Arachidonic Acid Pathway

Overview

• Arachidonic acid: Precursor of bioactive lipid metabolites (eicosanoids) like prostaglandins, leukotrienes, and epoxyeicosatrienoic acids.
• Pro-inflammatory: These substances trigger oxidative stress and stimulate the immune response.
• Treatment: Intervening in this pathway can manage inflammation.

Pathway Outline

• Release: Phospholipase A2 releases arachidonic acid from the membrane.
• Pathways:
  • Recycling: Arachidonic acid can be reincorporated into the phospholipid membrane.
  • Enzymatic Changes: Can be converted into active metabolites through different pathways.

Enzymatic Pathways

Lipoxygenase Pathway (LOX)

• Enzyme: 5-lipoxygenase
• Conversion: Arachidonic acid → 5-HPETE → leukotriene A4 (LTA4)
• Further Conversions:
  • LTA4 to LTC4/D4/E4: By LTC4 synthase (bronchoconstriction)
  • LTA4 to LTB4: By LTA4 hydrolase (neutrophil chemotaxis)

Cyclooxygenase Pathway (COX)

• Enzymes: COX-1 and COX-2
• Conversion: Arachidonic acid → PGG2 → PGH2 (cyclic endoperoxides)
• Further Conversions:
  • PGH2 to Prostacyclin (PGI2): By prostacyclin synthase (vasodilation, inhibits platelet aggregation)
  • PGH2 to Prostaglandins (PGE1, PGE2, PGF2α): By prostaglandin synthase (various effects)
  • PGH2 to Thromboxanes (TXA2, TXB2): By thromboxane synthase (vasoconstriction, promotes platelet aggregation)

Functions of Bioactive Products

• LTB4: Neutrophil chemotaxis ("B4 buses neutrophils").
• LTC4, LTD4, LTE4: Increase bronchial tone ("CDE increase bronchial tone").
• PGI2: Decreases platelet aggregation, vasodilation ("Platelet Gathering Inhibitor").
• PGE1: Vasodilation.
• PGE2, PGF2α: Increase uterine tone ("E and F increase uterine tone").
• TXA2: Increases platelet aggregation, vasoconstriction ("Thrombocytosis Extra Activator").

Medications and Their Mechanisms

• Glucocorticoids (e.g. cortisol): Inhibit phospholipase A2.
• NSAIDs (e.g. ibuprofen): Inhibit COX-1.
• Selective COX-2 Inhibitors (e.g. celecoxib): Inhibit COX-2.
• Epoprostenol: Inhibits PGI2.
• Carboprost: Inhibits PGF2α.
• Dinoprostone: Inhibits PGE2.
• Alprostadil: Inhibits PGE1.
• Montelukast, Zafirlukast: Inhibit leukotrienes (specifically LTC4, LTD4, LTE4).
• Zileuton: Inhibits 5-lipoxygenase, preventing LTA4 formation.

Key Points for Exams

• Neutrophil Chemotaxis: LTB4 (important mnemonic: "B4 buses neutrophils").
• Bronchial Tone: LTC4, LTD4, LTE4 increase (treat with inhibitors in asthma).
• Platelet Aggregation/Vasodilation: PGI2, PGE1, PGE2, PGF2α, TXA2 have specific roles highlighted above.