18.May.2012-Expires: 7 days - Do not archive

Acetaminophen

Acetaminophen
18.May.2012-Expires: 7 days - Do not archive

DESCRIPTION

SUBSTANCE NAME

Acetaminophen (Paracetamol)
 

SUBSTANCE CLASS

Para-Aminophenol Derivative

INTERVENTION CRITERIA

Intervention Level

Acute Exposure

 
6 years or under ingesting
200 mg/kg acetaminophen (paracetamol) or more over a period of less than 8 hours
Older than 6 years ingesting
At least 10 g or 200 mg/kg (whichever is lower) over a period of less than 8 hours
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 N-acetylcysteine infusion and investigate.
 

Chronic Exposure

 
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 the preceding 72 hours;
- Blood acetaminophen (paracetamol) >120 umol/L (>20 mg/L) or ALT greater than normal
 
Aged older than 6 years ingesting
- At least 10 g or 200 mg/kg (whichever is lower) over a single 24-hour period;
- At least 6 g or 150 mg/kg (whichever is lower) per 24-hour period for the preceding 48 hours;
- More than 4 g per day or 100 mg/kg (which ever is less) in patients with predisposing risk-factors;
- Blood acetaminophen (paracetamol) >120 umol/L (>20 mg/L) or ALT greater than normal.
 
Predisposing risk factors[2][1]
Chronic alcohol abuse
Patients on microsomal inducing drugs such as:
barbiturates, carbamazepine, rifampicin, isoniazid
Glutathione deficient patients:
recent prolonged fasting, acute illness, prolonged vomiting/dehydration, anorexia nervosa, bulimia
malnutrition, malignancy, HIV
Patients suffering liver injury:
viral hepatitis, alcoholic hepatitis
Also investigate if:
The dose or timing of ingestion is uncertain, or;
The patient is symptomatic.
 

Investigation and Initial Management

Acute Ingestion

 
1 to 8 hours post-ingestion
 
Administer activated charcoal to co-operative adults if within 2 hours of overdose of a solid formulation.[3]
 
Measure
Plasma acetaminophen (paracetamol) level;
At 2 hours, or immediately if presenting after this, for pediatric patients ingesting liquid formulations,[4] or;
At 4 hours, or immediately if presenting after this, for adults and following ingestion of a solid formulation by any age group.
In the case of ingestion of sustained release paracetamol formulations a second plasma acetaminophen (paracetamol) level should be measured 4 hours after the first level.[5][6][7]
 
The Plasma acetaminophen (paracetamol) level should then be plotted on the treatment nomogram to determine if treatment with the antidote N-acetylcysteine is indicated. In the case of sustained release formulations treatment with the antidote N-acetylcysteine should be commenced if either level falls above the paracetamol treatment nomogram line.[5][6][7]
 
NOTE: In cases where a 2 hour pediatric level is taken this should be plotted against the 4 hour line on the treatment nomogram
 
If the plasma acetaminophen (paracetamol) level will NOT be available within 8 hours:
Immediately commence an N-acetylcysteine infusion
If the plasma acetaminophen (paracetamol) level will be available within 8 hours:
Only commence N-acetylcysteine if indicated by the nomogram
 
If the acetaminophen (paracetamol) level is below the nomogram line, then medical treatment is not required and any N-acetylcysteine infusion can be stopped.
 
If the acetaminophen (paracetamol) level is above the nomogram line, then commence or continue a full course of N-acetylcysteine.
 
8 to 24 hours post-ingestion
 
Immediately commence an N-acetylcysteine infusion
Measure:
Plasma acetaminophen (paracetamol) level and plot on the treatment nomogram
Alanine aminotransferase (ALT)
 
If the plasma acetaminophen (paracetamol) level is below the nomogram line and the ALT is normal, then the N-acetylcysteine infusion can be halted and no further medical treatment is necessary.
 
If the plasma acetaminophen (paracetamol) level is above the nomogram line or the ALT is elevated, then complete a full course of N-acetylcysteine.
 
24 plus hours post-ingestion, or time of ingestion or dose are unknown
 
Immediately commence an N-acetylcysteine infusion
Measure:
Plasma acetaminophen (paracetamol) level
Alanine aminotransferase (ALT)
INR/prothrombin time
Creatinine and urea
Glucose
Arterial Blood Gas
Platelet count
 
If the plasma acetaminophen (paracetamol) level is non-detectable and the ALT is normal, then the infusion can be halted and no further medical treatment is necessary.
 
If plasma acetaminophen (paracetamol) is detectable or ALT is elevated, then complete a full course of N-acetylcysteine.
 
The other measurements are used as baseline values to guide future management.
 

Time of Ingestion Unknown

Immediately commence an N-acetylcysteine infusion
Measure:
Plasma acetaminophen (paracetamol)
Alanine aminotransferase (ALT)
 
If plasma acetaminophen (paracetamol) is not detectable and ALT is normal, the infusion may be halted immediately.
 
Otherwise, complete the infusion and re-measure plasma acetaminophen (paracetamol) and ALT. If plasma acetaminophen (paracetamol) is <120 umol/L (<20 mg/L) and ALT is normal or declining continued N-acetylcysteine infusion is not necessary.
 

Chronic Ingestion

 
In patients meeting intervention criteria for chronic ingestion
 
Measure:
Plasma acetaminophen (paracetamol) level
Alanine aminotransferase (ALT)
 
If plasma acetaminophen (paracetamol) is <120 umol/L (<20 mg/L) and ALT is normal, then no medical treatment is necessary.
 
If plasma acetaminophen (paracetamol) is >120 umol/L (>20 mg/L) or ALT greater than normal, then commence an N-acetylcysteine infusion.
 
If an N-acetylcysteine infusion has been started, then measure plasma acetaminophen (paracetamol) and ALT 8 hours from start of infusion:
If plasma acetaminophen (paracetamol) is <120 umol/L (<20 mg/L) and ALT is normal, static or declining, then the N-acetylcysteine can be halted and no further medical treatment is required.
 
Otherwise continue infusion and re-measure plasma acetaminophen (paracetamol) and ALT 12 hourly until:
 
Plasma acetaminophen (paracetamol) is <120 umol/L (<20 mg/L) and ALT is normal, static or declining, then the N-acetylcysteine can be halted and no further medical treatment is required.
 

Observation Period

Observation at Home

No observation is required for those patients with ingested doses or plasma 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 plasma acetaminophen (paracetamol) investigation is undertaken and levels are 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 plasma acetaminophen (paracetamol) and provide N-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 effective within 2 hours of ingestion of non-liquid forms of acetaminophen (paracetamol).[3][8] It is indicated for cooperative adult patients only. Rapid measurement of plasma acetaminophen (paracetamol) level is necessary to determine if an antidote is required. N-acetylcysteine is a life-saving antidote, and while its efficacy declines after approximately eight hours of the acetaminophen (paracetamol) ingestion,[9] it should be administered to all patients with a potentially toxic overdose, regardless of time,[10] and in all cases where there is uncertainty.
 
Supportive care includes the continued use of N-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:
If 
The International Normalized Ratio (INR) is greater or equal to 2 at 24 hours or 3 at any time after overdose
Or
Creatinine is greater or equal to 200 umol/L (2.2 mg/dL)
Or
pH is less than or equal to 7.3 or bicarbonate less than or equal to 18 mmol/L (18 mEq/L)
Or
Blood pressure is low after volume loading (mean arterial pressure less than or equal to 60 mmHg)
Or
The patient becomes encephalopathic
 
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
Single dose activated charcoal
Antidote(s)
Enhanced Elimination
Supportive Care
Monitoring
Hepatic
Acute hepatic failure
Renal
Acute renal failure
Metabolic
Metabolic acidosis
Hypoglycemia
Hypophosphatemia
Cardiovascular
Hypotension
Cardiotoxicity
Hematologic
Coagulopathy
Thrombocytopenia
Hemolysis
Respiratory
Pulmonary edema
Gastrointestinal
Pancreatitis
 

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. If stabilization is required, then carefully consider co-ingestants or non-toxicological causes. In massive overdoses coma has been associated with acidosis.[11]
 

DECONTAMINATION

Ingestion

Single Dose Activated Charcoal

Gastrointestinal decontamination is not indicated in any pediatric patient following acetaminophen (paracetamol) overdose.
 
Gastrointestinal decontamination with activated charcoal is only indicated:[1][3]
In co-operative adult patients
Within 2 hours of the overdose
If at least 10 g or 200 mg/kg (which ever is lower) is ingested
If the formulation is a solid (i.e. tablets, capsules)
 
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[12]
CHILD
1 to 2 g/kg orally
ADULT
50 to 100 g orally
 

ANTIDOTE(S)

N-acetylcysteine

Indications

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

Dose and Administration

While N-acetylcysteine is usually administered intravenously in 5% dextrose in water. However, 1/2 normal (0.45%) saline may be substituted.[13]

CHILD
 
Children 20 kg or less body weight:[1]
150 mg/kg in 3 mL/kg of 5% dextrose over 15 minutes
Followed by 50 mg/kg in 7 mL/kg of 5% dextrose over 4 hours
Followed by 50 mg/kg in 7 mL/kg of 5% dextrose over 8 hours
Followed by 50 mg/kg in 7 mL/kg of 5% dextrose over 8 hours
 
Children > 20 - < 40 kg body weight:
150 mg/kg in 100 mL of 5% dextrose over 15 minutes
Followed by 50 mg/kg in 250 mL of 5% dextrose over 4 hours
Followed by 50 mg/kg in 250 mL of 5% dextrose over 8 hours
Followed by 50 mg/kg in 250 mL of 5% dextrose over 8 hours
 
Closely monitor fluid and electrolyte balance

ADULT
 
Administer:[9]
150 mg/kg in 200 mL diluent IV over 15 minutes
Followed by 50 mg/kg in 500 mL diluent IV over 4 hours
Followed by 50 mg/kg in 500 mL diluent over 8 hours
And finally 50 mg/kg in 500 mL diluent IV over 8 hours
 

Antidote Endpoint

Acute
At the end of the infusion regimen measure alanine aminotransferase [ALT]. If this is normal, or normalizing, further N-acetylcysteine is not required.
 
However, if not normal or normalizing, then aspartate aminotransferase (AST), International Normalized Ratio (INR) and serum creatinine should also be determined, and the N-acetylcysteine infusion must continue at a rate of:
 
100 mg/kg in 1,000 mL diluent per 16 hours;
 
until hepatic transaminase levels, International Normalized Ratio (INR) and renal function are improving.
 
Chronic
Following chronic ingestions of acetaminophen (paracetamol), N-acetylcysteine can be ceased if plasma acetaminophen (paracetamol) is less than 66 umol/L; and, transaminases (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]), International Normalized Ratio (INR) and creatinine are normal or normalizing.
 

Precautions

Pregnancy
N-acetylcysteine should be administered to pregnant patients following the standard adult regimen. Transplacental transport of N-acetylcysteine is not thought to be clinically significant,[14] however delay in initiation of N-acetylcysteine treatment is associated with increased incidence of spontaneous abortion and fetal death.[15] N-acetylcysteine is not considered teratogenic.[16]

Adverse Effects

Anaphylactoid Reaction
6 to 23% of patients receiving IV N-acetylcysteine develop an anaphylactoid reaction.[17][18] These do not represent a 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 N-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 IV antihistamine (e.g. diphenhydramine); and the initial N-acetylcysteine dose infused over 30 to 60 minutes.[19]
 
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 N-acetylcysteine from any patient when indicated.[19]
 
Hyponatremia
Hyponatremia has been reported in children if administered N-acetylcysteine in 5% dextrose following adult protocols for dilution of infused dose.[20]
 

ENHANCED ELIMINATION

Enhanced Elimination Not Recommended

Hemodialysis, hemoperfusion, or other techniques to increase the rate of removal of this compound are not recommended.
 

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 bloood 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).[21] As hepatic function deteriorates International Normalized Ratio (INR) rises, and a range of complications develop including coagulopathy, hypoglycemia, metabolic acidosis, and hepatic encephalopathy.
 
Poor prognostic indicators are pH less than 7.3, prothrombin time greater than 100 seconds, serum creatinine greater than 300 umol/L (3.4 mg/dL), and an initial arterial lactate of greater than 3.5 mmol/L or a post-resuscitation arterial lactate of greater than 3.0 mmol/L.[22][23] N-acetylcysteine administration should be continued regardless of time after overdose as it appears beneficial even once hepatitis is apparent.[10] Advice should be sought from a liver transplant unit if the International Normalized Ratio (INR) is greater or equal to 2 at 24 hours or 3 at any time after overdose or if the patient becomes encephalopathic.
 
Hepatic monitoring should include:
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
International Normalized Ratio (INR)
Mental state
 

Renal

Acute Renal Failure

Acetaminophen (paracetamol) can be nephrotoxic, even in the absence of hepatotoxicity (though this is uncommon).[24] Onset ranges from 2 to 5 days after overdose, with peak serum creatinine measured at 3 to 16 days.[25][21] The cause is acute tubular necrosis and may be more common in those with risk factors to acetaminophen (paracetamol) toxicity.[26] 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.[21] Advice should be sought from a liver transplant unit if creatinine is greater or equal to 200 umol/L (2.2 mg/dL).

Patients should be monitored for the onset of renal failure:
Urine output
Creatinine
Blood urea nitrogen (urea)
Proteinuria
Hematuria
Loin pain may occur
 
Manage following standard treatment protocols for acute renal failure.
 

Hematologic

Coagulopathy

Coagulopathy occurs as a consequence of acute hepatic failure with acetaminophen (paracetamol) toxicity. Coagulopathy should be managed in conjunction with hepatic failure.
 
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,[27] but rarely of significance in those without hepatotoxicity.[28] 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.[29][30]
 
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 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.[21]
 
Patients suffering acute hepatic failure from acetaminophen (paracetamol) toxicity should be monitored with an ECG for cardiac dysrhythmia.

Metabolic

Metabolic Acidosis

Metabolic acidosis following acetaminophen (paracetamol) overdose is typically a consequence of hepatic failure and should be treated as such. However it has been described (associated with central nervous system depression) in the absence of clinical liver failure.[31][32][33] Patients should be monitored for onset of acidosis if presenting with either very high plasma acetaminophen (paracetamol) levels or depressed level of consciousness.[28] Advice should be sought from a liver transplant unit if pH is less than 7.3, bicarbonate less than or equal to 18 mmol/L (18 mEq/L) or an initial arterial lactate of greater than 3.5 mmol/L or a post-resuscitation arterial lactate of greater than 3.0 mmol/L.
 
Monitor:
Arterial blood gases (pH, bicarbonate, pCO2, pO2)
Plasma lactate
Base excess
 
Follow standard protocols for the management of metabolic acidosis.
 

Hypoglycemia

Hypoglycemia occurs as 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,[34] but would appear more likely due to the later.[35]

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.[36]

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.[28]

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 levels
 
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) N-acetylcysteine infusion provided:
 
- Clinically there is no nausea/vomiting, right upper quadrant tenderness, and no renal angle tenderness;
- 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; and
- Serum creatinine is normal with urine “dipstix” testing showing no blood or protein.
 
In other cases continued N-acetylcysteine infusion (100 mg/kg per 16 hours) is required until improvement. 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.[37][38] Rarely, following massive overdose, there may be an initial metabolic acidosis and coma.[11][32]
 
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.[38][39][40] Jaundice is not evident as an early sign but develops as hepatic failure progresses.[38] 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.[41] 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.[28] 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.[42]
 

Onset/Duration of Symptoms

Four phases of acute acetaminophen (paracetamol) toxicity have been described.[37]
 
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.[37][38]Rarely, following massive overdoses, metabolic acidosis and coma may occur in this phase as a direct toxic effect.[11][32]
 
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.[37][38]
 
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.[37][38]
 
Phase 4 (4 days to 2 weeks after overdose): If phase 3 is survived complete resolution of hepatic and renal function is usual.[37][43]
 

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
 

ACUTE EFFECTS (ORGAN SYSTEM)

Gastrointestinal

Anorexia[38][44]
Nausea[38][44]
Vomiting[38][44]
Abdominal pain[45][46][47]
Hyperamylasemia[45][48][49][50] (uncommon)
Pancreatitis[45][48][49][50] (uncommon)
 

Hepatic

Elevated liver enzymes[44][51][52][53][54][55]
Increased International Normalized Ratio (INR)[53][56][57]
Coagulopathy[39][56]
Hepatic encephalopathy[52][54][59]
Fulminant hepatic failure[46][53][57][60][61][62]
 

Renal

Proteinuria[63]
Hematuria[63]
Acute tubular necrosis[44][53][64][65]
 

Metabolic

Hypoglycemia[44]
Metabolic acidosis[11][32][68][69]
 

Cardiovascular

Hypotension[70]
Myocardiopathy[38]
 

Neurologic

Malaise[71]
Hepatic encephalopathy[52][54][59]
Confusion[71][72]
Altered mood[61]
Stupor[71][72]
Cerebral edema[73]
 

Dermatologic

Diaphoresis[38]
 

Hematologic

Coagulopathy[39][56]
Increased International Normalized Ratio (INR)[53][56][57][41]
 

TOXICITY

HUMAN

Acute

Child

Children appear less susceptible to hepatotoxicity from acetaminophen (paracetamol) than adults. However the exact toxic level is still subject to debate.
 
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]
 

Adult

Acetaminophen (paracetamol) induced hepatotoxicity may occur in adults after large doses.
 
Medical attention is warranted following ingestions of the lesser of 10 g or 200 mg/kg paracetamol.[1]
 

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.[76]
 
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 for 72 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 in patients with predisposing risk factors.[1]
 

ANIMAL

Cats
 
Cats are very susceptible to toxicity as they do not have the ability to metabolize acetaminophen (paracetamol). As little as 50 to 60 mg/kg orally may be toxic.[77]
 
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%.[77] 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.[77]
 
Cat
60 mg/kg acetaminophen (paracetamol)
21.7% methemoglobinemia within 4 hours; clinical effects included depression, hematuria, hemoglobinuria and increases in ALT[78]
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.[78]
 
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.[77]
 
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.[77]
 
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.[79]
 
Dog
200 mg/kg acetaminophen (paracetamol)
18.8% methemoglobinemia[78]
500 mg/kg acetaminophen (paracetamol)
51.9% methemoglobinemia[78]
1 g/kg acetaminophen (paracetamol)
Brown mucous membranes, recumbent, hypovolemic, severe hemolytic anemia, decreased coagulation, RBC glutathione concentration that was 10% of reference values[80]
 
Paracetamol (Acetaminophen):
LD50 Oral, Mouse
338 mg/kg338 mg/kg/[81]
LD50 Oral, Rat
2,400 mg/kg2,400 mg/kg/[81]
LD50 IP, Mouse
367 mg/kg367 mg/kg/[81]
LD50 IP, Rat
1,205 mg/kg1,205 mg/kg/[81]
LD50 SC, Mouse
310 mg/kg310 mg/kg/[81]

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 plasma concentration versus time curve or Acetaminophen (Paracetamol) Nomogram has been constructed to provide an indication of potentially hepatotoxic acetaminophen (paracetamol) plasma concentrations. Note this graph displays the paracetamol concentration in both in 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.[82]
 
Acetaminophen (paracetamol) crosses the placenta and is transformed by fetal hepatocytes into the toxic metabolite. While it is felt the fetus is less susceptible to hepatic damage than adults,[83] an association is indicated between maternal first trimester overdose and abortion within 2 to 3 weeks.[84] Though transplacental transport of N-acetylcysteine is not thought to be clinically significant,[14] delay in initiation of N-acetylcysteine treatment is associated with increased incidence of spontaneous abortion and fetal death.[15]
 
Neither acetaminophen (paracetamol) nor N-acetylcysteine appears teratogenic and termination of pregnancy is not indicated after acetaminophen (paracetamol) overdose.[16]
 
FDA Classification:
B
 
Australian Classification:
A
 
For full details of the FDA and Australian ADC pregnancy classifications, Click here.
 

LACTATION

Acetaminophen (paracetamol)  is excreted into breast milk in low concentration.

The American Academy of Pediatrics considers acetaminophen (paracetamol)  to be compatible with breast-feeding.[82]

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).[85] 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.[86] This means that NAPQI remains in its toxic form in the liver and can bind to cysteine containing macromolecules.[87] This can cause hepatocellular damage, in particular centrilobular necrosis.[37] The exact mechanism of damage in the liver is unknown. NAPQI can also be produced in the kidney leading to renal damage.[88]
 

THERAPEUTIC DRUG INFORMATION

INDICATIONS

Generally, indicated for:
Analgesia
Antipyretic effect
 
This is intended as a guide only. For a more comprehensive list, refer to manufacturer's information.
 

THERAPEUTIC DOSE RANGE

Child

Analgesic / Antipyretic

Oral[89]

These doses may be given every 4 to 6 hours when necessary up to a maximum of 4 doses in 24 hours.

Under 3 months

10 mg/kg (reduce to 5 mg/kg if jaundiced)
3 months to 1 year

60 to 120 mg
1 to 5 years

120 to 250 mg
6 to 12 years

250 to 500 mg

Rectal[89]

Doses may be administered up to 4 times daily.

1 to 5 years

125 to 250 mg
6 to 12 years

250 to 500 mg

Adult

Analgesic / Antipyretic

Oral[89]


Usual dose range is 500 to 1000 mg
4 to 6 hourly as required
Maximum 4000 mg daily

Rectal[89]


Usual dose range is 500 to 1000 mg
4 to 6 hourly as required
Maximum 4000 mg daily

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

PHARMACOLOGICAL ACTION

The pharmacological action of acetaminophen (paracetamol) is not fully understood. It has been hypothesized that the mechanism involved for producing analgesia and antipyresia 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.[90]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.[91]
 

KINETICS

ABSORPTION

Oral Absorption
Rapidly absorbed from the gastrointestinal tract[92]
Other Factors Affecting Absorption
Absorption was slow and incomplete in vegetarians compared with non-vegetarians[93]
Onset of Action
Within 30 minutes[37]
Duration of Action
~4 hours[37]
Time to Peak Plasma Levels
Immediate release 10 to 60 min
Extended release 60 to 120 min[94]
 
In overdose time to peak plasma levels is delayed
 

DISTRIBUTION

Distribution
  1. Rapidly and uniformly distributed to most of the body tissues[94]
Volume of Distribution
  1. 0.8 to 1.0 L/kg[37]
Plasma Protein Binding
  1. Variable,
  2. 5 to 20% at therapeutic doses[37]
  3. 20 to 50% during acute intoxication[95]
Lipid Solubility
Crosses the placenta
Is excreted in breast milk
 

METABOLISM

Metabolism
  1. Predominantly by the liver, 98%[96]
Metabolites
Inactive:
  1. Glucuronide metabolites
  2. Sulfate metabolites
  3. N-acetyl-p-benzoquinoneimine (NAPQI), minor hydroxylated metabolite
Major Metabolic Pathways
Parent:
  1. In adults - Acetaminophen (paracetamol) conjugation to glucuronide (42%) and sulfate (52%) metabolites.[96]
  2. After 12 years of age - Glucuronide conjugation predominates.[96] 
  3. In infants - Sulfate conjugation predominates with a gradual shift towards glucuronide conjugation in older children.[96]  
Saturation of Enzymes
  1. In overdose the glucuronidation and sulfation pathways become saturated[97]
 

ELIMINATION

Excretion
Urine
  1. Mainly as glucuronide and sulfate conjugates
  2. Less than 5% excreted unchanged
Half-life
Therapeutic
  1. 1 to 3 hours[37]
Potential for Accumulation
  1. N-acetyl-p-benzoquinoneimine may accumulate following overdose and cause tissue damage[97][85]
 

IDENTIFICATION

PRODUCT INFORMATION

Generally, tablets range from 250 mg to 500 mg acetaminophen (paracetamol), with junior strength tablets ranging from 80 mg to 160 mg acetaminophen (paracetamol). Sustained release forms are available.
 
Liquid formulations are usually 24 mg/mL (120 mg/5 mL, junior strength) or 50 mg/mL (250 mg/5 mL, full strength) acetaminophen (paracetamol). Some infant's formulations contain 100 mg/mL (500 mg/5 mL) acetaminophen (paracetamol).
 
Each specific trade name will state an exact quantity of the active ingredient and whether a non-standard release formulation (if this information is available).
 

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

DESCRIPTION
 
Large, monoclinic prisms
PHYSICAL PROPERTIES
 
Specific Gravity (water = 1)
1.293 1.293
Molecular Weight
151.16 151.16
Solubility
Cold water: very slightly soluble
Hot water: moderately soluble
 

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