Prostaglandins and Eicosanoids

Eicosanoid Basics - Tiny Lipid Titans

• Potent, short-lived local hormones (autacoids) from $C_{20}$ PUFAs.
• Main precursor: Arachidonic Acid (AA), an $\omega-6$ fatty acid.
• Classes: Prostaglandins (PGs), Thromboxanes (TXs) via cyclooxygenase (COX).
• Leukotrienes (LTs), Lipoxins (LXs) via lipoxygenase (LOX).
• Synthesized "on demand"; not stored.
• Mediate inflammation, pain, fever, platelet aggregation, smooth muscle.

⭐ Phospholipase A2 (PLA2) is the key enzyme releasing arachidonic acid from membrane phospholipids.

AA Metabolism - The Eicosanoid Factory

• Substrate: Arachidonic Acid (AA), a $C_{20:4}(\omega-6)$ PUFA.
  • Released from membrane phospholipids by Phospholipase A₂ (PLA₂).
  • PLA₂ inhibited by corticosteroids (via lipocortin).
• Pathways & Products:
  • Cyclooxygenase (COX) → PGH₂ (unstable intermediate) → Prostaglandins (PGs - inflammation, pain), Prostacyclin (PGI₂ - vasodilation, anti-platelet), Thromboxane A₂ (TXA₂ - vasoconstriction, pro-platelet).
    • COX-1 (constitutive), COX-2 (inducible).
    • Inhibited by NSAIDs.
  • Lipoxygenase (LOX) → Leukotrienes (LTs e.g., LTB₄ - chemotaxis; LTC₄, LTD₄, LTE₄ - bronchoconstriction, SRS-A), Lipoxins (anti-inflammatory).
    • 5-LOX inhibitors (Zileuton), LT receptor antagonists (Montelukast).

⭐ Aspirin irreversibly acetylates COX-1 & COX-2; its anti-platelet effect lasts for the platelet's lifespan (8-10 days) due to TXA₂ inhibition.

Prostaglandins/Thromboxanes - Inflammation & Clot Crew

• From arachidonic acid via COX pathway (COX-1/COX-2).
• Prostaglandins (PGs):
  • PGI₂ (Prostacyclin): Vasodilation, ↓platelet aggregation. Endothelial.
  • PGE₁: Maintains PDA (Alprostadil).
  • PGE₂: Uterine contraction, pain, fever (Dinoprostone).
  • PGF₂α: Uterine contraction, bronchoconstriction (Latanoprost).
• Thromboxanes (TXs):
  • TXA₂: Vasoconstriction, ↑platelet aggregation. Platelet origin.
• 📌 PGI₂: Platelet Inhibitor; TXA₂: Thrombus Activator.
• NSAIDs inhibit COX, ↓PG & TX.

⭐ Aspirin irreversibly inhibits platelet COX-1, ↓TXA₂ for platelet lifespan (7-10 days), key antiplatelet action.

Leukotrienes/Lipoxins - Allergy & Resolution Squad

• Leukotrienes (LTs): Pro-inflammatory; from Arachidonic Acid via 5-Lipoxygenase (5-LOX) & FLAP.
  • LTB4: Neutrophil chemoattractant, ↑adhesion.
  • Cysteinyl LTs (LTC4, LTD4, LTE4): Bronchoconstriction, ↑vascular permeability, mucus. (📌 "C" for Constriction). Formerly SRS-A.
  • Drugs: Zileuton (5-LOX inh.); Montelukast (CysLT1 antag.).
• Lipoxins (LXs): Anti-inflammatory "stop signals"; promote resolution.
  • LXA4, LXB4.
  • Synthesized by sequential LOX actions (e.g., 15-LOX then 5-LOX).
  • Inhibit neutrophil recruitment, stimulate monocyte clearance.

  ⭐ Aspirin acetylates COX-2, shifting it to produce Aspirin-Triggered Lipoxins (e.g., 15-epi-LXA4), enhancing resolution.

Eicosanoid Drugs - Drug Targets Galore

• COX Inhibitors (NSAIDs): Block cyclooxygenase → ↓Prostaglandins, Thromboxanes.
  • Non-selective: Aspirin (irreversible), Ibuprofen, Diclofenac. Uses: inflammation, pain, fever. Aspirin: antiplatelet.
  • COX-2 selective: Celecoxib, Etoricoxib. Less GI toxicity, ↑CV risk.
• Leukotriene Modifiers:
  • 5-LOX Inhibitor: Zileuton (asthma).
  • LT Receptor Antagonists (📌 LTRA): MonteLUKAST, ZafirLUKAST (asthma, allergic rhinitis).
• Prostaglandin Analogs:
  • PGE1: Misoprostol (ulcer prevention), Alprostadil (PDA, ED).
  • PGF2α: Latanoprost (glaucoma), Carboprost (PPH).
• Corticosteroids: Inhibit Phospholipase A2 → ↓Arachidonic Acid → ↓all eicosanoids. Broad anti-inflammatory.

⭐ Aspirin irreversibly acetylates COX, inhibiting platelet aggregation for their lifespan (8-10 days).

High‑Yield Points - ⚡ Biggest Takeaways

• Eicosanoids (PGs, TXs, LTs) derive from arachidonic acid via COX or lipoxygenase pathways.
• COX-1 (constitutive) & COX-2 (inducible) are key for PG/TX synthesis; inhibited by NSAIDs.
• Aspirin irreversibly inhibits COX; corticosteroids block phospholipase A₂, preventing AA release.
• Leukotrienes (via lipoxygenase) mediate allergic reactions and inflammation (e.g., asthma).
• PGI₂ (prostacyclin) causes vasodilation & ↓platelet aggregation; TXA₂ causes vasoconstriction & ↑platelet aggregation.