paracetamol

TOXICOLOGY
Chapter Two
Paracetamol
Dr. Tamara Hijjawi

Acetaminophen
(paracetamol)
Is a widely used drug found in many over-the-counter and prescription analgesics and cold
remedies.
When it is combined with another drug, such as diphenhydramine, codeine, hydrocodone,

oxycodone, dextromethorphan, the more dramatic acute symptoms caused by the other drug may
mask the mild and nonspecific symptoms of early acetaminophen toxicity, resulting in a missed
diagnosis or delayed antidote treatment.
Mechanism of toxicity
A. Hepatic injury. One of the products of normal metabolism of acetaminophen by cytochrome P450
(CYP) mixed-function oxidase enzymes is highly toxic; normally this reactive metabolite (NAPQI) N-
acetyl-p-benzoquinone imine, is detoxified rapidly by glutathione in liver cells.
However, in an overdose, production of NAPQI exceeds glutathione capacity and the metabolite reacts
directly with hepatic macromolecules, causing liver injury.
B. Overdose during pregnancy has been associated with fetal death and spontaneous abortion.
C. Very high levels of acetaminophen can cause lactic acidosis and altered mental status by uncertain
mechanisms, probably involving mitochondrial dysfunction.
Pharmacokinetics.
Acetaminophen is rapidly absorbed, with peak levels usually reached within 30–120 minutes.
(Note: Absorption may be delayed after ingestion of sustained-release products or with co-ingestion
of opioids or anticholinergics.)
Volume of distribution (Vd) is 0.8–1 L/kg.
Elimination is mainly by liver conjugation (90%) to nontoxic glucuronides or sulfates; mixed-function

oxidase (CYP2E1, CYP1A2) accounts for only about 3–8% but produces a toxic intermediate
The elimination half-life is 1–3 hours after a therapeutic dose but may be greater than 12 hours after
an overdose
Toxic dose
A. Acute ingestion of more than 200 mg/kg in children or 6-7 g in adults is potentially hepatotoxic.
•In contrast, the margin of safety is lower in patients with induced cytochromeP-450 microsomal enzymes,
because more of the toxic metabolite may be produced.
•High-risk patients include alcoholics and patients taking inducers of CYP 2E1 such as isoniazid.
•Chronic toxicity has been reported after daily consumption of supra-therapeutic doses by alcoholic
patients and persons taking isoniazid. Children have developed toxicity after receiving as little as 60-150
mg/kg/day for 2-8 days.
Therapeutic dose (1 month to 12 years)

10 to 15 mg/kg/dose every 4 to 6 hours as needed (Maximum: 5 doses in 24 hours)
Clinical presentation.
Clinical manifestations depend on the time after ingestion.

A. Early after acute acetaminophen overdose, there are usually no symptoms other than anorexia, nausea, or
vomiting.
Transient prolongation of the prothrombin time in the absence of hepatitis has been noted in the
first 24 hours
B. After 24-48 hours when transaminase levels [aspartate aminotransferase(AST) and alanine
aminotransferase(ALT)] begin to rise, hepatic necrosis becomes evident.
If acute fulminant-hepatic failure occurs, death may ensue. Encephalopathy, metabolic acidosis, and a continuing
rise in PT/INR indicate a poor prognosis.
Acute renal failure occasionally occurs, with or without concomitant liver failure.
CLINICAL PRESENTATION for Chronic excessive use of acetaminophen.
1. Patients often have nausea and vomiting, and may already show evidence of hepatic injury by
the time they seek medical care.
2. Glutathione depletion associated with chronic acetaminophen ingestion has also been associated
with anion gap metabolic acidosis due to the accumulation of 5-oxoproline.
Treatment
A. Emergency and supportive measures
1. Spontaneous vomiting may delay the oral administration of antidote or charcoal and should
be treated with metoclopramide or ondansetron.
2. Provide general supportive care for hepatic or renal failure if it occurs.
B. Specific drugs and antidotes.

initiate antidotal therapy with N-acetylcysteine(NAC, Acetylcysteine)
*Intravenous NAC infusion of 150 mg/kg in 200 ml 5% dextrose over 15 minutes,
•followed by 50 mg/kg in 500 ml 5% dextrose over 4 hours,
•and 100 mg/kg in 1000 ml 5% dextrose over 16 hours.
http://acetadote.net/dosecalc.php
Decontamination:
• Administer activated charcoal orally if conditions are appropriate.
• Gastric lavage is not necessary after small to moderate ingestions if activated charcoal can be
given promptly.
• Although activated charcoal adsorbs some of the orally administered antidote N-acetylcysteine,
this effect is not considered clinically important.
• Do not administer charcoal if more than 3-4 hours has passed since ingestion unless delayed
absorption is suspected (eg, co-ingestants containing opioids or anticholinergic agents).
Enhanced elimination
Hemodialysis effectively removes acetaminophen from the blood but is not generally indicated
because antidotal therapy is so effective.
Dialysis should be considered for massive ingestions with very high levels
Adverse effects for N-Acetylcysteine
A. Acetylcysteine typically causes nausea and vomiting when given orally.

(Use of a gastric tube, slower rate of administration, and a strong antiemetic agent (eg,
metoclopramide, ondansetron,) may be necessary.)
B. Rapid intravenous administration can cause flushing, rash, angioedema, hypotension, and
bronchospasm (anaphylactic reaction).
If an anaphylactic reaction occurs, stop the infusion immediately and treat with diphenhydramine if
urticaria and or angioedema is present, and epinephrine for more serious reactions (shock,
bronchoconstriction).
Once symptoms have resolved, the infusion may be recommenced at a slower infusion rate (by
further dilution and given over at least 1 hour).

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TOXICOLOGY

Dr. Tamara Hijjawi

When it is combined with another drug, such as diphenhydramine, codeine, hydrocodone,

Volume of distribution (Vd) is 0.8–1 L/kg.

Elimination is mainly by liver conjugation (90%) to nontoxic glucuronides or sulfates; mixed-function

Therapeutic dose (1 month to 12 years)

Clinical manifestations depend on the time after ingestion.

A. Emergency and supportive measures

2. Provide general supportive care for hepatic or renal failure if it occurs.

B. Specific drugs and antidotes.

• Administer activated charcoal orally if conditions are appropriate.

A. Acetylcysteine typically causes nausea and vomiting when given orally.

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