(8) Anti-inflammatory (NSAIDs) Drugs, Pharmacology, Animation

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

  • Most widely used anti-inflammatory agents.

  • Inhibit production of prostaglandins, compounds that contribute to inflammatory responses.

  • Effective without causing immunosuppression.

Prostaglandin Synthesis

  • Synthesized from arachidonic acid via cyclooxygenase (COX) enzymes.

  • COX enzymes metabolize arachidonic acid to prostaglandin H2 (PGH2), which is then converted to various isoforms for specific functions in different tissues.

  • Physiological roles of prostaglandins:

    • Maintain local homeostasis (temperature, bronchial and uterine tone, gastric mucosal barrier).

    • Balance maintained by opposing effects:

      • TXA2 constricts blood vessels and promotes platelet aggregation.

      • PGI2 dilates blood vessels and inhibits platelet aggregation.

Role in Inflammation

  • Prostaglandin levels increase significantly during acute inflammation, particularly PGE2, which is associated with cardinal inflammatory signs.

  • Two main COX enzymes:

    • COX-1:

      • Constitutively expressed in most cells.

      • Major source of physiological prostaglandins.

    • COX-2:

      • Induced by inflammatory stimuli.

      • Predominant source of inflammatory prostaglandins, but also has physiological functions in some tissues.

Classification of NSAIDs

  • NSAIDs are classified as:

    • Non-selective: Inhibit both COX-1 and COX-2 (except aspirin).

      • Act as reversible COX inhibitors; compete with arachidonic acid for enzyme binding.

    • COX-2 selective: Specifically inhibit COX-2.

Aspirin

  • Unique in actions as it covalently modifies and permanently inactivates COX enzymes, especially affecting blood platelets.

  • Effectively reduces TXA2 production, thus inhibiting platelet aggregation throughout the platelets' lifespan.

  • Commonly prescribed to prevent heart attacks and ischemic strokes.

  • Cautions:

    • Should not be taken with other non-selective NSAIDs due to competition for binding sites.

    • Prolongs bleeding; contraindicated in bleeding risks or hemorrhagic disorders.

    • Associated with Reye’s syndrome in children.

Gastrointestinal Effects of NSAIDs

  • COX-1 dependent prostaglandins:

    • Suppress gastric acid secretion.

    • Protects gastric mucosal barrier.

  • Non-selective NSAIDs may lead to:

    • Gastric irritation, peptic ulcer disease, and gastrointestinal bleeding.

COX-2 Specific NSAIDs (Coxibs)

  • Designed to reduce gastrointestinal toxicity.

  • Controversial due to potential increase in cardiovascular occlusive events:

    • Selective inhibition of COX-2 reduces PGI2 (vasodilatory and anti-thrombotic) while not affecting TXA2 (pro-thrombotic).

    • This imbalance may favor blood clot formation and vasoconstriction.

Cardiovascular and Renal Effects

  • Some non-selective NSAIDs show varying cardiovascular toxicity based on their COX-2 to COX-1 inhibition ratios.

  • Risks associated with suppression of physiological vasodilatory prostaglandins:

    • Increased likelihood of hypertension and edema.

    • May exacerbate underlying heart failures.

  • Inhibition of renal vasodilatory prostaglandins can lead to reduced renal blood flow and glomerular filtration, risking renal ischemia or failure.