What is the mechanism of action of paracetamol (acetaminophen) and diclofenac?

Mechanism of Action of Paracetamol and Diclofenac

Paracetamol (Acetaminophen)

Paracetamol exerts its analgesic and antipyretic effects primarily through central inhibition of prostaglandin synthesis, likely via a COX-1 variant enzyme (possibly COX-3), combined with modulation of descending serotonergic pain pathways, though its precise mechanism remains incompletely understood despite over a century of clinical use. 1, 2

Central Prostaglandin Inhibition

• Paracetamol inhibits prostaglandin synthesis predominantly in the central nervous system rather than peripherally, distinguishing it from traditional NSAIDs 3, 4
• The drug achieves therapeutic plasma concentrations of approximately 100 μM after standard 1g oral doses, which falls within the range (4-200 μM) needed for prostaglandin synthesis inhibition in cellular systems 5
• Evidence from COX-1 knockout mice demonstrates that paracetamol's antinociceptive action is mediated through a COX-1 gene-derived protein, likely the splice variant COX-3, as the drug's effects on writhing responses and brain prostaglandin E2 levels were abolished in COX-1 knockout mice but preserved in COX-2 knockout mice 2
• Paracetamol completely suppresses LPS-induced elevation of prostaglandin E2 in the brain, which directly explains its antipyretic effect 4

Serotonergic Pathway Modulation

• Paracetamol stimulates descending serotonergic (5-HT) pathways in the spinal cord that inhibit nociceptive signal transmission, though it does not directly bind to serotonergic receptors 6
• Spinally administered antagonists of several 5-HT receptor subtypes abolish paracetamol's antinociceptive activity, confirming indirect serotonergic involvement 6

Additional Mechanisms

• The drug is metabolized by the peroxidase component of prostaglandin H synthase, though the relationship to cyclooxygenase inhibition remains unclear 5
• Paracetamol metabolites, particularly AM404 (N-(4-hydroxyphenyl)-arachidonamide), may activate endocannabinoid and TRPV1 systems, contributing to analgesia 1
• TRPA1 channel activation by electrophilic paracetamol metabolites mediates hypothermia at higher doses but is independent of its antipyretic effect at therapeutic doses 4

Clinical Implications

• Paracetamol is analgesic and antipyretic but not anti-inflammatory, reflecting its central rather than peripheral mechanism 3
• The drug has minimal gastrointestinal toxicity at recommended doses (≤4g/24 hours) due to lack of peripheral COX inhibition 3
• Hepatotoxicity occurs when cytochrome P450 metabolism produces the toxic metabolite NAPQI after glutathione stores are saturated 3

Diclofenac

Diclofenac produces analgesia through non-selective inhibition of both COX-1 and COX-2 enzymes peripherally and centrally, blocking prostaglandin synthesis and thereby reducing inflammation, pain, and fever. 3

Prostaglandin Synthesis Inhibition

• NSAIDs including diclofenac produce analgesia by blocking the biosynthesis of prostaglandins, which are inflammatory mediators that initiate, cause, intensify, or maintain pain 3
• Unlike paracetamol, diclofenac inhibits peripheral prostaglandin production effectively, explaining its anti-inflammatory properties 2
• Diclofenac reduces prostaglandin E2 concentrations both peripherally and centrally 2

Clinical Pharmacology

• Diclofenac is available as a topical patch formulation for localized neuropathic pain, acting locally with some central inhibitory effects 3
• The drug demonstrates efficacy comparable to paracetamol in minor musculoskeletal trauma, with a Dutch randomized trial of 547 patients showing non-inferiority between acetaminophen and diclofenac 3

Adverse Effect Profile

• Diclofenac carries dose-dependent risks of gastrointestinal bleeding, cardiovascular events, and renal dysfunction due to prostaglandin inhibition in these organ systems 3
• History of peptic ulcer disease and advanced age (>60 years) increase risk of gastrointestinal complications 3
• Co-prescription with proton pump inhibitors significantly reduces gastrointestinal adverse events when NSAIDs are necessary 3
• Particular caution is required in patients on ACE inhibitors, diuretics, or antiplatelets due to drug interactions 3

Comparative Considerations

• Combination use of paracetamol and NSAIDs like diclofenac significantly increases hospitalization risk for upper gastrointestinal adverse events compared to either agent alone 3
• When combining these agents, gastroprotection should be strongly considered 3