Drug overdose paracetamol

This may be induced in the main by viral infection and by drugs, typically paracetamol (acetaminophen) overdose but occasionally dose independently by antidepressants and antituberculous drugs amongst others (Table 5). 

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. 

Drug overdose In a retrospective cohort study the presence of gastrointestinal manifestations after paracetamol poisoning predicted a risk of subsequent hepatotoxicity and nephrotoxicity [22 ]. 

Drug overdose Acute pancreatitis has been reported after an overdose of nifedipine and paracetamol, complicated by multiorgan failure, which responded to intensive treatment [23 ]. The most likely mechanism was ischemic injury of the pancreas secondary to severe collapse induced by nifedipine and possible direct paracetamol-induced pancreatic damage. 

Drug overdose A mixed overdose of methyldopa, theophylline, indapamide, and paracetamol led to prolonged severe hypotension in an 89-year-old man, who required vigorous intravenous fluid replacement and several days of intravenous noradrenaline to maintain his vital signs [101" ]. 

Prescott, L.F. (1983). Paracetamol overdose. Pharmacologic considerations and clinical management Drugs 25, 290-314. 

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. 

In contrast to local irritants and corrosive acids and alkalis, other chemicals, such as the drug paracetamol (see chap. 7), cause systemic toxicity, damaging the liver, possibly irreversibly and with some delay after an oral overdose. Penicillin can also cause systemic toxicity as a result of an immune reaction, which may be immediate and serious, if it is anaphylaxis (see chap. 7). However, this effect, if not fatal, is reversible. 

Alcohol is an inducer of CYP2E1, which can lead to situations of enhanced drug toxicity in alcoholics or heavy drinkers (e.g., from paracetamol overdose). 

Paracetamol is a widely used analgesic, which causes liver necrosis and sometimes renal failure after overdoses in many species. The half-life is increased after overdoses because of impaired conjugation of the drug. Toxicity is due to metabolic activation and is increased in patients or animals exposed to microsomal enzyme inducers. The reactive metabolite (NAPQI) reacts with GSH, but depletes it after an excessive dose and then binds to liver protein. Cellular target proteins for the reactive metabolite of paracetamol have been detected, some of which are enzymes that are inhibited. Therefore, a number of events occur during which ATP is depleted, Ca levels are deranged, and massive chemical stress switches on the stress response. 

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. 

Dextropropoxyphene Dextropropoxyphene, a drug of abuse, and any misuse or overdose of which causes intoxication if taken along with paracetamol or alcohol. The individual develops serious CNS depression leading to death.40-42 Adverse effects can be treated by gastric lavage and administration of activated charcoal and naloxone 43... 

Schmidt LE, Dalhoff K. Concomitant overdosing of other drugs in patients with paracetamol poisoning. Br J Clin Pharmacol 2002 53(5) 535 11. 

Despite case reports of hepatotoxicity in patients taking enzyme inducers and paracetamol concomitantly, there is currently no good evidence that the interactions are clinically significant when recommended doses of paracetamol are used [5]. However, because of the theoretical basis and the potentially severe outcome, patients taking enzyme-inducing drugs are treated with N-acetylcysteine at a reduced threshold in the event of paracetamol overdose. 

Paracetamol—Cresol-ammonia test. To 0.5 ml of urine add 0.5 ml of hydrochloric acid and heat for 10 minutes at 100° to 2 drops of the mixture add 10 ml of water, 1 ml of 1 % o-cresol in water, and 4 ml of 2M ammonium hydroxide. A blue colour appears if paracetamol is present. The test is very sensitive and can detect therapeutic concentrations. The presence of the parent drug and its conjugated metabolites can be detected for several days after overdose. If a positive result is obtained, a plasma-paracetamol determination should be carried out immediately (p. 23). 

Age can affect the uptake of drugs from the gut, so very young children, who have low levels of acid in the stomach, absorb penicillin more readily than adults but paracetamol less so. Once absorbed into the body, chemicals are distributed around the body in the blood (as explained earlier). Chemicals commonly bind to proteins in blood which limits the level available to distribute into organs and tissues. This binding may be reduced to as low as a third in newborn babies, which means that the circulating free level of the substance is effectively higher than in an adult. This can result in an overdose in a newborn baby. 

The crucial facts to be determined are the identity, and then the level(s), of the chemical(s) in the blood and when they were taken. The poisoning due to the most dangerous chemical that is at the highest level in the blood can then be treated. For example, if someone has taken an overdose of the drug combination Distalgesic, which contains paracetamol and dextropropoxyphene, the immediate treatment would be for the latter drug which can rapidly cause death from depression of the respiratory system. 

At first paracetamol (acetaminophen in the USA) was considered a safe and effective drug, ft became increasingly popular and was used by millions worldwide. A problem then began to appear, as some people began to take overdoses of the readily available drug. ... 

As discussed in Chapter 2, after a drug (or other chemical) is taken by mouth, it first reaches the stomach and then the small intestine. It is most likely to be absorbed from the small intestine, where it enters the bloodstream which will transport it directly to the liver (see Figure 3, p. 15). In the liver paracetamol is changed into two other substances, which are relatively harmless but another metabolite, which is produced in only small amounts, is potentially poisonous. This metabolite is normally safely removed by further metabolism, which employs the substance glutathione (see box, p. 24). After a large overdose, however, this process of detoxication is overwhelmed and the poisonous substance attacks the liver. 

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 is now sold in smaller packs to make it more difficult for suicidal people to acquire sufficient drug for an overdose. An understanding of why the drug is toxic has stimulated the development of other possibly less toxic analogues of this drug. 

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)... 

Interactions. Rifampicin is a powerful enzyme inducer and speeds the metabolism of numerous drugs, including warfarin, steroid contraceptives, narcotic analgesics, oral antidiabetic agents, phenytoin and dapsone. Appropriate increase in dosage, and alternative methods of contraception, are required to compensate for increased drug metabolism (see also paracetamol overdose, p. 287). 

It may be that limiting access to one type of drug simply increases the incidence of overdose with other potentially more dangerous medicines. If that is so, unless the availability of other medications is also controlled, the removal of one readily available medication, such as paracetamol, could lead to an increase in the use of other compounds with similar or even greater toxicity (for example aspirin, ibuprofen). 

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