Last revised by Joachim Feger on 21 Aug 2021

Paracetamοl (or acetaminοphen in North America) is the most widely used drug in the world. It is employed as an antipyretic and mild analgesic in both adults and children. Although once regarded as a benign agent, it is now viewed with increasing concern due to its acute hepatotoxicity following overdose.

Chemically the agent is known as N-acetyl-para-aminophenol, the name from which both the generic British and American names derive:

  • paracetamοl from N-acetyl-para-aminophenol
  • acetaminοphen from N-acetyl-para-aminophenol

Indeed, the American brand name, Tylenol®, is also derived from N-acetyl-para-aminophenol.

The systematic IUPAC name is N-(4-hydroxyphenyl)acetamide.

Acetaminophen produces a mild analgesic effect, similar in degree to that of aspirin 3.

It also acts as an antipyretic.

  • liver disease
  • asthma
  • allergy
  • certain medications (see Interactions)

With short-term use at treatment doses, acetaminophen is extremely well tolerated and most people experience no side effects whatsoever. Rarely, an allergic skin reaction may be seen.

Although historically acetaminophen was considered to be a very safe agent, it has now been fairly well-established that long term treatment-range dosing is associated with increased risk of cardiovascular morbidity, which is thought to be related to their effects on the cyclooxygenases (cfNSAIDs)  2.

Unfortunately, acetaminophen is associated with significant acute hepatotoxicity even with small and/or "staggered" overdoses, which is not uncommonly fatal. Indeed, some have stated that acetaminophen would not receive a commercial licence today if it was a new agent 1

In adults, 7.5 g, or 150 mg/kg in children, are thought to be the minimum acute doses (taken all at once, not over a day) associated with toxicity 3.

Post overdose, the amount of NAPQI in the liver may overwhelm the ability of the glutathione system to neutralise this toxic metabolite. This results in free NAPQI very quickly binding to and arylating key cellular proteins, such that cell death ensues 3.

The other major organ to be affected to any clinically significant degree is the kidney. About 1 in 4 patients with hepatotoxicity experience marked renal impairment, rising to 1 in 2 of those with fulminant liver failure. The primary nephrotoxicity is thought to occur as a result of a localized increase in NAPQI causing acute tubular necrosis. Patients needing haemodialysis is not uncommon 3. Isolated renal injury without simultaneous hepatotoxicity is occasionally seen 3.

Acute toxic damage to other organs, e.g. heart, is thought to be related to a general multiorgan failure rather than a cardiospecific effect 3. Acute pancreatitis due to acetaminophen is incredibly rare 6.

Toxicity has been subdivided into three stages, based upon time since overdose, most do not progress past stage one 3:

  • stage I (<24 hr)
    • non-specific: nausea and vomiting, sweating, loss of appetite, lethargy; many are asymptomatic
  • stage II (24-72 hr)
  • stage III (72-96 hr)
    • time of peak liver injury
    • death usually within 5 days of overdose from acute hepatic failure in conjunction with multiorgan failure

It is imperative to treat acetaminophen poisoning as soon as possible to maximize the chance of a good outcome. Unfortunately, there is a paucity of symptoms and signs in the early period post-overdose, and this may result in complacency. By the time the hepatic injury has manifested clinically, permanent liver damage may already have occurred 3.

The key parameter to be assessed is the serum acetaminophen concentration; from this, the “acetaminophen nomogram” may be used to determine whether active treatment is necessary 3.

N-acetylcysteine (NAC) is used as an antidote to acetaminophen poisoning with several concurrent neutralising mechanisms. These include

  • metabolism of NAC to glutathione, replenishing it
  • binding of NAC to NAPQI directly forming non-toxic moieties
  • promoting hepatic sulfation over NAPQI formation

As it takes time for the liver's glutathione to be consumed by the excessive NAPQI formed from the oxidation of acetaminophen, there is a golden period, up to 8-10 hours after the overdose during which NAC may be given with almost certain good outcomes. Unfortunately, NAC seems to provide no therapeutic value if it is first given after 15 hours have elapsed.

NAC is given orally, with an IV option in reserve if ingestion is not possible.

Certain medications via induction of the CYP450 system may accelerate the metabolism of acetaminophen, potentiating possible toxicity:

  • sulfinpyrazone
  • isoniazid
  • anticonvulsants

The mechanism of action of paracetamοl is complex and it acts at multiple levels throughout the pathway of conduction of pain sensation. The levels of action include cellular receptors in the spinal cord, the thalamus and centrally in the cerebral cortex 1-3:

  • cyclooxygenase (COX) inhibition both peripherally and centrally
  • cannabinoid system: via its AM404 metabolite

Its maximal analgesic effect is reached at ~1000 mg single dose 3. In general, acetaminophen dosing in adults is 500-1000 mg every four to six hours, with a maximal per diem dose of 4 g. It is advised to lengthen the interval between doses in those with renal impairment 3

The analgesic effect following ingestion takes about 30 minutes and it lasts about four hours 3.

Following oral administration, acetaminophen undergoes first-pass metabolism, and ~90% is metabolized by the liver. In adults, it is conjugated with glucuronic acid (50-60%), sulfuric acid (25-35%) and cystine (approximately 3%), resulting in biologically inert metabolites (most is conjugated with sulfates in children). of the remaining 10%, half is renally-excreted as the drug. The remaining 5% is hepatic N-hydroxylated by the CYP450 system, especially CYP2E1, forming N-acetyl-p-benzoquinone imine, better known as NAPQI 2,3

NAPQI is the mediator of hepatotoxicity (see Toxicity below) when acetaminophen is taken in excess. However, at treatment doses, the NAPQI is rapidly neutralised by glutathione and excreted as cysteine or mercapturic acid in the urine 2.

Its volume of distribution in adult patients is 1 to 2 L/kg, 0.7 to 1 L/kg in children. The drug freely passes into almost all bodily fluids with transit across both the placenta and blood-brain barrier 3.

Certain medications via induction of the CYP450 system may accelerate the metabolism of acetaminophen:

  • sulfinpyrazone
  • isoniazid
  • anticonvulsants

In some patients, acetaminophen toxicity may be worse due to increased activity of liver enzymes; conversely, when hepatic enzymatic degradation is impaired, toxicity may be ameliorated, e.g. acute ethanol excess 3.

In the 1880s Arnold Chan and Paul Heppa, two young physicians at the University of Strasbourg, erroneously gave acetanilide as an anthelmintic to a patient when they intended to administer naphthalene (the pharmacy had mistakenly supplied them with the wrong agent). Although acetanilide was not very successful as a treatment for worms it had a profound effect on the patient’s fever 1,2.

In 1886 they brought acetanilide to market as a novel antipyretic, Antifebrin. Although cheap to manufacture, acetanilide was ultimately unsuccessful due to its inherent toxicity, including causing methemoglobinemia.

Further research identified two derivatives of acetanilide which were much less toxic but retained potent antipyretic and analgesic properties. These were phenacetin and N-acetyl-p-aminophenol (i.e. acetaminophen), both discovered by Harmon Northrop Morse in 1878, and first administered to patients in 1887 by Joseph von Mering, a German clinical pharmacologist 2-5.

Initial work suggested that N-acetyl-p-aminophenol also caused methemoglobinemia, however, this was later found to be due to contaminants. However, by this time, phenacetin had become the predominant analgesic and it retained this pre-eminence until it was found to cause analgesic nephropathy.

In 1948, Bernard Brodie and Julius Axelrod were able to show that the primary metabolite responsible for the pharmacological properties of acetanilide and phenacetin in the body was acetaminophen. It was phenylhydroxylamine, a co-metabolite that caused the methemoglobinemia. Thus from the early 1950s has been an extraordinary rise in the popularity of acetaminophen which is now the most popular analgesic in the world 2,3.

Acetaminophen was first sold in 1955 when McNeil Laboratories introduced it to the American market as a prescription-only pediatric medication called Tylenol Children’s Elixir. In 1956 it became available in the UK as Panadol sold by Frederick Stearns & Co., a branch of Sterling Drug Inc. 2.

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Cases and figures

  • Figure 1: acetaminophen
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