Acetammophen
Classification:
• Analgesics
Description, Mechanism of Action, Pharmacokinetics
Description: Acetaminophen (APAP, paracetamol) is a para-aminophenol analgesic and is the active
metabolite ofphenacetin. Due to the toxic effects ofphenacetin at therapeutic doses and that it is
metabolized to acetaminophen, phenacetin is no longer used. Acetaminophen possesses analgesic and
antipyretic activity similar to aspirin; however, acetaminophen has no peripheral antiinflammatory
activity or effects on platelet firnction. Acetaminophen is effective in the relief of both acute and
chronic pain. It is important to note that doses effective for acute pain relief (I-2 tablets/day) may
not be effective in chronic pain states such as osteoarthritis, which require higher daily doses. The
American College ofRheumatology has recommended acetaminophen as first-line therapy for
osteoarthritis of the hip or knee. In a randomized, double-blind trial, acetaminophen 4 g/day was as
effective as ibuprofen in doses of 2.4 or 1.2 g/day for the short-term relief of joint pain and
improvement offUnction in patients with osteoarthritis of the knee. [2096] As with other NSAIDs, the
maximum single dose of acetaminophen is limited by a ceiling effect where after single doses of I g,
the side effects increase as to negate any analgesic benefit. Acetaminophen may be preferred in elderly
patients with osteoarthritis over other NSAIDs due to fewer Gl and renal side effects. Acetaminophen
is the preferred analgesic/antipyretic for patients in whom aspirin is contraindicated, such as those who
have a history of gastric ulcer or a coagulation disorder. Acetaminophen is the analgesic of choice for
the treatment of episodic pain in patients with underlying renal disease. However, chronic use should
be discouraged because chronic use of acetaminophen has been reported to cause chronic renal
insufficiency contributing to renal failure in a dose-dependent manner. [541] In addition,
acetaminophen has been recommended by the American Geriatrics Society as the analgesic of choice
for minor aches and pains in patients > 50 years of age and by the American Lung Association as the
first line treatment for aches and pains associated with the flu. Acetaminophen is an effective analgesic
for mild to moderate pain following oral surgery, episiotomy, headache, and dysmenorrhea. Chronic
ethanol ingestion can increase the incidence ofacetaminophen-induced hepatotoxicity; patients who
consume more than 3 ethanol-containing beverages per day should not take acetaminophen.
Mechanism of Action: Acetaminophen's exact mechanism of action is unknown, but it is known to
mediate it actions centrally. Acetaminophen is thought to act primarily in the CNS and increase the
pain threshold by inhibiting cyclooxygenase, a collection of enzymes involved in prostaglandin (PG)
synthesis. Acetaminophen appears to be a potent inhibitor of both isoforms of cyclooxygenase, COX-1
and COX-2, within the CNS. [2685] Unlike NSAIDs, acetaminophen does not inhibit cyclooxygenase
in peripheral tissues, which is the reason for its lack of peripheral antiinflammatory affects.
Acetaminophen may also inhibit the synthesis or actions of chemical mediators that sensitize the pain
receptors to mechanical or chemical stimulation. The antipyretic activity of acetaminophen is exerted
by blocking the effects of endogenous pyrogen on the hypothalamic heat-regulatmg center by
inhibiting PG synthesis. Heat is dissipated by vasodilatation, increased peripheral blood flow, and
sweating.
Acute acetaminophen overdose will lead to dose-dependent hepatotoxicity and possibly acute renal
failure. In addition, chronic ingestion of acetaminophen may also lead to hepatotoxicity or chronic
analgesic nephropathy. Acetaminophen-induced hepatotoxicity and nephrotoxicity are due to the
formation of the oxidative metabolite, N-acetyl-para-benzoquinoneimine (NAPQI), in the liver and to
a lesser degree in the kidney. NAPQI binds covalently to sulfhydryl groups on tissue macromolecules
leading to cell necrosis. Depletion ofglutathione reserves leads to hepatotoxicity. Administration of
N-acetylcysteine or methionine may reduce hepatotoxicity by binding to NAPQI. However, these
agents do not prevent renal toxicity. Other toxic glutathione metabolites such as aminophenol-S-
conjugates may play a role in acetaminophen-induced acute renal toxicity. Chronic analgesic
nephropathy is characterized by interstitial nephritis and papillary necrosis. The mechanism of chronic
analgesic necrosis is due to reactive metabolites or other products that inhibit renal cyclooxygenase.
Pharmacokinetics: Following oral administration, acetaminophen is rapidly and almost completely
absorbed from the Gl tract. Peak plasma concentrations are attained within 30-60 minutes, although
serum concentrations and analgesia are not necessarily correlated. Binding to serum protein is about
25% after normal therapeutic dosages. Approximately 25% of the dose is subject to first-pass
metabolism by the liver. Between 90-95% of the normal, therapeutic acetaminophen dose is
metabolized in the liver via glucuronidation and sulfate conjugation and is excreted in the urine as
glutathione and sulfate conjugates. The remaining 10-15% undergoes oxidative metabolism via
cytochrome P450 isoenzymes (CYP) 2EI and IA2 and then glucuronidation to cysteine and
mercapturic acid conjugates. In neonates and children (3-9 years), acetaminophen is excreted
primarily as the sulfate conjugate; however there is not any age-related differences in the total
clearance of acetaminophen. The difference in methods of clearance may be due to a deficiency in
glucuronide formation in younger age groups. [2097] After an acute acetaminophen overdose,
malnutrition, or with chronic ethanol use, hepatic stores of glucuronide and sulphate are depleted and
acetaminophen undergoes oxidation via CYP 2EI and IA2 to form N-acetyl-para-benzoquinoneimine
(NAPQI), which is hepatotoxic. Metabolism via CYP 2EI may occur in the kidney as well as the liver.
Excess NAPQI may be formed when acetaminophen is given concomitantly with hepatic enzyme-
inducing agents. [2098] At all doses, metabolites, but not unchanged drug, can accumulate in renal
impairment. The elimination half-life of acetaminophen is 2-4 hours in patients with normal liver
function. After about 8 hours, only traces of the drug are detectable. Half-life can be prolonged in
patients with hepatic disease, and, conversely, a prolonged half-life during an acute overdose can
predict the subsequent development of hepatic necrosis.
Indications
• arthralgia
• dental pain
• dysmenorrhea
• fever
• headache
• migrainef
• mild pain
• myalgia
• osteoarthritis
dosage
For the treatment of mild pain or fever; or for the temporary relief of headache, myalgia, back
pain, dental pain (e.g., toothache), dysmenorrhea, arthralgia, minor osteoarthritis pain, or
minor aches and pains associated with the common cold or flu:
NOTE: Acetaminophen should not be used for self-medication of pain for longer than 10 days in
adults or 5 days in children. In addition, acetaminophen should not be used for self-medication of
marked fever (greater than 39.5 degrees C), fever persisting longer than 3 days, or recurrent fever,
unless directed by a physician.
Oral or rectal dosage (regular-release forms):
Adults and children >= 12 years: 325-650 mg PO or PR every 4-6 hours, as needed.
Alternatively, 1000 mg PO or PR, three or four times per day can be given. Maximum dose should not
exceed 4 g per day.
Children < 12 years and infants: 10-15 mg/kg PO or PR every 4-6 hours. Do not exceed 5 doses
in 24 hours.
Neonates: 10-15 mg/kg PO or PR every 6-8 hours as needed.
Oral dosage (extended-release tablets only):
Adults and children >•= Ilyears: 650-1300 mg PO every 8 hours as needed. Total daily dose
should not exceed 6 extended-release tablets or 4 g per day.
Children < Ilyears: Safe and effective use not established for extended-release tablets in this
population.
For the treatment of headache pain due to acute migrainef:
Oral or rectal dosage:
Adults and adolescents: Single doses of 500-1000 mg PO or PR have been utilized.
Children >= 4 years: In one clinical trial, single doses of 15 mg/kg PO were twice as effective as
placebo in reducing severe or moderate headache pain within 2 hours. [817]
Patients with hepatic impairment:
Acetaminophen should be used with extreme caution in patients with impaired hepatic function or with
a history of overdose. Acetaminophen should not be used in patients a history of alcoholism. Patients
with stable hepatic disease may receive therapeutic doses of acetaminophen for episodic pain of short
duration "5 days).
Patients with renal impairment:
Acetaminophen is the analgesic of choice for episodic pain in patients with underlying renal disease
but, chronic use should be discouraged. Dosage should be modified depending on clinical response
and degree of renal impairment, but no quantitative recommendations are available.
fnon-FDA approved indication
Admimstration Guidelines
NOTE: Acute overdoses ofacetaminophen are extremely toxic and potentially fatal. Do not exceed
recommended daily dosage. In addition, ingestion of normal doses daily for many months has also
been associated with hepatotoxicity and/or nephrotoxicity.
Oral Administration
'All dosage forms: Administer with a full glass of water. May be taken without regard to meals.
•Extended release tablets: Do not crush.
•Oral solution: Administer using a calibrated measuring device.
•Oral suspension: Shake well before administration. Administer using a calibrated measuring device.
•Chewable tablets: May be swallowed whole or chewed.
•Oral granules: Mix with a small amount of soft food (i.e., applesauce, ice cream, or jam) prior to
administration.
•Oral powders: Do not administer the capsules containing the powder whole. Open capsule and
sprinkle over a small amount of water "5 ml) or mix with a small amount of soft food (i.e.,
applesauce, ice cream, or jam) prior to administration.
Rectal Administration
•Instruct patient on proper use of suppository (see Patient Information).
•Moisten the suppository with water prior to insertion. If suppository is too soft because of storage in
a warm place, chill in the refrigerator for 30 minutes or run cold water over it before removing the
wrapper.
•Suppository must be retained in rectum for at least I hour to ensure complete absorption.
Contramdications/Precautions
• alcoholism
• anemia
• asthma
• bone marrow suppression
• children
• G6PD deficiency
• hepatic disease
• hepatitis
• immunosuppression
• infection
• neutropenia
• phenyiketonuria
• renal disease
• salicylate hypersensitivity
Patients with alcoholic hepatic disease, viral hepatitis or alcoholism are at risk for acetaminophen-
induced hepatotoxicity since glucuronide conjugation of the drug may be decreased. Depletion of
hepatic glutathione reserves limits the ability of the liver to conjugate acetaminophen which
predisposes the patient to farther hepatic injury. Although it is always prudent to use the smallest dose
of acetaminophen for the shortest duration necessary, short courses (<5 days) of normal adult doses
have been administered safely to patients with stable chronic liver disease. [106] Acetaminophen
should not be used for self-medication in patients who consume 3 or more alcoholic beverages per
day. Acetaminophen-induced hepatotoxicity should be suspected in alcoholic patients with
aminotransferase levels > 1,000 U/L and acetaminophen blood levels should be checked in these
patients.
Chronic acetaminophen administration should be avoided in patients with underlying renal disease;
however it is the analgesic of choice for episodic pain in these patients. Case control studies have
found an increased risk of developing papillary necrosis, chronic' renal failure or end-stage renal
disease with chronic acetaminophen use. There are many confounding factors in these studies which
limit the ability to determine the actual role of chronic acetaminophen use as a single risk factor for
renal disease.
Repeated overdoses of acetaminophen in children in combination with decreased nutrition may lead to
changes in the metabolism ofacetaminophen leading to hepatotoxicity. This combination leads to
decreases in sulfation, glucuronidation and glutathione production. Factors which may lead to
inadvertent overdoses in children include finishing pediatric formulation and substituting adult
acetaminophen formulations for convenience, misreading or interpreting instructions or administering
more acetaminophen due to persistent fever. [2099]
Patients with G6PD deficiency who overdose with acetaminophen may be at increased risk for drug-
induced hemolysis. During acetaminophen overdose, cyanosis may not be apparent in patients with
pre-existing anemia, in spite of dangerously high blood concentrations of methemoglobin.
Acetaminophen should be used cautiously in patients with asthma who also have salicylate
hypersensitivity. A single-blind prospective study of 50 aspirin-sensitive asthmatic subjects and 20
other asthmatics who were not aspirin-sensitive revealed that 17 of 50 aspirin-sensitive subjects
reacted to acetaminophen while no subject in the other group reacted. Acetaminophen was
administered in doses of 1000 mg and 1500 mg. The majority of the reactions were mild
bronchospasm and were easily reversed. The authors concluded that high doses ofacetaminophen
(e.g., > 1,000 mg) should be avoided in patients with aspirin-sensitivity who are also asthmatic.[l 112]
Symptoms of acute infection (e.g., fever, pain) can be masked during treatment with acetaminophen in
patients with bone marrow suppression, especially neutropenia, or immunosuppression.
Certain acetaminophen products containing aspartame (Nutrasweet(r)) should be avoided in patients
who have phenyiketonuria or who must restrict intake ofphenylalanine.
Acetaminophen may interfere with some home blood glucose monitoring systems resulting in
decreases of>20% in mean glucose values. This effect seems to be drug, concentration and system
dependent.
Patients should not self-medicate with acetaminophen for the treatment of pain >5 days in children or
>10 days in adults. Fever should not be treated longer than 3 days in children or adults without
consulting a physician or other health care professional.
Drug Interaction
~ Antacids
~ Barbiturates
• Busulfan
• Carbamazepine
• Cimetidine
• Diflunisal
• Isoniazid, INK
~ Phenothiazine
• Phenytoin
• Rifampin
• Ritonavir
• Sulfinpyrazon(
• WarFrfann
Antacids or food can delay and decrease the oral absorption ofacetaminophen.
Phenothiazines can interfere with thermoregulation. Concomitant use ofacetaminophen with
phenothiazines can produce hypothermia ifacetaminophen is given in large doses and the patient is
exposed to cold ambient temperatures.
The risk of developing hepatotoxicity from acetaminophen appears to be increased in patients who
regularly consume ethanol. In these patients, hepatotoxicity is possible even at normal, therapeutic
dosages of acetaminophen. [1654] Chronic ethanol use increases acetaminophen-induced
hepatotoxicity by inducing cytochrome P450 (CYP) 2EI leading to increased formation of the
hepatotoxic metabolite of acetaminophen and depletion of liver glutathione stores. Administration of
acetaminophen should be limited or avoided altogether in alcoholics or patients who consume ethanol
regularly. However, acute ethanol ingestion may reduce acetaminophen-induced hepatotoxicity by
substrate competition for CYP2EI.
Agents which inhibit the hepatic CYP2EI or IA2 isoenzymes may theoretically decrease the risk for
hepatotoxicity from acetaminophen, by reducing the generation ofacetaminophen's toxic metabolites.
Agents that inhibit CYP 2EI or IA2 and may decrease acetaminophen-induced hepatotoxicity include
cimetidine, ciprofloxacin, clarithromycin, erythromycin, ketoconazole, levofloxacin, omeprazole and
paroxetine. This list may not be inclusive of all agents that inhibit CYP 2EI and/or IA2.
Agents which induce the hepatic isoenzymes CYP2EI and CYP IA2 may potentially increase the risk
for acetaminophen-induced hepatotoxicity via generation of a greater percentage ofacetaminophen's
hepatotoxic metabolites. Agents which induce one or both of these enzymes include carbamazepine,
barbiturates, isoniazid, INH, phenytoin, rifampin, and ritonavir. The combination ofisoniazid, INH
and acetaminophen has caused severe hepatotoxicity in at least one patient; studies in rats have
demonstrated that pre-treatment with isoniazid, INH potentiates acetaminophen hepatotoxicity. At
least one case has been reported ofphenobarbital enhancing acetaminophen hepatotoxicity. [107]
Despite the use of only moderate doses of acetaminophen, the patient had been consuming
acetaminophen regularly for 3 months. While chronic acetaminophen use should be discouraged
during phenobarbital therapy, intermittent use of acetaminophen is probably safe. The clinical
significance of the other interactions is not known.
Sulfinpyrazone can induce hepatic microsomal enzymes that metabolize acetaminophen and this, in
turn, may increase the risk of acetaminophen hepatotoxicity due to the formation of increased amounts
of toxic acetaminophen metabolites. The risk of acetaminophen hepatotoxicity in patients taking
sulfinpyrazone increases with larger acetaminophen doses, particularly overdoses.
Acetaminophen is routinely considered safer than aspirin and is the agent of choice when a mild
analgesic/antipyretic is necessary for a patient receiving therapy with warfarin. However,
acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Both
INR prolongation and clinical bleeding have been reported. Concomitant acetaminophen ingestion
with warfarin may increase the INR in a dose-related fashion. [1628] The exact mechanism of this
interaction is not known. Acetaminophen and R-warfarin are both metabolized by the cytochrome
P450 (CYP)IA2 and CYP3A4 isoenzymes to varying degrees. In some patients, metabolism of
acetaminophen may be shifted towards CYP IA2 and CYP3A4 due to genetic polymorphism of
CYP2EI resulting in the decreased metabolism of R-warfarin; although, this mechanism is
theoretical.[2678] Single doses or short courses (i.e., several days) of treatment with acetaminophen
are probably safe in most patients taking warfarin. Clinicians should be alert for an interaction with
warfarin if acetaminophen is co-administered daily in large doses (> 1.3 g/day) for longer than 10-14
days. The INR may need to be monitored more frequently.
Use of acetaminophen prior to "72 hours) or concurrently with busulfan may result in decreased
clearance of busulfan due to acetaminophen-induced decreases in glutathione levels.
Acetaminophen plasma concentrations can increase by approximately 50% following administration of
diflunisal. Acetaminophen has no effect on diflunisal concentrations. Acetaminophen in high doses has
been associated with severe hepatotoxic reactions; therefore, caution should be exercised when using
these agents concomitantly.
Adverse Reactions
• abdominal pain
• anemia
• anorexia
• elevated hepatic enzymes
• encephalopathy
• erythema
• fever
• hemolysis
• hemolytic anemia
• hepatic necrosis
• hvDODrothrombinemia
• jaundice
• leukopenia
• methemoglobinemia
• nausea/vomiting
• neutropenia
• pancytopenia
• rash (unspecified)
• renal papillary necrosis
• renal tubular necrosis
• thrombocytopenia
• urticaria
Acetaminophen can be hepatotoxic. In most cases, acetaminophen hepatotoxicity occurs as a result of
an acute overdose, however, moderately excessive doses, if taken chronically, can also produce
hepatotoxicity. Acetaminophen-induced hepatotoxicity is manifested as hepatic necrosis, jaundice,
bleeding and encephalopathy. After acute overdose, 2 or 3 days pass before maximum liver damage
becomes apparent. Nausea/vomiting, anorexia, and abdominal pain usually occur within 2-3 hours
after ingestion of toxic doses. Elevated hepatic enzymes and hypoprothrombinemia are seen. Gl
bleeding can occur secondary to low prothrombin levels. Recovery may occur within 5-10 days.
Regular use of acetaminophen for periods of 5-39 months produced hepatotoxicity in 11
patients. [108] If plasma acetaminophen half-life exceeds 4 hours, hepatic necrosis can occur, and if the
half-life exceeds 12 hours, hepatic encephalopathy and coma is likely to develop. Young children
appear to be at less risk of developing hepatotoxicity, possibly because of an age-related difference in
the metabolism of the drug. Agents which affect cytochrome P450 function and ethanol may affect the
severity of acetaminophen-induced hepatotoxicity (see Drug Interactions). It has also been suggested
that recent fasting is associated with hepatotoxicity in patients taking higher than recommended
doses.[583] Treatment of acetaminophen overdose is with prompt oral administration ofN-
acetylcysteine, which serves as a substitute sulfhydryl donor for glutathione.
Acetaminophen can cause acute renal tubular necrosis and chronic analgesic nephropathy, which is
characterized by interstitial nephritis and renal papillary necrosis, in patients receiving high doses (e.g.,
2.5-10 g/day) chronically or after acute overdose. Acute renal failure may occur in 25-30% of
patients secondary to liver dysfunction. Rarely, acute renal failure may occur without severe hepatic
toxicity. The risk of renal complications appears to be higher in alcoholic patients. Chronic
acetaminophen use has been implicated as a contributing factor in the decline of renal function in
patients with underlying renal disease, including diabetic nephropathy. [541]
Methemoglobinemia can occur after acute overdoses of acetaminophen and can lead to hemolysis
thereby causing hemolytic anemia. This can result in cyanosis of the fingernails, skin, and mucosa.
Children develop methemoglobinemia more readily than do adults. Other hematologic reactions
reported with acetaminophen include neutropenia, leukopenia, thrombocytopenia, and pancytopenia.
Hypersenstivity reaction to acetaminophen may be manifested by urticaria,erythema,rash and fever.