Acetaminophen hepatic toxicity

When taken in therapeutic doses (approximately 4 g 60mg/kg body weight) paracetamol (N-acetyl-para-ami nophenol, acetaminophen) is a safe and effective analgesic, but overdosage, possibly with the intent of self-harm, is a major cause of drug-induced hepatic toxicity. The cellular damage which may not be evident for up to... 

Oral 5 mg oxycodone plus 325 or 500 mg acetaminophen tablets. Note High-dose acetaminophen has potential for hepatic toxicity with repeated use. 

Moulding TS, Redeker AG, Kanel GC. Acetaminophen, isoniazid, and hepatic toxicity. Ann Intern Med 1991 114 431. 

Large doses of acetaminophen can cause renal and hepatic toxicity in rats and mice. Toxicity is characterized by renal tubular necrosis in the proximal tubules (Schnellmann, 2001). Acetaminophen toxicity has also been reported in humans. Generally, toxicosis is a result of large overdoses which result in proximal tubular necrosis. Aspirin, ibuprofen, and acetaminophen are the important analgesics, which are reported to cause toxicosis in veterinary medicine. Renal lesions including renal tubular necrosis and papillary necrosis have been reported in dogs. 

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-induced hepatic toxicity (see Chapter 26) has been associated with alcoholic cirrhosis as a result of alcohol-induced increases in microsomal production of toxic acetaminophen metabolites. Hepatitis C appears to be an important cofactor in the development of end-stage... 

Percy Veere s symptoms and laboratory abnormalities did not slowly subside over the next 6 weeks as they usually do in uncomplicated viral hepatitis A infections. Instead, his serum total bilirubin, ALT, AST, and alkaline phosphatase levels increased further. His vomiting became intractable, and his friend noted jerking motions of his arms (asterixis), facial grimacing, restlessness, slowed mentation, and slight disorientation. He was admitted to the hospital with a diagnosis of hepatic failure with incipient hepatic encephalopathy (brain dysfunction caused by accumulation of various toxins in the blood), a rare complication of acute type A viral hepatitis alone. The possibility of a superimposed acute hepatic toxicity caused by the use of acetaminophen was considered. 

In other instances, a nontoxic parent compound is transformed by CYP into a reactive metabolite that is toxic to the mitochondria. This is seen with acetaminophen, which is transformed by CYP2E1 to the chemically reactive, N-acetyl-p-benzoquinone imine. The hepatic toxicity of acetaminophen is increased in alcoholics (Seef et al. 1986). Ethanol abuse increases CYP2E1 in the endoplasmic reticulum and in the mitochondria (Robin et al. 2005). The mitochondrial localization of CYP2E1 may lead to the in situ generation of reactive metabolites of acetaminophen in the mitochondria, where the metabolite may trigger MPT (Weis et al. 1992 Masubuchi et al. 2005). Mitochondria also contain other inducible CYPs, such as CYPlAl and CYP2B1 (Anandatheerthavarada et al. 1997 Sepuri et al. 2007). The concomitant administration of CYP-inducers, phenobarbital or phenytoin increases the hepatotoxicity of valproic acid, which is transformed by microsomal and mitochondrial CYPs and then p-oxidation enzymes into a reactive... 

What type of toxicity should be observed when identifying a reactive intermediate For acetaminophen, hepatic necrosis was observed and depended upon the species. Most animals were affected at a 150 mg/kg dose to hamsters whereas, less than 10% of the animals were affected when rats were given 1,500 mg/kg. How can this concept be applied to the variety of classes of pesticides The question must be resolved on a... 

Duration of NAC treatment. The current widely used US protocol for treatment of acetaminophen poisoning calls for 17 doses of oral NAC given over approximately 72 hours. However, successful protocols in Canada, the United Kingdom, and Europe utilize intravenous NAC for only 20 hours. We give NAC orally until 36 hours have passed since the time of ingestion. Then, if the semm acetaminophen level Is below the limits of detection and liver transaminase levels are normal, NAC can be stopped. If there Is evidence of hepatic toxicity, then NAC should be continued until liver function tests are improving. 

The nurse immediately reportsany signs of acetaminophen toxicity, such as nausea, vomiting, anorexia, malaise, diaphoresis abdominal pain, confusion, liver tenderness hypotension, arrhythmias jaundice, and acute hepatic and renal failure. Early diagnoss is important because liver failure may be reversible. Toxicity is treated with gastric lavage, preferably within 4 hours of ingestion of the acetaminophen. Liver function studiesare perform ed frequently. Acetylcysteine (Mucomyst) is an antidote to acetaminophen toxicity and acts by protect-... 

Acetaminophen, which depletes hepatic glutathione, does not potentiate the toxicity of methyl parathion in mice. A possible mechanism of action may be competition between acetaminophen and methyl parathion for mixed function oxidases and subsequent prevention of activation of methyl parathion to methyl paraoxon (Costa and Murphy 1984). Diethyl maleate, an agent that depletes cytosolic glutathione and is not an enzyme inducer, potentiates toxicity of methyl parathion in mice (Mirer et al. 1977). 

Administration of chloroform to laboratory animals resulted in the depletion of renal GSH, indicating that GSH reacts with reactive intermediates, thus reducing the kidney damage otherwise caused by the reaction of these intermediates with tissue MMBs (Hook and Smith 1985 Smith and Hook 1983, 1984 Smith et al. 1984). Similarly, chloroform treatment resulted in the depletion of hepatic GSH and alkylation of MMBs (Docks and Krishna 1976). Other studies demonstrated that sulfhydryl compounds such as L-cysteine (Bailie et al. 1984) and reduced GSH (Kluwe and Hook 1981) may provide protection against nephrotoxicity induced by chloroform. The sulfhydryl compound N-acetylcysteine is an effective antidote for poisoning by acetaminophen, which, like chloroform, depletes GSH and produces toxicity by reactive intermediates. 

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. 

Acetaminophen (paracetamol) poisoning is common in Western countries and is increasing elsewhere. Single doses as low as 7.5 g in adults or 150 mg/kg in a child can cause severe toxicity. Very occasionally, lower doses cause harm. Mortality, from hepatic or occasionally renal failure, is related to blood concentration and the time between ingestion and the initiation of antidotal treatment. Even severely poisoned patients may be asymptomatic, although nausea and vomiting are fairly common. 

Hepatic necrosis can be classified by the zone of the liver tissue affected. Xenobiotics, such as acetaminophen or chloroform, that undergo bioactivation to toxic intermediates cause necrosis of the cells surrounding the central veins (centrilobular) because the components of the cytochrome P450 system are found in those cells in abundance. At higher doses or in the presence of agents that increase the synthesis of cytochrome P450 (inducers), the area of necrosis may incorporate the... 

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