Paracetamol liver damage

Mendoza, S., M. Noa, R. Mas, and N. Mendoza. Effect of D-003, a mixture of high molecular weight primary acids from sugar cane wax, on paracetamol-induced liver damage in rats. Int J Tissue React 2003 25(3) 91-98. 

N-acetyl-cysteine, a synthetic precursor of cysteine, is commonly used as an antidote to paracetamol-induced liver damage... 

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. 

Direct organ toxicity. Some substances may directly damage cells of a particular organ or system, either because they or their metabolites are specifically toxic to these cells, or because they are concentrated in one area, e.g. the renal fluoride ion toxicity of methoxyflurane, or the liver damage that occurs in paracetamol overdose because of a toxic intermediate product binding to hepatocytes. Secondary effects. Some effects are only indirectly related to the action of the drug, e.g. vitamin deficiency in patients whose gut flora have been modified by broad-spectrum antibiotics. 

The half-life will be independent of the dose, provided that the elimination is first order and therefore should remain constant. Changes in the half-life, therefore, may indicate alteration of elimination processes due to toxic effects because the half-life of a compound reflects the ability of the animal to metabolize and excrete that compound. When this ability is impaired, for example, by saturation of enzymic or active transport processes, or if the liver or kidneys are damaged, the half-life may be prolonged. For example, after overdoses of paracetamol, the plasma half-life increases severalfold as the liver damage reduces the metabolic capacity, and in some cases, kidney damage may reduce excretion (see chap. 7). 

By measurement of the blood level of paracetamol in overdose cases, it is possible to estimate the likely outcome of the poisoning, and hence determine the type of treatment. Measurement of the blood level of paracetamol and its various metabolites at various times after the overdose showed that the half-life was increased several folds (Table 7.3), and the patients who sustained liver damage had an impaired ability to metabolize paracetamol to conjugates (Fig. 7.16). 

Table 7.3 Mean Plasma Concentration and Half-Life of Unchanged Paracetamol in Patients with and Without Paracetamol-Induced Liver Damage...

Figure 7.17 Species differences in the dose-response relationship for paracetamol-induced liver damage. Source From Refs. 5 and 6.

Paracetamol causes skin rashes, blood dyscrasia, and liver damage and nephrotoxicity in overdose. Large doses of paracetamol cause nephritis and... 

Acute ethanol inhibits the microsomal oxidation of paracetamol (presumably through competition with the CYP2E1), both in animals and man. This protects against liver damage in animals and there is evidence that it also does so in man. 

It is necessary to be aware that paracetamol may cause liver damage in overdose in certain susceptible individuals, the toxic dose is reduced (>75mg/kg compared with 150 mg/kg for non-susceptible individuals). Malnutrition, chronic alcoholism and HIV infection all make people more susceptible. 

This case of fatal liver damage due to paracetamol overdose was reported in the British Medicai Journai. It was one of the first such cases to be described. Another case was reported in the same article, also from Edinburgh, and another in the same volume of the journal. Overdose cases now number in the hundreds and possibly even thousands each year throughout the world. 

The outcome, however, can depend on the individual patient. The recommended dose of paracetamol is i to 2 tablets (500 mg each) but the size of dose necessary to cause damage depends on the individual. The average individual who is not taking other drugs regularly, may have to take about twenty tablets to suffer liver damage, but with some individuals as few as ten tablets can have the same effect. There is individual variability in the sensitivity to paracetamol due to variation in the metabolism. A major factor is the use of alcohol and certain other drugs such as barbiturates (see case notes). 

A 43-year-old man was admitted to hospital suffering halluoinations. He had fallen off his bike, fraotured a bone in his shoulder, and was presoribed one to two tablets of Tylenol (paracetamol plus codeine) every four to six hours for two days. He oontinued to suffer occasional hallucinations and vomiting and from jaundice. Once in hospital liver function tests on his blood indioated that he had liver damage. He died in a hepatic coma thirty hours after being admitted to hospital. It was later revealed by relatives that the patient had also treated himself with nine Tylenol tablets plus ten tablets of another preparation after the bicycle accident. Another important factor was that he regularly drank half a case (twelve bottles) of beer each day. ... 

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... 

Muriel, R, Garciapina, T., Perez-Alvarez, V., Mourelle, M. Silymarin protects against paracetamol-induced lipid peroxidation and liver damage. J. y pl. Toxicol. 1992 12 439-442... 

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). 

To reduce the chance of liver damage and death in cases of paracetamol overdosage, guidelines have been produced in many countries (74,117,118) to identify patients at high risk who need to be treated soon with acetylcysteine. 

Experience in 59 pregnant patients suggested that use of N-acetylcysteine in pregnancy did not result in toxic effects on the fetus. In practice, the risk to the mother and baby of paracetamol-induced liver damage probably far outweighs any potential risk of N-acetylcysteine, and pregnancy should not be considered a contraindication to the use of this agent. 

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