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Acetaminophen

Acetaminophen
22.Nov.2017-Expires: 7 days - Do not archive

DESCRIPTION

SUBSTANCE NAME

Acetaminophen (Paracetamol)
 

SUBSTANCE CLASS

Para-Aminophenol Derivative

INTERVENTION CRITERIA

Intervention Level

Acute Exposure

 
Ingestion
 
Aged 6 years or under ingesting
- 200 mg/kg acetaminophen (paracetamol) or more over a period of less than 8 hours
 
For obese children, the weight used should be based on ideal body weight.
 
Aged older than 6 years ingesting
- At least 10 g or 200 mg/kg (which ever is lower) over a period of less than 8 hours
- Exposures with intent to self-harm
 
For obese children, the weight used should be based on ideal body weight.
 
Also investigate if:
- The dose or timing of ingestion is uncertain, or;
- The patient is symptomatic
 

Time of Ingestion Unknown

If the time of ingestion is unknown and the dose is above the acute intervention level or unknown: commence an acetylcysteine infusion and investigate.
 

Supratherapeutic Exposure

 
Ingestion
Aged 6 years or under ingesting
- 200 mg/kg acetaminophen (paracetamol) or more over a single 24-hour period;
- 150 mg/kg or more per 24-hour period for the preceding 48 hours;
- 100 mg/kg or more per 24-hour period for more than 48 hours.
 
For obese children, the weight used should be based on ideal body weight.
 
Aged older than 6 years ingesting
- At least 10 g or 200 mg/kg (whichever is less) over a single 24-hour period;
- At least 6 g or 150 mg/kg (whichever is less) per 24 hour period for the preceding 48 hours;
- More than 4 g per day or 100 mg/kg (whichever is less) per 24-hour period for more than 48 hours in those who also have symptoms indicating possible liver injury (e.g. abdominal pain, nausea or vomiting)
- Exposures with intent to self-harm.
 
For obese children, the weight used should be based on ideal body weight.
 
Also investigate if:
- The dose or timing of ingestion is uncertain
- The patient is symptomatic
 

Investigation and Initial Management

Acute Ingestion

 
 
Decontamination
 
Administer activated charcoal to co-operative adults if within 2 hours of overdose of immediate release solid formulations or within 4 hours for modified release solid formulations.[1]
 
2 to 8 hours post-ingestion
 
Ingestion by children < 6 years of age of liquid acetaminophen (paracetamol)
                                                                                                             
Measure:
Serum acetaminophen (paracetamol) concentration at least 2 hours post-ingestion:[1]
 
- If this concentration is less than 1,000 umol/L (150 mg/L) the child may safely be discharged. Otherwise, repeat the measurement at 4 hours and if above the paracetamol treatment nomogram line administer acetylcysteine.
 
Ingestion of standard release or liquid formulations
 
Measure:
Serum acetaminophen (paracetamol) concentration at least 4 hours and within 8 hours post-ingestion, and plot against the paracetamol treatment nomogram:[1]
 
- If this concentration is below the nomogram line, the patient does not require acetylcysteine;
- If this concentration is above the nomogram line, immediately commence a full course of acetylcysteine;
- If this concentration will not be available within 8 hours of ingestion, immediately commence a full course of acetylcysteine. This treatment can then be halted if the result subsequently returns below the nomogram line.
 
Ingestion of modified release formulations
 
If the ingestion is above the intervention level, immediately commence a full course of acetylcysteine, then:[1]
 
Measure:
Serum acetaminophen (paracetamol) concentration at least 4 hours post-ingestion and a second concentration 4 hours following the first:
 
- If these concentrations are both below the paracetamol treatment nomogram line, and the second concentration less than the first, the acetylcysteine infusion may be halted. Otherwise, the full treatment course must be completed.
 
8 to 24 hours post-ingestion
 
Immediately commence a acetylcysteine infusion, then
 
Measure:
Serum acetaminophen (paracetamol) concentration
Alanine aminotransferase (ALT)
 
- If the serum acetaminophen (paracetamol) concentration is below the paracetamol treatment nomogram line and the ALT is less than 50 U/L, then the acetylcysteine infusion can be halted and no further medical treatment is necessary.[1]
- If the serum acetaminophen (paracetamol) concentration is above the paracetamol treatment nomogram line or the ALT greater than 50 U/L, then complete a full course of acetylcysteine.[1]
 
If ALT is greater than 50 U/L then also measure:
BUN (Urea)
Creatinine
Electrolytes
Blood sugar
Phosphate
Venous Blood Gas (pH and lactate in particular)
 
24 plus hours post-ingestion, or time of ingestion unknown
 
Immediately commence a acetylcysteine infusion, then
 
Measure:
Serum acetaminophen (paracetamol) concentration
Alanine aminotransferase (ALT)
International Normalized Ratio (INR)
 
- If the serum acetaminophen (paracetamol) concentration is less than 66 umol/L (10 mg/L) and the ALT is less than 50 U/L, then the infusion can be halted and no further medical treatment is necessary.[1]
- If the serum acetaminophen (paracetamol) concentration is greater than 66 umol/L (10 mg/L) or the ALT is greater than 50 U/L, then complete the full course of acetylcysteine.[1]
 
If ALT is greater than 50 U/L then also measure:
BUN (Urea)
Creatinine
Electrolytes
Blood sugar
Phosphate
Venous Blood Gas (pH and lactate in particular)
 

Supratherapeutic Exposure

 
In patients meeting intervention criteria for supratherapeutic ingestion
 
Measure:
Serum acetaminophen (paracetamol) concentration
Alanine aminotransferase (ALT)
 
-If serum acetaminophen (paracetamol) is < 132 umol/L (< 20 mg/L) and ALT < 50 U/L, then no medical treatment is necessary.[1]
-If serum acetaminophen (paracetamol) is > 132 umol/L (> 20 mg/L) or ALT > 50 U/L, then commence an acetylcysteine infusion.[1]
 
After commencement of the infusion measure serum acetaminophen (paracetamol) and ALT concentrations 8 hours after the previous measurement.
-If serum acetaminophen (paracetamol) is < 66 umol/L (< 10 mg/L) and ALT < 50 U/L, then the infusion can be halted and no further medical treatment is necessary.[1]
 
Otherwise continue the infusion and check serum acetaminophen (paracetamol) and ALT at 12 hourly intervals until:
-Serum acetaminophen (paracetamol) is < 66 umol/L (< 10 mg/L) and ALT < 50 U/L, then the infusion can be halted and no further medical treatment is necessary.[1]
 

Observation Period

Observation at Home

No observation is required for those patients with ingested doses or serum acetaminophen (paracetamol) determinations below the intervention levels. However, review is warranted should nausea, vomiting, or abdominal pain occur after discharge, particularly if within 24 to 48 hours after the ingestion.
 

Medical Observation

Medical observation of asymptomatic patients is not required provided serum acetaminophen (paracetamol) investigation is undertaken and the concentration is below the appropriate intervention level.
 

Admission Criteria

Patients requiring intervention for acute acetaminophen (paracetamol) overdose should be appropriately decontaminated and managed in a medical facility able to rapidly determine serum acetaminophen (paracetamol) and provide acetylcysteine.
 
Referral to an intensive care unit and/or liver transplant unit may be required in severe poisoning.
 

TREATMENT

TREATMENT SUMMARY

Decontamination with activated charcoal is recommended in cooperative adults within 2 hours of ingestion of (solid) immediate-release forms, or within 4 hours of ingestion of either modified-release forms or greater than 30 g of acetaminophen (paracetamol).[2][1]
 
Following acute overdose, assessment of serum acetaminophen (paracetamol) concentration between 4 to 8 hours and use of the paracetamol treatment nomogram is necessary to determine requirement for the antidote acetylcysteine. If a result is not available within this timeframe acetylcysteine should be commenced and is considered beneficial at any time post-ingestion.[3] Acetylcysteine administration following supratherapeutic/chronic ingestions is dependent on dose and investigations.
 
In cases of massive acetaminophen (paracetamol) ingestion (greater than 50 g or serum concentrations greater than twice the nomogram line) doubling the final (16 hour) acetylcysteine infusion is recommended.[1] Hemodialysis may be beneficial in severe poisoning with very high blood concentrations and particularly if acetylcysteine is unavailable.[4]
 
Supportive care includes the continued use of acetylcysteine, monitoring of major organ function, and further management as indicated. Use of sedating drugs is not recommended due to their impact on the assessment of mental function/encephalopathy. Acute hepatic and renal failure are well recognized concerns. Most complications are a consequence of hepatic failure and rarely occur in its absence.
 
Advice should be sought from a specialist liver transplant unit:[1]
If 
The International Normalized Ratio (INR) is greater than 3 at 48 hours or 4.5 at any time after overdose
Or
Oliguria or creatinine is greater than 200 umol/L (2.2 mg/dL)
Or
Persistent acidosis (pH less than 7.3) or arterial lactate greater than 3 mmol/L
Or
Systolic hypotension with a blood pressure less than 80 mmHg, despite resuscitation
Or
Hypoglycemia
Or
Severe thrombocytopenia
Or
Encephalopathy of any degree, or any alteration of consciousness (Glasgow Coma Scale less than 15) not associated with co-ingestion of sedatives
 
Early discussion with a liver transplant unit is essential. Advice may be given and a decision to transport dependent upon results. In general it is considered desirable to transport patients prior to development of grade 2 encephalopathy.
 
Emergency Stabilization
Decontamination
Antidote(s)
Enhanced Elimination
Supportive Care
Hepatic
Renal
Metabolic
Cardiovascular
Hematologic
Respiratory
Gastrointestinal
 

EMERGENCY STABILIZATION

Emergency Stabilization Should Not Be Required

Emergency stabilization of patients following recent ingestion of acetaminophen (paracetamol), solely, is highly unlikely to be necessary. However, massive overdose may lead to early decline in level of consciousness and/or lactic acidosis.[5] Immediate attention should be given to the airways, assessment of blood glucose, and supportive care.[1] Definitive treatment is provided by the antidote acetylcysteine, with hemodialysis possibly indicated.[4] Carefully consider coingestant(s) or non-toxicological causes.
 

DECONTAMINATION

Ingestion

Single Dose Activated Charcoal

Gastrointestinal decontamination is not indicated in any pediatric (< 6 years old) patient following acetaminophen (paracetamol) overdose.[1]
 
Gastrointestinal decontamination with activated charcoal is only indicated:[1]
In co-operative adult patients
If the formulation is a solid (e.g. tablets, capsules)
If at least 10 g or 200 mg/kg (which ever is lower) is ingested
Within 2 hours of the overdose for standard release formulations
Within 4 hours of the overdose for modified release formulations (patients may benefit from activated charcoal beyond 4 hours following large ingestions)
If at least 30 g is ingested
Within 4 hours of the overdose for standard release formulations
 
Further decontamination with activated charcoal may be necessary for co-ingestants.
 
Induction of emesis and gastric lavage are both contra-indicated.
 
Single dose activated charcoal[6]
CHILD
1 to 2 g/kg orally
ADULT
50 to 100 g orally
 

ANTIDOTE(S)

Acetylcysteine

Acetylcysteine is the treatment of choice for acetaminophen (paracetamol) overdose, and its intravenous use considered preferable.[7] When administered within eight hours of acetaminophen (paracetamol) ingestion it is almost completely effective in preventing death.[8] Use beyond this time is also beneficial and recommended.[3]
 
In the case of modified release formulations, acetylcysteine may need to be continued after the initial 21 hour infusion.
 

Indications

Intra-venous acetylcysteine infusion is indicated as outlined in the following links:
 
 
 

Dose and Administration

While acetylcysteine is recommended to be administered intravenously in 5% dextrose in water, 1/2 normal (0.45%) saline may be substituted if necessary.[9] It is recommended that acetylcysteine dose for adults be calculated for actual body weight rounded up to the nearest 10 kg with a ceiling weight of 110 kg.[1]
 
CHILD
 
Children 20 kg or less body weight:[1]
150 mg/kg in 3 mL/kg of 5% dextrose over 60 minutes
Followed by 50 mg/kg in 7 mL/kg of 5% dextrose over 4 hours
Followed by 100 mg/kg in 14 mL/kg of 5% dextrose over 16 hours
 
Children > 20 kg body weight:[1]
150 mg/kg in 100 mL of 5% dextrose over 60 minutes
Followed by 50 mg/kg in 250 mL of 5% dextrose over 4 hours
Followed by 100 mg/kg in 500 mL of 5% dextrose over 16 hours
 
Closely monitor fluid and electrolyte balance.
 
ADULT
 
Administer:[1]
150 mg/kg in 200 mL diluent IV over 60 minutes
Followed by 50 mg/kg in 500 mL diluent IV over 4 hours
Followed by 100 mg/kg in 1,000 mL diluent over 16 hours
 
 
In the case of massive overdose (those whose acetaminophen (paracetamol) concentration is more than double the nomogram line) it is recommended that the final infusion over 16 hours is doubled to 200 mg/kg.[1]
 

Antidote Endpoint

Acute
Recommended investigations according to time from acetaminophen (paracetamol) ingestion to acetylcysteine treatment[1]
 
Time (hours) from ingestion to start of acetylcysteine
Investigations on admission
Investigations at the completion of acetylcysteine
Less than 8 hours
Serum acetaminophen (paracetamol) concentration
Nil*
8 to 24 hours
Serum acetaminophen (paracetamol) concentration and ALT
ALT, UEC*
Greater than 24 hours
Serum acetaminophen (paracetamol) concentration, ALT and INR
ALT, INR, UEC
Patients with an ALT > 50 U/L
UEC, LFTs, INR, BSL, serum phosphate, blood gas (pH and lactate)
Repeat investigations 12 hourly including: UEC, LFTs, INR, BSL, serum phosphate, VBG
ALT = alanine aminotransferase; BSL = blood sugar level; UEC = BUN (urea), electrolytes, and creatinine; LFTs = liver function tests; VBG = venous blood gases including pH and lactate.
 
* NOTE: If symptoms of hepatotoxicity (e.g. nausea, vomiting, abdominal pain or tenderness) then repeat ALT. Or if initial concentration more than double the nomogram line, then repeat ALT and paracetamol concentration at the completion of acetylcysteine.
 
Patients who have ALT > 50 U/L following completion of initial acetylcysteine require acetylcysteine to be continued at the rate of the last infusion stage (100 mg/kg acetylcysteine over 16 hours or 150 mg/kg/24 hours).[1]
 
Continue acetylcysteine until the patient is clinically improving, ALT is decreasing, INR is improving and < 2, and the acetaminophen (paracetamol) concentration is less than 66 umol/L (10 mg/L).[1][10]
 
Chronic
Following chronic ingestion of acetaminophen (paracetamol) and commencement of acetylcysteine infusion, measure serum acetaminophen (paracetamol) and ALT concentrations 8 hours after the previous measurement.
If serum acetaminophen (paracetamol) is <66 umol/L (<10 mg/L) and ALT is less than 50 U/L, then the infusion can be halted and no further medical treatment is necessary.[1]
 
Otherwise continue the infusion and check serum acetaminophen (paracetamol) and ALT at 12 hourly intervals until:
Serum acetaminophen (paracetamol) is <66 umol/L (<10 mg/L) and ALT is less than 50 U/L, then the infusion can be halted and no further medical treatment is necessary.[1]
 

Precautions

Pregnancy
Acetylcysteine should be administered to pregnant patients following the standard adult regimen. Transplacental transport of acetylcysteine is not thought to be clinically significant,[11] however, delay in initiation of acetylcysteine treatment is associated with increased incidence of spontaneous abortion and fetal death.[12] Acetylcysteine is not considered teratogenic.[13]
 

Adverse Effects

Anaphylactoid Reaction
Six to 23% of patients receiving IV acetylcysteine develop an anaphylactoid reaction.[14][15] These do not represent an immunological (allergic) reaction; rather, they are thought due to a direct dose-dependent effect on histamine release and generally occur within the first two hours of an infusion.
 
History of previous anaphylactoid reaction to acetylcysteine does not contraindicate use. If there is concern of recurrence of the reaction the patient may be pre-treated 15 minutes before commencement of the infusion with an antihistamine.[16]
 
Effects range from mild flushing to urticaria, angioedema, or bronchospasm. Hypotension may occasionally occur. Asthmatics appear more at risk. However, effects are usually easily managed and there is no reason to withhold acetylcysteine from any patient when indicated.[16]
 
Hyponatremia
Hyponatremia has been reported in children if administered acetylcysteine in 5% dextrose following adult protocols for dilution of infused dose.[17]
 
INR
Increased International Normalized Ratio (INR) in the absence of acetaminophen-induced hepatic injury is relatively common.[18][19][20] It is important that increased INR alone (below 2) is not misinterpreted as evidence of acetaminophen-induced hepatic injury, as this may lead to unnecessarily prolonged acetylcysteine administration.[19]
 

ENHANCED ELIMINATION

Hemodialysis

In the majority of cases NAC is the only specific treatment required as acetaminophen (paracetamol) has a high endogenous clearance. However, acetaminophen (paracetamol) is moderately dialyzable,[21][22][23] and extracorporeal techniques may be beneficial in excessively large overdoses if NAC cannot be administered or where there is mitochondrial paralysis or other signs of severe poisoning.
 
Intermittent hemodialysis is recommended in any of the following situations:[4]
- If the patient presents with an altered mental status, metabolic acidosis, an elevated lactate:
- NAC is administered, and
- The blood acetaminophen (paracetamol) concentration is > 5,960 umol/L (900 mg/L)
- NAC cannot be administered, and
- The blood acetaminophen (paracetamol) concentration is > 4,630 umol/L (700 mg/L)
- If the blood acetaminophen (paracetamol) concentration is > 6,620 umol/L (1,000 mg/L) and NAC cannot be administered
 
Intermittent hemodialysis is preferred but hemoperfusion or continuous renal replacement therapy are acceptable alternatives if hemodialysis is not available. Exchange transfusion is an adequate alternative to hemodialysis in neonates.[4]
 
As NAC is dialyzable, NAC administration should be increased during hemodialysis. Up to 25% of NAC is removed by continuous renal replacement therapy and up to 50% with intermittent hemodialysis. The increase should match the expected losses from the extracorporeal technique.[4] It is recommended the dose is doubled while undergoing hemodialysis.[24][25]Hemodialysis should continue until clinical improvement is apparent.[4]
 

SUPPORTIVE CARE

Monitoring

The following is initially recommended, however further monitoring will be required should toxic effects become apparent.
 
Liver function tests:
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
International Normalized Ratio (INR)
Serum electrolytes:
Phosphate
Urinalysis
Renal function
Creatinine
Blood glucose
Full blood count
Arterial blood gases
Mental function
 

Hepatic

Acute Hepatic Failure

Acute hepatic failure developing from the third to sixth day following acetaminophen (paracetamol) overdose is a major concern. It is characterized by highly elevated hepatic transaminase levels (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) but with little rise in alkaline phosphatase, and modest increase in plasma bilirubin (with the exception of chronic alcoholics and those with severe hepatic damage).[26] As hepatic function deteriorates International Normalized Ratio (INR) rises, and a range of complications develop including coagulopathy, hypoglycemia, metabolic acidosis, and hepatic encephalopathy. Acetylcysteine administration should be continued regardless of time after overdose as it appears beneficial even once hepatic failure is apparent.[3]
 
Advice should be sought from a liver transplant unit if:[1]
- The International Normalized Ratio (INR) is greater than 3 at 48 hours or 4.5 at any time after overdose;
- If oliguria or creatinine is greater than 200 umol/L (2.2 mg/dL);
- If persistent acidosis develops (pH less than 7.3) or arterial lactate greater than 3 mmol/L;
- Systolic hypotension with a blood pressure less than 80 mmHg despite resuscitation;
- Hypoglycemia;
- Severe thrombocytopenia, or;
- If there is encephalopathy of any degree or any alteration of consciousness (Glasgow coma scale less than 15) not associated with co-ingestants
 
Hepatic monitoring should include:
Liver function tests including;
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
International Normalized Ratio (INR)
Blood glucose level
Blood gases including;
pH
Lactate
Mental state
 

Renal

Acute Renal Failure

Acetaminophen (paracetamol) can be nephrotoxic, even in the absence of hepatotoxicity (though this is uncommon).[27] Onset ranges from 2 to 5 days after overdose, with peak serum creatinine measured at 3 to 16 days.[26][28] The cause is acute tubular necrosis and may be more common in those with risk factors to acetaminophen (paracetamol) toxicity.[29] While the insult is typically reversible, interim support with hemodialysis may be required. Urea production will be reduced in the presence of hepatic failure and is therefore not a good index of renal function.[26] Advice should be sought from a liver transplant unit if creatinine is greater or equal to 200 umol/L (2.2 mg/dL).[30]
 
Patients should be monitored for the onset of renal failure:
Urine output
Serum creatinine
Blood urea nitrogen (urea)
Proteinuria
Hematuria
Loin pain may occur
 
Manage following standard treatment protocols for acute renal failure.
 

Hematologic

Coagulopathy

Coagulopathy is a common occurrence following acute hepatic failure. Coagulopathy should be managed in conjunction with hepatic failure. Alteration of coagulopathy is often seen before peak hepatic dysfunction.[31]
 
Patients should be monitored for increased International Normalized Ratio (INR).
 

Thrombocytopenia

Common in those with acetaminophen (paracetamol) induced acute hepatic failure and likely related to disseminated intravascular coagulation,[32] but rarely of significance in those without hepatotoxicity.[33] Monitoring for thrombocytopenia should be undertaken if acute hepatic failure develops. Platelets may be administered if the count is less than 50 x 10 to the power of 9/L.

Monitor:
White blood cell count
Platelet count
 
Manage thrombocytopenia using standard treatment protocols.
 

Hemolysis

Patients with glucose-6-phosphate dehydrogenase deficiency may be at risk of hemolysis following acetaminophen (paracetamol) overdose.[34][35][36]
 
Patients should be monitored for evidence of hemolysis:
Jaundice
Pallor
Hemoglobinuria
Anemia
Peripheral blood smear
Reticulocytosis
Heinz bodies
Cell fragments
Whole blood hemoglobin (may be decreased)
Free plasma hemoglobin (may be increased) 
Serum haptoglobin (may be decreased)
Spherocytes (may be present)
Red cell glucose-6-phosphate dehydrogenase testing may be indicated
 
Follow standard protocols for the management of hemolysis.
 

Cardiovascular

Hypotension

Hypotension may follow acetaminophen (paracetamol) ingestion[37] and is usually related to hepatotoxicity.
 
Patients should be closely monitored for onset of hypotension. Should this occur in association with hepatic failure, invasive hemodynamic monitoring is recommended as part of management.

Cardiotoxicity

In those with severe acetaminophen (paracetamol) poisoning, an electrocardiogram (ECG) during the first 48 hours may show minor non-specific S-T changes and T-wave flattening with U-waves, possibly related to hypophosphatemia. Serious cardiovascular abnormalities and hypotension, if they occur, are likely secondary to acute hepatic failure.[26]
 
Patients suffering acute hepatic failure from acetaminophen (paracetamol) toxicity should be monitored with an ECG for cardiac dysrhythmia.

Metabolic

Metabolic Acidosis

Metabolic (lactic) acidosis following acetaminophen (paracetamol) overdose is typically a consequence of hepatic failure and should be treated as such. However, it has been described following massive overdose (associated with central nervous system depression) in the absence of clinical liver failure.[38][39] In such cases acidosis is considered due to early mitochondrial inhibition following glutathione depletion and before cellular damage.[40] Patients should be monitored for onset of acidosis if presenting with either very high acetaminophen (paracetamol) concentrations or depressed level of consciousness. Hemodialysis is recommended in patients presenting with an altered mental status, metabolic acidosis, and an elevated lactate with very high blood acetaminophen (paracetamol) concentrations, especially if NAC cannot be administered.[4] If hepatic injury is present, advice should be sought from a liver transplant unit if there is persistent acidosis (pH less than 7.3) or arterial lactate greater than 3 mmol/L.[1]
 
Monitor:
Arterial blood gases (pH, bicarbonate, pCO2, pO2)
Plasma lactate
Base excess
 
Follow standard protocols for the management of metabolic acidosis.
 

Hypoglycemia

Hypoglycemia has been reported[41] and is most likely a consequence of acute hepatic failure and should be managed in conjunction with this condition. Patients with severe hepatic failure should be monitored for hypoglycemia.
 
Monitor serum glucose.
 

Hypophosphatemia

Hypophosphatemia may occur as a result of either hepatic or renal failure due to acetaminophen (paracetamol) overdose,[42] but would appear more likely due to the later.[43]

Monitor serum phosphate

Treat following standard protocols for hypophosphatemia.

Respiratory

Pulmonary Edema

Acute lung injury has been reported as common in those suffering acetaminophen (paracetamol) induced fulminant hepatic failure.[44]

Non-cardiogenic pulmonary edema may manifest with desaturation and pulmonary rales. On occasion frothy, pink sputum may be apparent. Monitoring for this condition should include:
Chest auscultation
Oxygen saturations
Arterial blood gases
Chest X-ray
 
Follow standard protocols for the management of non-cardiogenic pulmonary edema.
 

Gastrointestinal

Pancreatitis

Pancreatitis occurs rarely following acetaminophen (paracetamol) overdose, and appears related to prior alcohol intake or hemorrhage rather than direct acetaminophen (paracetamol) toxicity. Patients should be monitored for pancreatitis if dehydration is suspected, or their presentation is late.[33]

Observe for:
Vomiting
Persistent, severe, abdominal pain (may radiate to the back)
 
Monitor:
Full blood count
Blood glucose
Urea and electrolytes
Serum amylase and lipase concentrations
 
Follow standard protocols for the management of pancreatitis.
 

DISCHARGE CRITERIA

Patients suffering acetaminophen (paracetamol) overdose may be medically discharged following the initial (20 to 21 hour) acetylcysteine infusion provided:
 
- Clinically there is no nausea/vomiting, right upper quadrant tenderness, and no renal angle tenderness, and;
- Hepatic transaminase levels (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]), and International Normalized Ratio (INR) remain normal or, if elevated, have peaked and are now falling.
 
In other cases continued acetylcysteine infusion (100 mg/kg per 16 hours) is required until improvement.[45] If continued infusion is required discharge may occur when liver function tests, International Normalized Ratio (INR), and creatinine are shown to be normalizing.
 
Discharge after development of hepatic or renal failure, or other consequences, should follow standard protocols for those conditions.
 

FOLLOW UP

Standard protocols should be used for follow-up of patients suffering hepatic or renal failure, including advice that patients should abstain from alcohol for six weeks to allow regeneration of the liver.
 
Patients should be referred for psychiatric assessment as appropriate.
 

PROGNOSIS

Full recovery from both hepatic and renal damage due to acetaminophen (paracetamol) toxicity is usual, but not inevitable.

SIGNS AND SYMPTOMS

Initial manifestations of acetaminophen (paracetamol) intoxication may be absent or may only include gastrointestinal effects, malaise, pallor, and diaphoresis.[46][47] Rarely, following massive overdose, there may be an initial metabolic acidosis and coma.[5][38]
 
Hepatic damage is a common feature of acetaminophen (paracetamol) toxicity and further signs and symptoms become apparent if hepatotoxicity develops. As time after overdose increases signs and symptoms associated with acute hepatic failure including right upper quadrant tenderness, hypotension, acidosis, coagulopathy, encephalopathy, and hypoglycemia may develop.[47][48][49] Jaundice is not evident as an early sign but develops as hepatic failure progresses.[47] Additionally, an initial increase in INR can be seen in the first 24 to 48 hours which appears to result from an inhibition of the activation of vitamin K dependent coagulation factors.[50] Later, coagulopathy is typically a result of liver failure.
 
Renal failure associated with acetaminophen (paracetamol) overdose may rarely appear acutely, or more usually over a period of days and in association with hepatotoxicity/failure.[33] Cardiovascular concerns are rarely an acute consequence of poisoning, but hypotension and myocardial injury may appear in patients with fulminant hepatic failure as part of multisystem organ failure.[51]
 

Onset/Duration of Symptoms

Acetaminophen (paracetamol) in the form of liquid formulations and oro-dispersable tablets are more quickly absorbed than standard tablets,[52] so may alter the onset of symptoms. Modified release tablets may additionally alter the time course of toxicity.
 
Four phases of acute acetaminophen (paracetamol) toxicity have been described.[46]
 
Phase 1 (0.5 to 24 hours after overdose): During the first 24 hours following acute overdose a patient may have few if any signs or symptoms. However, they may demonstrate malaise, anorexia, nausea, vomiting, pallor, and diaphoresis.[46][47]Rarely, following massive overdoses, metabolic acidosis and coma may occur in this phase as a direct toxic effect.[5][38]
 
Phase 2 (24 to 72 hours after overdose): Previous symptoms subside. Right upper quadrant pain may appear indicating hepatic damage with associated raised hepatic transaminases. International Normalized Ratio (INR) increases. Renal function may begin to deteriorate, however blood urea may remain low due to decreased hepatic urea formation.[46][47]
 
Phase 3 (72 to 96 hours after overdose): Continuing hepatic centrilobular necrosis with associated coagulation defects, hypoglycemia, metabolic acidosis, and jaundice. Renal failure and cardiac complications frequently occur. Hepatic encephalopathy and death may ensue.[46][47]
 
Phase 4 (4 days to 2 weeks after overdose): If phase 3 is survived complete resolution of hepatic and renal function is usual.[46][53]
 

Severity of Poisoning

Mild Acetaminophen (Paracetamol) ToxicityModerate Acetaminophen (Paracetamol) ToxicitySevere Acetaminophen (Paracetamol) Toxicity
Malaise
Nausea
Vomiting
Pallor
Diaphoresis
Upper right quadrant pain
Increased INR
Metabolic acidosis
Hypoglycemia
Jaundice
Renal failure
Fulminant hepatic failure
Hepatic encephalopathy
Coma
 

ACUTE EFFECTS (ORGAN SYSTEM)

Gastrointestinal

Anorexia[47][41][54]
Nausea[47][41]
Vomiting[47][41]
Abdominal pain[55][56][57]
Hyperamylasemia[55][58][59][60] (uncommon)
Pancreatitis[55][58][59][60] (uncommon)
 

Hepatic

Elevated liver enzymes[41][61][62][63][64][65]
Increased International Normalized Ratio (INR)[63][66][67]
Coagulopathy[48][66]
Hepatic encephalopathy[62][64][69][54]
Fulminant hepatic failure[56][63][67][70][71][54]
Centrilobular hepatic necrosis[54]
 

Renal

Proteinuria[72]
Hematuria[72]
Acute tubular necrosis[41][63][73][74][54]
 

Metabolic

Hypoglycemia[41][54]
Hypothermia[24]
Metabolic acidosis[5][38][77][78]
 

Cardiovascular

Tachycardia[54]
Hypotension[37][54]
Myocardiopathy[47]
ST elevation[79][80]
T wave inversion[79][80]
 

Neurologic

Malaise[81]
Confusion[81][82]
Altered mood[71]
Stupor[81][82]
Cerebral edema[83]
 

Dermatologic

Diaphoresis[47]
 

Hematologic

Coagulopathy[48][66]
Increased International Normalized Ratio (INR)[63][66][67][50]
 

CHRONIC EFFECTS

Symptoms in chronic situations are broadly similar to acute ones. Heptotoxicity and its complications are the major concern.[86][85]
 

TOXICITY

HUMAN

Acute

Child

Children appear less susceptible to hepatotoxicity from acetaminophen (paracetamol) than adults. Toxicity following pediatric exploratory ingestions is rare.[1][87] However, the exact toxic dose is still subject to debate. Oro-dispersible formulas may present an increased risk over standard tablets due to their near immediate disintegration when in contact with saliva.[52]
 
Medical attention is warranted for ingestions of 200 mg/kg or more in children 6 years or under, or the lesser of 10 g or 200 mg/kg in children over 6 years.[1][88]
 

Adult

Acetaminophen (paracetamol) induced hepatotoxicity may occur in adults after large doses. In a study of patients over 12 years of age, a single dose of less than 12 g can cause severe hepatotoxicity, and death has occurred with doses over 15 g.[89]
 
Medical attention is warranted following ingestions of the lesser of 10 g or 200 mg/kg acetaminophen (paracetamol).[1][88]
 
Case Studies
8 g modified release Acetaminophen (paracetamol)(ingested)
35 year female: 4 hour acetaminophen concentration was 695 umol/L, 6 hour concentration was 950 umol/L. Asymptomatic at all times
Supportive care, including acetylcysteine after 2nd acetaminophen concentration[90]
Recovered[90]
13 g (but potentially more) Acetaminophen (paracetamol)(ingested)
24 year female (alcohol abuse suspected): developed nausea, vomiting, and anorexia within hours of ingestion. Presented at hospital 2 days later with abdominal pain and discharged soon after. Nausea worsened and hematemesis occurred. On second admission was comatose and tachycardic. Later developed centrilobular hepatic necrosis, renal tubular necrosis, encephalopathy, hypotension, and hypoglycemia
Supportive care, including pressors[54]
Fatal[54]
249 mg/kg (19.95 g) modified release Acetaminophen (paracetamol)(ingested)
17 year male: Acetaminophen concentration of 1,291 umol/L at 9.5 hours. Peak ALT of 7,516 IU/L at 67 hours
Supportive care, including acetylcysteine over 101 hours[91]
Recovered[91]
290 mg/kg (17.6 g) modified release Acetaminophen (paracetamol)(ingested)
17 year female: Acetaminophen concentration of 738 umol/L at 12 hours. Peak ALT of 128 IU/L at 24 hours
Supportive care, including acetylcysteine over 53 hours[91]
Recovered[91]
318 mg/kg (23.725 g) modified release Acetaminophen (paracetamol)(ingested)
28 year male: Acetaminophen concentration of 1,177 umol/L at 12 hours. Peak ALT of 132 IU/L at 168 hours
Supportive care, including acetylcysteine over 21 hours[91]
Recovered[91]
332 mg/kg (23.9 g) modified release Acetaminophen (paracetamol)(ingested)
18 year male: Acetaminophen concentration of 502 umol/L at 4 hours. Peak ALT of 90 IU/L at 120 h
Supportive care, including acetylcysteine over 36 hours[91]
Recovered[91]
945 mg/kg (75.84 g) modified release Acetaminophen (paracetamol)(ingested)
58 year male: Acetaminophen concentration of 2,161 umol/L at 4.5 hours. Peak ALT of 1,232 IU/L at 89 hours
Supportive care, including acetylcysteine over 133 hours[91]
Recovered[91]
1,185 mg/kg (64 g) modified release Acetaminophen (paracetamol)(ingested)
25 year female: Nausea and vomiting within a couple of hours. Mild coagulopathy was noted at 48 hours. Blood acetaminophen concentration of 2,235 umol/L at 14.5 hours and 2,487 umol/L at 20 hours
Supportive care, including anti-emetics and acetylcysteine (treatment did not start until 14.5 hours post-ingestion)[92]
Recovered[92]
 

Chronic

Chronic overdose, for example ingestion of several high 'therapeutic' doses of acetaminophen (paracetamol) over 1 to 2 days, or multiple minor overdoses over a short period of time, may produce moderate or even severe hepatic damage.[86]
 
The staggered dose required to produce acetaminophen (paracetamol) toxicity has yet to be established.
 
Medical attention is warranted for children 6 years or under who ingest 200 mg/kg or more over a single 24 hour period, 150 mg/kg per 24 hours for the preceding 48 hours, or 100 mg/kg per 24 hours more than 48 hours.[1]
 
Medical attention is warranted for adults and children over 6 years who ingest the lesser of 10 g or 200 mg/kg or more over a single 24 hour period, the lesser of 6 g or 150 mg/kg per 24 hours for the preceding 48 hours, or the lesser of 4 g or 100 mg/kg per 24 hours for more than 48 hours in patients with symptoms indicating possible liver injury e.g. abdominal pain or nausea or vomiting.[1]
 

Child

Case Studies
233 mg/kg Acetaminophen (paracetamol) over a 36 to 48 hour period(ingested)
7 month male (pre-existing fever, it was unknown about the high dose of acetaminophen at the initial time of presentation at hospital): vomiting, tachycardia, drowsiness, melena, and abdominal distension. Six hours after admission developed seizures, hypoglycemia, increased liver enzymes, increased INR, and increased total bilirubin. Later developed metabolic acidosis and shock
Supportive care, including IV fluids, antibiotics, vitamin K, intubation, ventilation, and acetylcysteine[85]
Fatal. Life support was withdrawn[85]
 

Adult

Case Studies
17,000 mg acetaminophen (paracetamol) over 4 days and 1 morning(ingested)
45 year male (HIV positive, hepatitis B, Hepatitis C, IV heroin abuse, and starvation over the period of acetaminophen administration): worsening weakness, malaise, and nausea over the 4 days of acetaminophen ingestion, and hepatotoxicity
Supportive care, including acetylcysteine, IV infusions of glucose, electrolytes, amino acids, vitamin K, sucralfate, and methadone[93]
Recovered[93]
6 g acetaminophen (paracetamol) daily for 2 weeks(ingested)
22 year female (19 weeks pregnant): abdominal pain and fulminant hepatic failure
Supportive care, including acetylcysteine, bicarbonate, and liver transplant[94]
The mother required re-operation due to post-operative complications. The fetus was viable at this stage. From post-operative day 6 to 17 the fetus developed ascites, pericardial effusion, ventriculomegaly, hydrocephalus, subarachnoid fluid, compression of the cavum septum pellucidum, and lateral herniation of the brain. The fetus was electively aborted. The mother survived[94]
 

ANIMAL

Cats
 
Cats are very susceptible to toxicity as they have limited ability to metabolize acetaminophen (paracetamol) due to a limited capacity of their glucuronidation pathway and/or saturation of their sulfate conjugation pathway.[95] As little as 50 to 60 mg/kg orally may be toxic.[96]
 
Signs may occur within a few hours of ingestion and include depression, anorexia, vomiting, cyanosis, edema of the face and extremities, methemoglobinemia, dyspnea, hepatotoxicity, and death. Hematuria and hemoglobinuria usually appear first, when blood methemoglobin levels are around 20%.[96] Cats typically do not develop major hepatotoxicity although this may be due to cats dying from hypoxia secondary to methemoglobinemia at doses that are too low to produce hepatic necrosis.[96]
 
Cat
60 mg/kg acetaminophen (paracetamol)
21.7% methemoglobinemia within 4 hours; clinical effects included depression, hematuria, hemoglobinuria and increases in ALT[97]
120 mg/kg acetaminophen (paracetamol)
45.5% methemoglobinemia within 4 hours; clinical effects included salivation, vomiting, depression, mild facial edema, hematuria, and increases in ALT.[97]
 
Dogs
 
Dogs do have the ability to metabolize acetaminophen (paracetamol), however, methemoglobinemia is a concern as is hepatic damage. Toxic doses for dogs are probably greater than or equal to 150 mg/kg.[96]
 
Signs develop within one to two hours of ingestion and are progressive, consisting of anorexia, salivation, vomiting, hypovolemia, depression, methemoglobinemia, hematuria or hemoglobinuria, and edema of the face and/or paws. Muscle tremors or rarely seizures may occur, possibly through triggering of latent epilepsy. Hematuria and hemoglobinuria usually appear first, when blood methemoglobin levels are around 20%. Signs may persist 12 to 48 hours. Acute hepatic failure may follow initial signs. Death may occur 18 to 36 hours post ingestion.[96]
 
Dogs administered 3 doses of 750 mg/kg initially, 200 mg/kg 9 hours later, and 200 mg/kg at 24 hours after the initial dose by subcutaneous injection consistently developed fulminant hepatic failure. No deaths occurred within the first 36 hours.[98]
 
Dog
200 mg/kg acetaminophen (paracetamol)
18.8% methemoglobinemia[97]
500 mg/kg acetaminophen (paracetamol)
51.9% methemoglobinemia[97]
1 g/kg acetaminophen (paracetamol)
Brown mucous membranes, recumbent, hypovolemic, severe hemolytic anemia, decreased coagulation, RBC glutathione concentration that was 10% of reference values[99]
 
Paracetamol (Acetaminophen):
LD50 Oral, Mouse
338 mg/kg338 mg/kg/[100]
LD50 Oral, Rat
2,400 mg/kg2,400 mg/kg/[100]
LD50 IP, Mouse
367 mg/kg367 mg/kg/[100]
LD50 IP, Rat
1,205 mg/kg1,205 mg/kg/[100]
LD50 SC, Mouse
310 mg/kg310 mg/kg/[100]

BIOLOGICAL LEVELS - TOXIC

Acetaminophen (Paracetamol)
 

SI Unit Conversion

To convert an acetaminophen (paracetamol) concentration expressed in mg/L into umol/L:
Multiply the mg/L by 6.6155
 
To convert an acetaminophen (paracetamol) concentration expressed in umol/L into mg/L:
Multiply the umol/L by 0.1512
 
Outside of the United States most laboratories report acetaminophen (paracetamol) concentration expressed in umol/L. It is important to check what units your laboratory uses before referring to the nomogram.
 

Toxic Serum Level

A serum concentration versus time curve or Acetaminophen (Paracetamol) Nomogram has been constructed to provide an indication of potentially hepatotoxic acetaminophen (paracetamol) serum concentrations. Note this graph displays the acetaminophen (paracetamol) concentration in both umol/L and mg/L.
 

REPRODUCTION

PREGNANCY

Acetaminophen (paracetamol) is routinely used during all stages of pregnancy for pain relief and to lower elevated body temperature. In therapeutic doses, it probably is safe to use in the short term.[101]
 
Acetaminophen (paracetamol) crosses the placenta and is transformed by fetal hepatocytes into the toxic metabolite.[102] While it is felt the fetus is less susceptible to hepatic damage than adults,[102] an association is indicated between maternal first trimester overdose and abortion within 2 to 3 weeks.[103] Though transplacental transport of acetylcysteine is not thought to be clinically significant,[11] delay in initiation of acetylcysteine treatment is associated with increased incidence of spontaneous abortion and fetal death.[12] Neither acetaminophen (paracetamol) nor acetylcysteine appears teratogenic and termination of pregnancy is not indicated in most circumstances after acetaminophen (paracetamol) overdose.[13]
 
A 19 week pregnant female who was ingesting 6 g acetaminophen daily for 2 weeks developed hepatic encephalopathy and fulminant hepatic failure. As the fetus was initially deemed viable, maternal liver transplant took place. Due to maternal complications a further surgery was required. Six days post-operation the fetus developed complications of fetal ascites and pericardal effusion, and later developed ventriculomegaly, hydrocephalus, subarachnoid fluid, compression of the cavum septum pellucidum, and lateral herniation of the brain. The brain injury was deemed to be non-conducive with life and the fetus was aborted.[94]
 
FDA Classification (before July 2015):
 
Australian Classification:
 
For full details of the Australian ADC pregnancy classification, as well as the FDA classification (used prior to July 2015), Click here.
 

LACTATION

Acetaminophen (paracetamol) is excreted into breast milk in low concentrations.[104][105][106][107]
 
The American Academy of Pediatrics considers acetaminophen (paracetamol) to be compatible with breast-feeding.[108]
 

TOXIC MECHANISM

At therapeutic doses, 90% of acetaminophen (paracetamol) is converted to non-toxic glucuronide and sulfate conjugates, and 5% is excreted in the urine unchanged. The other 5% is oxidized in the liver by P450 2E1, P450 1A2 and P450 3A4 to N-acetyl-p-benzoquinoneimine (NAPQI).[109] At therapeutic amounts glutathione binds with NAPQI to form a non-toxic conjugate. In overdose, glucuronide and sulfate conjugation becomes saturated and an increased proportion of NAPQI is formed. Glutathione levels are depleted, as the demand for glutathione is higher than the formation of glutathione.[110] This means that NAPQI remains in its toxic form in the liver and can bind to cysteine containing macromolecules.[111] This can cause hepatocellular damage, in particular centrilobular necrosis.[46] The exact mechanism of damage in the liver is unknown. NAPQI can also be produced in the kidney leading to renal damage.[112]
 
Both acetaminophen (paracetamol) and NAPQI are capable of inhibiting hepatic mitochondrial respiration,[113] generally following massive ingestions.[38][24]
 

THERAPEUTIC DRUG INFORMATION

INDICATIONS

This is intended as a guide only. For a more comprehensive list, refer to manufacturer's information.
 
Generally, indicated for:[114][115][116]
Mild to moderate analgesia
Pyrexia
 

THERAPEUTIC DOSE RANGE

This is intended as a guide only. For a more comprehensive list, refer to manufacturer's information.
 

Child

Analgesia & Pyrexia[115][117][118][119][120]
Oral
Under 3 months
200 mg acetaminophen (paracetamol) daily (in divided doses)
Maximum dose is 60 mg/kg daily
4 to 11 months
240 to 480 mg acetaminophen (paracetamol) daily (in divided doses)
Maximum dose is 60 mg/kg daily
12 to 23 months
600 mg acetaminophen (paracetamol) daily (in divided doses)
Maximum dose is 60 mg/kg daily
2 to 3 years
800 mg acetaminophen (paracetamol) daily (in divided doses)
Maximum dose is 60 mg/kg daily
4 to 5 years
1,200 mg acetaminophen (paracetamol) daily (in divided doses)
Maximum dose is 60 mg/kg daily
6 to 8 years
1.600 mg acetaminophen (paracetamol) daily (in divided doses)
Maximum dose is 60 mg/kg daily
9 to 10 years
2,000 mg acetaminophen (paracetamol) daily (in divided doses)
Maximum dose is 60 mg/kg daily
11 years
2,400 mg acetaminophen (paracetamol) daily (in divided doses)
Maximum dose is 60 mg/kg daily
Over 12 years
Usual dose is 4  g acetaminophen (paracetamol) daily (in divided doses)
Maximum 4 g daily
 
Rectal
Under 6 months
Generally not recommended but may be prescribed by a doctor at individualized doses
6 months to 3 years
500 to 800 mg acetaminophen (paracetamol) daily (in divided doses)
4 to 5 years
1,200 mg acetaminophen (paracetamol) daily (in divided doses)
6 to 8 years
1.600 mg acetaminophen (paracetamol) daily (in divided doses)
9 to 10 years
1,600 to 2,000 mg acetaminophen (paracetamol) daily (in divided doses)
11 years
1,600 to 2,400 mg acetaminophen (paracetamol) daily (in divided doses)
Over 12 years
325 to 650 mg acetaminophen (paracetamol) daily (in divided doses)
 
Injection
<10 kg
7.5 mg/kg acetaminophen (paracetamol) up to 4 times daily
10 to 50 kg
15 mg/kg acetaminophen (paracetamol) up to 4 times daily
> 50 kg
1 g acetaminophen (paracetamol) up to 4 times daily
 

Adult

Analgesia or Pyrexia[114][115][117][118][119]
Oral
3.9 to 4 g acetaminophen (paracetamol) daily (in divided doses)
Maximum 4 g daily
Rectal
1.95 to 3.9 g acetaminophen (paracetamol) daily (in divided doses)
Maximum of 4 g daily
Injection
<50 kg
15 mg/kg acetaminophen (paracetamol) up to 4 times daily
>50 kg
1 g acetaminophen (paracetamol) up to 4 times daily
 

PHARMACOLOGICAL ACTION

The pharmacological action of acetaminophen (paracetamol) is not fully understood. It has been hypothesized that the mechanisms involved for producing analgesia and antipyrexia are similar to that of the salicylates but with only weak anti-inflammatory effects.
 
It is known that acetaminophen (paracetamol) selectively inhibits prostaglandin synthesis, predominantly in the central nervous system and to a lesser extent in the periphery.[121] Acetaminophen (paracetamol) also lowers body temperature by acting on the hypothalamus to increase vasodilatation and peripheral blood flow to aid heat dissipation. This occurs largely in patients with a fever, with little change in body temperature in subjects with normal body temperature. Acetaminophen (paracetamol) is also a weak inhibitor of the enzyme cyclo-oxygenase, but only in the presence of a high concentration of peroxides.[122]
 

KINETICS

ABSORPTION

Oral Absorption
Rapidly absorbed from the gastrointestinal tract[123][124]
Oro-dispersible tablets start disintegrating within seconds of contact with saliva[52]
Rectal Absorption
Slower than oral route[125][126]
Effect of Food
High carbohydrate meals appear to delay absorption[127]
Food does not affect the total amount absorbed[127]
Other Factors Affecting Absorption
Absorption was slow and incomplete in vegetarians compared with non-vegetarians[128]
Bioavailability
68 to 90%[123]
Oro-dispersible tablets absorption is 32% greater than standard tablets over the first hour[129]
Onset of Action
Within 30 minutes[46]
Duration of Action
~4 hours[46]
Time to Peak Plasma Levels
Immediate release: 10 minutes to 1.4 hours[123][130][131][132]
Extended release: 60 to 180 min[133][130][134]
 
In overdose time to peak plasma levels is delayed[123]
 

DISTRIBUTION

Distribution
  1. Rapidly and uniformly distributed to most of the body tissues[124][134]
Volume of Distribution
  1. 0.9 to 1.0 L/kg[46][135][136]
Plasma Protein Binding
  1. 5 to 20% at therapeutic doses[46]
  2. 15 to 50% during acute intoxication[137][138]
Lipid Solubility
Crosses the placenta[102]
Is excreted in breast milk[104][105][106][107]
 

METABOLISM

Metabolism
  1. Predominantly by the liver, 98%[139]
Metabolites
Inactive:
  1. Glucuronide metabolites[139]
  2. Sulfate metabolites[139]
  3. N-acetyl-p-benzoquinoneimine (NAPQI), minor hydroxylated metabolite[109][140]
Major Metabolic Pathways
Parent:
  1. Adults - Acetaminophen (paracetamol) conjugation to glucuronide (42%) and sulfate (52%) metabolites.[139] The remainder is oxidized in the liver by P450 2E1, P450 1A2, and P450 3A4 to NAPQI.[109]
  2. After 12 years of age - Glucuronide conjugation predominates.[139] 
  3. Infants - Sulfate conjugation predominates with a gradual shift towards glucuronide conjugation in older children.[139]
N-acetyl-p-benzoquinoneimine (NAPQI):
  1. Rapidly conjugated with glutathione at therapeutic doses[46][141]
  2. In overdose the glucuronidation pathway becomes saturated allowing NAPQI to cause cell toxicity[46][141]
Saturation of Enzymes
  1. In overdose the glucuronidation and sulfation pathways become saturated[141][142]
Other Factors Affecting Metabolism
  1. Metabolism is impaired in severe poisoning with liver damage; prolongation of plasma half-life occurs[143]
 

ELIMINATION

Excretion
Urine
  1. Mainly as glucuronide and sulfate conjugates[126]
  2. Less than 5% excreted unchanged[124][126][135]
Half-life
Therapeutic
  1. Standard release: 1 to 3 hours[133][46][123][130][135][144]
  2. Modified release: half-life is similar[133][130]
Overdose
  1. Half-life may be prolonged in severe poisoning with liver damage[63][143][145]
  2. Half-life following modified release overdose appears extremely variable, 3.3 to 11 hours[92][146][147]
Active Metabolites
Glucuronide metabolite
  1. 3.5 to 3.9 hours[130]
Sulfate metabolite
  1. 3.8 to 3.9 hours[130]
Clearance Rate
  1. 3.9 to 5.7 mL/kg/min[136][144][148]
Time to Completion
  1. 85 to 95% excreted within 24 hours[126]
Potential for Accumulation
  1. N-Acetyl-p-benzoquinoneimine may accumulate following overdose and cause tissue damage[109][142]
 

IDENTIFICATION

PRODUCT INFORMATION

Tablets and capsules range from 80 to 665 mg acetaminophen (paracetamol), commonly 500 mg. Sustained release formulations are available in 665 mg strength tablets and capsules. Oro-dispersible forms are available.

Formulations for injection contain 10 mg/mL acetaminophen (paracetamol).

Oral solutions range from 24 to 100 mg/mL acetaminophen (paracetamol).

Hot drink powders range from 500 to 1,000 mg/sachet, commonly 1,000 mg/sachet acetaminophen (paracetamol).

The packaging of each trade product will include information on the exact quantity of acetaminophen (paracetamol) and whether the formulation is sustained release.

OTHER NAME(S)

Common Names

4-HydroxyacetanilideAcetaminofenoAcetaminophen
APAPAsetaminofenN-Acetyl-p-aminophenol
N-acetyl-para-aminophenolP acetamidophenolParacetamol
ParacetamolisParacetamolumParasetamol
Parasetamoli
 
 
 

Chemical Name

Acetaminophen (Paracetamol):
N-(4-Hydroxyphenyl)acetamide 4'-Hydroxyacetanilide N-Acetyl-p-aminophenol
 

“Street” Names

CandiesCapricorn
DuckGreen Capricorn
Green clubsKO
Orange candiesPink KO
Pokemon
 
 
These street names refer to products which are contaminated with acetaminophen (paracetamol).
 

CODES

ATC CLASSIFICATION

Other Analgesics And Antipyretics - AnilidesOther Analgesics And Antipyretics
N02B E01
Paracetamol
N02B E51
Paracetamol, Combinations excl. Psycholeptics
N02B E71
Paracetamol, Combinations with Psycholeptics
N02B E
 

CAS NUMBER

Acetaminophen (Paracetamol):
103-90-2
 

MOLECULAR FORMULA

Acetaminophen (Paracetamol):
C8H9NO2
 

PHYSICOCHEMICAL PROPERTIES

Large, monoclinic prisms
 
Specific Gravity (water = 1)
1.293 1.293% degrees C[149]
Molecular Weight
151.16 151.16% degrees C[149]
Melting Point
169 to 170.5 169 to 170.5% degrees C[149]
Solubility
Cold water: very slightly soluble[149]
Hot water: moderately soluble[149]
Methanol: soluble[149]
Ethanol: soluble[149]
Acetone: soluble[149]
Ethyl acetate: soluble[149]
Ether: slightly soluble[149]
 

REFERENCES

 
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[3] Keays R, Harrison PM, Wendon JA, Forbes A, Gove C, Alexander GJ, Williams R. Intravenous acetylcysteine in paracetamol induced fulminant hepatic failure: a prospective controlled trial. BMJ 1991 Oct 26; 303 (6809): 1026-9.
[4] Gosselin S, Juurlink DN, Kielstein JT, Ghannoum M, Lavergne V, Nolin TD, Hoffman RS. Extracorporeal treatment for acetaminophen poisoning: recommendations from the EXTRIP workgroup. Clin Toxicol (Phila) 2014 Sep-Oct; 52 (8): 856-67.
[5] Zezulka A, Wright N. Severe metabolic acidosis early in paracetamol poisoning. Br Med J (Clin Res Ed) 1982 Sep 25; 285 (6345): 851-2.
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