NSAIDs & Your Stomach: What Every Med Student Should Know

Nonsteroidal anti-inflammatory drugs (NSAIDs)—such as ibuprofen, naproxen, and aspirin—are essential in clinical practice, but their effects on the gastric mucosa are often underestimated. A common belief is that taking NSAIDs with food reduces stomach irritation. But is this actually true? 

We have discussed this earlier in the week, so thought I would provide a bit more explanation ... featuring my favourite biochemical pathway!!! IYKYK 😁

 How Do NSAIDs Harm the Stomach?

NSAIDs work by inhibiting cyclooxygenase (COX) enzymes, which block prostaglandin synthesis. While this reduces inflammation and pain, it also removes the protective barrier that prostaglandins provide for the gastric mucosa. Without them:

•  Mucus & bicarbonate secretion drops → Stomach lining becomes more vulnerable to acid
•  Gastric blood flow decreases → Delayed healing of micro-injuries
•  Direct epithelial injury occurs → Increased risk of gastritis, ulcers, and GI bleeding

Understanding COX Pathways

The COX pathway plays a central role in inflammation and homeostasis, converting arachidonic acid into prostaglandins, thromboxanes, and prostacyclins—all key mediators in various physiological processes. There are two main isoforms:

🧬 COX-1 ("Housekeeping Enzyme")

• Constitutively expressed in most tissues
• Generates protective prostaglandins involved in gastric mucosa maintenance, renal function, and platelet aggregation
• Supports mucus and bicarbonate production to prevent acid-induced damage

🔥 COX-2 ("Inducible Enzyme")

• Upregulated during inflammation (e.g., injury, infection)
• Produces pro-inflammatory prostaglandins, leading to pain, fever, and swelling
• A major target for selective COX-2 inhibitors, which aim to reduce inflammation while sparing COX-1

🟢 NSAIDs & COX Inhibition

NSAIDs block COX enzyme activity, preventing prostaglandin synthesis. However, inhibition of each isoform leads to distinct effects:

🔴 Non-Selective NSAIDs (Ibuprofen, Naproxen, Aspirin)

• Inhibit both COX-1 and COX-2, reducing inflammation but increasing gastric risks
• Aspirin irreversibly inhibits COX-1, impairing platelet aggregation—used in cardioprotection

🟢 Selective COX-2 Inhibitors (Celecoxib, Etoricoxib)

• Target COX-2 preferentially, reducing inflammation while sparing COX-1 (gastric protection maintained)
• However, increased cardiovascular risks due to unopposed thromboxane A2

🤔 So what about unopposed thromboxane A2?

Thromboxanes (TXA2) and prostacyclins (PGI2) are closely tied to the COX pathway and have opposing effects, especially in vascular homeostasis.

• Thromboxane A2 (TXA2): Produced mainly by platelets via COX-1, TXA2 promotes vasoconstriction and platelet aggregation, increasing the risk of clot formation. This is why aspirin, which irreversibly inhibits COX-1, helps prevent thrombosis in cardiovascular patients.
• Prostacyclin (PGI2): Mainly produced by vascular endothelial cells via COX-2, PGI2 induces vasodilation and inhibits platelet aggregation, counteracting TXA2’s effects.

When NSAIDs non-selectively inhibit both COX-1 and COX-2, they disrupt this balance, potentially leading to:

✔ Increased bleeding risk (if TXA2 is suppressed too much, reducing clotting)

✔ Increased cardiovascular risk (if PGI2 inhibition removes protective vasodilation)

This is why COX-2 selective inhibitors (like celecoxib) carry increased cardiovascular risk—they preserve TXA2 but suppress PGI2, tilting the balance toward pro-thrombotic effects.

🍽 Does Taking NSAIDs With Food Protect the Stomach?

Eating before taking NSAIDs can reduce direct irritation, but it does NOT prevent the core mechanism of injury related to COX inhibition. Here’s the breakdown:

✔ Food delays absorption, so peak NSAID levels rise more gradually → May reduce acute discomfort

✔ Gastric emptying slows, giving stomach tissue more time to respond → Can lower irritation

❌ Prostaglandin inhibition still occurs → Ulcer risk remains

❌ No protection against systemic effects (e.g., GI bleeding)

🚑 So What Actually Helps?

✔ For high-risk patients, consider PPIs (e.g., omeprazole) or misoprostol to offset mucosal damage

✔ Weigh COX-2 selective inhibitors carefully—they may spare gastric mucosa but have cardiovascular risks

✔ Use the lowest effective dose for the shortest duration—NSAIDs should never be taken long-term without medical oversight. 

Key Takeaway: Eating with NSAIDs might soften local irritation, but it does NOT eliminate ulcer or GI bleed risk. Understanding the COX pathway helps us predict and mitigate NSAID-related risks. Its my favourite pathway for a reason ! Proactive strategies—like gastroprotection for vulnerable patients—are essential.

What are the other common risk factors and protective factors for gastric erosions / ulcers. Share your thoughts below! 👇