Overdoses of paracetamol

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). 

Paracetamol (acetaminophen) is a widely used analgesic and antipyretic drug that is relatively safe when taken at prescribed therapeutic doses. However, it has become increasingly common for overdoses of paracetamol to be taken for suicidal intent. In the United Kingdom, for example, around 200 deaths a year result from overdoses of paracetamol. This has prompted some to call for changes in its availability, with newspaper headlines such as "Doctors demand curbs on killer paracetamol" (Sunday Times, London, 14th November, 1993). When taken in overdoses, paracetamol causes primarily centrilobular hepatic necrosis, but this may also be accompanied by renal damage and failure. 

It now seems that an overdose of paracetamol causes a massive chemical stress, which causes an immediate adaptive defense response in the liver cell, which senses danger via redox-sensitive transcription factors. A number of mechanisms are involved, including the release, as a result of the stress, of a transcription factor Nrf-2 from its binding with Keap 1, a cytoplasmic inhibitor. Nrf-2 translocates to the nucleus and with other activators binds to an antioxidant-response element. This leads to transcription of a number of genes, so producing a... 

Overdoses of paracetamol can be very dangerous, as the drug has a narrow therapeutic index and may cause hepatic and renal necrosis. Nausea, vomiting, lethargy, and sweating are the early overdose symptoms. Paracetamol must be given with caution in alcoholics and patients with liver and kidney damage. 

If an overdose of paracetamol combined with other drugs is taken, the situation may be very different. For example, the combined preparation Distalgesic contains not only paracetamol but also a drug called... 

Paracetamol crosses the placenta readily. However, there has been no published evidence of a teratogenic effect in the offspring of mothers who have taken paracetamol during pregnancy. A case of fetal death after a maternal overdose of paracetamol (30 g) has been described (SEDA-10, 73), but in another similar case, in which 22.5 g was taken in the 36th week, the fetus survived (SEDA-9, 96). PreUminary data from a longitudinal study have shown no adverse effects of therapeutic doses of paracetamol on either pregnancy or infant development (69). 

However, a report (119) has described fatal overdose of paracetamol in four patients who presented within... 

A 37-year-old man with a history of ethanol abuse presented with hepatic failure and non-cardiogenic pulmonary edema after an overdose of paracetamol, codeine, ibuprofen, and diazepam. He received two... 

Figure 5.52., 400 MHz H-NMR spectrum of urine from a patient who had taken an overdose of paracetamol. Valine was added as an internal...

Dahlin DC, Miwa GT, Lu AY, Nelson SD (1984) N-acetyl-p-benzoquinone imine a cytochrome P-450-mediated oxidation product of acetaminophen. Proc Natl Acad Sci USA 81 1327-1331 Davem TJ 2nd, James LP, Hinson JA, Poison J, Larson AM, Fontana RJ, Lalani E, Munoz S, Shakil AO, Lee WM (2006) Measurement of serum acetaminophen-protein adducts in patients with acute liver failure. Gastroenterology 130 687-694 Davidson DG, Eastham WN (1966) Acute liver necrosis following overdose of paracetamol. Br Med J 5512 497 99... 

Thompson RP, Clark R, Willson RA, Borirakchanyavat V, Widdop B, Goulding R, Williams R (1972) Hepatic damage from overdose of paracetamol. Gut 13 836 Thummel KE, Lee CA, Kunze KL, Nelson SD, Slattery JT (1993) Oxidation of acetaminophen to N-acetyl-p-aminobenzoquinone imine by human CYP3A4. Biochem Pharmacol 45 1563-1569 Tirmenstein MA, Nelson SD (1989) Subcellular binding and effects on calcium homeostasis produced by acetaminophen and a nonhepatotoxic regioisomer, 3 -hydroxyacetanilide, in mouse liver. J Biol Chem 264 9814-9819... 

Complete heart block occurred when flumazenil was given to a woman who had taken an overdose of paracetamol and temazepam [lOS J. 

Paracetamol itself isn t, but its metabolite, NAPQI, is very toxic. Happily, the body contains a substance called glutathione (GSH) which mops up small amounts of NAPQI. But if an overdose of paracetamol is taken, then the body s supply of GSH becomes depleted, and the excess NAPQI can attack the liver, often with fatal consequences. In the United Kingdom, paracetamol is responsible for some 30,000-40,000 visits to casualty departments a year, with around 200 fatalities. 

---