Diagnostic Guide and

treatment of poisoning
for paracetamol
Toxicological Information Center of Veracruz
20 de Noviembre Avenue No. 1074. Veracruz, Ver., Zip Code 91700
(229) 932 97 53
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Table of contents
Paracetamol 1
1. Mechanism of action and toxicity.....................................................................................1
2. Toxic dose........................................................................................................................1
3. Clinical manifestations
3.1 StadiumI
3.2 Stadium II
3.3 Stadium III
3.4 Stadium IV
4. Diagnosis ........................................................................................................................3
5. Treatment.......................................................................................................................4
5.1 Antidote
Paracetamol
Paracetamol or acetaminophen (n-acetyl-para-aminophenol) is a derivative of
for aminophenol just like phenacetin, maintaining, like it, an effect
antipyretic and analgesic, but with hardly any anti-inflammatory effect, unlike others
non-steroidal anti-inflammatory drugs (NSAIDs).
1. Mechanism of action and toxicity
Digestive absorption (oral and rectal) is rapid achieving levels
therapeutic (10-20 µg/Kg) and clinical effect between 30 min. and 2 hours after a
dose (10-15 mg/Kg every 4 hours).
The volume of distribution is 0.9-1 L/Kg, and the binding to transport proteins
it is practically insignificant.
Normally, 90-93% of paracetamol is conjugated in the liver to
glucuronides or sulfates, which are excreted in urine, and about 2% of paracetamol
is excreted in the urine unchanged.
Approximately 3-8% of paracetamol is metabolized in the liver by
cytochrome P450 enzyme complex, through oxidation processes, this metabolic pathway
creates a reactive toxic metabolite, N-acetyl-p-benzoquinone imine (NAPQI), which
is quickly bound to glutathione and detoxified.
When glutathione levels fall below 30% of normal or there is a
excess NAPQI that exceeds the detoxification system, free NAPQI adheres to
the cell membranes of hepatocytes causing cell death and the
consequence of hepatic necrosis.
It can also cause acute kidney failure due to the production of this.
toxic metabolite in the kidney.
2. Toxic dose
• The therapeutic dose: 10-15 mg/Kg every 4-6 hours.
• The maximum dose: 90 mg/kg/day in Pediatrics and 4 grams/day in adults.
• The required dose to produce toxicity varies depending on the activity.
of cytochrome P-450 (variable between individuals), amount of glutathione, and its
regenerative capacity.
• However, several retrospective studies suggest that there may be
toxicity with doses greater than 150-200 mg/kg in children or 6-7 g in adults is
potentially acutely toxic.
• The lethal dose is 13-25 g.
• Chronic toxicity occurs if more than 4 grams of paracetamol are ingested.
day, then after 2-8 days.
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• Hepatic toxicity may occur, although now in a very minimal way.
frequent during chronic ingestion of therapeutic doses of paracetamol,
especially in alcoholic patients, but this statement is highly debated
and it is unknown what amount and how frequently in the dosage could lead to
this type of toxicity.
3. Clinical manifestations
Paracetamol poisoning produces a clinical picture primarily dominated by
due to the development of liver failure due to necrosis. This condition can be
divided into four well-defined clinical stages according to the time interval that
it runs from the moment of ingestion:
3.1 Stadium I
It is generally a latent period. It is considered to be between 0 and 24 hours after the
ingestion. Patients often remain completely asymptomatic but
It is also common to experience nausea, vomiting, and general discomfort, which can
accompanied by paleness and sweating.
There is no correlation whatsoever between the appearance of symptoms.
minor injuries initially and the subsequent development of a greater or lesser injury
hepatic, but rather it seems like an idiosyncratic process.
3.2 Stage II
Between 24 and 48 hours post-ingestion. They signify the beginning of the
Hepatotoxicity, typical of hepatitis, includes pain in the right hypochondrium.
nausea, fatigue, and general discomfort.
In the physical examination, hepatomegaly is often palpated. The elevation of the
transaminases begin between 24 and 36 hours, but in some cases it may occur as
the 16 hours or earlier. In laboratory studies, the bilirubin and the time of
prothrombin levels are normal or slightly elevated.
Stage III
It is the phase of greatest liver injury. It encompasses the time elapsed between the
48 and 96 hours after ingestion. The markers of liver failure become more evident.
However, when the treatment has been successful, the peak of transaminases may
happen before.
The death occurs three to seven days after ingestion and is caused by
untreatable metabolic alterations, secondary complications such as cerebral edema
arrhythmias, or bleeding due to coagulopathy, which may be compounded by renal failure
sharp.
Anuric or oliguric renal failure is usually due to acute tubular necrosis and with
frequency is accompanied by pain in the flanks. Even if renal failure is severe, this
it is also almost always reversible.
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The vast majority of patients will make a full recovery.
3.4 Stadium IV
Understand the period between the fourth day and two weeks. Recovery is at
It usually resolves in 5-6 days in mildly affected patients, but if the toxicity has been
importantly, recovery lasts two weeks or more.
The liver regenerates if enough hepatocytes remain viable and the
the patient survives. However, there are patients in whom they persist in a manner
chronicle some liver alterations.
4. Diagnosis
A good detailed medical history and the background of ingestion.
In most cases, the patient themselves goes to an Emergency Service.
disclosing which drug or drugs are consumed, and indicating the quantity and
the moment of ingestion.
To start a treatment, one must
take as a guiding point the adapted nomogram of
Therefore, determinations must be made.
of acetaminophen levels in plasma and start the
timely antidote treatment, based on the
four hours after ingestion in case those
are above the line of
nomogram: these are 150 mg/L at 4 hours, and 30
mg/L at 12 hours.
Evidently the determination of risk
Toxicity does not only depend on the levels.
plasmatic, but also of other factors
impossible to know what the state is like and
regeneration of that person's glutathione,
activity of cytochrome P450 and formation of
NAPBQ.
Rumack Nomogram
In case of doubt about the time of the poisoning, it should always be
to place, for its application in the nomogram, the value of the plasma level as closely as possible
possible delay, in such a way that this will be an attitude in which one will begin
treatment with the most likely antidote.
The serial determination of plasma levels can also help to
determine approximately at what post-ingestion time we are.
in the event that the patient has surpassed the plasma peak and the levels are
Descending means that the treatment should start as quickly as possible.
possible, especially when the patient has taken a product with a longer half-life,
therefore needing to extend the treatment schedule.
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But the usual treatment line can be modified. In patients
alcoholics may be at risk with lower concentrations of paracetamol, as
both hepatic and plasma glutathione levels are lower,
also producing nephrotoxicity in a large number of patients with
plasma concentrations higher than 200 mg/L. In this type of patient,
The nomogram will drop to 100 mg/L at 4 hours and 15 mg/L at 15 hours.
5. Treatment
• Start the ABC of initial resuscitation.
• Start decontamination measures with gastric lavage according to some
studies showed an average decline of 39% in paracetamol concentration
in plasma.
• Place a nasogastric tube and aspirate the gastric contents. Subsequently
perform the washing with isotonic saline solution, with bicarbonate solution
5% sodium or clean tap water with an amount of fluids not
less than 5 L in adults until the liquid comes out clear and without a toxic smell.
• In children, the amount of liquid to be used will depend on age.
it is recommended to administer between 200 to 300 ml in each irrigation
adult and 15 ml/kg in the child.
• The use of activated carbon reduces the curve by an average of 52%.
concentration of paracetamol, provided it is administered within the
first hour post-ingestion.
• If the patient is conscious, administer activated charcoal as follows
dose
− Adults: 1 g/kg of body weight diluted in 300 ml of water. /sulfate of
Sodium Adults and seniors over 12 years: 20 to 30 g. of weight dissolved in
200ml of water (cathartic).
− Children: 0.5 g/kg of body weight dissolved in 100 ml of water. /sulfate of
Sodium for children under 12 years: 250 mg/kg of body weight dissolved in
200ml of water (cathartic).
• The use of cathartics like mannitol is indicated in cases of multiple dosing.
of activated carbon.
• In addition to helping with the elimination of the toxin, the following dosage is suggested.
− Mannitol 3 - 4 ml/kg of body weight (cathartic).
− In children, 3 ml of Milk of Magnesia can be administered for every 10.
kilos of weight (cathartic).
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• The indication of activated charcoal may conflict with the indication
from oral antidote. Therefore, the use of intravenous antidote is preferred.
currently, so this problem is solved.
5.1 Antidote
The treatment that has improved survival for about 20 years
The main substance has been the supreme antidote: NAC (N-acetylcysteine), whose effect
reside, above all, in the possibility of glutathione regeneration.
The indication of NAC should be done as early as possible, with the existence of a
decrease in therapeutic capacity as the indication is delayed.
The mechanisms of action of NAC include following its administration the
primary mitochondrial and cytosolic repletion of depleted glutathione levels.
It can repair the oxidative damage caused by NAPBQ. Moreover, when administered
Many time after the overdose, NAC can protect against liver injury.
due to its action on neutrophils and by restoring microcirculation flow. This
it suggests that NAC is a drug with inotropic properties and a potent
vasodilator.
There are several treatment guidelines with NAC, both oral and intravenous.
• Oral route: the recommended dose is an initial load of 140 mg/kg followed by
17 doses of 70 mg/kg every 4 hours.
• Intravenous route: initial dose of 140 mg/Kg in one hour. Four hours
then 12 doses of 70 mg/kg maintenance are started in one hour
every 4 hours. A total of 980 mg/Kg in 48 hours.
Despite having a significant adsorption degree on activated carbon, the
the treatment of these patients with hemoperfusion has been displaced by the enormous
value of NAC in the treatment of paracetamol poisoning, and probably,
In addition, it does not play an important role in preventing the development of liver failure.
fulminant.
Another medication with this power is methionine. The treatment protocol.
oral methionine is simple, and the therapy is completed within 12 hours
comparison with three days for oral acetylcysteine and 20 hours of acetylcysteine
intravenous.
The dosage for Methionine is 10 g divided over 12 hours, 2.50 g every 4 hours.
oral hours.
Another therapeutic possibility to consider would be liver transplantation; for
supposedly, the patients eligible for this treatment would be the most severe
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