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CLINICAL

TOXICOLO
GY
I.

BACKGROUND

Paracetamol is also known as


acetaminophen. It is widely used
PARACETAMOL
as an analgesic and antipyretic. It is
generally considered as a safe
drug though it still can cause death through overdose, idiopathic reaction, or synergism with alcoholic
liver disease.
Paracetamol is available as:

tablets

caplets

capsules

soluble tablets (these dissolve in water, which you then drink)

an oral suspension (liquid medicine)

suppositories, which are inserted into your anus (the opening through which waste leaves your
body)

Absorption
It is well absorbed in the gastrointestinal tract, stomach and small intestine. Oral bioavailability is
dose dependent: with larger doses bioavailability is increased due to the reduced first pass effect.
Rectal administration of paracetamol has 30-70% bioavailability. In this case, bioavailability is
overall reduced, due to incomplete dissolution of the suppository in the rectum.
Distribution
Paracetamol is distributed throughout the body. The analgesic activity can be attributed to the small
fraction that penetrates into the brain. Paracetamol given at therapeutic doses binds to plasma
proteins at less than 20%. In case of intoxication, this proportion may increase to up to 50%.
Metabolism

Paracetamol is essentially metabolized in the liver by conjugation to non-toxic water-soluble


compounds. Hepatotoxic metabolites are produced in small amounts by the cytochrome P450
(isoenzyme CYP2E1). In the therapeutic plasma concentration range, this metabolite is
detoxified by conjugation with glutathione.
In case of intoxication the amount of this toxic metabolite increases and outweighs the amount
of available glutathione, which can lead to hepatic failure and renal tubular necrosis.
When the maximum daily dose is exceeded over a prolonged period of time, the hepatotoxic
reactive metabolite N -acetyl-p -benzoquinoneimine (NAPQI) is produced.
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Excretion

Metabolites are excreted through the kidneys in the urine. Only 2-5% of the dose is excreted in
an unchanged form in the urine. As a consequence of its short elimination half-life (1-3h), 24
hours after the ingestion of a single dose of paracetamol, 98% of the dose is eliminated.

Clinical implications

II.

Since paracetamol is mostly eliminated by hepatic metabolism, patients with severe hepatic
failure have a considerably longer elimination half-life, and therefore, paracetamol must be
used cautiously in such patients.

Epidemiology
Paracetamol toxicity is the most common cause of hepatic failure requiring liver
transplantation in Great Britain. In the United States, paracetamol toxicity has replaced viral
hepatitis as the most common cause of acute hepatic failure and is the second most common
cause of liver failure requiring transplantation. Although acetaminophen toxicity is particularly
common in children, adults have accounted for most of the serious and fatal cases.

CHEMISTRY
Chemical structure

pKa = 9.46
solubility = 4.15
partition coefficient = log P 0.31
III.

MECHANISM OF TOXICITY
Organ System
Acetaminophen overdose is associated liver failure, which is caused by massive
hepatic necrosis, the distinct feature of acetaminophen toxicity. In addition to liver, however,
many organ systems may fail under acute overdose such as renal, cardiac, and central
nervous systems. It is thought that the liver is the target organ for acetaminophen toxicity
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because this is primarily where the drug is detoxified. Under normal conditions, acetaminophen
is mainly metabolized by undergoing sulfation and glucuronidation. It has been proposed that a
small amount of drug goes through the cytochrome P450 mixed function oxidase system and is
metabolized into the reactive intermediateN-acetyl-P-benzoquinoneimine (NAPQI), which is in
turn detoxified by reaction with glutathione. When large quantities of acetaminophen are
consumed, the three detoxification pathways become saturated.

Cellular
The precise mechanism by which acetaminophen causes cell death remains unknown,
although there are two theories possible. The first theory, the oxidative stress theory, maintains
that acetaminophen metabolites cause oxidative stress in the cell ultimately leading to its
demise. The depletion of cellular glutathione, a natural antioxidant, leaves the cell particularly
vulnerable to oxidative insults following acetaminophen overdose. The second theory, the
covalent binding theory, states that the binding of the highly reactive acetaminophen
metabolites to cell macromolecules causes cell death
IV.

TOXICOKINETICS
ABSORPTION:
Paracetamol is normally rapidly absorbed and peak concentrations occur within 1-2
hours for standard tablet or capsules and even quicker (< 0.5 h) in liquid preparations. There
are two sustained release preparations and absorption from these continues for up to 12 hours
in therapeutic doses and much longer in overdose. Prolonged absorption is seen following
large ingestions( > 500 mg/kg) and with coingestion of drugs that slow gastrointestinal motility (
opiates & anticholinergic)
DISTRIBUTION:
After absorption, paracetamol distributes rapidly with a volume of distribution of 0.9
L/kg.
Absorption and distribution are completed by 4 hours post overdose with standard release
preparations and within 2 hours in liquid preparations.
PROTEIN BINDING: 25%

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Paracetamol is metabolised by a number of pathways. The majority of metabolism is by


glucuronidation and sulphation. There is some first pass metabolism (about 20%) due to
sulfation in the gut wall. The half-life of paracetamol in therapeutic use is 1.5 to 3 hours. The
half-life may become prolonged in overdose to greater than 4 hours. A prolonged half-life has
been linked to a higher risk of toxicity, which may indicate this is due to saturation of
conjugation pathways and an increasing proportion of paracetamol being metabolised by P450
enzymes.
The minor pathways involving P450 enzymes account only for about 5-10% of
paracetamol metabolism in therapeutic use. These lead to production of a toxic metabolite, Nacetyl-p-benzoquinonimine (NAPQI). This conjugates with glutathione and is excreted as a
non-toxic conjugate in the urine. As glutathione is depleted, this reactive metabolite binds
covalently to hepatic macromolecules leading to cell dysfunction death and apoptosis.
EXCRETION
Approximately 80% of acetaminophen is excreted in the urine after conjugation and
about 3% is excreted unchanged.
V.

CLINICAL TOXICOLOGY

Evidence of end-organ toxicity often does not manifest until 24-48 hours after an acute
ingestion. To identify whether a patient is at risk, the clinician should determine the time(s) of
ingestion, the quantity, and the formulation of acetaminophen ingested.
Minimum toxic doses of acetaminophen for a single ingestion, posing significant risk of severe
hepatotoxicity, are as follows:
Adults: 7.5-10 g
Children: 150 mg/kg; 200 mg/kg in healthy children aged 1-6 years
The clinical course of acetaminophen toxicity generally is divided into four phases. Physical findings
vary, depending primarily on the level of hepatotoxicity.
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Phase 1
o
o
o

0.5-24 hours after ingestion


Patients may be asymptomatic or report anorexia, nausea or vomiting, and malaise
Physical examination may reveal pallor, diaphoresis, malaise, and fatigue
Phase 2

o
o
o
o
o

18-72 h after ingestion


Patients generally develop right upper quadrant abdominal pain, anorexia, nausea, and
vomiting
Right upper quadrant tenderness may be present
Tachycardia and hypotension indicate ongoing volume losses
Some patients may report decreased urinary output (oliguria)
Phase 3: Hepatic phase

o
o
o
o
o

72-96 h after ingestion


Patients may have continued nausea and vomiting, abdominal pain, and a tender hepatic edge
Hepatic necrosis and dysfunction are associated with jaundice, coagulopathy, hypoglycemia,
and hepatic encephalopathy
Acute renal failure develops in some critically ill patients
Death from multi organ failure may occur
Phase 4: Recovery phase

o
o

4 days to 3 weeks after ingestion


Patients who survive critical illness in phase 3 have complete resolution of symptoms and
complete resolution of organ failure
First Aid and Management

Gastrointestinal decontamination agents can be used in the emergency department setting in the
immediate post-ingestion time frame. Administer activated charcoal (AC) if the patient is alert and
presents, ideally, within 1 hour post ingestion. This time frame can be extended if the patient ingested
an acetaminophen-based sustained-release medication or if the ingestion includes agents that are
known to slow gastric emptying. Patients with acetaminophen levels below the possible" line for
hepatotoxicity on the Rumack-Matthew nomogram may be discharged home after they are medically
cleared.
Admit patients with acetaminophen plasma levels above the possible line on the Rumack-Matthew
nomogram for treatment with N -acetylcysteine (NAC). NAC is nearly 100% hepatoprotective when it
is given within 8 hours after acute acetaminophen ingestion, but can be beneficial in patients who
present more than 24 hours after ingestion. NAC is approved for both oral and IV administration.
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The FDA-approved regimen for oral administration of NAC is as follows:
o
o
o
o

Loading dose of 140 mg/kg


17 doses of 70 mg/kg given every 4 hours
Total treatment duration of 72 hours
The IV formulation of NAC (Acetadote) is commonly used in many institutions for the treatment
of acetaminophen ingestion. Use of the IV formulation of NAC is preferred in the following
situations:

o
o
o
o
o

Altered mental status


GI bleeding and/or obstruction
A history of caustic ingestion
Potential fetal acetaminophen toxicity in a pregnant woman
Inability to tolerate oral NAC because of emesis refractory to proper use of antiemetics.

Surgical evaluation for possible liver transplantation is indicated for patients who have severe
hepatotoxicity and potential to progress to hepatic failure. Criteria for liver transplantation include the
following:
o
o
o
o

Metabolic acidosis
Renal failure
Coagulopathy
Encephalopathy

Signs & Symptoms:


Patients may complain of anorexia, nausea, vomiting, and hepatic tenderness.
They may develop any of the following complications:
Hypoglycaemia
hepatic encephalopathy
jaundice
coagulopathy
FIRST AID of Poisoning
For small amounts, you may be told to watch the person carefully at home.
For a larger amount, you may need to take the person to a hospital emergency department.

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In high doses, acetaminophen can cause damage to the liver. At the hospital, doctors will check the
level of acetaminophen in the blood and may give activated charcoal or antidote medication to prevent
the toxic effect on the body.
MECHANICAL ANTIDOTAL MEASURES

Emptying of the stomach: In the very few cases in which a person comes to the hospital
minutes after taking the overdose, the doctor may attempt to empty the stomach. This can be
accomplished by inducing vomiting or by placing a large tube through the person's mouth and

into the stomach, putting fluid in and then pumping it out (gastric lavage).
Activated charcoal: Activated charcoal can be given by mouth to bind any drug remaining in
the gastrointestinal tract.

ALGORITHM OF TREATMENT

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Initial appropriate supportive care is essential in acetaminophen poisoning. Immediate
assessment of the patient's airway, breathing, and fluid status (ie, ABCs) is critical before treatment for

suspected acetaminophen overdose is initiated. In addition, assessing for other potential lifethreatening co-ingestions (eg, salicylate) is very important.
Administer activated charcoal (AC) if the patient has a stable mental and clinical status and presents
to the emergency department within 1 hour of ingestion. Draw a 4-hour serum acetaminophen
concentration to determine the risk for hepatotoxicity, plot this value using the Rumack-Matthew
nomogram.
Patients with acetaminophen levels below the possible line for hepatotoxicity on the RumackMatthew nomogram may be discharged home after they are medically cleared. If the ingestion
occurred with intent to do self-harm, a thorough psychosocial, psychological and/or psychiatric
evaluation is indicated before the patient can be discharged safely from the medical care facility.
Admit patients with acetaminophen plasma levels above the possible line on the Rumack-Matthew
nomogram for treatment with N -acetylcysteine (NAC). Treat patients with evidence of hepatic failure,
metabolic acidosis, coagulopathy, and/or encephalopathy in an intensive care unit (ICU). Transfer
patients with evidence of clinically significant hepatotoxicity to a medical facility with
intensive care support and organ transplant services.
More important than GI decontamination after APAP ingestion is the early administration of NAC. NAC
is nearly 100% hepatoprotective when it is given within 8 hours after an acute acetaminophen
ingestion. Guidelines from the American College of Emergency Physicians recommend the use of
NAC to treat acute acetaminophen overdose in patients with either possible or probable risk for
hepatotoxicity, according to the Rumack-Matthew nomogram, ideally within 8-10 hours post ingestion.
Because of the benign nature of NAC, and the risk of adverse effects from acetaminophen toxicity,
NAC should be given even if the history is unclear but a potentially toxic acetaminophen ingestion is
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suspected. NAC should be administered while awaiting a serum APAP level if the patient presents
close to or later than 8 hours after an acute ingestion, or if the patient is pregnant.
A late presentation should not preclude NAC administration if the history or presentation suggests
potential toxicity. Failure to administer NAC because of late presentation is considered medically and
legally inappropriate.
Surgical evaluation for possible liver transplantation is indicated for patients who have severe
hepatotoxicity and potential to progress to hepatic failure. Criteria for liver transplantation include the
following:

Metabolic acidosis

Renal failure

Coagulopathy

Encephalopathy
Diagnosis

AST, ALT, and serum acetaminophen levels

The Rumack-Matthew nomogram cannot be used, but likelihood of clinically significant hepatotoxicity
can be estimated based on AST, ALT, and serum acetaminophen levels.

If AST and ALT levels are normal (< 50 IU/L) and the acetaminophen level is < 10 g/mL,
significant hepatotoxicity is very unlikely.

If AST and ALT levels are normal but the acetaminophen level is 10 g/mL, significant
hepatotoxicity is possible; AST and ALT levels are remeasured after 24 h. If repeat AST and ALT
levels are normal, significant hepatotoxicity is unlikely; if the levels are high, significant
hepatotoxicity is assumed.

If initial AST and ALT levels are high, regardless of the acetaminophen level, significant
hepatotoxicity is assumed.
SPECIFIC ANTIDOTAL THERAPY

Oral or IV N-acetylcysteine
Possibly activated charcoal

Activated charcoal may be given if acetaminophen is likely to still remain in the GI tract.
N-Acetylcysteine
is an antidote for acetaminophen poisoning. This drug is a glutathione precursor that decreases
acetaminophen toxicity by increasing hepatic glutathione stores and possibly via other mechanisms. It
helps prevent hepatic toxicity by inactivating the toxic acetaminophen metabolite NAPQI before it can
injure liver cells. However, it does not reverse damage to liver cells that has already occurred.
For acute poisoning, N-acetylcysteine is given if hepatotoxicity is likely based on acetaminophen dose
or serum level. The drug is most effective if given within 8 h of acetaminophen ingestion. After 24 h,
the benefit of the antidote is questionable, but it should still be given.
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liver transplantation.
VI.

BIBLIOGRAPHY

http://dmd.aspetjournals.org/content/31/12/1499.full
http://www.jbc.org/content/274/15/10349.full
http://www.remergs.com/WEBPAGE%20Notes/Toxicology/Acetaminophen.pdf
http://www.ambonsall.com/pdf/Paracetamol.pdf
http://curriculum.toxicology.wikispaces.net/2.1.1.1+Acetaminophen
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1285692/
http://www.drugbank.ca/drugs/db00316

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