Acetaminophen

Acetaminophen is an over-the-counter nonopioid analgesic and antipyretic medication

and the most commonly used analgesic worldwide. Despite the widespread use of
acetaminophen, its mechanism of action is not entirely understood. However,
acetaminophen is believed to exert its effects through indirect and reversible inhibition of
cyclooxygenase (COX)-1 and COX-2. The effects are generally limited to the CNS.
Acetaminophen is primarily metabolized by the liver; therefore, an overdose can lead to
life-threatening hepatotoxicity. In adults, limiting the total acetaminophen dose (from all
sources and routes) to < 4000 mg/day is highly recommended. Contraindications to
acetaminophen use include hypersensitivity, severe hepatic impairment, or severe active
hepatic disease.
Last update:

 July 22, 2021

 10:53 am

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Table of Contents
 Chemistry and Pharmacodynamics
 Pharmacokinetics
 Indications
 Adverse Effects and Contraindications
 Comparison of Medications
 References

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Chemistry and Pharmacodynamics

Definition
Acetaminophen, also known as paracetamol (N-acetyl-p-aminophenol), is a nonopioid
analgesic and antipyretic agent used to treat pain and fever.
Chemical structure
 Derivative of p-aminophenol
 Chemical formula: C8H9NO2

Acetaminophen (N-acetyl-p-aminophenol)
Image: “Acetaminophen (N-acetyl-p-aminophenol)” by Huang. License: CC BY 3.0

Mechanism of action
 The exact mechanism of action is not fully understood.
 The effects are believed to be via the indirect inhibition of cyclooxygenase
(COX)-1 and COX-2 enzymes in the CNS (by central COX inhibition).
 Weak inhibitor of COX in the peripheral tissues
Physiologic effects
 Prostaglandins (PGs) play a key role in acute inflammation.
 The cardinal signs of inflammation are observed:
o Rubor (redness)
o Calor (heat)
o Dolor (pain)
o Tumor (swelling)
 PG production is dependent on COX-1 and COX-2.
  Indirect inhibition of COX → ↓ PG synthesis → ↓ inflammatory response
Pharmacokinetics

Absorption
 Oral:
o High bioavailability (88%)
o Onset of action < 1 hour
o Peak concentration attained after 90 minutes
 Rectal:
o Bioavailability approximately 50%
o Onset of action < 1 hour
o Peak concentration not reached until 3 hours
 IV:
o Bioavailability up to 100%
o Onset of action < 10 minutes
o Peak concentration attained in about 60 minutes
Distribution
 Even distribution throughout most tissues and fluids except in fat
 Crosses the blood-brain barrier and placenta; found in breast milk
 Low plasma protein binding (25%)
Metabolism
 Metabolized primarily by the liver and follows 1st-order kinetics:
o Conjugation with glucuronide
o Conjugation with sulfate
o Oxidation via the cytochrome P450 (CYP) pathway (primarily
CYP2E1)
 Metabolism via the CYP2E1 pathway results in the production of N-acetyl-
p-benzoquinone imine (NAPQI).
  NAPQI is a toxic metabolite:
o Rapidly conjugated with glutathione
o Detoxified by glutathione → nontoxic cysteine and mercaptate
compounds → renal excretion
 Note: Drugs administered orally are subject to 1st-pass metabolism.
Excretion
 Metabolites are primarily excreted in the urine:
o Majority as glucuronide metabolites, then as sulfate metabolites
o < 10% as metabolites of cysteine and mercapturic acid
Indications
Acetaminophen is an equivalent of aspirin and has analgesic and antipyretic effects;
however, acetaminophen does not have platelet-inhibiting effects nor does it affect uric
acid levels.
Fever
 Temporary reduction of fever
 Can be used in individuals of all ages
Pain
 Oral/rectal: temporary relief from minor aches, pain, and headaches
 IV: 
o Relief from mild-to-moderate pain
o Relief from moderate-to-severe pain when combined with an opioid
o Should only be used in individuals ≥ 2 years of age
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Adverse Effects and Contraindications

Adverse effects of oral/rectal acetaminophen

 Hepatic (most significant): 
 o Associated with doses > 4000 mg/day and the use of > 1
acetaminophen-containing product (can lead to acetaminophen
overdose)
o Limit total dose from all sources and routes to < 4000 mg/day
(adults).
o Manifestations:
 Increased liver enzymes
 Acute hepatic failure
 Hepatotoxicity
 Other effects:
o Otic: hearing loss
o Dermatologic: erythema, rash, Stevens-Johnson syndrome, toxic
epidermal necrolysis
o Hypersensitivity: hypersensitivity reactions, anaphylaxis
Adverse effects of IV acetaminophen
 Hepatic (most significant):
o Increased ALT and AST levels
o Acute hepatic failure
o Hepatotoxicity
 GI (> 10%): nausea, vomiting, constipation, diarrhea
 ≤ 10%:
o Cardiovascular: hypertension or hypotension,
peripheral edema (adults)
o Dermatologic: rash, Stevens-Johnson syndrome, toxic epidermal
necrolysis
o Endocrine and metabolic: hypoalbuminemia, hypokalemia,
hypomagnesemia, hypophosphatemia
o Genitourinary: oliguria
o Hematologic: anemia
 o Hypersensitivity: hypersensitivity reaction, anaphylaxis
o Local: pain at infusion site
o Nervous system: agitation, headache, insomnia, trismus
o Musculoskeletal: muscle spasms
o Respiratory: dyspnea, stridor, wheezing, pleural effusion, pulmonary
edema
Drug-drug interactions
Table: Drug-drug interactions

Drugs Interactions/effects

Alcohol (ethyl) ↑ Hepatotoxicity

Barbiturates
 ↑ Metabolism of
acetaminophen
 ↓ Therapeutic
effect of
acetaminophen
 ↑ Risk of
hepatotoxicity

Carbamazepine
 ↑ Metabolism of
acetaminophen
 ↓ Therapeutic
effect of
acetaminophen
 ↑ Risk of
hepatotoxicity
 Table: Drug-drug interactions

Drugs Interactions/effects

Fosphenytoin-
phenytoin  ↓ Serum
concentration of
acetaminophen
 ↑ N-acetyl-p-
benzoquinone
imine formation

Isoniazid ↑ Hepatotoxicity

Lamotrigine ↓ Serum concentration of

lamotrigine

Local ↑ Risk
anesthetics of methemoglobinemia

Prilocaine ↑ Likelihood
of methemoglobinemia

Rifampin ↑ Hepatotoxicity of
acetaminophen

Contraindications
 Hypersensitivity to acetaminophen or any components of the IV formulation
 Severe impairment of liver function or active hepatic disease
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Comparison of Medications

Table: Comparison of acetaminophen and NSAIDs

Drug class Acetaminophen NSAIDs

Mechanism of Indirect inhibition of Inhibition of COX

action COX

Physiologic Decreased Decreased inflammatory

effect inflammatory response
response

Indications
 Pain  Inflammatory
 Fever diseases
 Rheumatoid
disorders
 Pain
 Fever
 Dysmenorrhea
 Osteoarthritis

Contraindicati
ons  Anaphylaxis  Anaphylaxis
 Hypersensi  Hypersensitivity
 Table: Comparison of acetaminophen and NSAIDs

Drug class Acetaminophen NSAIDs

tivity  Aspirin- or NSAID-

induced asthma or ur
 Severe ticaria
hepatic
impairment  Renal impairment
(CrCl < 30)
 Severe
active  Pregnancy after 20-
hepatic weeks gestation
disease  Use in the setting of
CABG

COX: cyclooxygenase
CrCl: creatinine clearance
CABG: coronary artery bypass graft
References
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