Paracetamol

poisoning

Paracetamol poisoning, also known as

acetaminophen poisoning, is caused by
excessive use of the medication
paracetamol (acetaminophen).[3] Most
people have few or non-specific symptoms
in the first 24 hours following overdose.[1]
This may include feeling tired, abdominal
pain, or nausea.[1] This is typically followed
by a couple of days without any symptoms
after which yellowish skin, blood clotting
problems, and confusion occurs as a
result of liver failure.[1] Additional
complications may include kidney failure,
pancreatitis, low blood sugar, and lactic
acidosis.[1] If death does not occur, people
tend to recover fully over a couple of
weeks.[1] Without treatment some cases
will resolve while others will result in
death.[1]
 Paracetamol poisoning
Synonyms Acetaminophen toxicity,
paracetamol toxicity,
acetaminophen
poisoning, paracetamol
overdose,
acetaminophen
overdose, Tylenol
toxicity

Paracetamol

Specialty Toxicology

Symptoms Early: Non specific,

feeling tired, abdominal
pain, nausea[1]
Later: Yellowish skin,
 blood clotting
problems, confusion[1]

Complications Liver failure, kidney

failure, pancreatitis, low
blood sugar, lactic
acidosis.[1]

Usual onset After 24 hours

(toxicity)[2]

Causes Paracetamol
(acetaminophen)
usually > 7 g[3][2]

Risk factors Alcoholism,

malnutrition, certain
other medications[2]

Diagnostic method Blood levels at specific

times following use[2]

Differential diagnosis Alcoholism, viral

hepatitis,
 hepatitis,
gastroenteritis[2]

Treatment Activated charcoal,

acetylcysteine, liver
transplant[2][1]

Prognosis Death occurs in

~0.1%[2]

Frequency >100,000 per year

(US)[2]

Paracetamol poisoning can occur

accidentally or as an attempt to end one's
life.[1] Risk factors for toxicity include
alcoholism, malnutrition, and the taking of
certain other medications.[2] Liver damage
results not from paracetamol itself, but
from one of its metabolites, N-acetyl-p-
benzoquinone imine (NAPQI).[4] NAPQI
decreases the liver's glutathione and
directly damages cells in the liver.[5]
Diagnosis is based on the blood level of
paracetamol at specific times after the
medication was taken.[2] These values are
often plotted on the Rumack-Matthew
nomogram to determine level of
concern.[2]

Treatment may include activated charcoal

if the person presents soon after the
overdose.[2] Attempting to force the
person to vomit is not recommended.[4] If
there is a potential for toxicity, the antidote
acetylcysteine is recommended.[2] The
medication is generally given for at least
24 hours.[4] Psychiatric care may be
required following recovery.[2] A liver
transplant may be required if damage to
the liver becomes severe.[1] The need for
transplant is often based on low blood pH,
high blood lactate, poor blood clotting, or
significant hepatic encephalopathy.[1] With
early treatment liver failure is rare.[4] Death
occurs in about 0.1% of cases.[2]

Paracetamol poisoning was first described

in the 1960s.[4] Rates of poisoning vary
significantly between regions of the
world.[6] In the United States more than
100,000 cases occur a year.[2] In the
United Kingdom it is the medication
responsible for the greatest number of
overdoses.[5] Young children are most
commonly affected.[2] In the United States
and the United Kingdom paracetamol is
the most common cause of acute liver
failure.[7][2]

Signs and symptoms

The signs and symptoms of paracetamol
toxicity occur in three phases. The first
phase begins within hours of overdose,
and consists of nausea, vomiting, a pale
appearance, and sweating.[8] However,
patients often have no specific symptoms
or only mild symptoms in the first 24 hours
of poisoning. Rarely, after massive
overdoses, patients may develop
symptoms of metabolic acidosis and
coma early in the course of
poisoning.[9][10]

The second phase occurs between 24 h

and 72 h following overdose and consists
of signs of increasing liver damage. In
general, damage occurs in liver cells as
they metabolize the paracetamol. The
individual may experience right upper
quadrant abdominal pain. The increasing
liver damage also changes biochemical
markers of liver function; International
normalized ratio (INR) and the liver
transaminases ALT and AST rise to
abnormal levels.[11] Acute kidney failure
may also occur during this phase, typically
caused by either hepatorenal syndrome or
multiple organ dysfunction syndrome. In
some cases, acute kidney failure may be
the primary clinical manifestation of
toxicity. In these cases, it has been
suggested that the toxic metabolite is
produced more in the kidneys than in the
liver.[12]

The third phase follows at 3 to 5 days, and

is marked by complications of massive
liver necrosis leading to fulminant liver
failure with complications of coagulation
defects, low blood sugar, kidney failure,
hepatic encephalopathy, brain swelling,
sepsis, multiple organ failure, and death.[8]
If the third phase is survived, the liver
necrosis runs its course, and liver and
kidney function typically return to normal
in a few weeks.[13] The severity of
paracetamol toxicity varies depending on
the dose and whether appropriate
treatment is received.

Cause
The toxic dose of paracetamol is highly
variable. In general the recommended
maximum daily dose for healthy adults is
4 grams.[14][15] Higher doses lead to
increasing risk of toxicity. In adults, single
doses above 10 grams or 200 mg/kg of
bodyweight, whichever is lower, have a
reasonable likelihood of causing
toxicity.[16][17] Toxicity can also occur when
multiple smaller doses within 24 hours
exceed these levels.[17] Following a dose
of 1 gram of paracetamol four times a day
for two weeks, patients can expect an
increase in alanine transaminase in their
liver to typically about three times the
normal value.[18] It is unlikely that this dose
would lead to liver failure.[19] Studies have
shown significant hepatotoxicity is
uncommon in patients who have taken
greater than normal doses over 3 to 4
days.[20] In adults, a dose of 6 grams a day
over the preceding 48 hours could
potentially lead to toxicity,[17] while in
children acute doses above 200 mg/kg
could potentially cause toxicity.[21] Acute
paracetamol overdose in children rarely
causes illness or death, and it is very
uncommon for children to have levels that
require treatment, with chronic larger-than-
normal doses being the major cause of
toxicity in children.[17]

Intentional overdosing (self-poisoning,

with suicidal intent) is frequently
implicated in paracetamol toxicity.[22] In a
2006 review, paracetamol was the most
frequently ingested compound in
intentional overdosing.[23]

In rare individuals, paracetamol toxicity

can result from normal use.[24] This may
be due to individual ("idiosyncratic")
differences in the expression and activity
of certain enzymes in one of the metabolic
pathways that handle paracetamol (see
paracetamol's metabolism).

Risk factors
A number of factors can potentially
increase the risk of developing
paracetamol toxicity. Chronic excessive
alcohol consumption can induce CYP2E1,
thus increasing the potential toxicity of
paracetamol. In one study of patients with
liver injury, 64% reported alcohol intakes of
greater than 80 grams a day, while 35%
took 60 grams a day or less.[25] Whether
chronic alcoholism should be considered a
risk factor has been debated by some
clinical toxicologists.[26][27] For chronic
alcohol users, acute alcohol ingestion at
the time of a paracetamol overdose may
have a protective effect.[26][28] For non-
chronic alcohol users, acute alcohol
consumption had no protective effect.

Fasting is a risk factor, possibly because

of depletion of liver glutathione
reserves.[17] The concomitant use of the
CYP2E1 inhibitor isoniazid increases the
risk of hepatotoxicity, though whether 2E1
induction is related to the hepatotoxicity in
this case is unclear.[29][30] Concomitant
use of other drugs that induce CYP
enzymes, such as antiepileptics including
carbamazepine, phenytoin, and
barbiturates, have also been reported as
risk factors.[31]
Pathophysiology

Main pathways of paracetamol metabolism (click to

enlarge). The pathway leading to NAPQI is shown in
red.

When taken in normal therapeutic doses,

paracetamol has been shown to be
safe.[11] Following a therapeutic dose, it is
mostly converted to nontoxic metabolites
via Phase II metabolism by conjugation
with sulfate and glucuronide, with a small
portion being oxidized via the cytochrome
P450 enzyme system.[32] Cytochromes
P450 2E1 and 3A4 convert approximately
5% of paracetamol to a highly reactive
intermediary metabolite, N-acetyl-p-
benzoquinone imine
(NAPQI).[32][11][33][34][35] Under normal
conditions, NAPQI is detoxified by
conjugation with glutathione to form
cysteine and mercapturic acid
conjugates.[32][36]

In cases of paracetamol overdose, the

sulfate and glucuronide pathways become
saturated, and more paracetamol is
shunted to the cytochrome P450 system
to produce NAPQI. As a result,
hepatocellular supplies of glutathione
become depleted, as the demand for
glutathione is higher than its
regeneration.[36] NAPQI therefore remains
in its toxic form in the liver and reacts with
cellular membrane molecules, resulting in
widespread hepatocyte damage and
death, leading to acute liver necrosis.[32][37]
In animal studies, the liver's stores of
glutathione must be depleted to less than
70% of normal levels before liver toxicity
occurs.[33]

Diagnosis
Rumack Matthew Nomogram with treatment line
added at 150

A person's history of taking paracetamol is

somewhat accurate for the diagnosis.[38]
The most effective way to diagnose
poisoning is by obtaining a blood
paracetamol level. A drug nomogram
developed in 1975, called the Rumack-
Matthew nomogram, estimates the risk of
toxicity based on the serum concentration
of paracetamol at a given number of hours
after ingestion.[8] To determine the risk of
potential hepatotoxicity, the paracetamol
level is traced along the nomogram. Use of
a timed serum paracetamol level plotted
on the nomogram appears to be the best
marker indicating the potential for liver
injury.[17] A paracetamol level drawn in the
first four hours after ingestion may
underestimate the amount in the system
because paracetamol may still be in the
process of being absorbed from the
gastrointestinal tract. Therefore, a serum
level taken before 4 hours is not
recommended.[16]

Clinical or biochemical evidence of liver

toxicity may develop in one to four days,
although, in severe cases, it may be
evident in 12 hours.[39] Right-upper-
quadrant tenderness may be present and
can aid in diagnosis. Laboratory studies
may show evidence of liver necrosis with
elevated AST, ALT, bilirubin, and prolonged
coagulation times, particularly an elevated
prothrombin time.[40] After paracetamol
overdose, when AST and ALT exceed
1000 IU/L, paracetamol-induced
hepatotoxicity can be diagnosed.[39] In
some cases, the AST and ALT levels can
exceed 10,000 IU/L.[41]

Detection in body fluids

Paracetamol may be quantified in blood,

plasma, or urine as a diagnostic tool in
clinical poisoning situations or to aid in the
medicolegal investigation of suspicious
deaths. The concentration in serum after a
typical dose of paracetamol usually peaks
below 30 mg/l, which equals 200
µmol/L.[42] Levels of 30–300 mg/L (200–
2000 µmol/L) are often observed in
overdose patients. Postmortem blood
levels have ranged from 50–400 mg/L in
persons dying due to acute overdosage.
Automated colorimetric techniques, gas
chromatography and liquid
chromatography are currently in use for
the laboratory analysis of the drug in
physiological specimens.[43][44]

Prevention
Limitation of availability

Limiting the availability of paracetamol

tablets has been attempted in some
countries. In the UK, sales of over-the-
counter paracetamol are restricted to
packs of 32 x 500 mg tablets in
pharmacies, and 16 x 500 mg tablets in
non-pharmacy outlets. Pharmacists may
provide up to 100 tablets for those with
chronic conditions at the pharmacist's
discretion.[45][46] In Ireland, the limits are
24 and 12 tablets, respectively.[47]
Subsequent study suggests that the
reduced availability in large numbers had a
significant effect in reducing poisoning
deaths from paracetamol overdose.[48]

One suggested method of prevention is to

make paracetamol a prescription-only
medicine, or to remove it entirely from the
market. However, overdose is a relatively
minor problem; for example, 0.08% of the
UK population (over 50 thousand people)
present with paracetamol overdose each
year. In contrast, paracetamol is a safe
and effective medication that is taken
without complications by millions of
people.[49] In addition, alternative pain
relief medications such as aspirin are
more toxic in overdose, whereas non-
steroidal anti-inflammatory drugs are
associated with more adverse effects
following normal use.[50]

Combination with other agents

One strategy for reducing harm done by

acetaminophen overdoses is selling
paracetamol pre-combined in tablets
either with an emetic[49] or an antidote.
Paradote was a tablet sold in the UK which
combined 500 mg paracetamol with
100 mg methionine,[51] an amino acid
formerly[17] used in the treatment of
paracetamol overdose.

There have been no studies so far on the

effectiveness of paracetamol when given
in combination with its most commonly
used antidote, acetylcysteine.[52]

Calcitriol, the active metabolite of vitamin

D3, appears to be a catalyst for glutathione
production.[53] Calcitriol was found to
increase glutathione levels in rat astrocyte
primary cultures on average by 42%,
increasing glutathione protein
concentrations from 29 nmol/mg to 41
nmol/mg, 24 and 48 hours after
administration; it continued to have an
influence on glutathione levels 96 hours
after administration.[54] It has been
proposed that co-administration of
calcitriol, via injection, may improve
treatment outcomes.

Paracetamol replacements

Paracetamol ester prodrug with L-

pyroglutamic acid (PCA), a biosynthetic
precursor of glutathione, has been
synthesized to reduce paracetamol
hepatotoxicity and improve bioavailability.
The toxicological studies of different
paracetamol esters show that L-5-oxo-
pyrrolidine-2-paracetamol carboxylate
reduces toxicity after administration of an
overdose of paracetamol to mice. The liver
glutathione values in mice induced by
intraperitoneal injection of the ester are
superimposable with the GSH levels
recorded in untreated mice control group.
The mice group treated with an equivalent
dose of paracetamol showed a
significative decrease of glutathione of
35% (p<0.01 vs untreated control group).
The oral LD50 was found to be greater
than 2000 mg kg-1, whereas the
intraperitoneal LD50 was 1900 mg kg-1.
These results taken together with the good
hydrolysis and bioavailability data show
that this ester is a potential candidate as a
prodrug of paracetamol.[55]

Treatment
Gastric decontamination

In adults, the initial treatment for

paracetamol overdose is gastrointestinal
decontamination. Paracetamol absorption
from the gastrointestinal tract is complete
within two hours under normal
circumstances, so decontamination is
most helpful if performed within this
timeframe. Gastric lavage, better known as
stomach pumping, may be considered if
the amount ingested is potentially life-
threatening and the procedure can be
performed within 60 minutes of
ingestion.[56] Activated charcoal is the
most common gastrointestinal
decontamination procedure as it adsorbs
paracetamol, reducing its gastrointestinal
absorption.[57][58] Administering activated
charcoal also poses less risk of aspiration
than gastric lavage.[59]
It appears that the most benefit from
activated charcoal is gained if it is given
within 30 minutes to two hours of
ingestion.[60][61] Administering activated
charcoal later than 2 hours can be
considered in patients that may have
delayed gastric emptying due to co-
ingested drugs or following ingestion of
sustained- or delayed-release paracetamol
preparations. Activated charcoal should
also be administered if co-ingested drugs
warrant decontamination.[39] There was
reluctance to give activated charcoal in
paracetamol overdose, because of the
concern that it may also absorb the oral
antidote acetylcysteine.[62] Studies have
shown that 39% less acetylcysteine is
absorbed into the body when they are
administered together.[63] There are
conflicting recommendations regarding
whether to change the dosing of oral
acetylcysteine after the administration of
activated charcoal, and even whether the
dosing of acetylcysteine needs to be
altered at all.[63][64] Intravenous
acetylcystine has no interaction with
activated charcoal.

Inducing vomiting with syrup of ipecac has

no role in paracetamol overdose because
the vomiting it induces delays the effective
administration of activated charcoal and
oral acetylcysteine.[16] Liver injury is
extremely rare after acute accidental
ingestion in children under 6 years of age.
Children with accidental exposures do not
require gastrointestinal decontamination
with either gastric lavage, activated
charcoal, or syrup of ipecac.[17]

Acetylcysteine

Acetylcysteine is the antidote for paracetamol toxicity

Acetylcysteine, also called N-
acetylcysteine or NAC, works to reduce
paracetamol toxicity by replenishing body
stores of the antioxidant glutathione.
Glutathione reacts with the toxic NAPQI
metabolite so that it does not damage
cells and can be safely excreted.[65] NAC
was usually given following a treatment
nomogram (one for patients with risk
factors, and one for those without) but the
use of the nomogram is no longer
recommended as the evidence base to
support the use of risk factors was poor
and inconsistent and many of the risk
factors are imprecise and difficult to
determine with sufficient certainty in
clinical practice.[66] Cysteamine and
methionine have also been used to prevent
hepatotoxicity,[67] although studies show
that both are associated with more
adverse effects than acetylcysteine.[17]
Additionally, acetylcysteine has been
shown to be a more effective antidote,
particularly in patients presenting greater
than 8 hours post-ingestion[68] and for
those who present with liver failure
symptoms.[58]

If the person presents less than eight

hours after paracetamol overdose, then
acetylcysteine significantly reduces the
risk of serious hepatotoxicity and
guarantees survival.[17] If acetylcysteine is
started more than 8 hours after ingestion,
there is a sharp decline in its effectiveness
because the cascade of toxic events in the
liver has already begun, and the risk of
acute liver necrosis and death increases
dramatically. Although acetylcysteine is
most effective if given early, it still has
beneficial effects if given as late as
48 hours after ingestion.[69] If the person
presents more than eight hours after the
paracetamol overdose, then activated
charcoal is not useful, and acetylcysteine
is started immediately. In earlier
presentations, charcoal can be given when
the patient arrives and acetylcysteine is
initiated while waiting for the paracetamol
level results to return from the
laboratory.[17]

In United States practice, intravenous (IV)

and oral administration are considered to
be equally effective and safe if given
within 8 hours of ingestion.[70][71] However,
IV is the only recommended route in
Australasian and British practice.[17][72]
Oral acetylcysteine is given as a
140 mg/kg loading dose followed by
70 mg/kg every four hours for 17 more
doses, and if the patient vomits within 1
hour of dose, the dose must be
repeated.[73][74] Oral acetylcysteine may be
poorly tolerated due to its unpleasant
taste, odor, and its tendency to cause
nausea and vomiting.[70] If repeated doses
of charcoal are indicated because of
another ingested drug, then subsequent
doses of charcoal and acetylcysteine
should be staggered.[39]

Intravenous acetylcysteine is given as a

continuous infusion over 20 hours for a
total dose 300 mg/kg. Recommended
administration involves infusion of a
150 mg/kg loading dose over 15 to
60 minutes, followed by a 50 mg/kg
infusion over four hours; the last
100 mg/kg are infused over the remaining
16 hours of the protocol.[17] Intravenous
acetylcysteine has the advantage of
shortening hospital stay, increasing both
doctor and patient convenience, and
allowing administration of activated
charcoal to reduce absorption of both the
paracetamol and any co-ingested drugs
without concerns about interference with
oral acetylcysteine.[75] Intravenous dosing
varies with weight, specifically in children.
For patients less than 20 kg, the loading
dose is 150 mg/kg in 3 mL/kg diluent,
administered over 60 minutes; the second
dose is 50 mg/kg in 7 mL/kg diluent over
4 hours; and the third and final dose is
100 mg/kg in 14 mL/kg diluent over 16
hours.[74]

The most common adverse effect to

acetylcysteine treatment is an
anaphylactoid reaction, usually manifested
by rash, wheeze, or mild hypotension.
Adverse reactions are more common in
people treated with IV acetylcysteine,
occurring in up to 20% of patients.[76][77]
Anaphylactoid reactions are more likely to
occur with the first infusion (the loading
dose).[76] Rarely, severe life-threatening
reactions may occur in predisposed
individuals, such as patients with asthma
or atopic dermatitis, and may be
characterized by respiratory distress,
facial swelling, and even death.[76][78][79]

If an anaphylactoid reaction occurs the

acetylcysteine is temporarily halted or
slowed and antihistamines and other
supportive care is administered.[76][80][81]
For example, a nebulised beta-agonist like
salbutamol may be indicated in the event
of significant bronchospasm (or
prophylactically in patients with a history
of bronchospasm secondary to
acetylcysteine). It is also important to
closely monitor fluids and electrolytes.[76]

Liver transplant
In people who develop acute liver failure or
who are otherwise expected to die from
liver failure, the mainstay of management
is liver transplantation.[49] Liver transplants
are performed in specialist centers. The
most commonly used criteria for liver
transplant were developed by physicians
at King's College Hospital in London.
Patients are recommended for transplant
if they have an arterial blood pH less than
7.3 after fluid resuscitation or if a patient
has Grade III or IV encephalopathy, a
prothrombin time greater than 100
seconds, and a serum creatinine greater
than 300 mmol/L In a 24-hour period.[82]
Other forms of liver support have been
used including partial liver transplants.
These techniques have the advantage of
supporting the patient while their own liver
regenerates. Once liver function returns
immunosuppressive drugs are
commenced and they have to take
immunosuppressive medication for the
rest of their lives.[83][84]

Prognosis
The mortality rate from paracetamol
overdose increases two days after the
ingestion, reaches a maximum on day four,
and then gradually decreases. Acidosis is
the most important single indicator of
probable mortality and the need for
transplantation. A mortality rate of 95%
without transplant was reported in
patients who had a documented pH less
than 7.30. Other indicators of poor
prognosis include renal insufficiency
(stage 3 or worse), hepatic
encephalopathy, a markedly elevated
prothrombin time, or an elevated blood
lactic acid level (lactic acidosis).[82][85] One
study has shown that a factor V level less
than 10% of normal indicated a poor
prognosis (91% mortality), whereas a ratio
of factor VIII to factor V of less than 30
indicated a good prognosis (100%
survival).[86] Patients with a poor
prognosis are usually identified for likely
liver transplantation.[82] Patients that do
not die are expected to fully recover and
have a normal life expectancy and quality
of life.[87]

Epidemiology
Many over-the-counter and prescription-
only medications contain paracetamol.
Because of its wide availability paired with
comparably high toxicity, (compared to
ibuprofen and aspirin) there is a much
higher potential for overdose.[88]
Paracetamol toxicity is one of the most
common causes of poisoning
worldwide.[22] In the United States, the
United Kingdom, Australia, and New
Zealand, paracetamol is the most
common cause of drug
overdoses.[17][89][90] Additionally, in both
the United States and the United Kingdom
it is the most common cause of acute liver
failure.[91][7]

In England and Wales an estimated 41,200

cases of paracetamol poisoning occurred
in 1989 to 1990, with a mortality of 0.40%.
It is estimated that 150 to 200 deaths and
15 to 20 liver transplants occur as a result
of poisoning each year in England and
Wales.[77] Paracetamol overdose results in
more calls to poison control centers in the
US than overdose of any other
pharmacological substance, accounting
for more than 100,000 calls, as well as
56,000 emergency room visits, 2,600
hospitalizations, and 458 deaths due to
acute liver failure per year.[92] A study of
cases of acute liver failure between
November 2000 and October 2004 by the
Centers for Disease Control and
Prevention in the USA found that
paracetamol was the cause of 41% of all
cases in adults, and 25% of cases in
children.[93]

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