophen, specific proteins to which acetaminophen was covalently bound were isolated and sequenced by our laboratory and by Cohen s laboratory (Cohen et al. 1997). The proteins that were identified by this approach were glutamine synthase, glutamate dehydrogenase,... 

A number of studies have examined the importance of mitochondrial dysfunction in acetaminophen toxicity. Electron microscopic examination of livers from acetaminophen treated livers by Racz s laboratory indicated alterations in mitochondrial morphology (Walker et al. 1980). JoUow et al. reported that mitochondria were a target for the acetaminophen-reactive metabolite (follow et al. 1973), and a number of arylated proteins were found in mitochondria (Bulera et al. 1996 Pumford et al. 1990). Functional alterations in the ability to sequester calcium have been reported (Tirmenstein and Nelson 1989). Inhibition of mitochondrial respiration at complexes 1 and 11, but not at complex III was reported in isolated rat hepatocytes (Burcham and Harman 1991) and in vivo (Donnelly et al. 1994). In addition, ATP levels decrease in vivo and in treated hepatocytes (Burcham and Harman 1991 Vendemiale et al. 1996). Similar changes have been shown by adding NAPQI to hepatocytes (Andersson et al. 1990). Moldeus and Orrenius s laboratory reported that addition of NAPQI to isolated rat liver mitochondria caused release of sequestered calcium (Weis et al. 1992, 1994). 

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