7.18 Eicosanoids & NSAIDs – Complete Study Notes

Arachidonic Acid & Eicosanoid Biochemistry

• Cell-membrane phospholipids supply $\text{arachidonic acid (AA)}$, a 20-carbon poly-unsaturated fatty acid (rate-limiting release by $\text{PLA}_2$).

• Four parallel metabolic routes:
  • Cyclo-oxygenase (COX-1 & COX-2) → prostanoids (prostaglandins, prostacyclin, thromboxane).
  • 5-Lipoxygenase (5-LOX) → leukotrienes & lipoxins (key in asthma).
  • Cytochrome P450 epoxygenase → epoxyeicosatrienoic acids (CV & renal modulation).
  • Free-radical, non-enzymatic → isoprostanes (oxidative stress markers).

• Prostanoid abbreviation map: PGI$<em>2$ = prostacyclin, TXA$</em>2$ = thromboxane, PGE$<em>2$, PGF$</em>{2\alpha}$, PGD$_2$.

• Local (autacoid) action: synthesized on demand, not stored; rapidly inactivated → short half-lives, confined to tissue of origin.

Physiologic & Pathologic Roles of Endogenous Prostanoids

• Kidney
  • PGE$<em>2$/PGI$</em>2$ ↑ renal blood flow → ↑ GFR, diuresis, natriuresis, kaliuresis.
  • TXA$_2$ ↓ renal blood flow.

• CV System / Ductus Arteriosus
  • PGE$<em>2$/PGI$</em>2$ = potent vasodilators → ↓ BP with reflex tachycardia.
  • Maintain patency of ductus arteriosus in utero.

• Blood
  • PGI$<em>2$ inhibits, TXA$</em>2$ stimulates platelet aggregation → central to aspirin therapy.

• Smooth Muscle / Uterus
  • PGF$<em>{2\alpha}$, PGE$</em>2$ cause uterine contraction (labor induction, medical abortion).

• CNS
  • PGE$_2$ ⇒ fever (hypothalamic set-point) & pain sensitization.

• Eye
  • PG analogues (e.g. latanoprost) ↑ uveoscleral outflow ↓ IOP in glaucoma.

COX Isoenzymes – COX-1 vs COX-2

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

• Definition: Non-steroidal inhibitors of $\text{COX}$ possessing
  • anti-inflammatory,
  • antipyretic,
  • analgesic activity.

• Core mechanism: reversible, competitive inhibition of COX-1/2 → ↓ PG/TXA synthesis.
  • Exception: Aspirin irreversibly acetylates COX (covalent).

• Drug families
  • Traditional non-selective: ibuprofen, naproxen, diclofenac, indomethacin, ketorolac, meloxicam, mefenamic acid, acetaminophen (weak anti-inflammatory).
  • COX-2–selective ("coxibs"): celecoxib (market survivor; rofecoxib, valdecoxib withdrawn).

Aspirin (Acetyl-Salicylic Acid)

• Unique irreversible acetylation of COX-1/2 → permanent TXA$_2$ blockade in anucleate platelets (effect lasts platelet lifetime $\approx 8\text{–}12\,\text{d}$).

• Low-dose (75–100 mg/day) clinical focus: cardioprotection (TIA, unstable angina, MI prophylaxis).

• At higher doses ( ≥3 g/day) full anti-inflammatory but ↑ toxicity.

• Dose-dependent uric-acid handling:
  • Low doses ↓ tubular secretion → ↑ serum urate (worsens gout).
  • High doses (>3 g) inhibit re-absorption → uricosuric.

• Possible secondary CV benefit: acetylated COX-2 → 15-R-HETE → 15-epi-lipoxin A$_4$ (anti-inflammatory, vasculo-protective).

Pharmacokinetics (All NSAIDs)

• Weak organic acids, pKa 3–5; well absorbed PO (enteric coating used to spare gastric COX-1).

• Highly (>95 %) albumin-bound → displacement DDIs (warfarin, sulfonylureas).

• Renal elimination: $\text{GF} + \text{tubular secretion}$ (acidic drugs compete for OAT).

• Aspirin → active metabolite salicylate; t½ rises with dose (saturation kinetics).

Therapeutic Uses

• Musculoskeletal inflammation: rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, gouty flare (symptomatic).

• Mild–moderate pain: dental, dysmenorrhea, post-op, soft-tissue injury.

• Fever (except aspirin in children).

• Closure of patent ductus arteriosus: indomethacin, ibuprofen IV.

• Obstetrics: PGE$<em>2$, PGF$</em>{2\alpha}$ analogues (dinoprostone, carboprost) for cervical ripening, labor induction, postpartum hemorrhage.

• Ophthalmology: latanoprost for open-angle glaucoma.

• Asthma adjuncts (NOT NSAIDs): 5-LOX inhibitor (zileuton), LTD$_4$ antagonists (montelukast, zafirlukast).

Class Adverse Effects

1. Gastro-intestinal (PG deficit)

   • Dyspepsia, ulcer, hemorrhage, perforation.

   • Mitigation: $\text{PPIs}$, misoprostol, COX-2 selective agents (still "less" not "zero").

2. Platelet / Bleeding

   • Reversible COX-1 blockade prolongs bleeding; aspirin irreversible.

3. Renal & Fluid

   • Salt/H$_2$O retention, edema, ↑ K$^+$, possible acute renal failure in volume-depleted or CHF patients.

4. CV Risk (esp. COX-2 selective)

   • ↑ MI, stroke, CHF, sudden death (PGI$<em>2$ suppression w/ intact TXA$</em>2$).

5. Hypersensitivity / Samter’s Triad

   • Asthma + nasal polyps + aspirin intolerance (shift toward leukotrienes).

6. CNS

   • Headache, dizziness; high-dose salicylate → tinnitus, confusion.

7. Pregnancy

   • Prolonged gestation & labor, premature ductus closure (avoid 3rd trimester).

8. Reye’s Syndrome

   • Aspirin use in viral illness <20 y → hepatic encephalopathy; absolute contraindication.

Drug–Drug Interactions

Structural Basis of COX-2 Selectivity

• Val$^{523}$ in COX-2 ⇒ accessory hydrophobic pocket.

• Bulky sulfonamide/ sulfone of celecoxib, rofecoxib fits pocket (won’t fit COX-1).

• Diagrammatically:
  \text{Entrance width}{\text{COX-2}} > \text{Entrance width}{\text{COX-1}}.

Key Exam-Style Facts Highlighted by Lecturer

• COX enzymes convert AA → prostanoids (NOT leukotrienes).

• Prostanoids = PGs + PGI$<em>2$ + TXA$</em>2$.

• Leukotriene D$_4$ is NOT a prostanoid.

• Aspirin: irreversible, non-selective COX inhibitor; primary clinical use = antiplatelet.

• Low-dose aspirin worsens gout; high-dose may be uricosuric (theoretical only).

Practical / Ethical Notes

• Misoprostol (PGE$_1$ analogue) for medical abortion & ulcer prophylaxis—politically sensitive usage; clinician must understand local law.

• Industry withdrew many coxibs (rofecoxib, valdecoxib) voluntarily after CV event signal; celecoxib remains with boxed warning.

• Pain management is ethically central; NSAIDs fill "mild–moderate" niche without opioid dependence liability.