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Acetaminophen

Paracetamolum

For medical students2 min readUpdated 2026-10-10

Acetaminophen (widely known as paracetamol) is a non-opioid analgesic derived from para-aminophenol. It acts on the central nervous system and is used primarily as an antipyretic and analgesic agent.

Drug ClassNon-opioid analgesic (acting on the CNS)
MechanismInhibition of COX primarily within the CNS
ToxicityHepatotoxicity (hepatocyte necrosis upon glutathione depletion)
Formulation0.2 g tablets

Mechanism of Action

Chemically, acetaminophen is a weak acid (pKa 9.5) capable of donating a proton. It serves as an active metabolite of phenacetin.

The primary mechanism of action involves inhibiting cyclooxygenase (COX). Unlike classic nonsteroidal anti-inflammatory drugs (NSAIDs), the drug blocks the enzyme predominantly in the central nervous system. Additionally, its analgesic effect is thought to involve modulation of the brain's serotonergic and cannabinoid systems.

Pharmacological Effects and Indications

The drug produces two prominent pharmacological effects:

Crucially: acetaminophen completely lacks anti-inflammatory activity. Its clinical efficacy in reducing fever and relieving pain is comparable to that of acetylsalicylic acid (Acidum acetylsalicylicum).

Indications:

Metabolism and Biotransformation

The metabolism of Paracetamolum is a complex hepatic process involving multiple biotransformation pathways:

  1. Microsomal Oxidation (N-oxidation): Carried out by endoplasmic reticulum enzymes (cytochrome P450 system). The isoenzymes CYP1A2 and CYP2E1 are involved.
  2. CYP1A2 is influenced by diet and environment: it is induced by tobacco smoke components, charcoal-broiled foods, cruciferous vegetables, and certain drugs (omeprazole, rifampin, phenobarbital). It is inhibited by antibiotics (ciprofloxacin, macrolides) and cimetidine.
  3. CYP2E1 is closely linked to alcohol metabolism. It is induced by chronic ethanol (Spiritus aethylicus) intake and isoniazid. It is inhibited by disulfiram and ritonavir.
  4. Biosynthetic Reactions (Conjugation): The drug undergoes glucuronidation (forming glucuronic acid esters or amides) and sulfation (forming sulfates).

Toxicology and Side Effects

At therapeutic doses, the drug is safe, and side effects are rare. However, acetaminophen has a narrow therapeutic index: the toxic dose is only about 3 times the therapeutic dose.

Pathogenesis of Toxicity (Toxicification): During microsomal oxidation (primarily via CYP2E1), a reactive and highly toxic intermediate metabolite is formed: N-acetyl-p-benzoquinone imine (NAPQI). Under normal conditions, this metabolite is rapidly detoxified in the cytosol by the enzyme glutathione S-transferase via conjugation with glutathione.

In overdose or when CYP2E1 is induced (e.g., chronic alcoholism or isoniazid use), the production of this toxic metabolite surges dramatically, depleting hepatic glutathione stores. Unbound NAPQI causes severe cellular damage—hepatocyte necrosis (hepatotoxicity) and renal tubular injury.

In cases of toxicity, emergency administration of sulfhydryl group donors (acetylcysteine, methionine) is required. These agents are effective only within the first 8–12 hours following ingestion, as they replenish glutathione stores to inactivate the metabolite.

Formulation and Prescribing Guidelines

The drug is administered orally.

Mnemonic

PARA: Liver toxicity (P), Analgesic & Antipyretic without anti-inflammatory action (A), Reduces central COX (R), Acetylcysteine is the antidote (A).

Frequently asked questions

What are the absolute contraindications for paracetamol use?

Absolute contraindications to Paracetamolum include severe hepatic impairment and chronic alcoholism. Chronic alcohol use induces CYP2E1, significantly increasing the risk of hepatotoxicity when paracetamol is administered.

What pediatric formulations of paracetamol are available?

For pediatric patients, paracetamol is available in several formulations:

  • Infusion solution — contraindicated in neonates under 1 month of age.
  • Rectal suppositories — used from 3 months of age.
  • Oral suspension — used from 3 months of age.
Why doesn't acetaminophen have anti-inflammatory effects?

The drug inhibits cyclooxygenase predominantly within the central nervous system. It has virtually no effect on peripheral prostaglandin synthesis, and thus lacks peripheral anti-inflammatory activity.

What is the danger of combining paracetamol and alcohol?

Chronic ethanol consumption induces the CYP2E1 isoenzyme. This accelerates the formation of the toxic metabolite NAPQI, rapidly depleting glutathione and creating a high risk of hepatic necrosis even at therapeutic doses.

How does the antidote work in overdose?

Acetylcysteine and methionine act as sulfhydryl group donors. They restore depleted stores of endogenous glutathione, which is essential for binding and detoxifying the reactive intermediate metabolite.

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