NSAIDs Block the COX-1 Active Site
Placeholder: NSAIDs competitively inhibit cyclooxygenase-1 in gastric mucosa.
- COX-1: Target enzyme (Constitutive isoform)
- Competitive: Binding mode (Active-site channel)
- Minutes: Onset (After absorption)
- Varies: Reversibility (Aspirin is irreversible)
How NSAIDs inhibit COX-1
Placeholder: drug occupies the cyclooxygenase channel, blocking arachidonic acid access.
Placeholder: irreversible acetylation (aspirin) differs from reversible NSAID binding.
Prostaglandin Output Falls Sharply
Placeholder: less PGE2 and PGI2 are made once COX-1 is inhibited.
- PGE2: Key mediator (Mucosal defense)
- Arachidonic acid: Pathway step (→ PGH2 blocked)
- Hours: Effect onset (Cumulative with dose)
- Dose-dependent: Dose relation (Higher dose, less PG)
Why prostaglandins matter here
Placeholder: PGE2 normally stimulates mucus, bicarbonate, and mucosal blood flow.
Placeholder: loss of prostaglandins removes the stomach's main defense signal.
The Protective Mucus-Bicarbonate Barrier Thins
Placeholder: reduced prostaglandin signaling thins the gel mucus layer.
- Mucus-HCO3: Barrier type (Gel layer)
- ~200 µm: Normal thickness (Unstimulated stomach)
- Thinning: Change (Reduced turnover)
- Barrier loss: Consequence (Acid can diffuse in)
Mucus barrier breakdown
Placeholder: mucus and bicarbonate secretion slow without prostaglandin stimulation.
Placeholder: a thinner barrier lets hydrogen ions reach epithelial cells.
Gastric Acid Reaches the Epithelium
Placeholder: hydrochloric acid now contacts unprotected epithelial cells.
- ~1–2: Luminal pH (Highly acidic)
- Epithelium: Exposed tissue (Surface mucosal cells)
- Back-diffusion: Cell effect (H+ ions enter cells)
- Erosion: Damage type (Superficial injury first)
Acid back-diffusion injury
Placeholder: hydrogen ions back-diffuse into cells, disrupting normal function.
Placeholder: repeated acid exposure converts erosions into deeper lesions.
Epithelial Erosion Becomes an Open Ulcer
Placeholder: sustained injury erodes through the mucosa into a crater.
- Full-thickness: Lesion depth (Through muscularis mucosae)
- Antrum/duodenum: Common site (NSAID-associated)
- PPI co-therapy: Prevention (Reduces acid burden)
- Dose & duration: Risk factor (Higher dose, higher risk)
From erosion to ulcer crater
Placeholder: unresolved erosion progresses to a defined ulcer crater with raised edges.
Placeholder: PPI co-therapy substantially lowers NSAID ulcer risk.