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wikitox:2.1.1.1_acetaminophen [2024/04/23 19:37] – kharriswikitox:2.1.1.1_acetaminophen [2025/02/24 21:27] (current) – kharris
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-Link to [[:wikitox:2.1.1.1_acetaminophen_paracetamol_teaching_resources|Acetaminophen Paracetamol Teaching Resources]]\\ +====== Paracetamol (acetaminophen) ======
-Link to [[:wikitox:problems_for_discussion_1_paracetamol|Problems for Discussion]]\\ +
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- <font 36px/inherit;;#b12c04;;inherit>Paracetamol (Acetaminophen)</font> +
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 ===== Overview ===== ===== Overview =====
 +
 +=====   =====
  
 Paracetamol is a readily available analgesic and is commonly taken in overdose. It is available in immediate and slow-release preparations as well as in combination products often containing opioids, caffeine or ibuprofen. Several strengths of liquid paracetamol are also available. Paracetamol is a readily available analgesic and is commonly taken in overdose. It is available in immediate and slow-release preparations as well as in combination products often containing opioids, caffeine or ibuprofen. Several strengths of liquid paracetamol are also available.
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-===== Mechanism of Toxic Effects Paracetamol Metabolism =====+===== Mechanism of Toxic Effects =====
  
 {{  :wikitox:paracetamol_metabolism.png?direct&350}} {{  :wikitox:paracetamol_metabolism.png?direct&350}}
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 In overdose, glutathione stores are depleted, and NAPQI instead binds to sulfhydryl containing proteins in the liver cells and causes lipid peroxidation, disrupting the cell membrane. These events eventually lead to cell death. Any organ with P450 enzymes can suffer damage, particularly the liver and kidney, but the heart and pancreas can also be affected. In overdose, glutathione stores are depleted, and NAPQI instead binds to sulfhydryl containing proteins in the liver cells and causes lipid peroxidation, disrupting the cell membrane. These events eventually lead to cell death. Any organ with P450 enzymes can suffer damage, particularly the liver and kidney, but the heart and pancreas can also be affected.
  
-In massive ingestion with very high paracetamol concentrations (generally >600mg/L) patients can develop altered level of consciousness, including coma, and a lactic acidosis. This results from mitochondiral toxicity due to inhibition of the electron transport chain. This resolves as the paracetamol level reduced, but in some cases, if the acidosis is severe, dialysis may be required. +In massive ingestion with very high paracetamol concentrations (generally >600mg/L) patients can develop altered level of consciousness, including coma, and a lactic acidosis. This results from mitochondrial toxicity due to inhibition of the electron transport chain. This resolves as the paracetamol level reduced, but in some cases, if the acidosis is severe, dialysis may be required.
- +
-=====   ===== +
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-=====   ===== +
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-=====   ===== +
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 ===== Risk Assessment ===== ===== Risk Assessment =====
  
-There are numerous guidelines published for the treatment of paracetamol related toxicity. The risk assessment and treatment outlines in this monograph are based on the Australian Guidelines for the Treatment of Paracetamol Toxicity ( +There are numerous guidelines published for the treatment of paracetamol related toxicity. The risk assessment and treatment outlines in this monograph are based on the {{:wikitox:chiew_-_mja_updated_guidelines_for_the_management_of_paracetamol_poisoning_in_australia.pdf|Australian Guidelines for the Treatment of Paracetamol Toxicity}}.
- <font inherit/inherit;;inherit;;#f1c40f>add link)</font> .+
  
 An accurate risk assessment is crucial in determining the need for investigation and treatment following overdose. Important information in the risk assessment includes: An accurate risk assessment is crucial in determining the need for investigation and treatment following overdose. Important information in the risk assessment includes:
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   * Clinical and laboratory features of acute liver injury (late).   * Clinical and laboratory features of acute liver injury (late).
  
-[[:wikitox:paracetamol-picture1.png?id=wikitox:2.1.1.1_acetaminophen&media=wikitox:paracetamol-picture1.png|{{:wikitox:paracetamol-picture1.png?nolink&}}]] <font 20px/inherit;;#c12b04;;inherit>__Acute single ingestion of **immediate release paracetamol**__</font>+[[:wikitox:paracetamol-picture1.png?id=wikitox:2.1.1.1_acetaminophen&media=wikitox:paracetamol-picture1.png|{{:wikitox:paracetamol-picture1.png?direct&}}]] 
 + <font 20px/inherit;;#c12b04;;inherit>__Acute single ingestion of **immediate release paracetamol**__</font>
  
-An acute single ingestion of paraetamol that may be associated with acute liver injury if defined as ** <font 11.0pt/inherit;;inherit;;inherit>≥10g or ≥200mg/kg (whichever is less).</font> **+An acute single ingestion of paracetamol that may be associated with acute liver injury if defined as ** <font 11.0pt/inherit;;inherit;;inherit>≥10g or ≥200mg/kg (whichever is less).</font> **
  
 For acute single dose ingestion of immediate release paracetamol with a known time of ingestion, the paracetamol treatment nomogram (Image 2) can be used to determine the need for NAC therapy. For acute single dose ingestion of immediate release paracetamol with a known time of ingestion, the paracetamol treatment nomogram (Image 2) can be used to determine the need for NAC therapy.
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   * ≥ 10g or ≥ 200mg/kg (whichever is less) over a 24hr period   * ≥ 10g or ≥ 200mg/kg (whichever is less) over a 24hr period
   * ≥ 12g or ≥ 300mg/kg (whichever is less) over a 48hr period   * ≥ 12g or ≥ 300mg/kg (whichever is less) over a 48hr period
-  * ≥ a daily therapeutic dose per day for more than 48hr in pateints who also have abdominal pain or nausea or vomiting+  * ≥ a daily therapeutic dose per day for more than 48hr in patients who also have abdominal pain or nausea or vomiting
  
 //Image 5. Click to enlarge.// //Image 5. Click to enlarge.//
  
 //{{  :wikitox:paraflowrsti.png?direct&200  }}// //{{  :wikitox:paraflowrsti.png?direct&200  }}//
- 
-=====   ===== 
- 
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 ===== Kinectics in Overdose ===== ===== Kinectics in Overdose =====
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   * **Bloods gas:**  for large ingestions with concern for mitochondrial toxicity or for monitoring for acidosis in hepatotoxicity.   * **Bloods gas:**  for large ingestions with concern for mitochondrial toxicity or for monitoring for acidosis in hepatotoxicity.
   * **Coagulation studies:**  to monitor synthetic function if liver injury present   * **Coagulation studies:**  to monitor synthetic function if liver injury present
-=====   ===== +===== Treatment =====
- +
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- +
-===== TREATMENT =====+
  
 ==== Supportive ==== ==== Supportive ====
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 ==== Decontamination ==== ==== Decontamination ====
  
-**Acute Immediate Release ingestion**: 50g activated charcoal should be offered to patients who have presented within 2 hours of ingestion a potential toxic dose. If a large ingestion (>30g or >500mg/kg) charcoal can be offered up to 4 hours post ingestion. +Acute Immediate Release ingestion : 50g activated charcoal should be offered to patients who have presented within 2 hours of ingestion a potential toxic dose. If a large ingestion (>30g or >500mg/kg) charcoal can be offered up to 4 hours post ingestion. Modified release paracetamol ingestions : 50g activated charcoal should be offered to patients who have presented within 4 hours of ingestion of a potential toxic dose. In large ingestion (>30g or >500mg/kg) absorption may continue up to 24 hours and so charcoal can be offered up to 24 hours post ingestion. As per the treatment guideline (Box 4) a second paracetamol level 4 hours after the first should be taken – if this is static or increasing from the first level, offer a second 50g dose of activated charcoal.
- +
-**Modified release paracetamol ingestions**: 50g activated charcoal should be offered to patients who have presented within 4 hours of ingestion of a potential toxic dose. In large ingestion (>30g or >500mg/kg) absorption may continue up to 24 hours and so charcoal can be offered up to 24 hours post ingestion. As per the treatment guideline (Box 4) a second paracetamol level 4 hours after the first should be taken – if this is static or increasing from the first level, offer a second 50g dose of activated charcoal.+
  
 ==== Enhanced Elimination ==== ==== Enhanced Elimination ====
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-===== REFERENCES =====+===== Further Reading =====
  
-[[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10484791&dopt=Abstract|Anderson BJ, Holford NHG, Armishaw JC, Aicken R.]] Predicting concentrations in children presenting with acetaminophen overdose. J Paediatr 1999;13:290-95 [[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10484791&dopt=Abstract|PMID 10484791]] \\ +  - Chiew AL, Reith D, Pomerleau A, Wong A, Isoardi KZ, Soderstrom J, Buckley NA. Updated guidelines for the management of paracetamol poisoning in Australia and New Zealand. Med J Aust. 2020 Mar;212(4):175-183. doi: 10.5694/mja2.50428. Epub 2019 Dec 1. PMID: 31786822. {{:wikitox:chiew_-_mja_updated_guidelines_for_the_management_of_paracetamol_poisoning_in_australia.pdf|PDF}} 
-Brok J, Buckley N, Gluud C. Interventions for paracetamol (acetaminophen) overdose. Cochrane.Database.Syst.Rev. 2006;19;(2):CD003328. \\ [[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10584588&dopt=Abstract|Buckley NA, Whyte IM, O'Connell DL, Dawson AH.]] Oral or intravenous N-acetylcysteine: which is the treatment of choice for acetaminophen (paracetamol) poisoning? J.Toxicol.Clin.Toxicol. 1999;37:759- 67. \\ [[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10584587&dopt=Abstract|Buckley NA, Whyte IM, O'Connell DL, Dawson AH.]] Activated charcoal reduces the need for N- acetylcysteine treatment after acetaminophen (paracetamol) overdose. J.Toxicol.Clin.Toxicol. 1999;37:753-7. \\ +  - Chiew AL, Isbister GK, Kirby KA, et al. Massive paracetamol overdose: an observational study of the effect of activated charcoal and increased acetylcysteine dose (ATOM-2). Clin Toxicol (Phila) 2017; 55: 1055–1065. {{:wikitox:massive_paracetamol_overdose_an_observational_study_of_the_effect_of_activated_charcoal_and_increased_acetylcysteine_dose_atom-2_.pdf|PDF}} 
-Craig DGN, Ford AC, Hayes PC, Simpson KJ. Systematic review: prognostic tests of paracetamol-induced acute liver failure. Aliment Pharmacol and Theurapeutics;31:1064-1076 \\ [[http://www.ncbi.nlm.nih.gov/pubmed/18312195?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum|Daly FF, Fountain JS, Murray L, Graudins A, Buckley NA; Panel of Australian and New Zealand clinical toxicologists]].Guidelines for the management of paracetamol poisoning in Australia and New Zealand–explanation and elaboration. A consensus statement from clinical toxicologists consulting to the Australasian poisons information centres.[[http://javascript.toxicology.wikispaces.net/AL_get(this, 'jour', 'Med J Aust.');|Med J Aust.]] 2008 Mar 3;188(5):296-301. \\ [[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2716644&dopt=Abstract|Dawson AH, Henry DA & McEwen J.]] Adverse reactions to N-acetylcysteine during treatment for paracetamol poisoning. Med J Aust 1989; 150:329-331. \\ +  - Chiew AL, Isbister GK, Page CB, et al. Modified release paracetamol overdose: a prospective observational study (ATOM-3). Clin Toxicol (Phila) 2018; 56: 810–819. {{:wikitox:modified_release_paracetamol_overdose_a_prospective_observational_study_atom-3_.pdf|PDF}} 
-Ding GK, Buckley NA. Evidence and consequences of spectrum bias in studies of criteria for liver transplant in paracetamol hepatotoxicity. QJM. 2008;101(9):723-9. \\ +  - Chiew AL, Isbister GK, Duffull SB, Buckley NA. Evidence for the changing regimens of acetylcysteine. Br J Clin Pharmacol 2016; 81: 471–481. {{:wikitox:evidence_for_the_changing_regimens_of_acetycysteine.pdf|PDF}} 
-Duffull SB, Isbister GK. Predicting the requirement for N-acetylcysteine in paracetamol poisoning from reported dose. Clin.Toxicol. 2013;51(8):772-6. \\ +  - Wong A, Isbister GK, McNulty R, et al. Efficacy of a two bag acetylcysteine regimen to treat paracetamol overdose [Abstract], 39th International Congress of the European Association of Poisons Centres and Clinical Toxicologists (EAPCCT); 21–24 May 2019, Naples, Italy. Clin Toxicol (Phila) 2019; 57: 535. {{:wikitox:wong_-_efficacy_of_a_two_bag_acetylcysteine_regimen_to_treat_paracetamol_overdose_2nac_study_.pdf|PDF}} 
-Ferner RE, Dear JW, Bateman DN. Management of paracetamol poisoning. BMJ. 2011;19;342 \\ +  - Salmonson H, Sjoberg G, Brogren J. The standard treatment protocol for paracetamol poisoning may be inadequate following overdose with modified release formulation: a pharmacokinetic and clinical analysis of 53 cases. Clin Toxicol (Phila) 2018; 56: 63–68. {{:wikitox:salmonson_-_the_standard_treatment_protocol_for_paracetamol_poisoning_may_be_inadequate_following_overdose_with_modified_release_formulation_a_pharmacokinetic_an.pdf|PDF}} 
-Harrison PM, O'Grady JG, Keays RT, Alexander GJ, Williams R. Serial prothrombin time as prognostic indicator in paracetamol induced fulminant hepatic failure. BMJ. 1990;301(6758):964-6. \\ [[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1972496&dopt=Abstract|Harrison PM, Keays R, Bray GP, et al.]] Improved outcome of paracetamol-induced fulminant hepatic failure by late administration of acetylcysteine. Lancet 1990; 335:1572-1573 \\ [[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1904133&dopt=Abstract|Harrison PM, Wendon JA, Gimson AES, et al. ]]Improvement by acetylcysteine of hemodynamics and oxygen transport in fulminant hepatic failure. N Engl J Med 1991; 324:1852-1857. \\ +  - Shah AD, Wood DM, Dargan PI. Understanding lactic acidosis in paracetamol (acetaminophen) poisoning. Br J Clin Pharmacol. 2011 Jan;71(1):20-8. doi: 10.1111/j.1365-2125.2010.03765.x. PMID: 21143497; PMCID: PMC3018022. {{:wikitox:shah_-understanding_lactic_acidosis_in_paracetamol_acetaminophen_poisoning.pdf|PDF}} 
-Heard KJ. Acetylcysteine for acetaminophen poisoning. N.Engl.J.Med. 2008;359(3):285-92. \\ +  - Thanacoody HK, Gray A, Dear JW, Coyle J, Sandilands EA, Webb DJ, Lewis S, Eddleston M, Thomas SH, Bateman DN. Scottish and Newcastle antiemetic pre-treatment for paracetamol poisoning study (SNAP). BMC Pharmacol Toxicol. 2013 Apr 4;14:20. doi: 10.1186/2050-6511-14-20. PMID: 23556549; PMCID: PMC3626543. {{:wikitox:thanacoody_-_snap_protocol.pdf|PDF}} 
-James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA et al. Pharmacokinetics of acetaminophen-protein adducts in adults with acetaminophen overdose and acute liver failure. Drug Metab Dispos. 2009;37(8):1779-84. \\ +  - Buckley NA, Whyte IM, O'Connell DL, Dawson AH. Activated charcoal reduces the need for N-acetylcysteine treatment after acetaminophen (paracetamol) overdose. J Toxicol Clin Toxicol. 1999;37(6):753-7. doi: 10.1081/clt-100102452. PMID: 10584587. {{:wikitox:buckley_-_activated_charcoal_reduces_the_need_for_n-acetylcysteine_treatment_after_acetaminophen_paracetamol_overdose.pdf|PDF}} 
-Keays R, Harrison PM, Wendon JA, Forbes A, Gove C, Alexander GJ et al. Intravenous acetylcysteine in paracetamol induced fulminant hepatic failure: a prospective controlled trial. BMJ. 1991;303(6809):1026-9. \\ [[http://www.ncbi.nlm.nih.gov/sites/entrez|Kerr F, Dawson A, Whyte IM, Buckley N, Murray L, Graudins A, Chan B, Trudinger B]].The Australasian Clinical Toxicology Investigators Collaboration randomized trial of different loading infusion rates of N-acetylcysteine.[[http://javascript.toxicology.wikispaces.net/AL_get(this, 'jour', 'Ann Emerg Med.');|Ann Emerg Med.]] 2005 Apr;45(4):402-8. \\ [[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7820317&dopt=Abstract|Makin AJ, Wendon J, Williams R.]] Management of severe cases of paracetamol overdosage. British Journal of Hospital Medicine 1994;52:210-213. \\ +  - Whyte IM, Buckley NA, Reith DM, Goodhew I, Seldon M, Dawson AH. Acetaminophen causes an increased International Normalized Ratio by reducing functional factor VII. Ther Drug Monit. 2000 Dec;22(6):742-8. doi: 10.1097/00007691-200012000-00015. PMID: 11128244. {{:wikitox:acetaminophen_causes_an_increased_international_normalized_ratio_by_reducing_functional_factor_vii.pdf|PDF}}
-Meredith TJ, Jacobsen D, Haines JA, Berger J-C (eds). Antidotes for poisoning by paracetamol. IPCS/CEC evaluation of antidotes series Vol 3. Cambridge University Press 1995. \\ [[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=519312&dopt=Abstract|Prescott LF, Illingworth RN, Critchley JA et al. ]]Intravenous N-acetylcysteine: the treatment of choice for paracetamol poisoning. Br Med J 1979; 2:1097-1100. \\ [[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=4100436&dopt=Abstract|Prescott LF, Wright N, Roscoe P & Brown SS. ]]Plasma paracetamol half-life and hepatic necrosis in patients with paracetamol overdosage. Lancet 1971; :519-522. \\ +
-Schmidt LE, Dalhoff K. Serum phosphate is an early predictor of outcome in severe acetaminophen-induced hepatotoxicity. Hepatology. 2002;36(3):659-65. \\ +
-Shah AD, Wood DM, Dargan PI. Understanding lactic acidosis in paracetamol (acetaminophen) poisoning. Br.J.Clin.Pharmacol. 2011;71(1):20-8. \\ +
-Shihana, F et Al. A Modified Low-cost Colorimetric Method for Paracetamol (acetaminophen) Measurement in Plasma. Clinical toxicology 2010;48(1): 42-46. \\ +
-Sivilotti ML, Yarema MC, Juurlink DN, Good AM, Johnson DW. A risk quantification instrument for acute acetaminophen overdose patients treated with N-acetylcysteine. Ann.Emerg.Med. 2005;46(3):263-71. \\ +
-Sivilotti ML, Green TJ, Langmann C, Yarema MC, Juurlink DN, Johnson DW. Multiplying the serum aminotransferase by the acetaminophen concentration to predict toxicity following overdose .Clinical Toxicology 2010;48:793–799 \\ [[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3059186&dopt=Abstract|Smilkstein MJ, Knapp GL, Kulig KW, Rumack BH. ]]Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose: Analysis of the national multicenter study (1976 to 1985). N Engl J Med 1988; 319:1557-1562. \\ [[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8135427&dopt=Abstract|Spiller HA, Krenzelok EP, Grande GA, Safir EF, Diamond JJ. ]]A prospective evaluation of the effect of activated charcoal before oral N-acetylcysteine in acetaminophen overdose. Ann Emerg Med 1994;23:519-523. \\ +
-Thanacoody HK, Gray A, Dear JW, Coyle J, Sandilands EA, Webb DJ et al. Scottish and Newcastle antiemetic pre-treatment for paracetamol poisoning study (SNAP). BMC.Pharmacol.Toxicol. 2013;14:20. \\ [[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7658783&dopt=Abstract|Vale JA, Proudfoot AT. ]]Paracetamol (acetaminophen) poisoning. Lancet 1995;346:547-552. \\ +
-Waring WS, Jamie H, Leggett GE. Delayed onset of acute renal failure after significant paracetamol overdose: A case series. Hum.Exp.Toxicol. 2010;29(1):63-8. \\ [[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11128244&dopt=Abstract|Whyte IM, Buckley NA, Reith DM, Goodhew I, Seldon M, Dawson AH.]] Acetaminophen causes an increased INR by reducing functional factor VII. Therapeutic Drug Monitoring 2000;22:742-48+