Arachidonic acid pathway

• Overview: A key inflammatory cascade that produces potent, short-acting lipid mediators called eicosanoids. It starts with the release of AA from the cell membrane phospholipids by phospholipase A2. AA is then metabolized by two major enzymatic pathways: cyclooxygenase (COX) and lipoxygenase (LOX).

Pharmacological Inhibition

• Corticosteroids: Inhibit phospholipase A2, preventing the release of AA from the membrane. This blocks the entire cascade, providing powerful, broad anti-inflammatory effects.
• NSAIDs: Inhibit COX enzymes.
• Zileuton: Inhibits 5-lipoxygenase.
• Montelukast, Zafirlukast: Block leukotriene receptors (specifically CysLT1 receptor for LTD4).

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1. Cyclooxygenase (COX) Pathway

• Enzymes: COX-1 and COX-2 convert AA to prostaglandin H2 (PGH2).
  • COX-1: Constitutively expressed. Responsible for “housekeeping” functions like gastric mucosal protection, renal blood flow, and platelet aggregation.
  • COX-2: Inducible enzyme, upregulated by inflammatory stimuli. Major source of prostaglandins in inflammation.
• Products & Functions:
  • Prostaglandins (PGE2, PGD2): Mediate inflammation (vasodilation, increased vascular permeability), pain (sensitize nerve endings), and fever. PGE2 also maintains a patent ductus arteriosus (PDA) and protects gastric mucosa.
  • Prostacyclin (PGI2): Produced by vascular endothelium. Causes vasodilation and inhibits platelet aggregation.
  • Thromboxane A2 (TXA2): Produced by platelets. Causes vasoconstriction and promotes platelet aggregation.
• Clinical Correlations:
  • NSAIDs (e.g., Ibuprofen, Indomethacin): Reversibly inhibit both COX-1 and COX-2.
    • Therapeutic effects: Anti-inflammatory, analgesic, antipyretic.
    • Adverse effects (due to COX-1 inhibition): Gastric ulcers, GI bleeding, renal damage (by constricting afferent arteriole).
  • Aspirin: Irreversibly inhibits COX-1 and COX-2. Its anti-platelet effect lasts for the life of the platelet (~8-10 days).
  • Celecoxib (COX-2 selective inhibitor): Provides anti-inflammatory effects with less risk of GI side effects. However, it can increase the risk of cardiovascular events (MI, stroke) by tipping the balance towards a prothrombotic state (↓ PGI2, unopposed TXA2).

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2. Lipoxygenase (LOX) Pathway

• Enzyme: 5-Lipoxygenase converts AA into 5-HPETE, which is then converted to leukotrienes (LTs).
• Products & Functions:
  • Leukotriene B4 (LTB4): A potent neutrophil chemotactic agent. “Neutrophils get here B4 others.”
  • Cysteinyl-Leukotrienes (LTC4, LTD4, LTE4):
    • Bronchoconstriction (potent effect).
    • Increase vascular permeability.
    • Mediate vasoconstriction.
  • Lipoxins: Have anti-inflammatory effects, helping to resolve inflammation.
• Clinical Correlations:
  • Asthma & Allergic Rhinitis: Leukotrienes are key mediators.
    • Zileuton: 5-LOX inhibitor, used for asthma.
    • Montelukast, Zafirlukast: Leukotriene receptor antagonists (LTRAs), block the effects of LTC4, LTD4, and LTE4. Used for asthma, especially aspirin-exacerbated respiratory disease (AERD).
  • Aspirin-Exacerbated Respiratory Disease (AERD): NSAID-induced inhibition of the COX pathway shunts AA down the LOX pathway, leading to an overproduction of pro-inflammatory leukotrienes, causing bronchospasm in susceptible individuals.

Feature	Prostaglandins (PGs)	Prostacyclin (PGI₂)
Primary Source	Most tissues, inflammatory cells	Vascular Endothelium
Vascular Action	Vasodilation (e.g., PGE₂)	Potent Vasodilation
Platelet Action	No direct pro-aggregatory effect (unlikeThromboxane A₂)	Potently INHIBITS platelet aggregation
Key Roles	Mediates fever, pain, uterine contraction, & gastric protection.	Maintains vascular homeostasis; prevents thrombosis on healthy endothelium.
Clinical Use	- Misoprostol (PGE₁ analog): Labor induction, gastric protection. - Latanoprost (PGF₂α analog): Glaucoma Tx.	- Epoprostenol, Iloprost (PGI₂ analogs): Pulmonary HTN Tx.
Inhibition	NSAIDs block synthesis of both PGs and PGI₂.	NSAIDs block synthesis.