Lecture 2: Acetaminophen Overdose

Objectives
I. Know the potential toxic dose of APAP according to age
II. Know the symptoms and signs of APAP OD
III. Know the indications of NAC therapy

Abbreviations
APAP Acetaminophen NAC N-Acetylcysteine
NAPQI N-acetyl-p-benzoquinone imine AST Aspartate transaminase
GSH Glutathione ALT Alanine transaminase
CYP P450 cytochromes OD Over dose
 Acetaminophen
ü Also known as Paracetamol or N-acetyl-p-aminophenol (APAP)
ü Trade names: Tylenol - Panadol.
ü Approved as an Over-the-counter (OTC) drug since 1960
ü 1st cases of hepatic damage after APAP OD 1966

✪Therapeutic dose
§ Children: 10-15 mg/kg/dose
§ Adults: 325-1000 mg/dose
ü Every 4-6 hours, with a maximum of 4g/day

✪Toxic dose
§ Children:
< 12 months 1–6y 1 – 6 y with risk factors 7 – 12 y
150 mg/kg 200 mg/kg 150 mg/kg 150 mg/kg

§ Adults: More than 6 g (1)

(1) 60% chance of liver damage

 ✪ Normal Metabolic Pathway
Hepatic glucuronide
(40-65%)
conjugation
90%
(20-45%) Hepatic sulfate conjugation

5% Excreted unchanged in the urine

Oxidation by P450 cytochromes (CYP 2E1,
1A2, and 3A4) to NAPQI (TOXIC)

5-15% Glutathione (GSH) combine with NAPQI (1)

Cysteine/mercaptate conjugates
(NONTOXIC)

✪ In Over Dose
Rate and quantity of 1- Elimination of
Saturation of P450 takes NAPQI formation NAPQI prolonged
glucuronidation over hence overwhelms GSH
NAPQI 2- Free NAPQI binds
and sulfation increases
supply and critical cell proteins
regeneration with sulfhydryl groups cellular dysfunction
and cell death (2) (3)
(1) Normally NAPQI is detoxified by reduced GSH (glutathione) and thiol-containing substances
(2) Animal models: hepatotoxicity when GSH stores fall <30% of baseline
(3) Cellular death and hence liver enzymes will increase
✪ Factors which adversely affect APAP metabolism
ü Up regulation (i.e. induction) of CYP 2E1 enzyme activity
ü Decreased glutathione stores (How?) Eating - NAC
ü Frequent dosing interval of APAP
ü Prolonged duration of excessive dosing
ü Smoking, barbituates, rifampin, carbamazepine, phenytoin, INH + ethanol
ü Use of APAP by alcoholics has not been associated with higher risk of liver injury in prospective trials

✪ Clinical manifestation

Stage I Stage II Stage III * Stage IV

48-96 h
0.5-24 h 24-48 h 4-14 d
Coagulopathy, peaking of enzymes,
Nausea/Vomiting, 1- resolution of stage I
Acidosis, Hypoglycemia, Bleeding Resolution
anorexia or 2- RUQ pain diathesis, Jaundice / anuria /
asymptomatic 3- elevation of PTT, cerebral edema, Coma, ARF in 25%
INR bilirubin+ of pts with hepatotoxicity.
enzymes. (at the latest
by 36h) * Fulminant hepatic failure.
 ✪ Diagnosis
ü Serum APAP level should be measured between 4 and 24 hours after ingestion.
ü The value obtained should be evaluated according to the Rumack-Matthew nomogram for determining the risk of
hepatotoxicity and the need for NAC therapy.

✪ The Rumack-Matthew nomogram

ü APAP level to predict which patients will develop an AST
elevation >1000 IU/L without antidotal treatment (4)
ü Derived from acute ingestion of immediate release
acetaminophen
ü Begins at 4 h post ingestion
ü Recommended line of treatment has been lowered by 25% to
increase its sensitivity and safety.
What percent of pts whose APAP level falls above the upper line
of the Rumack-Matthew nomogram will develop
hepatotoxicity? (1)
60%
Which lab test is the most sensitive for early detection of
hepatotoxicity?
AST
(1) defined as elevation of the plasma transaminases above 1,000 U/L
(2) We can’t measure the drug level before 4 hours
(3) Any patient that comes after 24hrs of ingestion with symptoms or any detectable APAP you start him on NAC
(4) If you already started NAC the Rumack-Matthew-nomogram becomes useless
✪ Toxicology History
ü Often incomplete, unreliable or unobtainable
➥ Source: Patient, friends, family, EMS or pill containers
➥ Past medical history: liver/renal disease, concurrent medications, previous overdoses, psychiatric hx, substance abuse
➥ 5 W’s of toxicology:

WHO WHAT WHEN WHERE WHY

• Age, weight, • Name and dose • Time of • Route of • Intentional vs.

relation to of medication, ingestion, single ingestion, unintentional
others. coingestants and vs. multiple geographical
amount ingested ingestions. location (1)

✪ Management Guidelines(3):

Decontamination Find antidote

Airway Breathing Circulation
(Activated Charcoal) (2) (NAC)

ü NAC should optimally be given within 8 to 10 hours after ingestion

ü More delayed therapy is associated with a progressive increase in hepatic toxicity
ü Some benefit may still be seen 24 hours or later after ingestion
(1) Location may be important for environmental or occupational exposures
(2) Activated Charcoal will ADSORBE the drug
(3) When the patient comes late There is no indication for Elimination of the drug from the systemic circulation in case of Acetaminophen toxicity
✪ N-Acetylcysteine (NAC) (Antidote)
➥ Action
Early Late (12-24 h)
1. Prevents binding of NAPQI to hepatocytes 1. Modulates the inflammatory response
2. GSH precursor à increases GSH stores 2. Antioxidant, free radical scavenger
3. Increases sulfation metabolism of APAP à less NAPQI 3. Reservoir for thiol groups (i.e. GSH)
formed 4. Impairs WBC migration and function à anti-inflammatory
4. Reduces NAPQI back to APAP (at least in animal 5. Positive inotropic and vasodilating effects (NO) à improves
models) microcirculatory blood flow and O2 delivery to tissues
5. Sulfur group of NAC binds and detoxifies NAPQI to 6. Decreases cerebral edema formation, prevents progression
cysteine and mercaptate conjugate (= GSH substitute) of hepatic encephalopathy and improves survival

➥ Indications for NAC

ü APAP level above the treatment line
ü History of significant APAP ingestion presenting close to 8h(1) (give while waiting for level)
ü All APAP ingestions who present late >24h with either detectable APAP or elevated transaminases
ü Chronic ingestions (>4g/day in adult, >120mg/d in child) with elevated transaminases
ü History of exposure and Fulminant Hepatic Failure (FHF)
✪ Poor prognostic indicators
ü pH <7.3 (2 days after OD, after fluids)
ü Hepatic encephalopathy
ü PT >1.8 times normal.
ü Serum creatinine >300mmol/L
ü Coagulation factor VIII/V ratio of >30
1) Optimally it should be given 8-10 hours after the ingestion and if the patient came after that period you should give NAC while waiting for the drug level
when the patient is symptomatic or if APAP overdose is confirmed by clinical assessment.
2) NAC is also given in case of Fulminant Hepatic Failure outside the context of APAP toxicity due to its anti-inflammatory action (e.g. in hepatitis)
✪ Paracetamol (acetaminophen) poisoning Vale, JA, Proudfoot, AT. Lancet 1995; 346:547
Treatment delay below Treatment at 10 to 24 hours
10 hours
ü 200 patients had a 2.0 to 7.4 percent mortality,
Mortality ü No deaths ü 5.3 to 10.7 mortality in 85 patients who received only
supportive care.
liver damage (defined
ü 27 to 63 per cent in patients treated at 10 to 24 hours
as a plasma ALT or AST ü 1.6 to 10 percent incidence
ü 58 to 89 percent in those receiving supportive care
level above 1000 IU/L)

✪ Improved outcome of Paracetamol-induced fulminant hepatic failure by late

administration of NAC Lancet 1990 Jun 30;335(8705):1572-3]
The influence of NAC, administered at presentation to hospital, on the subsequent clinical course of 100 patients who
developed APAP-induced fulminant hepatic failure was analyzed retrospectively
ü Mortality was 37% in patients who received NAC 10-36 h after the overdose, compared with 58% in patients not given
the antidote
ü In patients given NAC, progression to grade III/IV coma was significantly less common than in those who did not receive
the antidote (51% vs 75%)

✪ XR tablets
ü Several studies show that elimination of extended and immediate-release acetaminophen are nearly identical
after 4 hours.
ü Some case reports APAP levels falling above the treatment nomogram line as late as 11-14 hours post ingestion of
the extended-release preparation
 Clinical Cases
1- 15 month old child (wt. 10 kg) accidentally took full bottle of Tylenol 60cc(120mg/5cc) 30 mint
ago. Clinically looked well. What will be your treatment plan:
A. Give Ipecac STAT
B. Give 1g/kg activated charcoal
C. Insert OGT and perform gastric lavage
D. Should be observed for 4h then to do drug level
E. None of the above

[ (120÷5) × 60 ] ÷ 10 = he took 144 mg

*Toxic dose is 200 mg for his age group

2- A mother brought her 4 M (5 kg) old son who was febrile for the last 3 days . She was giving .2
him Tylenol (120mg/5 ml) 7ml every 4 h for the last 3 days, she found him today more
lethargic, vomiting occasionally, clinically, ill looking slightly jaundiced, afebrile, no meningeal
signs, mild injected throat, CSF was obtained & was not suggestive of meningitis. What will be
your next step:
A. Obtain CBG, LFT, PT, PTT, INR, drug level if abnormal start NAC
B. Give activated charcoal immediately
C. Admit for observation
D. D/C home, most likely it is related to current URTI
3- 19 years old girl brought to ED with GCS 8 following drug ingestion (empty bottle of Tylenol .3
was found in her room). What will be your first response
A. 1g/kg activated charcoal STAT
B. Orotracheal intubation
C. Observation for 4 h
D. Do CBC, CBG, PT, PTT, INR, Drug level
E. NAC loading dose followed by infusion over 24 h

4- 3 y old boy with accidental Tylenol ingestion on NAC for high drug level, after 48 h course .3
LFT ,INR are high. What will be your recommendation:
A. D/C NAC if drug level undetectable
B. D/C NAC and repeat LFT, INR, drug level after 4h
C. Continue on NAC until all his labs become normal
D. D/C NAC, most likely it is secondary to concurrent viral illness

5- 20 yr old pregnant girl ingested 20g of Tylenol in a suicidal gesture 36h ago because she found
out it is too late for her to have an abortion. Her APAP is <10 and her AST is 90
How will you manage her medically?
Management is the same in case of APAP toxicity.
If you have any questions You can always
contact us at : [email protected]

Done By: Sara Alkharashi Revised By: Abdullah Alatar