Link to [[:wikitox:2.1.1.1_acetaminophen_paracetamol_teaching_resources|Acetaminophen Paracetamol Teaching Resources]]\\
Link to [[:wikitox:problems_for_discussion_1_paracetamol|Problems for Discussion]]\\
\\
\\
\\
 <font 36px/inherit;;#b12c04;;inherit>Paracetamol (Acetaminophen)</font>

----

===== 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.

Excess paracetamol ingestion results in the accumulation of a toxic intermediate metabolite N-acetyl-p-benzoquinonimine (NAPQI). Untreated paracetamol toxicity can be fatal and is characterised by hepatotoxicity which can progress to fulminant hepatic failure.

Fortunately, an effective antidote, N-acetylcysteine (NAC), is readily available and treatment within 8 hours of ingestion should prevent serious hepatic toxicity.

----

===== Mechanism of Toxic Effects =====

{{  :wikitox:paracetamol_metabolism.png?direct&350}}

In therapeutic use, 20% of an ingested dose of paracetamol undergoes first pass metabolism, with further metabolism occurring in the liver by biotransformation. The majority (90%) is metabolised to sulphate and glucuronide conjugates that are excreted in the urine. The remainder (less than 10%) is metabolised via cytochrome p450 (mainly 2E1 and 3A4) resulting in the highly reactive intermediary compound NAPQI. Normally, NAPQI is immediately bound by intracellular glutathione and eliminated in the urine.

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.

===== 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 {{:wikitox:chiew_-_mja_updated_guidelines_for_the_management_of_paracetamol_poisoning_in_australia.pdf|Australian Guidelines for the Treatment of Paracetamol Toxicity}}.

An accurate risk assessment is crucial in determining the need for investigation and treatment following overdose. Important information in the risk assessment includes:

  * Dose ingested.
  * Formulation (IR vs XR).
  * Time of ingestion.
  * If staggered or supratherapeutic use, the period over which the ingestion was taken.
  * Serum paracetamol level (early).
  * 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?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> **

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.

The treatment guidelines for an acute single ingestion are shown in (Image 3). Multiple or staggered ingestions (over a period of more than 2hr) are distinct from repeated supratherapeutic ingestions and should be treated as per the single ingestion guideline (Box 3) using the earliest ingestion time for plotting on the nomogram.

For accidental ingestion of liquid paracetamol in children <;6yo then a paracetamol level can be taken 2 hours post ingestion, if it is <;150mg/L then no treatment is needed, if it is above 150mg/kg then a 4-hour level should be taken, NAC therapy is indicated if this level is 150mg/kg or higher.

//Images 2-3. Click to e////nlarge//

{{  :wikitox:paracetamol_nomogram.png?direct&300  }}{{  :wikitox:paraflowacute.png?direct&200  }} <font 20px/inherit;;#c12b04;;inherit>__**Modified release paracetamol** ingestions__</font>

Modified release paracetamol ingestions were previously treated similarly to immediate release paracetamol ingestions however, evidence has shown that this approach is inadequate with some patients developing a liver injury despite following these guidelines.

Image 4 shows the treatment protocol for modified release paracetamol ingestions. Of note, all patients ingesting >10g of modified release paracetamol require at least a complete course of NAC.

//Image 4. Click to enlarge.//

//{{  :wikitox:paraflowmr.png?direct&200  }}//

 \\  \\
 <font 20px/inherit;;#c12b04;;inherit>__**Repeated Supratherapeutic** paracetamol ingestion__</font>

A repeated supratherapeutic ingestion (RSTI) is defined as any of the following:

  * ≥ 10g or ≥ 200mg/kg (whichever is less) over a 24hr 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

//Image 5. Click to enlarge.//

//{{  :wikitox:paraflowrsti.png?direct&200  }}//

===== Kinectics in Overdose =====

==== Absorption ====

Paracetamol is rapidly absorbed with peak concentrations within 1-2h for the standard tablet formulation and within 30 min for liquid preparations. Peak concentrations are delayed to over 12 hours and sometimes longer in slow-release preparations.

Prolonged absorption is seen following very large ingestions (>500mg/kg).

==== Distribution ====

After absorption, paracetamol distributes rapidly with a volume of distribution of 0.9L/kg. Absorption and distribution are completed by 4 hours post overdose with standard release preparations and within 2 hours for liquid preparations.

==== Metabolism - Elimination ====

Metabolism is mainly via glucuronidation and sulphation. Half-life in therapeutic use is 1.5-3 hours, however in overdose this can be delayed to more than 4 hours. A higher half-life has been linked to a higher risk of toxicity, which may indicate saturation of conjugation pathway and an increasing proportion of paracetamol being metabolised by P450 enzymes.

----

===== Clinical Effects =====

Hepatotoxicity is the major clinical effect.

A rise in the transaminases (ALT/AST) occurs within 24 hours and will usually peak 3-4 days later. Very high AST and/or ALT (>1000 U/L) is seen with significant toxicity. The extent and speed of ALT rise has been linked with subsequent severity.

Clinically patients may complain of nausea, anorexia and right upper quadrant tenderness. In severe toxicity hypoglycaemia, encephalopathy, jaundice and coagulopathy can develop.

Acute renal failure with acute tubular necrosis secondary to NAPQI, is usually reversible. It occurs in a small proportion of patients with hepatotoxicity. It can occur in some patients with little hepatotoxicity.

----

===== Investigations =====

  * **Paracetamol level:**  for plotting on the paracetamol nomogram or ensuring that paracetamol has cleared before ceasing NAC.
  * **Liver function:**  looking for evidence of toxicity if delayed presentation or before ceasing NAC.
  * **Renal function:**  looking for evidence of toxicity if delayed presentation.
  * **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
===== Treatment =====

==== Supportive ====

Patients with paracetamol toxicity often have anorexia and nausea. Maintain hydration as required with IV fluids and provide antiemetics.

Paracetamol overdose is associated with a dose dependant hypokalaemia and patients may require supplemental potassium.

==== 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. 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 ====

Paracetamol is dialyzable, however given the ready availability of an effective antidote, dialysis primarily for paracetamol clearance is not indicated.

Dialysis may be used following paracetamol overdose for other indications such as metabolic acidosis (either associated with liver impairment or due to mitochondrial toxicity) or for renal failure. In these situations, it should be noted that NAC is also dialysable and if intermittent haemodialysis is used then dose of NAC should be doubled to compensate for this. NAC clearance during continuous forms of dialysis is not high enough for this to be of concern.

==== Antidote ====

N-acetylcysteine (NAC) is a glutathione precursor and acts to replenish glutathione stores, allowing ongoing conjugation of NAPQI to non-toxic metabolites. It may also have secondary benefits as an antioxidant and free radical scavenger.

Use the above treatment flowcharts to determine if a patient meets criteria for treatment with NAC.

__NAC Dosing__

A standard course on NAC is a two-bag regime, given over 20 hours.

  * Bag 1: 200mg/kg NAC (max 22g) in 500ml 5% dextrose over 4 hours
  * Bag 2: 100mg/kg NAC (max 11g) in 1000ml 5% dextrose over 16 hours

//In children bag 1 should be given in 7ml/kg of fluid (max 500ml) and bag 2 in 14ml/kg (max 1000ml). NAC is traditionally given in 5% dextrose but can also be given in 0.9% NaCl if hyponatraemia is a concern for the patient.// \\  \\
In situations where a very large dose of paracetamol has been ingested or if there is a very high paracetamol level (as shown in the flowcharts) then the dose in the second bag on NAC may need to be increase (usually doubled to 200mg/kg). Even higher doses of NAC are infrequently required when the paracetamol level is more than 3 times the nomogram level.

----

===== Observation and Disposition =====

**Non-toxic ingestions**

Patients who do not meet criteria for NAC therapy can be discharged from a toxicology perspective. If NAC was already commenced whilst awaiting paracetamol levels, then this can be discontinued.

**Toxic ingestions**

A standard 20-hour course of NAC will be sufficient in most cases. Patient should have a paracetamol level and LFTs taken 2 hours before the second NAC bag is due to finish (an INR should also be taken if there is evidence of liver injury). Depending on these results (detailed in each treatment flowchart) an extended course of NAC may be required. In this situation repeat bag 2 (100mg/kg in 1000ml) back-to-back and repeat bloods twice daily until the following criteria are met:

  * Paracetamol level <10
  * ALT <50, or if already elevated it is static or falling.
  * INR <2
  * Patient clinically well

**Established Liver Toxicity**

Most patients who develop an acute liver injury will improve with NAC therapy, however patients meeting the following criteria should be discussed with the local liver transplant unit:

  * INR >3 at 48hr or >4.5 at any time
  * Oliguria or creatinine >200umol/L
  * Persistent acidosis (pH <7.3) or arterial lactate >3mmol/L
  * Systolic BP <80mmHg despite resuscitation
  * Hypoglycaemia, severe thrombocytopenia or encephalopathy of any degree
  * Altered level of consciousness not associated with sedative co-ingestion.

----

===== Further Reading =====

  - 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}}
  - 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}}
  - 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}}
  - 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}}
  - 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}}
  - 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}}
  - 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}}
  - 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}}
  - 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}}
  - 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}}