10,11 This approach thus facilitated the development of antidotes, as it allowed comparison of outcomes in patients in pre-defined risk categories.įig. In the early 1970s the development of an assay for paracetamol, and presence of a body of patients who had ingested paracetamol in overdose in Edinburgh, lead to the development of nomograms in man that illustrated the dose–response relationship of paracetamol toxicity ( Fig. The problem then, and now, is to determine the dose threshold for toxicity in order to tailor therapy optimally. 9 This elegant chemistry explains why at standard doses paracetamol remains one of the safest drugs used in clinical practice, but that with increasing dose hepatic toxicity becomes more likely. 6–8 The important finding was that toxicity was glutathione dependant. Animal experiments clearly demonstrated that the hepatic toxicity of some molecules was by metabolism which could be both induced and inhibited, and that it involved production of reactive intermediates in metabolism that were normally neutralised by glutathione. The breakthrough came in the early 1970s with the development of the concept that free radical generation during drug metabolism was a potential cause of toxicity.

The major clinical presentation was of hepatic failure due to acute liver necrosis.

4,5 At that time the biochemical mechanisms underlying paracetamol toxicity were unknown, and thus treatment was entirely symptomatic. The first documented cases of organ toxicity from paracetamol were in Scotland in 1966. 3 The precise psychosocial factors behind this increase are unclear, but by the early 1970s admissions to hospital from patients deliberately ingesting aspirin and paracetamol had become a regular, problematic medical emergency. The profile of the epidemiology of poisoning changed over the next 40 years with poisoning becoming a common reason for emergency admission to hospital. 1,2 At that time presentations with poisoning, either accidental or from self-harm, were unusual in Europe. Introduction Paracetamol was introduced into clinical medicine in the 1950s as an antipyretic analgesic. We offer suggestions for improvements in the way NAC may be administered and outline new developments that should have major impacts on the way we manage paracetamol poisoning in the near future. This article examines the history of the development of NAC and recent developments in its use. The development of antidotes followed within 10 years, and by 1980 acetylcysteine (NAC) was acknowledged as the optimal therapy available. Paracetamol poisoning was first reported in 1966.

Antidote for acetaminophen toxicity