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.

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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)

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:
    • Rubor (redness)
    • Calor (heat)
    • Dolor (pain)
    • Tumor (swelling)
  • PG production is dependent on COX-1 and COX-2.
  • Indirect inhibition of COX → ↓ PG synthesis → ↓ inflammatory response

Pharmacokinetics

Absorption

  • Oral:
    • High bioavailability (88%)
    • Onset of action < 1 hour
    • Peak concentration attained after 90 minutes
  • Rectal:
    • Bioavailability approximately 50%
    • Onset of action < 1 hour
    • Peak concentration not reached until 3 hours
  • IV:
    • Bioavailability up to 100%
    • Onset of action < 10 minutes
    • 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:
    • Conjugation with glucuronide
    • Conjugation with sulfate
    • 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:
    • Rapidly conjugated with glutathione
    • 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:
    • Majority as glucuronide metabolites, then as sulfate metabolites
    • < 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: 
    • Relief from mild-to-moderate pain
    • Relief from moderate-to-severe pain when combined with an opioid
    • Should only be used in individuals ≥ 2 years of age

Adverse Effects and Contraindications

Adverse effects of oral/rectal acetaminophen

  • Hepatic (most significant): 
    • Associated with doses > 4000 mg/day and the use of > 1 acetaminophen-containing product (can lead to acetaminophen overdose)
    • Limit total dose from all sources and routes to < 4000 mg/day (adults).
    • Manifestations:
      • Increased liver enzymes
      • Acute hepatic failure
      • Hepatotoxicity
  • Other effects:
    • Otic: hearing loss
    • Dermatologic: erythema, rash, Stevens-Johnson syndrome, toxic epidermal necrolysis
    • Hypersensitivity: hypersensitivity reactions, anaphylaxis

Adverse effects of IV acetaminophen

  • Hepatic (most significant):
    • Increased ALT and AST levels
    • Acute hepatic failure
    • Hepatotoxicity
  • GI (> 10%): nausea, vomiting, constipation, diarrhea
  • ≤ 10%:
    • Cardiovascular: hypertension or hypotension, peripheral edema (adults)
    • Dermatologic: rash, Stevens-Johnson syndrome, toxic epidermal necrolysis
    • Endocrine and metabolic: hypoalbuminemia, hypokalemia, hypomagnesemia, hypophosphatemia
    • Genitourinary: oliguria
    • Hematologic: anemia
    • Hypersensitivity: hypersensitivity reaction, anaphylaxis
    • Local: pain at infusion site
    • Nervous system: agitation, headache, insomnia, trismus
    • Musculoskeletal: muscle spasms
    • Respiratory: dyspnea, stridor, wheezing, pleural effusion, pulmonary edema

Drug-drug interactions

Table: Drug-drug interactions
DrugsInteractions/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
Fosphenytoin-phenytoin
  • ↓ Serum concentration of acetaminophen
  • ↑ N-acetyl-p-benzoquinone imine formation
Isoniazid↑ Hepatotoxicity
Lamotrigine↓ Serum concentration of lamotrigine
Local anesthetics↑ Risk 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

Comparison of Medications

Table: Comparison of acetaminophen and NSAIDs
Drug classAcetaminophenNSAIDs
Mechanism of actionIndirect inhibition of COXInhibition of COX
Physiologic effectDecreased inflammatory responseDecreased inflammatory response
Indications
  • Pain
  • Fever
  • Inflammatory diseases
  • Rheumatoid disorders
  • Pain
  • Fever
  • Dysmenorrhea
  • Osteoarthritis
Contraindications
  • Anaphylaxis
  • Hypersensitivity
  • Severe hepatic impairment
  • Severe active hepatic disease
  • Anaphylaxis
  • Hypersensitivity
  • Aspirin- or NSAID-induced asthma or urticaria
  • Renal impairment (CrCl < 30)
  • Pregnancy after 20-weeks gestation
  • Use in the setting of CABG
COX: cyclooxygenase
CrCl: creatinine clearance
CABG: coronary artery bypass graft

References

  1. Burns, M.J., Friedman, S.L., Larson, A.M. (2021). Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and evaluation. UpToDate. Retrieved July 14, 2021, from https://www.uptodate.com/contents/acetaminophen-paracetamol-poisoning-in-adults-pathophysiology-presentation-and-evaluation
  2. Candido, K.D., Perozo, O.J., Knezevic, N.N. (2017). Pharmacology of acetaminophen, Nonsteroidal antiinflammatory drugs, and steroid medications: Implications for anesthesia or unique associated risks. Anesthesiol Clin 35, e145–e162.
  3. Forrest, J.A.H., Clements, J.A., Prescott, L.F. (1982). Clinical pharmacokinetics of paracetamol. Clin Pharmacokinet 7, 93–107.
  4. Gerriets, V., Anderson, J., Nappe, T.M. (2021) Acetaminophen. StatPearls. Treasure Island (FL): StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK482369/
  5. Ghanem, C.I., Pérez, M.J., Manautou, J.E., Mottino, A.D. (2016). Acetaminophen from liver to brain: New insights into drug pharmacological action and toxicity. Pharmacol Res 109, 119–131.
  6. Ghlichloo, I., Gerriets, V. (2021). Nonsteroidal anti-inflammatory drugs (NSAIDs). StatPearls. Treasure Island (FL): StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK547742/
  7. Grosser, T., Smyth, E., FitzGerald, G. (2017). Pharmacotherapy of inflammation, fever, pain, and gout. Brunton, L.L., Hilal-Dandan, R., Knollmann B.C. (Eds.), Goodman & Gilman’s: The Pharmacological Basis of Therapeutics, 13e. McGraw Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2189&sectionid=170271972
  8. Heard, K., Dart, R. (2021). Clinical manifestations and diagnosis of acetaminophen (paracetamol) poisoning in children and adolescents. UpToDate. Retrieved July 14, 2021, from https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-acetaminophen-paracetamol-poisoning-in-children-and-adolescents
  9. Mazaleuskaya, L.L., et al. (2015). PharmGKB summary: Pathways of acetaminophen metabolism at the therapeutic versus toxic doses. Pharmacogenet Genom 25, 416–426.
  10. Raffa, R.B., et al. (2015). Pharmacokinetics of oral and intravenous paracetamol (acetaminophen) when co-administered with intravenous morphine in healthy adult subjects. Clin Drug Invest 38, 259–268.
  11. Ricciotti, E., FitzGerald, G.A. (2011). Prostaglandins and inflammation. Arteriosclerosis Thrombosis Vasc Biology 31, 986–1000.
  12. Shagroni, T.T., Cazares, A., Kim, J.A., Furst, D.E. (2021). Nonsteroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs, nonopioid analgesics, & drugs used in gout. Katzung, B.G., Vanderah, T.W. (Eds.), Basic & Clinical Pharmacology, 15e. McGraw Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2988&sectionid=250600111
  13. Solomon, D.H., Furst, D.E., Romain, P.L. (2020). NSAIDs: Therapeutic use and variability of response in adults. UpToDate. Retrieved July 14, 2021, from https://www.uptodate.com/contents/nsaids-therapeutic-use-and-variability-of-response-in-adults

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