Mechanism of Action of Diclofenac

Mechanism of Action of Diclofenac

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Introduction

Diclofenac is a widely used nonsteroidal anti-inflammatory drug (NSAID) belonging to the phenylacetic acid class. It exhibits potent anti-inflammatory, analgesic, and antipyretic properties and is commonly prescribed for musculoskeletal disorders, postoperative pain, arthritis, and dysmenorrhea. Diclofenac is a high-yield NSAID in pharmacology and clinical examinations because of its strong COX inhibition, relative COX-2 preference, and characteristic safety profile.

Mechanism of Action of Diclofenac
MOA of diclofenac
Diclofenac Mechanism of Action Flowchart
Stepwise mechanism of action of diclofenac

Mechanism of Action (Step-wise)

Diclofenac exerts its effects primarily by inhibiting cyclooxygenase-mediated prostaglandin synthesis.

Step-wise mechanism:

  1. Arachidonic Acid Release
    Tissue injury or inflammation activates phospholipase A₂, releasing arachidonic acid from cell membrane phospholipids.
  2. Cyclooxygenase (COX) Enzymes
    Arachidonic acid is converted into prostaglandin H₂ by cyclooxygenase enzymes (COX-1 and COX-2).
  3. Inhibition of COX Enzymes
    Diclofenac reversibly inhibits both COX-1 and COX-2, with a relatively higher functional selectivity toward COX-2 at therapeutic doses.
  4. Reduced Prostaglandin Synthesis
    Inhibition of COX enzymes decreases formation of pro-inflammatory prostaglandins (PGE₂, PGI₂).
  5. Anti-inflammatory Effect
    Reduced prostaglandins lead to decreased vasodilation, capillary permeability, and inflammatory mediator sensitization.
  6. Analgesic Effect
    Lower prostaglandin levels reduce peripheral and central nociceptor sensitization.
  7. Antipyretic Effect
    Inhibition of prostaglandin synthesis in the hypothalamus lowers the fever set point.
  8. Additional Actions
    Diclofenac also inhibits leukocyte migration and reduces free radical formation, contributing to its strong anti-inflammatory efficacy.

Pharmacokinetics

  • Absorption: Well absorbed orally; also available IM, IV, topical, and rectal
  • Bioavailability: ~50% due to first-pass hepatic metabolism
  • Distribution: Highly protein bound (>99%)
  • Metabolism: Hepatic metabolism (CYP2C9)
  • Elimination: Renal and biliary excretion of metabolites
  • Half-life: Short plasma half-life (~1–2 hours), but prolonged tissue persistence

Clinical Uses

Diclofenac is widely used in inflammatory and painful conditions:

  • Osteoarthritis
  • Rheumatoid arthritis
  • Ankylosing spondylitis
  • Acute musculoskeletal pain
  • Postoperative and post-traumatic pain
  • Dysmenorrhea
  • Migraine (acute attacks)
  • Gout (acute attacks, short-term use)

Topical diclofenac is preferred for localized pain to reduce systemic adverse effects.

Adverse Effects

Adverse effects are characteristic of NSAIDs and dose dependent:

  • Gastrointestinal:
    • Gastritis
    • Peptic ulcer disease
    • GI bleeding
  • Renal:
    • Reduced renal perfusion
    • Fluid retention
  • Cardiovascular:
    • Increased risk of thrombotic events (MI, stroke)
  • Hepatic:
    • Elevated liver enzymes
    • Rare hepatotoxicity
  • Hypersensitivity:
    • Rash
    • Bronchospasm (aspirin-sensitive asthma)

Comparative Analysis (must include a table + explanation)

Comparison of Common NSAIDs

FeatureDiclofenacIbuprofenCelecoxib
COX selectivityCOX-2 > COX-1 (functional)Non-selectiveCOX-2 selective
Anti-inflammatory potencyHighModerateHigh
GI riskModerate–HighModerateLow
CV riskModerate–HighLow–ModerateHigh
Topical availabilityYesLimitedNo

Explanation:
Diclofenac provides strong anti-inflammatory action comparable to selective COX-2 inhibitors but with higher gastrointestinal and cardiovascular risk. Ibuprofen is safer for short-term use, while celecoxib offers GI protection at the cost of increased cardiovascular risk.

MCQs (10–15)

  1. Diclofenac exerts its effect primarily by inhibiting:
    a) Phospholipase A₂
    b) Cyclooxygenase
    c) Lipoxygenase
    d) Histamine receptors

Answer: b) Cyclooxygenase

  1. Diclofenac belongs to which drug class?
    a) Salicylates
    b) Propionic acid derivatives
    c) Phenylacetic acid derivatives
    d) Oxicams

Answer: c) Phenylacetic acid derivatives

  1. Diclofenac reduces inflammation by decreasing synthesis of:
    a) Leukotrienes
    b) Bradykinin
    c) Prostaglandins
    d) Cytokines directly

Answer: c) Prostaglandins

  1. The analgesic effect of diclofenac is due to:
    a) Opioid receptor activation
    b) Reduced nociceptor sensitization
    c) NMDA receptor blockade
    d) Sodium channel inhibition

Answer: b) Reduced nociceptor sensitization

  1. Diclofenac has relatively greater inhibition of:
    a) COX-1 only
    b) COX-2 only
    c) COX-2 over COX-1
    d) Lipoxygenase

Answer: c) COX-2 over COX-1

  1. A major gastrointestinal adverse effect of diclofenac is:
    a) Constipation
    b) Pancreatitis
    c) Peptic ulcer
    d) Hepatitis

Answer: c) Peptic ulcer

  1. Diclofenac is contraindicated in patients with:
    a) Osteoarthritis
    b) Active peptic ulcer disease
    c) Migraine
    d) Dysmenorrhea

Answer: b) Active peptic ulcer disease

  1. Diclofenac reduces fever by acting on the:
    a) Pituitary gland
    b) Cerebellum
    c) Hypothalamus
    d) Brainstem

Answer: c) Hypothalamus

  1. Which route reduces systemic adverse effects of diclofenac?
    a) Oral
    b) Intramuscular
    c) Intravenous
    d) Topical

Answer: d) Topical

  1. Diclofenac increases cardiovascular risk primarily by:
    a) Platelet activation
    b) COX-2 inhibition
    c) Sodium retention only
    d) Bradycardia

Answer: b) COX-2 inhibition

FAQs (minimum 5)

  1. What is the primary mechanism of diclofenac?
    Inhibition of COX enzymes leading to reduced prostaglandin synthesis.
  2. Is diclofenac COX-2 selective?
    It shows functional preference for COX-2 but is not fully selective.
  3. Why does diclofenac cause gastric irritation?
    Due to inhibition of COX-1–mediated protective prostaglandins in the stomach.
  4. Does diclofenac affect renal function?
    Yes, it can reduce renal prostaglandins and impair renal perfusion.
  5. Is diclofenac safe for long-term use?
    Long-term use increases GI, renal, and cardiovascular risks.
  6. Why is topical diclofenac preferred in elderly patients?
    To minimize systemic adverse effects.

References

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