- Tablets Panadol®
- Oral Suspension Calpol®, Panadol®
- Intravenous infusion Perfalgan®
Paracetamol is an extremely safe anti-pyretic and analgesic agent. The main catch is hepatotoxicity in overdose or those with enhanced cytochrome hepatic metabolism. Indeed the poor cytochrome metabolism of young children makes it safer than in adults, while alcoholics, those with liver disease, the poorly nourished and patients on cytochrome inducing drugs such isoniazid and many anti-epileptics may develop toxicity at just above usual maximium doses. The mainstay of treatment of paracetamol toxicity is N-acetylcysteine, if administered soon enough.
Paracetamol, a rather simple organic molecule, is a classic case of lost knowledge rediscovered and better characterised. The excellent German chemists and physiologists of the last decades of the 18th century had the mishap of having an impure and therefore toxic preparation to evaluate and such was their standing that the compound had to wait almost another 50 years for its introduction into clinical practice.
It was first synthesised in 1873 and was discovered to be in the urine of those using phenacetin in 1893. In 1899 it was also found to be a metabolic product of acetanilide. Acetanilide which was the first commercially successful synthetic analgesic and anti-pyretic agent causes methaemoglobinaemia and to a large degree was replaced by phenacetin which was from the late 1880s a very successful anti-pyretic and analgesic agent until analgesic nephropathy was recognised in the 1940s. It has also subsequently transpired that phenacetin was carcinogenic and increased the risk of ischaemic heart disease.
In 1948, Brodie and Axelrod discovered it was the active metabolite of phenacetin and after further characterisation that suggested its safety it was marketed worldwide from 1955 onwards. It has proved to have an excellent toxicity profile apart from a relatively low therapeutic index which is problematical and potentially fatal in untreated overdose. Various countries limit package size or adopt other measures to minimise inadvertent overdose which is possible due to multiple brand name and compound remedies available in most markets. In 1987 the US advisory committee on immunisation recommended the administration of antipyretics (such as acetaminophen) at the time of vaccination and up to 72 hours later as a result of evidence that this was effective with whole cell pertussis vaccines. It is now known that paracetamol might impair optimal immunogenic response after most vaccination, such as with the acellular pertussis vaccines now used. As of 2010 further studies are required to determine if an association with childhood atropy and asthma is causal.
Mechanism of Action
This exact mechanism is still not certain, mainly because 3 pathways are probably active in the CNS . There is evidence now for both effective inhibition of a receptor that has been termed COX 3 but has now been characterised as a separate site on prostaglandin H2 synthetase, the peroxidase (POX) site which paracetamol acts as a reducing cosubstrate and by modulation of central serotonergic pathways.. This later mechanism is important as it has now been observed that the 5-hydroxytryptamine type 3 antagonists tropisetron or granisetron block analgesia with paracetamol. Lastly an active metabolite p-aminophenol is conjugated with arachidonic acid by fatty acid amide hydrolase to form AM404 (N-(4-hydroxyphenyl)-(5Z,8Z,11Z,14Z)-icosatetra-5,8,11,14-enamide) a known endogenous cannabinoid.
See paracetamol toxicity. Treatment is usually with N-acetylcysteine or methionine and can be very successful if the risk is recognised promptly. Be aware that chronic superdose exposure can cause toxicity that needs treatment whatever the detectable paracetamol level and some patients are more at risk of toxicity than others. Administration of just less than twice the recommended iv dose has resulted in death in an adult. Treatment guidance should be obtained from an approved source.
- In children (or adults weighing less than 50kg for the iv preparation) please refer to appropriate guidance:
- Adults (please refer to specialist sources for those with conditions or drug therapy associated with increased toxicity): 500mg to 1 gram orally up to every 4 to 6 hours to a maximum of 4 grams in every 24 hour period.
It may be given by the oral, rectal or iv routes. In a non-nauseated patient with a functioning gut, the oral route is perfectly adequate and the preferred route. There is some evidence for using higher initial loading doses of oral paracetamol in adults with say migraine to achieve quick response, but like iv paracetamol such practice is likely to require adjustment of dose based on weight and other individual patient parameters to be safe.
Where parenteral administration is required the i.v. route is available. Previously this was supplied as a prodrug propacetamol but this is no longer available in Europe as the more recent iv formulation of paracetamol has superior properties. This formulation for paracetamol called Perfalgan® is effective in analgesia and more recently licensed for treating pyrexia. It has different pharmacokinetics to oral dosing so needs different adjustment for weight. Indeed where this has been forgotten death has occurred. Recent studies have shown differential pharmacodynamics in the fit very old that decrease clearance by the order of 50% but its relevance to hepatotoxicity is unclear. It has an evidence base that fails to show clinical superiority when the oral route is available. The safety profile can not be regarded as established for off license use, although it is reassuring in the analgesic indication. ITU studies have shown that like propacetamol, in cases of severe sepsis where it has been used to treat pyrexia, it can be associated with marked hypotension needing intervention. Cases of air embolism have occurred, perhaps because the formulation is in a rigid container. The price of the intravenous drug is comparable to suppositories but the indirect costs of safe administration are likely to be higher. It has a niche in the peri-operative period.
Pharmacokinetics has been described but it is likely to be the concentrations across the blood brain barrier that determine activity.
- ↑ Prymula R, Siegrist CA, Chlibek R, Zemlickova H, Vackova M, Smetana J, Lommel P, Kaliskova E, Borys D, Schuerman L. Effect of prophylactic paracetamol administration at time of vaccination on febrile reactions and antibody responses in children: two open-label, randomised controlled trials. Lancet. 2009 Oct 17; 374(9698):1339-50.(Link to article – subscription may be required.)
- ↑ Wickens K, Beasley R, Town I, Epton M, Pattemore P, Ingham T, Crane J. The effects of early and late paracetamol exposure on asthma and atopy: a birth cohort. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology. 2010 Sep 29.(Epub ahead of print) (Link to article – subscription may be required.)
- ↑ Graham GG, Scott KF. Mechanism of action of paracetamol. Am J Ther. 2005 Jan-Feb;12(1):46-55.
- ↑ Anderson BJ. Paracetamol (Acetaminophen): mechanisms of action. Paediatric anaesthesia. 2008 Oct; 18(10):915-21.(Link to article – subscription may be required.)
- ↑ Warner TD, Mitchell JA. Cyclooxygenase-3 (COX-3): filling in the gaps toward a COX continuum? Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13371-3. Epub 2002 Oct 8.
- ↑ Pickering G, Loriot MA, Libert F, Eschalier A, Beaune P, Dubray C. Analgesic effect of acetaminophen in humans: first evidence of a central serotonergic mechanism. Clin Pharmacol Ther. 2006 Apr;79(4):371-8.
- ↑ Högestätt ED, Jönsson BA, Ermund A, Andersson DA, Björk H, Alexander JP, Cravatt BF, Basbaum AI, Zygmunt PM. Conversion of acetaminophen to the bioactive N-acylphenolamine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system. The Journal of biological chemistry. 2005 Sep 9; 280(36):31405-12.(Link to article – subscription may be required.)
- ↑ Sinning C, Watzer B, Coste O, Nüsing RM, Ott I, Ligresti A, Di Marzo V, Imming P. New analgesics synthetically derived from the paracetamol metabolite N-(4-hydroxyphenyl)-(5Z,8Z,11Z,14Z)-icosatetra-5,8,11,14-enamide. Journal of medicinal chemistry. 2008 Dec 25; 51(24):7800-5.(Link to article – subscription may be required.)
- ↑ Watkins PB, Kaplowitz N, Slattery JT, Colonese CR, Colucci SV, Stewart PW, et al. Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial. JAMA : the journal of the American Medical Association. 2006;296:87-93. (Direct link – subscription may be required.)
- ↑ a b c Determination as to the causes of death of Danielle Welsh. Finding under Fatal Accidents and Sudden Deaths Inquiry (Scotland) Act 1976 Accessed 19.3.2011
- ↑ Krenzelok EP. The FDA Acetaminophen Advisory Committee Meeting - what is the future of acetaminophen in the United States? The perspective of a committee member. Clinical toxicology (Philadelphia, Pa.). 2009 Sep; 47(8):784-9.(Link to article – subscription may be required.)
- ↑ Liukas A, Kuusniemi K, Aantaa R, Virolainen P, Niemi M, Neuvonen PJ, Olkkola KT. Pharmacokinetics of intravenous paracetamol in elderly patients. Clinical pharmacokinetics. 2011 Feb 1; 50(2):121-9.(Link to article – subscription may be required.)
- ↑ Wininger SJ, Miller H, Minkowitz HS, Royal MA, Ang RY, Breitmeyer JB, Singla NK. A randomized, double-blind, placebo-controlled, multicenter, repeat-dose study of two intravenous acetaminophen dosing regimens for the treatment of pain after abdominal laparoscopic surgery. Clinical therapeutics. 2010 Dec; 32(14):2348-69.(Link to article – subscription may be required.)
- ↑ Mrozek S, Constantin JM, Futier E, Zenut M, Ghardes G, Cayot-Constantin S, Bonnard M, Ait-Bensaid N, Eschalier A, Bazin JE. Acetaminophene-induced hypotension in intensive care unit: a prospective study. Annales françaises d'anesthèsie et de rèanimation. 2009 May; 28(5):448-53.(Link to article – subscription may be required.)
- ↑ Forrest JA, Clements JA, Prescott LF. Clinical pharmacokinetics of paracetamol. Clin Pharmacokinet. 1982 Mar-Apr;7(2):93-107.
- ↑ Siau K, Khanna A. Hypernatremia secondary to soluble paracetamol use in an elderly man: a case report. Cases journal. 2009; 2:6707.(Epub) (Link to article – subscription may be required.)