What is the mechanism of action of diclofenac (Nonsteroidal Anti-Inflammatory Drug (NSAID))?

Mechanism of Action of Diclofenac (NSAID)

Diclofenac primarily works by inhibiting cyclooxygenase (COX-1 and COX-2) enzymes, which blocks prostaglandin synthesis in peripheral tissues, resulting in analgesic, anti-inflammatory, and antipyretic effects. 1

Primary Mechanism

• Diclofenac is a potent inhibitor of prostaglandin synthesis through inhibition of both COX-1 and COX-2 enzymes, though it demonstrates relatively greater selectivity for COX-2 1, 2
• By inhibiting these enzymes, diclofenac prevents the conversion of arachidonic acid to prostaglandins, which are key mediators of inflammation, pain, and fever 3, 1
• The reduction in prostaglandin production in peripheral tissues is believed to be the primary mechanism responsible for diclofenac's therapeutic effects 1

Additional Mechanisms

• Beyond COX inhibition, diclofenac has several other pharmacological actions that contribute to its efficacy:
  • Inhibition of the thromboxane-prostanoid receptor 2
  • Alteration of arachidonic acid release and uptake 2
  • Inhibition of lipoxygenase enzymes 2
  • Activation of the nitric oxide-cGMP antinociceptive pathway 2
  • Potential inhibition of substance P 2
  • Blockage of acid-sensing ion channels 2

Spinal and Central Effects

• Diclofenac can cross the blood-brain barrier, allowing it to exert effects on spinal nociception 4
• It may suppress neuronal hyperexcitability by blocking neuronal potassium channels in a concentration-dependent manner 4
• These central effects may explain why diclofenac is particularly effective for certain types of pain compared to other NSAIDs 4

Pharmacokinetic Properties

• Diclofenac is rapidly and completely absorbed after oral administration (100% bioavailability compared to IV administration) 1
• However, due to first-pass metabolism, only about 50% reaches systemic circulation 1
• Peak plasma concentrations are achieved approximately 1 hour after administration in fasting individuals 1
• Despite its relatively short plasma half-life (1.5-2 hours), diclofenac persists in synovial fluid, which may contribute to its sustained anti-inflammatory effects in joints 1, 5

Clinical Implications and Safety Considerations

• Like other NSAIDs, diclofenac's inhibition of COX enzymes can lead to adverse effects:

  • Gastrointestinal complications due to COX-1 inhibition (though fewer than with aspirin or indomethacin) 5
  • Cardiovascular risks, particularly with higher doses and longer duration of use 3
  • Renal effects due to prostaglandin inhibition 3

• The relative COX-2 selectivity of diclofenac places it at a higher cardiovascular risk profile compared to less COX-2 selective NSAIDs 3

• Diclofenac, like etoricoxib, lies on the more COX-2-selective end of the spectrum, which may contribute to its cardiovascular risk profile 3

Formulation Advances

• Various formulations of diclofenac have been developed to improve efficacy, tolerability, and convenience:
  • Delayed and extended-release forms to improve safety and provide once-daily dosing 6
  • Potassium salt formulations for faster absorption and rapid onset of pain relief 6
  • Topical formulations to enable local treatment while minimizing systemic absorption 6
  • Submicron particle formulations to provide efficacy at reduced doses with lower systemic absorption 6

Understanding diclofenac's mechanism of action helps explain both its therapeutic benefits and potential risks, allowing for more informed clinical decision-making when prescribing this medication.