Paracetamol overdosage

Wright JN, Prescott LF. Potentiation by previous drag therapy of hepatotoxicity following paracetamol overdosage. Scott Med J 1973 18 56-58. 

Dose. As a mucolytic, 600 mg daily by mouth. In the treatment of paracetamol overdosage, initially 150 mg/kg by rapid intravenous infusion. 

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. 

Theoretically, inhibitors of cytochrome P450, like cime-tidine, might be of value in the treatment of paracetamol overdosage, and preliminary animal data also suggest this (115). 

Paracetamol can cause false-positive reactions for glucose in serum and blood specimens examined using the YSI glucose analyser. The effect could be of considerable importance in patients admitted with suspected paracetamol overdosage. 

POHL, L.R. (1979) Biochemical toxicology of chloroform. In Reviews of Biochemical Toxicology, Vol. 1, edited by J.Bend, R.M.Philpot and E.Hodgson (Amsterdam Elsevier-North Holland). PRESCOTT, L.F. (1983) Paracetamol overdosage pharmacological considerations and clinical management. Drugs, 25, 290. 

Note. The drug when administered either orally or parenterally serves as a potential antidote to check or lower the hepatotoxicity caused due to acetaminophen (paracetamol) overdosage. 

Prescott LF, Newton RW, Swainson CP, Wright N, Forrest ARW, Matthew H (1974) Successful treatment of severe paracetamol overdosage with cysteamine. Lancet 1 588-592... 

Paracetamol overdosage is an increasing problem in some countries and is often complicated by acute centrilobular hepatic necrosis which may be fatal (215 —224, 225, 226 —230, 257 ). The current importance of the phenomenon naturally results from the trend to replace other simple analgesics by paracetamol, especially in Britain. 

Eastham, E. J., Bell, J. I. and Douglas, A. P. (1976) Serum ferritin levels in acute hepatoceF lular damage from paracetamol overdosage. Brit, med. J., 1, ISO. 

When taken in therapeutic doses (approximately 4 g 60mg/kg body weight) paracetamol (N-acetyl-para-ami nophenol, acetaminophen) is a safe and effective analgesic, but overdosage, possibly with the intent of self-harm, is a major cause of drug-induced hepatic toxicity. The cellular damage which may not be evident for up to... 

Overdosage with paracetamol is extremely dangerous and potentially fatal, due to liver... 

Prescott LF, Wright N. The effects of hepatic and renal damage on paracetamol metabolism and excretion following overdosage. A pharmacokinetic study. Br J Pharmacol 1973 49(4) 602-613. 

Side-effects are rare and may include hematological reactions, leucopenia, agranulocytosis and other hypersensitivity reactions. Paracetamol has a narrow therapeutic dose range and overdosage induces severe liver and renal damage (Lewis and Paloucek, 1991) via accumulation of a toxic metabolite, N- acetyl-benzoquinoneimine (NABQI). Acetylcysteine or methionine, which increase glutathione conjugation of the metabolite, are used as the antidote. 

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... 

Toxicity. The minimum lethal dose is about 10 g. Symptoms of hepatic damage do not occur for at least 12 hours after overdosage but may not appear until 4 to 6 days later. Plasma concentrations have been used to indicate possible hepatic necrosis at 4 hours, hepatic necrosis is possible at concentrations of paracetamol of 120 to 300 pg/ml, probable at concentrations above 300pg/ml, and unlikely at concentrations below 120pg/ ml. Similarly, at 12 hours, concentrations above 120pg/ml indicate the probability of necrosis, concentrations of 50 to 120 pg/ml indicate that it is possible, and concentrations below 50 pg/ml indicate that it is unlikely. 

In cases of suspected benorilate overdosage, both salicylate and paracetamol should be assayed. 

Paracetamol is a widely-used, effective, and well-tolerated analgesic, but thanks also to its ready availability, it is the most commonly used substance in self-poisoning (SEDA-18, 94) (74) and a frequent cause of accidental overdose, especially in children (SEDA-22,114), although children of 6 years and under are rarely subject to hepatotoxicity, even with accidental overdosage (75), possibly owing to age-dependent differences in paracetamol kinetics (76). 

Potentiation of the toxic effects of paracetamol by fasting has been previously shown in animals. In 21 cases of paracetamol hepatotoxicity not due to intentional overdosage, fasting was significantly more common than recent alcohol use among patients who developed hepatotoxicity after a dosage of 4-10 g/day (SEDA-20, 96). 

Paracetamol poisoning is particularly dangerous as the toxic level may not be greatly above the therapeutic level. Also, symptoms of overdose may not appear for 2 days or more, allowing unwitting overdosage to continue. 

Acetaminophen (paracetamol JV-acetyl-p-aminophenoF, TYLENOL, others) is an effective alternative to aspirin as an analgesic-antipyretic agent however, its anti-inflammatory effects are much weaker. While it is indicated for pain relief in patients with noninflammatory osteoarthritis, it is not a suitable substitute for aspirin or other NSAIDs in chronic inflammatory conditions such as rheumatoid arthritis. Acetaminophen is well tolerated and has a low incidence of GI side effects. It is available without a prescription. Acute overdosage can cause severe hepatic damage, and the number of accidental or deliberate poisonings with acetaminophen continues to grow. Chronic use of less than 2 g/day is not typically associated with hepatic dysfunction. 

Paracetamol hits no signiftcam anti-innammatoty action, but is widely used as a mild analgesic when pain has no inllummaioty component. It is well absorbed orally and does not cause gastric irritation, it has the disadvantage that, in overdosage, serious hepatotoxicily is likely to occur (Chapters 4 and 44),... 

A 15-year-old girl taking phenelzine 15 mg three times daily (as well as thioridazine, procyclidine and metronidazole) took 13 capsules of Romilar CF (containing dextromethorphan hydrobromide 15 mg, phenindamine tartrate 6.25 mg, phenylephrine hydrochloride 5 mg and paracetamol (acetaminophen) 120 mg in each capsule). She became comatose, hyper-pyrexic (lOS F), had a blood pressure of 100/60 mmHg, a pulse of 160 bpm and later died ofa cardiac arrest. This case is complicated by the overdosage and multiplicity of drugs present, particularly the phenylephrine. See MAOIs or RIMAs + Sympathomimetics Phenylephrine , p.1148. 

EC oxidation is commonly employed in the analysis of some basic drugs, especially morphine and related opioids (Chapter 6, Section 1). Even if a compound is not amenable to EC oxidation, its metabolites may be. Phase I metabolism of aromatic xenobiotics often proceeds with aromatic hydroxylation. Hydrolysis of phenolic esters, reduction of diazo double bonds to primary amines and other reactions also occur. EC detection is not widely used to measure acidic or neutral compounds, such as salicylate or paracetamol after overdosage, since these compounds, although easily oxidised, are normally present at relatively high concentrations and UV detection is adequate. However, EC methods may be useful in measuring the plasma concentrations of these compounds attained after a single oral dose. ... 

Enteric-coated aspirin is not free of the dangers of gastric irritation, and death from perforation has been reported following gross overdosage with a preparation containing 250 mg of paracetamol surrounding an enteric-coated core of 300 mg of aspirin ( Safapryn ) (108 ). 

Paracetamol is a remarkably safe drug and serious toxicity is almost unheard of following therapeutic doses. However, acute hepatic necrosis is a serious complication of overdosage. 

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