Gastric Mucosa Protection Strategies

Strategies for Protecting the Gastric Mucosa from Acid Exposure

• Mechanisms:
  • Inhibiting acid secretion (e.g., cimetidine, omeprazole, prostaglandins, muscarinic antagonists)
  • Preventing acid-contact (e.g., sucralfate)
  • Neutralizing acid (e.g., antacids)

Multiple Mechanisms Regulate Gastric Acid

• Hormonal:
  • Gastrin: increases HCl production
  • Histamine: increases HCl production
• Neural:
  • Acetylcholine: increases HCl production
• Paracrine:
  • Histamine: increases HCl production

Strategies for Inhibiting Parietal Cell Acid Secretion

• Mechanisms:
  • Gastrin antagonists: block gastrin's effect
  • Histamine antagonists: block histamine's effect
  • Muscarinic antagonists: block acetylcholine's effect

Strategies for Inhibiting Parietal Cell Acid Secretion

• Mechanisms:
  • Histamine: Inhibits acid secretion by influencing cAMP and protein kinase
  • Prostaglandins: Inhibit acid secretion by influencing cAMP and protein kinase, also stimulating mucus, bicarbonate secretion. and mucosal blood flow.

H+, K+-ATPase (Proton Pump)

• Located in the apical membrane of parietal cells in secretory canaliculi.
• Requires ATP for function.
• Inhibition blocks both basal and stimulated acid secretion.

Omeprazole (Prilosec)

• A proton pump inhibitor
• Irreversibly inhibits acid production
• Rapidly reduces gastric acid (95% reduction with 20 mg/day for 7 days)
• Highly protein-bound, metabolized by CYP2C and CYP3A.
• Short half-life (1-2 hours), but prolonged duration of action.
• Taken just before meals, not with other acid-suppressing agents

Other Proton Pump Inhibitors

• Esomeprazole
• Rabeprazole
• Lansoprazole
• Pantoprazole

Proton Pump Inhibitors (PPI) Side Effects

• Well-tolerated; possible hypergastrinemia (tumor growth)
• Nausea or vomiting
• Headaches; skin rashes

Histamine H₂ Antagonists

• Cimetidine
• Ranitidine
• Famotidine
• Nizatidine

Cimetidine

• Competitive H₂ receptor antagonist
• Markedly inhibits basal acid secretion, including nocturnal secretion.
• Readily absorbed after oral administration.
• Relatively short duration of action (4-8 hours).
• Given in multiple doses (300-400 mg, 2-4 times daily).

Ranitidine, Famotidine, Nizatidine

• Similar mechanism to cimetidine, but longer duration of action (8-12 hours).
• Less frequent administration (150 or 300 mg, 1-2 times daily).
• Fewer interactions with P450 enzymes than cimetidine.

Anticholinergics

• Pirenzepine
• Telenzepine
• Blocks acetylcholine at muscarinic (M3) receptors.
• Effectively reduces acid secretion (30-40 percent).
• Limited by side effects.

Prostaglandins (PGE2 & PGI2)

• Act on prostaglandin EP3 receptors in parietal and epithelial cells.
• Inhibits acid secretion, gastrin release, and pepsin secretion
• Stimulates mucus secretion, bicarbonate secretion, and mucosal blood flow.
• Cytoprotective: Effective against direct damage from alcohol, aspirin, and NSAIDs.

Misoprostol (Cytotec)

• Synthetic prostaglandin E1 analog
• Reduces acid secretion (85-95 percent with 0.1-0.2 mg);
• Prevents NSAID-induced gastric ulcers
• Side effects: diarrhea and abortion

Antacids

• Weak bases that neutralize HCl in the stomach
• Raise gastric pH
• Common examples: magnesium hydroxide, magnesium trisilicate, magnesium-aluminum mixtures, calcium carbonate, sodium bicarbonate

Antacid Characteristics

• Sodium bicarbonate: rapid onset; short duration; systemic alkalosis
• Calcium hydroxide: intermediate onset; moderate duration; constipating
• Magnesium hydroxide: rapid onset; moderate duration; diarrhea
• Aluminum hydroxide: slow onset; moderate duration; constipating

Sucralfate

• Basic aluminum salt of sucrose octasulfate
• Forms a viscous paste-like substance in acidic environments (pH < 3-4) which adheres to gastric and duodenal mucosa, especially to partially denatured proteins.
• Protects mucosal damage and inhibits ulcer formation.

H. pylori Treatment

• If present, eradicate with antibiotics and acid inhibition (e.g., omeprazole and amoxicillin).

Prokinetic Drugs

• Enhance transit of materials through the GI tract (enhances GI motility)
• Increases neuromuscular transmission
• Often used for GERD (Gastroesophageal reflux disease), gastroparesis, nighttime heartburn, severe refractory constipation.

Metoclopramide (Reglan)

• Antiemetic that improves gastric emptying by indirectly releasing acetylcholine
• Dopamine D2 receptor antagonist
• Oral bioavailability, crosses blood-brain barrier
• Side effects: sedation, dystonic reactions, anxiety, gynecomastia, galactorrhea

Domperidone (Motilium)

• Antiemetic that improves gastric emptying and is a dopamine receptor antagonist;ganglionic stimulant
• Low oral bioavailability, does not cross the blood-brain barrier
• Side effects: headaches; gynecomastia

Anti-emetic Classification

• Prokinetics (e.g., metoclopramide, domperidone)
• 5-HT3 antagonists (e.g., ondansetron, granisetron):
• Antimuscarinics (e.g., hyoscyamine, atropine):
• H₁ antihistamines (e.g., cyclizine, promethazine):
• Neuroleptics (e.g., chlorpromazine, haloperidol)

Preferred Drugs for Vomiting

• Motion sickness: Hyoscyamine, cyclizine, promethazine
• Vomiting from anticancer drugs: Ondansetron, metoclopramide
• Post-operative vomiting: Ondansetron, metoclopramide

Constipation

• Condition of difficulty emptying the bowels, often associated with hard stool.
• Purgatives: Promote defecation (e.g., bisacodyl, castor oil, lactulose, magnesium sulfate).
• Some drugs can cause constipation (e.g., anticholinergics, opioids, iron, calcium channel blockers).

Diarrhea

• Condition with at least three loose or watery stools daily.
• Most commonly caused by intestinal infection due to a virus, bacteria, or parasite (e.g., gastroenteritis).
• Bacteria that cause diarrhea include Campylobacter, Salmonella, and E. coli

Diarrhea Treatment

• Replacement of fluids and electrolytes: Oral rehydration salts (ORS) containing NaCl, KCl, sodium citrate, and glucose mixed in water.
• Treatment of the cause: Antibiotics (if needed)
• Antidiarrheal agent: Kaolin-pectin, adsorbents (e.g., charcoal), antimotility agents (e.g., codeine, diphenoxylate, loperamide).