Paracetamol toxicity

This is known as Michaelis-Menten or saturation kinetics. The processes that involve specific interactions between chemicals and proteins such as plasma protein binding, active excretion from the kidney or liver via transporters, and metabolism catalyzed by enzymes can be saturated. This is because there are a specific number of binding sites that can be fully occupied at higher doses. In some cases, cofactors are required, and their concentration may be limiting (see chap. 7 for salicylate, paracetamol toxicity). These all lead to an increase in the free concentration of the chemical. Some drugs, such as phenytoin, exhibit saturation of metabolism and therefore nonlinear kinetics at therapeutic doses. Alcohol metabolism is also saturated at even normal levels of intake. Under these circumstances, the rate of... 

As well as microsomal enzymes showing diurnal variation, other factors important in toxicology also show differences over time. For example, the level of glutathione varies significantly. Studies have shown that the hepatic GSH level in mice is significantly lower at 8 p.m. versus 8 a.m. Correspondingly, the susceptibility to paracetamol toxicity is much greater when administered at 8 p.m. versus 8 a.m. (Table 5.18). 

Table 5.18 Variation in Liver Glutathione Levels with Time and Effect on Paracetamol Toxicity...

The proposed activation of acetylhydrazine involves N-hydroxylation, followed by loss of water to yield acetyldiazine, an intermediate that would fragment to yield acetyl radical or acetyl carbonium ion (Fig. 7.24). GSH was not depleted by hepatotoxic doses of acetylhydrazine, indicating that unlike bromobenzene or paracetamol toxicity, it does not have a direct protective role. 

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... 

Children under six years of age seem to be less susceptible to paracetamol toxicity, possibly owing to a more efficient detoxification pathway or greater glutathione content, or simply a greater liver size in relation to body mass [8]. 

Isolated cases of chronic paracetamol toxicity have been reported, such as hepatocellular necrosis, hepatic inflammation and fibrosis. These cases occurred in patients taking 2-6 g of paracetamol daily for months... 

This patient has a massively raised ALT, indicating considerable hepato-cyte damage. All functions of the liver are likely to be affected, including reduced secretory and excretory function, demonstrated in this case by a raised bilirubin reduced synthetic function, shown by the raised INR (albumin is imaffected at this time due to its long half life) reduced metabolic function, indicated by accumulation of ammonia and other toxins leading to encephalopathy. Blood flow through the liver is likely to be unaffected, as there is no cirrhosis/portal hypertension. As with all other functions of the liver, this patient s ability to metabolise drugs is likely to be severely affected. Renal function is also impaired secondary to paracetamol toxicity. 

PARACETAMOL ISONIAZID Risk of paracetamol toxicity at regular, therapeutic doses when co administered with isoniazid Uncertain it seems that formation of toxic metabolites is t in fast acetylators when isoniazid levels i (i.e. at the end of a dosing period) There have been cases of hepatic pathology regular paracetamol should be avoided in patients taking isoniazid... 

Primary cells are typically cells from the liver, as these are the most easily obtained and the majority are the same type of cell, whereas those from most other organs are a mixture of types of cells. Primary liver cells are the most likely to be representative of the organ in the whole animal. These cells however, will indicate the effects (if any) that the chemical has only on the liver. They do not necessarily predict the effects on other organs or tissues. Furthermore, research has shown that the way in which isolated cells in the laboratory respond to chemicals is not always the same as the way they respond in the animal or human. They are often less sensitive, sometimes requiring a concentration of chemical many times higher than that which causes an effect in the live whole animal. For example, when isolated human liver cells are exposed to paracetamol, toxic effects are observed only if a concentration of paracetamol is used that is at least ten times higher than the level that causes liver damage in humans after an overdose. Unlike a cell in vitro, a cell in an animal is... 

Fulminant hepatic failure occurs in 1-5% of cases of paracetamol overdosage 3-6 days after ingestion (71), with frequent deaths in people who take 20-25 g. There is only a narrow margin between the normal maximum 24-hour dosage and that which can cause liver damage and acute hepatic failure. Undoubtedly, some people are more susceptible than most to paracetamol toxicity, since although 6 g has been reported as toxic in some cases, most toxicity is seen with 12 g upwards (72,73). Nomograms have been developed to show the relation between plasma paracetamol concentrations over time and the risk of a serious outcome (SEDA-18, 94). 

Analgesic cocktails or the concurrent use of potentially hepatotoxic drugs increase the risk of paracetamol toxicity. 

Smith JAE, Hine ID, Beck P, Routledge PA. Paracetamol toxicity is enzyme induction important Human Toxicol 1986 5 383-5. 

Sheen CL, Dillon JF, Bateman DN, Simpson KJ and McDonald TM (2002). Paracetamol toxicity epidemiology, prevention and costs to the healthcare system. Quarterly Journal of Medicine 95, 609-619. 

Note The quinine-imine system is almost identical to the acetaminophen (paracetamol) toxic metabolite. 

Hinson JA (1980) Biochemical toxicology of acetaminophen. Rev Biochem Toxicol 2 103-129 Hinson JA, Monks TJ, Hraig M, Highet RJ, Pohl LR (1982) 3-(glutathion-S-yl) acetaminophen a biliary metabolite of acetaminophen. Dmg Metab Dispos 10 47-50 Hinson JA, Roberts DW, Benson RW, Dalhoff K, Loft S, Poulsen HE (1990) Mechanism of paracetamol toxicity. Lancet 335 732... 

A patient taking zidovudine and co-trimoxazole took 3.3 g of paracetamol over 36 hours. Within 2 days he developed severe hepatotoxicity, and as other causes were excluded, the reaction was attributed to the paracetamol. The authors suggested that zidovudine may have augmented the paracetamol toxicity. However, in a single-dose study, reduced paracetamol glucuronidation and increased formation of hepatotoxic metabolites was seen in patients with advanced HIV infection compared with healthy HIVpositive subjects and those without HIV, and this effect was independent of zidovudine use.In contrast, in another study, disease state (AIDS versus healthy HIV-positive subjects) was not found to alter paracetamol metabolism, and zidovudine was found to increase paracetamol glucuronidation in some patients."... 

Dear, J.W., et al., Letter to the editor early detection of paracetamol toxicity using circulating liver microRNA and markers of ceU necrosis. BrJ Clin Pharmacol, 2013. doi 10.1111/bcp.l2214. 

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