PARACETAMOL POISONING – REVIEW

Paracetamol (acetaminophen) is included in more than 200 medicines of various trade names, including numerous preparations for children used as analgesic and antipyretic drugs. Poisoning usually occurs after taking a large single dose of paracetamol or combination paracetamol-containing preparations, and as a result of prolonged use of paracetamol in smaller doses by persons with increased sensitivity, alcohol abuse, diet error, or in combination with drugs, which affect its metabolism in the liver. Paracetamol poisoning is among the intoxications that have a latent period. Clinical manifestations of acute poisoning develop in stages. The intensity of the initial symptoms does not always determine the outcome of the disease. Paracetamol poisoning is a common cause of liver damage and is a leading etiologic factor in acute liver failure. The worldwide spread of poisoning with this drug is epidemic.

The poet and the poison

Mercury is not a particularly promising homicidal poison, but it is possible to dispose of someone by feeding them mercury(II) chloride provided you disguise its metallic taste. In the 1800s solutions of corrosive sublimate, as it was then called, were used as an antiseptic and as an insecticide against bedbugs, and its very availability resulted in thousands of poisonings being reported to the health authorities, although these were mainly accidents or as a result of its being taken deliberately in order to procure an abortion. Mercury was not a poison to feature in many murder cases because it was so easily detectable by the intended victims, especially if they started to vomit, which they almost always did. Then the metallic taste became particularly noticeable, and the presence of mercury could easily be confirmed by simple analytical tests. The poisoners who chose mercury had to use a large dose and this would kill within a day or two. Despite these inherent drawbacks, a few poisoners made use of it. Two of the murderers whose cases we are about to analyse opted for the large single dose approach, but the third murderer achieved her ends by targeting her victim with multiple doses. That murder became famous because of whom she killed and the political repercussions it caused. It was also notorious for the manner in which the final fatal dose of poison was administered. Mary Bateman was known as the Yorkshire Witch and she had a plan that she thought would lead her victims into taking a fatal single dose of mercury. Instead it led her to the gallows. At the time of her crime, Bateman lived in Leeds, Yorkshire, where she earned her living telling fortunes and swindling gullible clients out of their cash and possessions. She claimed to receive her supernatural information from a spirit medium, a Miss Blythe, into whose mouth she put the advice that always seemed to result in her clients handing over their money and saleable goods, with the promise that if they did as Miss Blythe said, then good luck would soon come their way, and they would be more than compensated.

Antimony, the great cure-all

Gram-for-gram, antimony is about as toxic as arsenic but on a dose-for-dose basis it is less life-threatening simply because antimony salts rapidly cause violent vomiting which expels most of the toxin from the body before it can be absorbed. This curious ability of antimony to trigger the muscles of the stomach to expel its contents generally prevented antimony’s misuse as a murder weapon, but occasionally a large single dose did lead to death, as happened to Charles Bravo – see Chapter 10. The fatal dose can be as little as 120 mg, so long as the body retains it. Alternatively, it was possible to kill someone by giving them many small doses, which was George Chapman’s way, as we shall discover in Chapter 11. Antimony is not as widespread in nature as arsenic. It occurs to the extent of only 0.3 ppm of the Earth’s crust, and only 0.3 ppb in seawater, values which are a tenth of those of arsenic. Consequently, the amount of antimony that gets into the food chain is correspondingly less. The amount of antimony released to the atmosphere each year is about 1600 tonnes, most coming from the burning of coal, which contains 3 ppm on average, with metal smelters and municipal incinerators also releasing significant amounts. Over the centuries the amount of antimony in the environment has increased, mainly in line with lead and copper production, whose ores often contain it as an impurity. While the release of this element is of some concern the impact of antimony may have been underestimated. Professor William Shotyk of the University of Heidelberg, Germany, is an authority on antimony and his researches on peat samples taken from Swiss and Scottish bogs show that the level of antimony today is up to a thousand times higher than it was 5000 years ago. Like lead, antimony has no biological role and indeed it is ten times more toxic, and like lead it is a cumulative poison. In Chapter 5, we saw how arsenic can pass through the gut wall into the bloodstream and it can substitute for phosphate in metabolic processes, but this is not possible for antimony despite the fact that it resembles arsenic chemically.

Modification of doxorubicin-induced cardiotoxicity: manipulation of the dosage schedule

Modification of the dosing schedule for doxorubicin (DOX) administration represents a possible method of reducing cardiotoxicity from this potent anti-cancer drug, while at the same time maintaining its cytotoxic action. The quantitative effects of modified dosage scheduling have been investigated in a clinically relevant rat model. Cardiotoxicity to DOX was assessed by the degree of reduction in cardiac output at 4–24 weeks after the intravenous administration of DOX. The effects of dose schedules involving three or six small dose administrations, over one and two weeks, were compared with that produced by large single doses of DOX. The total drug dose administered for each schedule was varied in order to establish dose–effect relationships. After a total dose of 3 mg/kg DOX, given as three or six equal small doses, there was a gradual decline in cardiac output in the first 12 weeks after drug administration. Between 12 and 24 weeks, the reduction in cardiac function was relatively stable at between 65% and 85% of that of age-matched controls for three and six equal small doses, respectively. Dose–effect curves for animals showing a ¶30% reduction in cardiac function after 12 weeks indicated the degree of reduction in cardiac function produced by the modified dose scheduling. Compared with a large single dose, larger total doses were required to produce the same severity of damage. Thus, schedules based on three and six equal small doses resulted in dose modification factor of 1.5 ‘0.23 and 2.1’ 0.28, respectively, when compared with the same effect produced by a large single dose. This appeared to be independent of the severity of cardiac damage, suggesting a simple mathematical relationship between the total acceptable dose of DOX and the dose administered at each intravenous injection. These modifications in the cardiotoxicity of DOX produced by the administration of multiple small doses were of the same order of magnitude as that produced by other methods introduced to reduce anthracycline cardiotoxicity.