Liver hepatotoxicity, paracetamol

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. 

The converse is true of drugs requiring metabolic activation for toxicity. For example, paracetamol is less hepatotoxic to newborn than to adult mice, as less is metabolically activated in the neonate. This is due to the lower levels of cytochromes P-450 in neonatal liver (Fig. 5.30). Also involved in this is the hepatic level of glutathione, which is required for detoxication. Although levels of this tripeptide are reduced at birth, development is sufficiently in advance of cytochrome P-450 levels to ensure adequate detoxication (Fig. 5.30). The same effect has been observed with the hepatotoxin bromobenzene. (For further details of paracetamol and bromobenzene see chap. 7.) Similarly, carbon tetrachloride is not hepatotoxic in newborn rats as metabolic activation is required for this toxic effect, and the metabolic capability is low in the neonatal rat. 

Concomitant administration of paracetamol with other hepatotoxic drugs or drugs acting on liver microsomal enzymes enhances paracetamol toxicity. Other drugs that interact with paracetamol are metoclopramide, probenecid, and cholestyramine.81... 

Acetaminophen (paracetamol, 4-hydroxyacetanilide, APAP), a commonly used analgesic drug, causes centrilobular hepatic necrosis upon overdosage. APAP displays toxicity characteristics that demonstrate, very clearly, dependence upon GSH for protection. Hepatotoxicity, including liver failure, often occurs when APAP is... 

If you have answered yes or no to this question, think again Many people would answer no, perhaps because of the worries about paracetamol hepatotoxicity. The answer, however, is most likely to be yes, but in actual fact you cannot answer it without knowing more about the patient. The question is too vague. Chapters 1 to 6 explain why this is the case and give you the background information to enable you to adequately consider drug choice in patients with liver dysfunction. 

Most studies investigating paracetamol pharmacokinetics in patients with liver disease used single doses only. A 50% reduction in clearance and a corresponding increase in half-life have been seen in severe acute hepatitis, the longest half-life being seen in patients with a raised prothrombin time (PT). It may therefore be prudent to extend the dose interval in these patients. Cirrhotic patients with a low albumin and a raised PT were also noted to have a prolonged paracetamol half-life, although no accumulation or hepatotoxicity was observed when normal therapeutic doses were administered to these patients for up to five days. In contrast, cirrhotic patients with normal albumin and PT demonstrated... 

The evidence suggests that paracetamol is safe to use in the majority of patients with liver disease, with no increased risk of hepatotoxicity when normal doses are used. 

Other studies have also demonstrated similar increases in half-life when comparing paracetamol pharmacokinetics in patients with decompensated chronic liver disease to normal subjects. Patients with cirrhosis who have a normal plasma albumin concentration and PT have been shown to have a similar paracetamol half-life and clearance to those of healthy subjects. However, cirrhotic patients with a low plasma albumin and an increased PT were found to have a prolonged paracetamol half-life. Despite this, no accumulation and no evidence of hepatotoxicity was demonstrated when therapeutic doses of paracetamol were given to patients with decompensated liver diseases for three to five days [21]. 

Domperidone may be the antiemetic of choice, but as the patient has very little metabolic and synthetic liver function, owing to massive hepatocellular necrosis secondary to the hepatotoxic effects of the paracetamol overdose, accumulation of the domperidone may occur. However, it may be of benefit as a pro-kinetic agent. 

PARACETAMOL ANTIVIRALS Cases of hepatotoxicity have been reported when paracetamol was added to either didanosine or zidovudine Uncertain possible additive hepatotoxic effect Monitor liver function regularly during co-administration... 

Drug toxicity may be more likely. A patient who becomes enzyme-induced by taking rifampicin is more likely to develop liver toxicity after paracetamol overdose by increased production of a hepatotoxic metabolite. (Such a patient will also present with a deceptively low plasma concentration of paracetamol due to accelerated metabolism, see p. 287)... 

The activity of cytosolic enzymes such as the glutathione transferases is also lower in the foetus, being only 5-10% of the adult value in rabbits and guinea-pigs. The glutathione content of foetal mouse liver was found to be approximately 10% of that of the adult, but studies indicate that the mouse foetus is still protected from the hepatotoxic effects of compounds such as paracetamol by this level of glutathione. 

Toward understanding the mechanistic action of toxicology using 2DE, Foun-toulakis et al. showed the hepatotoxic effects of paracetamol (acetaminophen) overdose in human and rodent liver [74]. They found that the expression of 35 proteins was altered after treatment with paracetamol or its nontoxic regioisomer 3-acetamidophenol. Paracetamol selectively increases or decreases the phosphorylation state of proteins. This effect translates to a decrease in protein phosphatase activity [80]. The control of cellular functions of cells may be lost as a result of the dephosphorylation of certain regulatory proteins due to paracetamol overdose. 

Zhu JH, Zhang X, McClung JP, I-ei XG (2006) Impact of Cu, Zn-superoxide dismutase and Se-dependent glutathione peroxidase-1 knockouts on acetaminophen-induced cell death and related signaling in murine liver. Exp Biol Med (Maywood) 231(11) 1726-1732 Zimmerman HJ, Maddrey WC (1995) Acetaminophen (paracetamol) hepatotoxicity with regular intake of alcohol analysis of instances of th apeutic misadventure. Hepatology 22 (3) 767-773... 

Roberts DW, Bucci TJ, Benson RW, Warbritton AR, McRae TA, Pumford NR, Hinson JA (1991) Immunohistochemical localization and quantification of the 3-(cystein-S-yl)-acetaminophen protein adduct in acetaminophen hepatotoxicity. Am J Pathol 138 359-371 Rose PG (1969) Paracetamol overdose and liver damage. Br Med J 1 381-382 Rumack BH, Peterson RG (1978) Acetaminophen overdose incidence, diagnosis, and management in 416 patients. Pediatrics 62 898-903... 

Yamada M, Kim S, Egashira K, Takeya M, Dceda T, Mimura O, Iwao H (2003) Molecular mechanism and role of endothelial monocyte chemoattractant protein-1 induction by vascular endothelial growth factor. Arterioscler Thromb Vase Biol 23 19%-2001 Yee SB, Bourdi M, Masson MJ, Pohl LR (2007) Hepatoprotective role of endogenous interleukin-13 in a murine model of acetaminophen-induced liver disease. Chem Res Toxicol 20 734-744 Younes M, Cornelius S, Siegers CP (1986) Ferrous ion supported in vivo lipid peroxidation induced by paracetamol - its relation to hepatotoxicity. Res Commun Chem Pathol Pharmacol 51 89-99... 

Acetaminophen (paracetamol) is a commonly used analgesic which is hepatotoxic at high doses in humans and in laboratory animals. Toxicity is believed to be mediated by the reactive metabolite N-acetyl-p-benzoquinone imine which binds to protein thiols as 3-(cystein-S-yl)acetaminophen adducts. Ultrasensitive immimoassays for 3-(with parallel elevations in serum adducts and serum levels of the liver-specific transaminase ALT. This suggested that the serum adducts were of hepatic origin and could be monitored as a biomarker of acetaminophen toxicity. Analysis of serum samples from acetaminophen overdose patients demonstrated a positive correlation between immunochemically detectable serum adducts and hepatotoxicity. 

Many case reports describe severe liver damage, sometimes fatal, in some alcoholics and persistent heavy drinkers who take only moderate doses of paracetamol. However, other controlled studies have found no association between alcoholism and paracetamol-induced hepatotoxicity. There is controversy about the use of paracetamol in alcoholics. Some consider standard therapeutic doses can be used, whereas others recommend the dose of paracetamol should be reduced, or paracetamol avoided. Occasional and light to moderate drinkers do not seem to be at any extra risk. One study found that chronic alcohol intake, bnt not acute alcohol intake, enhanced paracetamol hepatotoxicity following overdose. 

In a retrospective review of 553 cases of paracetamol-induced severe hepatotoxicity treated at a liver failure unit over a 7-year period, there was no association between the level of alcohol consumption and the severity of the hepatotoxicity (mean INR and serum creahnine levels in the first 7 days after overdose). Alcohol consumption was categorised into 4 groups ranging from non-drinkers to heavy drinkers (greater than 60 g of alcohol daily in men and 40 g daily in women). ... 

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