Paracetamol mechanism of action – central COX inhibition and antipyretic action via hypothalamus

Paracetamol – Mechanism of Action

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Introduction

Paracetamol (also known as Acetaminophen) is one of the most commonly used drugs for fever and mild-to-moderate pain. Unlike NSAIDs, it has minimal anti-inflammatory action and does not cause gastric irritation.

It is classified as:

  • An analgesic and antipyretic
  • Belonging to the para-aminophenol derivative class

Despite its widespread use, its exact mechanism of action has long been debated and is often misunderstood—making it a favorite question in exams like GPAT, NEET-PG, NIPER, MBBS, and NCLEX.

Stepwise Mechanism of Action of Paracetamol

  1. Central COX Inhibition (COX-3 Hypothesis):
    Paracetamol acts predominantly in the central nervous system (CNS). It inhibits cyclooxygenase (COX) enzymes, especially a brain-specific COX variant (possibly COX-3), leading to reduced synthesis of prostaglandins in the hypothalamus.
  2. Antipyretic Effect via Hypothalamus:
    By inhibiting prostaglandin E₂ (PGE₂) in the preoptic area of the hypothalamus, it lowers the set-point for body temperature → antipyretic effect.
  3. Analgesic Action (Spinal and Supraspinal Sites):
    Decreased central prostaglandin levels also reduce the activation of pain receptors → analgesic effect.
  4. No Peripheral Anti-inflammatory Effect:
    In peripheral tissues, high levels of peroxides in inflamed areas limit paracetamol’s COX inhibition, explaining its poor anti-inflammatory action.
  5. TRPV1 & Serotonin Modulation (Additional):
    Emerging evidence suggests that paracetamol’s metabolites (like AM404) may also activate TRPV1 receptors and enhance serotoninergic descending pain pathways—contributing to analgesia.

Pharmacokinetic Parameters of Paracetamol

ParameterValue
Bioavailability60–90% (oral)
Onset of Action30–60 minutes
Half-life2–3 hours
Protein Binding20–25%
MetabolismLiver (Phase I & II – glucuronidation, sulfation)
ExcretionRenal (as conjugates)

At high doses, metabolism shifts to CYP2E1 pathway, producing the toxic metabolite NAPQI → hepatotoxicity risk.

Clinical Uses of Paracetamol

  • Fever (any age group, preferred antipyretic in children)
  • Mild to moderate pain: headache, muscle pain, dental pain
  • Osteoarthritis (preferred in patients with GI risk)
  • Safe option in gastritis or peptic ulcer disease
  • Can be used in pregnancy

Adverse Effects of Paracetamol

  • Hepatotoxicity in overdose due to NAPQI accumulation
  • Rare: skin reactions (Stevens-Johnson syndrome), anemia
  • Usually safe at therapeutic doses

🛡️ Antidote: N-acetylcysteine (NAC) – restores hepatic glutathione and detoxifies NAPQI.

Comparative Analysis: Paracetamol vs Ibuprofen

FeatureParacetamolIbuprofen
Anti-inflammatoryMinimalStrong
AntipyreticYesYes
Gastric irritationRareCommon (COX-1 inhibition)
Platelet effectNoneMild, reversible inhibition
Preferred in childrenYesYes (but avoid long-term use)
Liver toxicity riskYes (overdose)Minimal
Kidney safetySafer (unless prolonged/high dose)Nephrotoxic risk in dehydration

Practice MCQs

Q1. The primary mechanism of paracetamol’s antipyretic effect is:
A. COX-1 inhibition in peripheral tissues
B. Inhibition of PGE₂ synthesis in hypothalamus ✅
C. Activation of opioid receptors
D. Suppression of histamine release

Q2. Which organ is primarily affected in paracetamol toxicity?
A. Kidney
B. Liver ✅
C. Brain
D. Heart

Q3. The antidote for acute paracetamol poisoning is:
A. Atropine
B. Naloxone
C. N-acetylcysteine ✅
D. Activated charcoal

Q4. Why does paracetamol lack anti-inflammatory action?
A. It inhibits prostacyclin only
B. It acts only on peripheral COX
C. It’s a weak inhibitor of COX-2
D. Peroxide-rich environments reduce its efficacy ✅

Q5. Paracetamol is safe in which of the following conditions?
A. Severe liver disease
B. Peptic ulcer disease ✅
C. Chronic alcoholism
D. Uncontrolled diabetes

Q6. The toxic metabolite responsible for liver injury in overdose is:
A. Acetylsalicylate
B. AM404
C. NAPQI ✅
D. Serotonin

Q7. Which phase of metabolism converts paracetamol to safe conjugates?
A. Phase 0
B. Phase I oxidation
C. Phase II glucuronidation & sulfation ✅
D. CYP3A4 hydroxylation

Q8. The TRPV1 receptor involvement in paracetamol MOA is linked to:
A. Fever reduction
B. Analgesic effect ✅
C. Vasodilation
D. Platelet inhibition

Q9. Which statement is FALSE about paracetamol?
A. It can be given to infants
B. It is a good anti-inflammatory agent ✅
C. It acts centrally
D. It is safer for gastric patients

Q10. Which statement is TRUE?
A. Paracetamol causes GI bleeding like aspirin
B. It irreversibly inhibits COX-2
C. It works via prostaglandin suppression in CNS ✅
D. It enhances serotonin breakdown

FAQs

Q1: Can paracetamol be used in pregnancy?
Yes, it is considered safe when used in recommended doses.

Q2: Is paracetamol an NSAID?
No, it lacks significant anti-inflammatory properties and does not affect platelets or gastric mucosa like traditional NSAIDs.

Q3: What happens in paracetamol overdose?
It leads to the accumulation of NAPQI, a hepatotoxic metabolite, causing potential liver failure.

Q4: How soon should N-acetylcysteine be given after overdose?
Best within 8 hours of ingestion for maximum effectiveness.

References

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