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Acetaminophen Toxicity
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Counselor,
Acetaminophen is the most widely used
pharmaceutical analgesic and antipyretic agent in the
United States and the world; it is contained in more
than 100 products. As such, acetaminophen is one of
the most common pharmaceuticals associated with
both intentional and accidental poisoning.
Acetaminophen-induced hepatotoxicity is well
recognized. Acetaminophen also is known as
paracetamol and N-acetyl-p-aminophenol (APAP).
Acetaminophen is also a component of many over-
the-counter medications and prescription
combinations, such as propoxyphene-acetaminophen
(e.g.: Darvocet) and oxycodone-acetaminophen (e.g.:
Percocet).
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Pathophysiology:
The maximum daily dose of APAP is 4 g in adults and
90 mg/kg in children. The toxic dose of APAP after a
single acute ingestion is 150 mg/kg or approximately 7
g in adults. The at-risk dose may be lower in some
susceptible patient populations, such as persons with
alcohol abuse. When dosing recommendations are
followed, the risk of hepatotoxicity is extremely small.
In acute overdose or when the maximum daily dose is
exceeded over a prolonged period, the normal
conjugative pathways of metabolism in the liver
become saturated. Excess APAP is oxidatively
metabolized in the liver via the mixed function oxidase
P450 system to a toxic metabolite, N-acetyl-p-
benzoquinone-imine (NAPQI). NAPQI has an
extremely short half-life and is rapidly conjugated with
glutathione, a sulfhydryl donor, and is renally
excreted. Under conditions of excessive NAPQI
formation or reduced glutathione stores, the end result
is hepatocellular death and centrilobular liver
necrosis.
The antidote for APAP poisoning is N-acetylcysteine
(NAC). NAC is theorized to work through a number of
protective mechanisms. NAC is a precursor of
glutathione and increases glutathione availability to
bind to NAPQI. It may also enhance sulfate
conjugation of any unmetabolized APAP. NAC also
functions as an anti-inflammatory and antioxidant and
has positive inotropic effects. NAC increases local
nitric oxide concentrations, and this vasodilatory effect
on microcirculatory blood flow enhances local oxygen
delivery to peripheral tissues. These vasodilating
effects decrease morbidity and mortality even in the
setting of established hepatotoxicity.
NAC is most effective when administered within 8
hours of ingestion. When indicated, however, NAC
should be administered regardless of the time since
the overdose. Therapy with NAC has been shown to
decrease mortality rates in late-presenting patients
with fulminant hepatic failure, even in the absence of
measurable serum acetaminophen levels.
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Frequency/Morbidity/Mortality:
Acetaminophen is one of the most common
pharmaceutical agents involved in overdose, as reported
to the American Association of Poison Control Centers.
APAP toxicity is the second most common cause of
hepatic failure requiring liver transplantation in the
United States.
The majority of patients with APAP overdose survive
with supportive care alone, in conjunction with
antidotal therapy. If correctly treated in a timely
manner, most patients do not suffer significant
sequelae. Case series report that fewer than 4% of
patients who suffer severe hepatotoxicity develop
hepatic failure; fatalities or liver transplantation occurs
in less than one half of these patients. Patients with
malnutrition, AIDS, chronic ethanol abuse, or anorexia
nervosa may be at increased risk for morbidity
because of deficient glutathione stores and
inadequate detoxification of NAPQI. Patients with
enhanced ability to make NAPQI due to induction of
the P450 system, specifically cyp2E1, may be at
increased risk of morbidity. The agents that induce this
enzyme activity include rifampin, phenobarbital,
isoniazid, phenytoin, carbamazepine, or chronic
ethanol ingestion. Pediatric patients younger than 5
years appear to fare better than adults after APAP
poisoning, perhaps owing to a greater capacity to
conjugate acetaminophen, enhanced detoxification of
NAPQI, or greater glutathione stores. However, since
no controlled studies have supported any alternative
pediatric therapy, treatment in children should be the
same as in adults.
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History/Physical:
The course of acetaminophen toxicity generally is
divided into 4 phases. Clinical evidence of end-organ
(hepatic, renal) toxicity is often delayed 24-48 hours
postingestion. Because antidotal therapy is most
effective when initiated within 8 hours postingestion,
the clinician must obtain an accurate history of the
time(s) of ingestion, the quantity, and formulation of
acetaminophen ingested, and any co-ingestants,
which may delay APAP absorption (e.g.:
anticholinergic drugs or opioids). Because a patient's
history may be inaccurate, the serum acetaminophen
concentration is important for diagnosis and treatment,
even in the absence of symptoms. After a single
ingestion, NAC therapy is guided by the serum APAP
concentration.
- Phase 1 (0-24 h): loss of appetite, vomiting,
general malaise
- Phase 2 (24-72 h): abdominal pain, increased
liver enzymes
- Phase 3 (72-96 h): liver necrosis, jaundice,
encephalopathy, renal failure, death
- Phase 4 (>4d -3 weeks h): complete resolution
symptoms and organ failure
Physical findings range from malaise to vomiting,
abdominal pain, diaphoresis, tachycardia, hypotension,
jaundice, GI bleeding, coagulopathy, hepatic
encephalopathy.
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Lab Studies:
A serum acetaminophen level drawn 4 or more hours
after a single ingestion may be plotted on the Rumack-
Matthew nomogram in order to guide therapy. The
nomogram is not applicable after multiple or chronic
ingestions. Liver enzymes and coagulation factors
should be tracked, as should serum ammonia. The
patient should have a chem panel and CBC and
should be typed and crossed. Renal functions and a
urine analysis should be obtained.
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Treatment:
If treatment occurs within a few hours of ingestion,
gastric contamination with oral activated charcoal
should be initiated since it readily absorbs
acetaminophen. N-acetylcysteine (NAC) if given within
8 hours of ingestion is virtually 100%
hepatoprotective. It is also indicated in long term
chronic cases and can be given orally or intravenously
even in children over 80 pounds.
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Medical/Legal Concerns:
Failure to administer NAC because of a possible late
presentation could be medically and legally risky. It is
always best to give a dose of NAC when in question
and not to delay this administration. Failure to
consider and evaluate for possible co-ingestants
could be a major pitfall so a thorough history is
essential. When in doubt it is always best to contact
the regional poison control center for further direction
of treatment.
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