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Acetaminophen Toxicity: What Pharmacists

Need to Know
Erica Dimitropoulos, PharmD Candidate 2015
St. Johns University
College of Pharmacy & Health Sciences
Queens, New York
Emily M. Ambizas, PharmD, CGP
Associate Clinical Professor
St. Johns University
College of Pharmacy & Health Sciences
Queens, New York
Clinical Specialist, Rite Aid Pharmacy
Whitestone, New York


3/19/2014

US Pharm. 2014;39(3):HS2-HS8.
ABSTRACT: Acetaminophen toxicity is one of the most common causes of both intentional and
unintentional poisoning in the United States. It has become the most common cause of acute liver
failure and the second most prevalent cause of liver failure requiring transplantation.
Acetaminophen is often recommended by doctors and highly utilized by patients in both
prescription and OTC products for a variety of conditions. The FDA has long been updating its
recommendations regarding acetaminophen use to help improve patient safety. This article
reviews the etiology, signs, and symptoms of acetaminophen toxicity and the role of the
pharmacist in the prevention of acetaminophen misuse.
Acetaminophen is often recommended by doctors and highly utilized by patients in both
prescription and OTC products for a variety of conditions, making it undoubtedly one of the
most common drugs encountered by pharmacists.
1-3
In the United States, 40% of the adult
population reported using OTC acetaminophen monthly, and 23% of the adult population
reported using either OTC or prescription acetaminophen weekly.
1,2

Acetaminophen (paracetamol or APAP) has analgesic and antipyretic properties similar to
aspirins, but minimal anti-inflammatory properties.
4
It is indicated for mild-to-moderate pain or
fever, and it is not associated with stomach discomfort or bleeding at recommended doses. When
used appropriately, it has a very well-established safety and efficacy profile.
5
However,
hepatotoxicity is a common consequence of overconsumption, which can result in a range of
problems, including abnormalities in liver function, acute liver failure, and even death.
6

Acetaminophen toxicity is one of the most common causes of both intentional and unintentional
poisoning in the U.S. In fact, there has been a steady increase in the incidence of acetaminophen-
related toxicity over the past decade.
7,8
This is likely attributed to the widespread availability of
acetaminophen as both a single ingredient and in combination with other OTC and prescription
medications in various concentrations and formulations. Acetaminophen-associated overdoses
account for approximately 56,000 emergency department visits, 26,000 hospitalizations, and
over 450 deaths annually.
9
Acetaminophen-induced liver toxicity has become the most common
cause of acute liver failure and the second most common cause of liver failure requiring
transplantation.
10,11
Therefore, it is imperative that pharmacists recognize signs and symptoms of
overdose and toxicity, and counsel their patients on proper dosing and usage.
Pharmacokinetics
Upon ingestion, acetaminophen is rapidly absorbed from the gastrointestinal (GI) tract and
quickly distributed throughout the body. Peak plasma concentrations are achieved within 30 to
60 minutes
4
; food may delay time to peak concentration, but the extent of absorption is not
affected.
12
With overdoses, peak plasma concentrations are usually achieved within 4 hours.
13

The half-life of acetaminophen is approximately 2 to 3 hours after therapeutic doses, yet can be
increased to more than 4 hours in patients with hepatic injury.
4,12,14

Acetaminophen is extensively metabolized by the liver via three main hepatic pathways:
glucuronidation, sulfation, and CYP450 2E1 oxidation.
12
Approximately 90% of acetaminophen
is conjugated to sulfated and glucuronidated metabolites that are renally eliminated.
14
Of the
remaining acetaminophen, approximately 2% is excreted unchanged in the urine and the rest
undergoes CYP450-mediated oxidation to form a reactive metabolite, N-acetyl-p-benzoquinone
imine (NAPQI).
15-18
Under normal circumstances, this toxic metabolite reacts with sulfhydryl
groups in glutathione, converting it to harmless metabolites before being excreted in the urine.
4

Toxicity
Drugs may have toxic effects due to various reasons. Toxicity of some drugs is related to the
formation of an undesirable metabolite; consequently, toxicity of acetaminophen is related to the
production of NAPQI. With large acute doses or with chronic use, the major metabolic
pathwaysthe glucuronide and sulfate conjugation systemsbecome saturated, and more
acetaminophen is metabolized by the CYP450 system. This results in increased production of
NAPQI. When glutathione is approximately 70% depleted, NAPQI begins to accumulate in the
hepatocytes, resulting in hepatic damage.
15,16,18
Therefore, the replacement of glutathione with
glutathione-mimicking compounds such as N-acetylcysteine serves as a useful antidote to
acetaminophen toxicity.
Acetaminophen toxicity can result from either an acute overdose or from chronic overuse. Acute
overdose is defined as consumption of a toxic amount of a drug within an 8-hour period, whereas
chronic overdose occurs as a result of repeated doses at or above the recommended limit.
12

Unintentional overdoses may also occur as a result of ingestion of multiple products containing
acetaminophen. The recommended dose of acetaminophen in adults is 650 to 1,000 mg every 4
to 6 hours, not to exceed 4,000 mg in a 24-hour period; in children, the recommended dose is 10
to 15 mg/kg every 4 to 6 hours, not to exceed 50 to 70 mg/kg in 24 hours.
12
Single doses of more
than 150 mg/kg or 7.5 g in adults have been considered potentially toxic, although the minimal
dose associated with liver injury can range anywhere from 4 to 10 g.
6,12,14,19
In children, single
doses of 120 mg/kg to 150 mg/kg have been associated with hepatotoxicity; however, doses
<200 mg/kg are unlikely to result in toxicity.
14,20

While the exact maximum dose has not been well defined, the American Association of Poison
Control Centers (AAPCC) has recommended that regardless of the amount of drug ingested, a
patient should be brought for medical evaluation if he or she displays signs or symptoms
consistent with toxicity.
21
The AAPCC has provided guidelines for hospital referral both for
acute, single, unintentional ingestion of acetaminophen and for repeated supratherapeutic
ingestion of acetaminophen (TABLE 1).
21


Clinical Presentation
Regardless of whether acetaminophen toxicity occurs because of a single overdose or after
repeated supratherapeutic ingestion, the progression of acetaminophen poisoning can be
described in four sequential phases: preclinical toxic effects (phase one), hepatic injury (phase
two), hepatic failure (phase three), and recovery (phase four).
6,22
Patients treated during the
preclinical stage may develop transient liver damage but fully recover.
22
Patients who are not
treated until hepatic injury is already evident have a variable prognosis; however, those who
present with hepatic failure have a mortality rate of 20% to 40%.
22

The first phase occurs a few hours after ingestion of a toxic dose, and lasts 12 to 24 hours. It is
important to note the delay in the appearance of symptoms, as healthcare providers should
understand the implications of toxicity that will follow this quiescent period. Symptoms during
the first 24 hours are not diagnostic or specific and include nausea, vomiting, diaphoresis,
anorexia, and lethargy, the severity of which will be in direct correlation to the size of the dose
ingested.
8

In the second phase, occurring up to 24 to 48 hours after ingestion, there may be a false sense of
recovery as GI symptoms improve or disappear.
6,8
However, as hepatotoxicity continues to
emerge, abdominal pain or right upper quadrant tenderness may surface. In addition, laboratory
values will begin to show evidence of hepatotoxicity; hepatic enzymes, lactate, phosphate,
prothrombin time, and international normalized ratio (INR) will increase dramatically.
6,8,12
Most
patients do not progress beyond this stage, especially if the antidote acetylcysteine is
administered.
8,12

A few patients will progress to phrase three, usually occurring 3 to 5 days postingestion. This
phase is characterized by the reappearance or worsening of nausea and vomiting accompanied by
malaise, jaundice, and central nervous symptoms including confusion, somnolence, and coma.
6

Serious and possibly fatal hepatic necrosis may occur. Although less common, renal
insufficiency, as demonstrated by oliguria, can manifest as a result of acetaminophen-induced
tubular necrosis.
6,8,12
Hepatic enzyme levels will reach their peak, measuring as high as 10,000
IU/L. Jaundice, hypoglycemia, bleeding and coagulation abnormalities, and hepatic
encephalopathy will also be evident.
8,12
Death may occur as a consequence of complications
associated with hepatic failure, including multiorgan system failure, cerebral edema, and
sepsis.
15

Lastly, phase four involves survival and recovery, generally with return of full liver function and
no long-term effects.
6
Approximately 70% of patients who enter phase four recover completely,
while 1% to 2% of patients develop fatal hepatic failure.
6
Severe, untreated acetaminophen
toxicity will result in death within 4 to 18 days after ingestion.
6

Patients at Increased Risk
Because the mechanism of acetaminophen toxicity occurs via the formation of NAPQI, any
factors that influence the availability of metabolic enzymes will therefore affect toxicity. Alcohol
use, malnutrition, and induction of CYP450 enzymes by drugs, including long-term treatment
with carbamazepine, primidone, rifampin, efavirenz, and St. Johns wort, may impact how an
individual responds to acetaminophen.
23
Patients affected by any of the above factors should be
identified so that pharmacists may counsel them closely on how to safely use acetaminophen.
Acutely, ethanol serves as both a substrate for and inhibitor of CYP2E1, limiting the amount of
NAPQI formed. Conversely, in chronic alcohol use, ethanol is an inducer of CYP2E1, leading to
a potential increase in the formation of NAPQI should an overdose of acetaminophen occur.
Another consequence of chronic alcohol use is the depletion of glutathione stores, reducing the
last defense against the formation of NAPQI.
17
There is no evidence to suggest that use of
acetaminophen in therapeutic doses is toxic in an alcoholic person; therefore, in therapeutic
amounts acetaminophen can be used safely both acutely and chronically.
23-25

Although controversial, starvation (prolonged fasting) and malnutrition are additional risk factors
for acetaminophen toxicity.
16,18,23
Similar to chronic alcohol use, malnutrition causes depletion of
glutathione stores. However, there is also evidence that CYP2E1 function is markedly reduced in
this patient population. These effects would thereby counteract each other, potentially resulting
in no change in toxicity.
26
Nevertheless, it is still prudent to identify such patients and caution
them about their increased risk potential.
Management
Upon presentation, the patient should be thoroughly assessed. A detailed recent drug history
should be obtained. Serum acetaminophen levels should ideally be drawn at least 4 hours after
ingestion. Pharmacists can play an important role by gathering pertinent information such as the
amount of drug taken, the dosage form ingested, the amount of time that has elapsed since the
last ingested dose, and if any other drugs were consumed. All of these factors are important when
analyzing serum acetaminophen concentrations.
If the patient presents within an hour of ingestion, gastric decontamination may be considered;
activated charcoal is the only GI decontamination method recommended. Administration of
activated charcoal may be considered, especially in patients who ingested delayed-release
formulations of acetaminophen or who consumed other medications that would slow
acetaminophens absorption.
12
However, due to acetaminophens quick absorptive and
distributive phases, there is otherwise little role for this method as time passes.
27-29
Activated
charcoal should only be administered if the patient is mentally alert with an intact airway. It
should also be avoided in those with an increased risk of aspiration, uncontrolled vomiting, or
coingestion of a corrosive or proconvulsant.
30

Acetylcysteine: The mainstay of treatment for acetaminophen toxicity is acetylcysteine. This
agent replenishes hepatic glutathione stores and increases sulfate conjugation, preventing
accumulation of NAPQI.
31
Acetylcysteine may be beneficial in patients presenting with
acetaminophen-induced hepatic failure, as it improves hemodynamics and oxygen use, decreases
cerebral edema, and improves mitochondrial energy production.
14,22

Acetylcysteine may prevent hepatic failure from an acetaminophen overdose when administered
early enough (within 8-10 hours following an acute overdose) but may still be of value up to 48
hours after ingestion.
6,11,14,31
The standard acetaminophen toxicity nomogram, the Rumack-
Matthew nomogram, can be utilized to determine the likelihood of serious liver damage.
However, it is rendered ineffective when evaluating possible toxicity due to multiple ingestions
over time, when time of ingestion is unknown, or when altered metabolism occurs.
11
Taking this
into consideration, acetylcysteine should be administered in any case of acute liver failure or
when there is any evidence of liver toxicity in which acetaminophen overdose is suspected.
11

Acetylcysteine is available orally and intravenously; the choice is dependent on the clinical
scenario.
21
Oral administration may be beneficial for patients with preclinical toxic effects or
hepatic injury, although the presence of altered mental status and vomiting may limit its use.
22

The dosing regimen for oral acetylcysteine is a loading dose of 140 mg/kg, followed by 17 doses
of 70 mg/kg every 4 hours for a total of 72 hours.
11
Patients with hepatic failure should receive
IV therapy.
22
Continuous IV infusion is recommended at a loading dose of 150 mg/kg IV in 200
mL D5W infused over 60 minutes followed by a maintenance dose of 50 mg/kg over 4 hours,
followed by a second maintenance dose of 100 mg/kg in 1,000 mL D5W administered over 16
hours.
11
If the patient is under 40 kg, fluid should be adjusted as per guidelines to avoid fluid
overload, hyponatremia, and seizures. If the patient is doing well yet has not fully recovered after
the recommended dosing, acetylcysteine therapy can be continued using either the last oral dose
or the last IV infusion rate. Acetylcysteine should be continued beyond the protocol length until
acetaminophen concentrations are undetectable, serum AST has normalized or significantly
improved, and there is resolution of any evidence of hepatic failure.
13

Because its unpleasant taste and smell, vomiting frequently occurs with oral acetylcysteine
administration.
31,32
Adverse effects associated with IV acetylcysteine include anaphylactoid
reactions, including rash, pruritus, angioedema, bronchospasm, tachycardia, and hyper-
tension.
31,32
In addition, when using IV acetylcysteine, pharmacists must be aware of the
potential for medication errors. The complicated regimen, length of therapy, and need for
multiple health professionals to administer doses at various treatment sites greatly increase the
risk for errors.
33
One retrospective study identified a 33% incidence of medication errors with IV
acetylcysteine.
33
The most common type of error found in this study was a delay in therapy,
which can potentially reduce the efficacy of acetylcysteine. Another common error identified
was the unnecessary administration of acetylcysteine, resulting in unnecessary costs. It is
important for healthcare providers to consult with poison centers in cases of acetaminophen
overdoses. They can provide the most up to date dosing information and protocols to ensure
proper administration of acetylcysteine.
FDA Labeling
In hopes of increasing safety and reducing toxicity, the FDA has long been updating its
recommendations regarding acetaminophen use. In the late 1990s, research demonstrated that
acetaminophen was a leading cause of acute liver failure in the U.S., the majority of cases having
resulted from accidental overdoses.
34
In 1998, the FDA issued a warning label on acetaminophen
products that urged patients who consumed more than three alcoholic beverages per day to
consult a physician before using this medication. As years passed and the correlation between
acetaminophen and liver toxicity became even more evident, the FDA convened a meeting to act
upon these findings. In 2002, the FDA Advisory Committee recommended that a liver toxicity
warning be placed on all acetaminophen-containing products. In 2009, new labeling was
developed to help patients easily identify which products contained acetaminophen, reducing the
potential for accidental overdoses. A black box warning was later placed on all prescription
acetaminophen products emphasizing the potential risk for severe liver injury, and a warning for
rare but serious anaphylaxis and other hypersensitivity reactions was implemented.
34

In August 2013, the FDA alerted consumers of rare but serious and potentially fatal skin
reactions, such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and acute
generalized exanthematous pustulosis (AGEP), linked to acetaminophen use.
35
Patients should be
counseled for signs and symptoms of skin reactions, such as peeling, blistering, reddening, and
detachment of skin, wherein they should stop any further drug use and seek medical attention
immediately.
The FDA has also announced that as of January 2014, the amount of acetaminophen found in
prescription combination products must be limited to 325 mg per tablet or capsule.
36,37
In May
2011, manufacturers of nonprescription acetaminophen products voluntarily announced that a
single childrens strength of liquid acetaminophen (160 mg/5 mL) will be the only concentration
available; the concentrated infant drops will no longer be produced.
38

Although progress has been made, some things are still to be determined. The FDA Advisory
Committee has voted in favor of many changes thought to improve safety and decrease toxicity,
yet the FDA has not yet taken action. For example, while the maximum daily dose of
acetaminophen was previously set at 4 g/day, the FDA Advisory Committee suggests decreasing
it in an effort to reduce overdoses.
37
It is important to note that some manufacturers have already
updated their labeling to reflect these recommendations, although it is not yet mandatory to do
so. Efforts are also being made to improve product labeling, enhance patient education, create a
universal pediatric formulation, eliminate acetaminophen combination products, and reduce the
strength of OTC acetaminophen products to 325 mg per tablet with a maximum single dose of
650 mg.
37
While no final consensus on any of these issues has been reached, healthcare providers
should educate their patients on the importance of following labeling instructions.
Role of the Pharmacist
Pharmacists are in a position to effectively promote the safe use of acetaminophen. Many
patients are not aware of the maximum daily dose of acetaminophen and the potential for
toxicity.
39
In addition, patients may not understand that acetaminophen is contained in more than
600 different products.
39
All patients receiving a prescription for an acetaminophen-containing
product need to be counseled to ensure awareness of the active ingredient. Pharmacists must take
a proactive role in educating patients who purchase OTC acetaminophen products. Pharmacists
are vital to preventing acetaminophen misuse by guaranteeing the safe use of the drug through
patient education and a review of patients medication histories.
In addition, pharmacists should recommend that patients contact the national Poison Help Line if
they suspect an acetaminophen overdose. The toll-free number is 1-800-222-1222.
40
By calling
this number, patients will be connected to the nearest regional poison control center with
specialists available 24 hours a day, 7 days a week. These specialists will be able to help assess
and manage the potential acetaminophen overdose. Such activities will minimize the risk of
inappropriate dosing, duplication of therapy, and inappropriate drug use.
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