Acetaminophen liver damage

If liver damage is present, the older adult should use acetaminophen with caution. 

Acetaminophen is usually well tolerated, but potentially fatal hepatotoxicity with overdose is well documented. It should be used with caution in patients with liver disease and those who chronically abuse alcohol. Chronic alcohol users (three or more drinks daily) should be warned about an increased risk of liver damage or GI bleeding with acetaminophen. Other individuals do not appear to be at increased risk for GI bleeding. Renal toxicity occurs less frequently than with NSAIDs. 

Liver damage can be avoided if the thiol group donor, N-acetylcysteine, is given intravenously within 6-8 h after ingestion of an excessive dose of acetaminophen. Whether chronic regular intake of acetaminophen leads to impaired renal function remains a matter of debate. 

The best evidences are studies from preclinical animal models [86, 87, 105], or knockout animals lacking appropriate anti-oxidative pathways [106]. For example, Balb/c mice administered a variety of anti-oxidants in their chow were protected from acetaminophen hepatotoxicity [107]. Rats fed with the anti-oxidant melatonin were protected from cholesterol mediated oxidative liver damage [108]. The best clinical evidence that oxidative stress is a key player in a variety of liver injury diseases is the beneficial application of silymarin in these disease indications [109]. Silymarin is a polyphenolic plant fiavonoid (a mixture of flavonoid isomers such as silibinin, isosilibinin, silidianin and silichristin) derived from Silymarin maria-num that has antioxidative, antilipid peroxidative, antifibrotic and anti-inflammatory effects [109, 110]. 

Bioactivation is a classic toxicity mechanism where the functional group or the chemical structure of the drug molecule is altered by enzymatic reactions. For example, the enzymatic breakdown of the analgesic acetaminophen (paracetamol), where the aromatic nature and the hydroxyl functionality in paracetamol are lost, yields A -acetyl-p-benzoquinone imine, a hepatotoxic agent. Paracetamol can cause liver damage and even liver failure, especially when combined with alcohol. 

Acetaminophen is ordinarily safe at the recommended dosages, but large amounts exhaust the reserve of glutathione and may cause fatal liver damage. By 1989, more than 1000 cases of accidental or intentional (suicide) overdoses had been reported with many deaths. Prompt oral or intravenous administration of N-acetylcysteine over a 72-hour period promotes synthesis of glutathione and is an effective antidote.)... 

Since most codeine is dispensed as part of a compound preparation, potential side effects of the other drug(s) must also be considered. For instance, someone with stomach ulcers should not take codeine that is combined with a nonsteroidal anti-inflammatory drug (NSAID) such as aspirin or ibuprofen. Another type of risk from a compound preparation relates to codeine abuse. For instance, a person who abuses codeine might routinely take a dose of 100-200 mg of codeine to produce noticeable euphoria. Using Tylenol 3 to obtain this dose would also mean ingesting 1,000-2,000 mg of acetaminophen. Taking that amount of acetaminophen for any extended period presents a risk for liver damage, especially in combination with alcohol. 

Similarly, alcohol should be avoided when taking oxycodone. It, too, increases feelings of drowsiness and can cause dizziness when combined with oxycodone. Avoiding alcohol is especially important when taking pain-relievers containing oxycodone and acetaminophen, as studies have shown that liver damage can occur when even relatively small amounts of alcohol are combined with acetaminophen. A current or past history of alcohol or drug abuse should be carefully considered before oxycodone is prescribed. 

In adults, hepatotoxicity may occur after ingestion of a single dose of acetaminophen (10-15 g) doses of 20-25 g or more are potentially fatal. Severe liver damage occurs in 90 percent of patients with plasma concentrations of acetaminophen in excess of 300 pg/ml at 4 hours or 45 pg/rnl at 15 hours after ingestion of the drug. Administration of N-acetylcysteine is recommended if less than 36 hours has elapsed since ingestion of acetaminophen, although the antidote is most effective if administered within 10 hours. 

Unlike aspirin, acetaminophen does not alter the body s blood-clotting abilities and therefore does not have aspirin s potential benefits in reducing heart attacks and strokes. On the other hand, acetaminophen does not have the toxic side effects of aspirin such as intestinal bleeding and stomach ulcers. However, like most OTC drugs, acetaminophen is metabolized by the liver, and when taken repeatedly in amounts that exceed the recommended dosage, it can cause liver damage. 

Acetaminophen can interact with other drugs, both in good and bad ways. For example, hospitals often combine acetaminophen with the narcotic pain reliever codeine (CoTylenol ) to treat more severe pain. Caffeine can increase the effectiveness of acetaminophen similarly to the way it does with aspirin. Brand names that use a combination of aspirin, caffeine, and acetaminophen include Excedrin and Vanquish . Combining these ingredients for their additive effects also reduces the dose needed for each one and thereby reduces the risk of side effects. However, there are a few drugs that should not be mixed with acetaminophen. These include anticonvulsants and alcohol, both of which increase the risk of liver damage. 

Large quantities of acetaminophen can be toxic because the body transforms it to the imine of benzoquinone. This highly reactive metabolite causes extensive liver damage and can be deadly. 

Although cell injury results in increased calcium, which causes a variety of damaging effects, the cause and effect relationship of calcium in cell damage is not known. The chemicals that cause liver damage by this mechanism include quinines, peroxides, acetaminophen, iron, and cadmium. 

Acetaminophen reduces pain and fever, but it is not anti-inflammatory, so it is ineffective in treating conditions like arthritis, which have a significant inflammatory component. In large doses, acetaminophen causes liver damage, so dosage recommendations must be carefully followed. 

Muriel, R, Qnlntanar, E., Perez-Alvarez, V. Effect of colchicine on acetaminophen-induced liver damage. Liver 1993 13 217-221... 

Barker JD Jr, de Carle DJ, Anuras S. Chronic excessive acetaminophen use and liver damage. Ann Intern Med 1977 87(3) 299-301. 

Acetaminophen is not an NSAID but an analgesic and antipyretic. Its properties are compared with I those of ASA. It has the potential for creating severe liver damage. 

Answer C. Acetylcysteine is the antidote to acetaminophen in overdose and should be administered within 12 h for maximum effectiveness. It enhances the elimination of the reactive metabolite N-acetyl-benzoquinoneimine, which is responsible for liver damage. In overdose of acetaminophen, the metabolite accumulates because there is limited availability of reduced glutathione (GSH). The precise mechanism of action of acetylcysteine is undear, but it either increases the availability of GSH, which would normally inactivate the reactive metabolite, or itself interacts with and inactivates the metabolite. 

Beckett, G. J., Foster, G. R., Hussey, A. J., Oliveira, D. B.G., Donovan, J. W., Prescott, L. F., and Proudfoot, A. T., Plasma glutathione S-transferase and F protein are more sensitive than alanine aminotransferase as markers of paracetamol (acetaminophen)-induced liver damage. Clin. Chem. (Winston-Salem, N.C.) 35, 2186-2189 (1989). 

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