Upper GI pharmacology - important classes of drugs to know

 Acid suppression therapy

Acid suppression therapy plays a central role in the management of a range of upper gastrointestinal conditions, including gastro-oesophageal reflux disease (GORD), peptic ulcer disease, and dyspepsia. By reducing gastric acid secretion, these therapies help relieve symptoms, promote mucosal healing, and prevent complications such as bleeding or strictures. 

With the widespread use of proton pump inhibitors (PPIs) and H2-receptor antagonists, it’s important for medical students and clinicians alike to understand their mechanisms, appropriate indications, and potential risks—especially given rising concerns about long-term use.

🔬 Proton pump inhibitors (PPIs) – irreversible acid blockers

💡 Mechanism:

• PPIs (e.g., omeprazole, pantoprazole, esomeprazole) inhibit H⁺/K⁺ ATPase (proton pump) in parietal cells, preventing gastric acid secretion regardless of upstream stimulation.
• Since PPIs bind irreversibly, acid suppression continues until new proton pumps are synthesised (~24-48 hours).

💊 Clinical applications:

• ✅ Peptic ulcer disease – Reduces acidity for ulcer healing.
• ✅ GORD (gastro-oesophageal reflux disease) – Decreases oesophageal exposure to acid, relieving symptoms.
• ✅ Zollinger–Ellison syndrome – Controls gastrin-secreting tumours (gastrinoma).
• ✅ NSAID-induced gastropathy – Protects mucosa in long-term NSAID use.

🚫 Contraindications & precautions: (think about why?)

• ❌ Long-term use increases infection risk (Clostridioides difficile, pneumonia).
• ❌ Reduced calcium & magnesium absorption, increasing fracture risk.
• ❌ Risk of rebound acid hypersecretion after abrupt discontinuation.

💡 Physiological Interaction:

• PPIs override physiological regulation (gastrin, histamine, vagal stimulation) by directly inhibiting the terminal acid secretion step.
• Chronic use increases gastrin secretion (via feedback), causing ECL cell hyperplasia—though not typically clinically significant.

🔬 H₂-Receptor antagonists – Competitive histamine blockers

💡 Mechanism:

• H₂ blockers (e.g., ranitidine, famotidine) competitively inhibit histamine binding at parietal cell H₂ receptors, reducing cAMP-dependent acid secretion.
• Unlike PPIs, they do not block basal- acid production entirely.

💊 Clinical applications:

• ✅ GORD (mild cases) – Symptomatic relief by reducing acid output.
• ✅ Peptic ulcers – Slows acid-driven ulceration without complete shutdown.
• ✅ Stress ulcer prophylaxis – Common in hospitalised patients (ICU).

🚫 Contraindications & precautions:

• ❌ Tolerance develops over time → Reduced effectiveness with prolonged use.
• ❌ Cimetidine inhibits CYP450 enzymes, causing drug interactions (e.g., warfarin, theophylline).
• ❌ May worsen delirium in elderly patients (CNS penetration).

💡 Physiological Interaction:

• Blocks histamine’s amplification effect on gastrin and vagal stimulation but does not override direct acetylcholine-mediated acid secretion.
• Reduces volume of gastric juice, but pepsin activation still occurs due to residual acidity.

🔬 Antacids – Rapid neutralisation of acid

💡 Mechanism:

• Antacids (e.g., aluminium hydroxide, magnesium hydroxide, calcium carbonate) chemically neutralise gastric acid, raising pH in the stomach.
• Do not inhibit acid production, but temporary relief from hyperacidity symptoms.

💊 Clinical Applications:

• ✅ GORD (short-term symptom relief) – Quick acid neutralisation.
• ✅ Dyspepsia – Reduces acidity discomfort after meals.
• ✅ Peptic ulcer support – Temporary relief while healing occurs.

🚫 Contraindications & Precautions:

• ❌ Aluminium-based antacids cause constipation, magnesium-based cause diarrhoea.
• ❌ Calcium carbonate may trigger rebound acid hypersecretion after prolonged use.
• ❌ Interferes with absorption of some drugs (e.g., tetracyclines, fluoroquinolones).

💡 Physiological Interaction:

• No effect on gastrin, histamine, or vagal pathways, just direct chemical neutralisation of acid.
• Does not prevent acid secretion, only modifies stomach pH temporarily.

🔬 PPI vs. H₂ Blockers – Mechanism & Effectiveness

🔹 PPIs (omeprazole, pantoprazole, esomeprazole) → Irreversibly block H⁺/K⁺ ATPase in parietal cells, suppressing nearly all acid production.

🔹 H₂ Blockers (ranitidine, famotidine) → Competitively inhibit histamine at H₂ receptors, reducing stimulated acid secretion but not basal acid output.

💡 Key Difference:

• PPIs are far more potent & longer-lasting (24–48 hours of acid suppression).
• H₂ blockers work faster but develop tolerance, limiting their long-term effectiveness.

🩺 Clinical Decision-Making: When to Use Each?

✅ PPIs – Best for Persistent, Severe & High-Risk Conditions

💊 Use PPIs for:

• ✔️ GORD (moderate to severe cases) – Long-term suppression prevents oesophageal mucosal damage.
• ✔️ Peptic ulcer disease (PUD) – Superior ulcer healing & prevention of recurrence.
• ✔️ NSAID-induced gastric injury – Protective against NSAID-related gastropathy.
• ✔️ Zollinger–Ellison syndrome (gastrinoma) – Controls excessive acid production.

🚫 When NOT to Use PPIs:

• ❌ Mild acid reflux or occasional dyspepsia (risk outweighs benefit).
• ❌ If long-term use poses risks (fractures, infections, vitamin deficiencies).

✅ H₂ Blockers – Useful for Mild, Intermittent Symptoms

💊 Use H₂ Blockers for:

• ✔️ Mild to moderate reflux (short-term relief) – Reduces nocturnal acid production effectively.
• ✔️ Stress ulcer prophylaxis (hospital patients) – Prevents stress-related mucosal damage.
• ✔️ Breakthrough symptoms in PPI therapy – Occasional use can complement PPI treatment.

🚫 When NOT to Use H₂ Blockers:

• ❌ Severe reflux or ulcers (they don’t suppress acid enough).
• ❌ Long-term use due to tolerance – Effectiveness declines over weeks.

⚠️ Clinical Considerations – Side Effects & Long-Term Implications

🚨 PPIs Risks:

• Increased risk of infections (C. difficile, pneumonia).
• Reduced calcium & magnesium absorption → Possible fractures with long-term use.
• Rebound acid hypersecretion if stopped abruptly.

🚨 H₂ Blockers Risks:

• Drug interactions (cimetidine inhibits CYP450 → risk for warfarin, theophylline interactions).
• May worsen delirium in elderly patients.
• Tolerance develops with continuous use.

🔄 Summary: When to Choose PPI vs. H₂ Blocker?

✅ Use PPIs for chronic, severe acid-related conditions (e.g., GORD, ulcers, gastrinoma).

✅ Use H₂ blockers for mild, intermittent symptoms or as short-term therapy.

✅ Avoid long-term PPI use when unnecessary (minimise side effects).

✅ H₂ blockers lose effectiveness with continuous use—best for short-duration relief.

💡 Final Thought: PPIs are the stronger and longer-lasting option, while H₂ blockers may be better for short-term or mild symptoms. Choosing depends on symptom severity, recurrence risk, and patient-specific factors

Anti-Emetics & Nausea Control

🔬 5-HT₃ Antagonists – Serotonin Blockers for Vomiting

💡 Mechanism:

• Ondansetron blocks 5-HT₃ receptors in the chemoreceptor trigger zone (CTZ) & GI tract, preventing serotonin-mediated nausea.
• Especially effective for chemotherapy-induced and post-operative nausea.

💊 Clinical Applications:

• ✅ Chemotherapy-induced nausea (CINV) – Prevents serotonin surge in response to cell damage.
• ✅ Post-operative nausea – Reduces vagal-induced nausea post-surgery.

🚫 Contraindications & Precautions:

• ❌ Prolongs QT interval, increasing risk of arrhythmias.
• ❌ May cause constipation due to slowed gut transit.

💡 Physiological Interaction:

• Blocks vagal afferent serotonin signalling, preventing brainstem activation of vomiting reflex.
• Does not affect vestibular nausea pathways, so ineffective for motion sickness.

🔬 D₂-Receptor Antagonists – Dopamine Blockers for Nausea

💡 Mechanism:

• Metoclopramide, prochlorperazine block D₂ receptors in the CTZ, reducing nausea signalling.
• Metoclopramide also increases gastric motility, reducing delayed gastric emptying-induced nausea.

💊 Clinical Applications:

• ✅ Gastroparesis-induced nausea – Improves gastric motility.
• ✅ Post-surgical & drug-induced nausea (opioids, anaesthetics).

🚫 Contraindications & Precautions:

• ❌ May cause extrapyramidal side effects (dystonia, Parkinsonism-like symptoms).
• ❌ Contraindicated in Parkinson’s disease (worsens dopamine depletion).
• ❌ Increases prolactin levels, causing gynaecomastia & galactorrhoea.

💡 Physiological Interaction:

• Blocks central nausea pathways, but enhances gastric emptying via cholinergic effects.
• Less effective for motion sickness, which has a vestibular-mediated pathway.

🔬 H₁ & Muscarinic Antagonists – Motion Sickness Control

💡 Mechanism:

• Promethazine, diphenhydramine (H₁ antagonists) and hyoscine (anticholinergic) block vestibular-mediated vomiting pathways.
• Best for motion sickness and vestibular nausea (e.g., vertigo, labyrinthitis).

💊 Clinical Applications:

• ✅ Motion sickness prevention – Used for travel-related nausea.
• ✅ Vestibular disorders – Reduces vertigo-induced vomiting.

🚫 Contraindications & Precautions:

• ❌ Sedation common due to CNS penetration.
• ❌ Anticholinergic side effects (dry mouth, blurred vision, urinary retention).

💡 Physiological Interaction:

• Inhibits histamine & acetylcholine transmission in the vestibular nuclei, preventing nausea triggered by movement.
• Has no effect on toxin-mediated nausea (e.g., chemotherapy-related nausea).

🔬 Choosing the Right Anti-Emetic: Nausea Pathways & Drug Selection

Nausea arises from different physiological pathways, meaning not all anti-emetics work for every cause. Understanding the source of nausea helps target the correct receptors, improving efficacy while avoiding unnecessary side effects.

For example:

• ✅ Motion sickness (vestibular nausea) → H₁ antihistamines & anticholinergics (Promethazine, Hyoscine).
• ✅ Drug-induced nausea (CTZ-mediated) → D₂ antagonists (Metoclopramide, Prochlorperazine) & 5-HT₃ antagonists (Ondansetron).
• ✅ GI stasis or irritation (visceral nausea) → Metoclopramide (prokinetic) & Ondansetron (for irritation-related nausea).
• ✅ Severe multi-system nausea → Combination therapy (Ondansetron + NK₁ antagonists for chemotherapy, Metoclopramide + steroids for surgery).

💡 Final Thought:

Anti-emetics are highly specific to their nausea pathway—understanding physiology ensures optimal drug selection, minimising side effects while maximising relief.

#Pharmacology #Gastroenterology #MedicalEducation