GI Pharmacology: Drugs for Peptic Ulcer

Introduction / Overview

Peptic ulcer disease (PUD) remains a significant gastrointestinal disorder worldwide, manifesting as mucosal erosions in the stomach or duodenum that result in pain, bleeding, or perforation. The prevalence of ulcerative lesions continues to pose diagnostic and therapeutic challenges, particularly in populations with increasing use of non‑steroidal anti‑inflammatory drugs (NSAIDs) and proton‑pump inhibitor (PPI) resistance. A thorough understanding of pharmacologic interventions is essential for clinicians and pharmacists to optimize ulcer management, mitigate complications, and improve patient outcomes.

Learning objectives for this chapter include:

• Describe the principal drug classes employed in the treatment of peptic ulcer disease and their chemical classifications.
• Explain the pharmacodynamic mechanisms that underlie acid suppression and mucosal protection.
• Summarize absorption, distribution, metabolism, and excretion profiles for key ulcer therapeutics.
• Identify indications, contraindications, and off‑label uses for antacid, H₂‑receptor antagonist, proton‑pump inhibitor, sucralfate, and antibiotic regimens.
• Recognize common adverse events, serious complications, and major drug interactions associated with ulcer pharmacotherapy.

Classification

1. Antacids

Antacids constitute a heterogeneous group of basic compounds that neutralize gastric acid by direct chemical reaction. Their principal classes include magnesium hydroxide, aluminum hydroxide, calcium carbonate, and sodium bicarbonate. These agents are typically administered orally, either as immediate‑release tablets or liquid suspensions, and provide rapid, albeit transient, symptomatic relief.

2. H₂‑Receptor Antagonists (H₂RAs)

H₂RAs target histamine‑2 receptors on parietal cells, thereby inhibiting cyclic‑AMP–mediated proton secretion. Representative members include ranitidine, famotidine, cimetidine, and nizatidine. Although historically considered first‑line therapy, the emergence of PPIs has altered their relative positioning in clinical practice.

3. Proton‑Pump Inhibitors (PPIs)

PPIs irreversibly inhibit the H⁺/K⁺‑ATPase (proton pump) in gastric parietal cells, producing a profound and sustained reduction in acid output. Commonly prescribed agents comprise omeprazole, esomeprazole, pantoprazole, lansoprazole, rabeprazole, and dexlansoprazole. Molecularly, PPIs are prodrugs that undergo activation in the acidic canaliculi of the parietal cell, forming sulfenamide intermediates that covalently bind cysteine residues on the pump.

4. Cytoprotective Agents

Sucralfate, a sodium salt of sulfated polysaccharide, forms a viscous, adhesive complex over ulcer surfaces, shielding the mucosa from acid, pepsin, and bile salts. It also stimulates prostaglandin synthesis and mucosal blood flow. Other agents, such as misoprostol (a prostaglandin E₁ analogue) and colchicine, are occasionally employed in specific scenarios, though their use is limited by tolerability and side‑effect profiles.

5. Antibiotic Regimens for H. pylori Eradication

H. pylori infection is a principal etiologic factor in PUD. Triple and quadruple therapy regimens typically combine a PPI with clarithromycin and amoxicillin or metronidazole, or a bismuth‑containing quadruple regimen. The selection of antibiotic combinations is influenced by local resistance patterns and patient factors such as allergies and prior exposure.

Mechanism of Action

1. Antacids

Neutralization of gastric hydrochloric acid occurs through ionic exchange between the basic metal hydroxides and the acidic gastric milieu, yielding water and inorganic salts. The resultant pH elevation diminishes pepsin activity and reduces mucosal irritation. Because antacids act locally, systemic absorption is minimal, and their therapeutic effect is limited to the time of contact.

2. H₂‑Receptor Antagonists

Histamine binds to H₂ receptors on the basolateral membrane of parietal cells, activating Gq proteins that stimulate phospholipase C. This cascade increases intracellular Ca²⁺ and activates protein kinase C, which in turn stimulates adenylate cyclase, raising cAMP levels. In contrast, H₂RAs competitively inhibit histamine binding, attenuating cAMP production and thereby reducing proton secretion. These agents also modestly inhibit acid secretion mediated by gastrin and acetylcholine.

3. Proton‑Pump Inhibitors

PPIs traverse the gastric lumen in a proton‑acidic environment, becoming protonated and penetrating the parietal cell canaliculi. Within the acidic microenvironment, they are converted to active sulfenamide forms that covalently attach to cysteine residues (Cys‑S5) on the proton pump. This irreversible inhibition necessitates de novo synthesis of pumps, resulting in acid suppression lasting 24–48 h. In addition, PPIs reduce gastrin‑driven acid secretion by blocking the secretomotor pathway.

4. Sucralfate

Sucralfate’s large polysaccharide backbone adsorbs to ulcer surfaces via hydrogen bonding and electrostatic interactions, forming a protective barrier that resists acid and pepsin infiltration. The complex also serves as a reservoir for growth factors, such as epidermal growth factor, promoting mucosal healing. By physically covering the ulcer, sucralfate reduces pain and facilitates epithelial restitution.

5. Antibiotic Regimens

Clarithromycin interferes with bacterial 50S ribosomal subunits, inhibiting protein synthesis. Amoxicillin targets bacterial cell wall synthesis by binding penicillin‑binding proteins. Metronidazole is a prodrug that, upon reduction in anaerobic bacterial cells, forms free radicals that damage DNA. Bismuth compounds exert bacteriostatic effects and coat the mucosa, offering a multifaceted approach to eradication.

Pharmacokinetics

1. Antacids

Oral antacids are largely non‑absorbed; however, some fractions of magnesium and aluminum may be absorbed, particularly in individuals with renal impairment. Distribution is primarily extracellular, and elimination occurs via renal excretion. The half‑life of magnesium hydroxide is approximately 8 h, whereas aluminum hydroxide may persist up to 24 h in the gastrointestinal tract. The lack of systemic absorption limits drug–drug interactions but necessitates caution in patients with compromised renal function due to potential accumulation of metal ions.

2. H₂‑Receptor Antagonists

H₂RAs exhibit rapid absorption from the gastrointestinal tract with peak plasma concentrations reached within 1–2 h. Famotidine demonstrates a plasma half‑life of 2–3 h and is largely renally excreted unchanged, warranting dose adjustment in chronic kidney disease. Cimetidine is metabolized hepatically via CYP enzymes, particularly CYP1A2, and exhibits a longer half‑life of approximately 4 h. Ranitidine and nizatidine have similar pharmacokinetic profiles, with elimination predominantly renal. Drug–drug interactions may arise through inhibition or induction of CYP enzymes, especially with cimetidine.

3. Proton‑Pump Inhibitors

PPIs are absorbed rapidly with peak concentrations achieved within 1–2 h. They are highly protein‑bound (>90 %) and undergo extensive hepatic metabolism, primarily via CYP2C19 and CYP3A4. The metabolite of omeprazole, 5‑methoxy‑4‑hydroxy‑2‑(1H‑indol‑3‑yl)‑phenol, is active and exhibits a half‑life of 2–3 h, whereas the parent drug’s half‑life is 0.5–1 h. Genetic polymorphisms in CYP2C19 significantly affect PPI metabolism, with poor metabolizers experiencing higher systemic exposure. Renal impairment has minimal impact on PPI pharmacokinetics, but hepatic dysfunction can delay clearance.

4. Sucralfate

Sucralfate is poorly absorbed (<1 %) and remains largely within the gastrointestinal lumen. It is excreted unchanged in feces, with minimal renal elimination. Because of its hydrophilic nature, it is not substantially metabolized, and its pharmacokinetics are independent of hepatic function. Concomitant ingestion of antacids or calcium supplements can impair sucralfate’s mucosal adhesion, necessitating staggered dosing schedules.

5. Antibiotic Regimens

Clarithromycin is well absorbed orally, reaching peak plasma concentrations within 1–2 h. It is extensively metabolized by CYP3A4, with a half‑life of approximately 3–4 h. Amoxicillin exhibits high bioavailability (~100 %) and a half‑life of 1–2 h, cleared predominantly by renal excretion. Metronidazole is absorbed rapidly, with a half‑life of 6–8 h, and is metabolized by hepatic reductases. Bismuth subsalicylate is minimally absorbed (<1 %) and is eliminated via fecal excretion. The pharmacokinetic properties of these agents influence dosing intervals and the duration of therapy in eradication regimens.

Therapeutic Uses / Clinical Applications

1. Antacids

Antacids are primarily used for immediate symptomatic relief of mild gastritis, heartburn, and post‑prandial acid reflux. They are also employed as adjuncts to other ulcer therapies to mitigate residual acid exposure. Off‑label, antacids are sometimes administered in combination with PPIs to achieve rapid pH elevation while awaiting maximal acid suppression.

2. H₂‑Receptor Antagonists

H₂RAs are indicated for the treatment of uncomplicated peptic ulcer pain, prophylaxis of NSAID‑induced gastric ulcers, and maintenance therapy following ulcer healing. They are also utilized in patients intolerant or contraindicated for PPIs. Off‑label applications include the management of gastroesophageal reflux disease (GERD) and Zollinger‑Ellison syndrome in combination with PPIs.

3. Proton‑Pump Inhibitors

PPIs constitute the cornerstone of peptic ulcer management. Indications encompass acute ulcer episodes, prevention of ulcer recurrence, eradication of H. pylori, and healing of NSAID‑induced mucosal damage. PPIs are also employed in patients with Zollinger‑Ellison syndrome and severe GERD refractory to H₂RAs. Off‑label uses extend to ulcerative colitis flare management and prevention of upper gastrointestinal bleeding in critically ill patients receiving anticoagulants.

4. Sucralfate

Sucralfate is indicated for the treatment of active gastric or duodenal ulcers, especially when mucosal protection is paramount. It is also used prophylactically in patients on high‑dose NSAIDs or corticosteroids. Off‑label indications include the management of chemotherapy‑induced mucositis and non‑ulcer dyspepsia with functional abdominal pain.

5. Antibiotic Regimens

H. pylori eradication regimens are indicated for patients diagnosed with peptic ulcer disease attributable to H. pylori infection. Triple therapy (PPI + clarithromycin + amoxicillin or metronidazole) is recommended for first‑line treatment in regions with low clarithromycin resistance. In areas with high resistance, bismuth quadruple therapy (PPI + bismuth + tetracycline + metronidazole) is preferred. Off‑label, these regimens are employed in chronic atrophic gastritis and gastric cancer prevention where H. pylori infection is implicated.

Adverse Effects

1. Antacids

Common side effects include constipation (aluminum hydroxide) and diarrhea (magnesium hydroxide). Rare events comprise hypocalcemia with calcium carbonate use and hypermagnesemia in renal impairment. Long‑term use may precipitate metabolic alkalosis or disturbed electrolyte balance.

2. H₂‑Receptor Antagonists

Typical adverse reactions involve headache, dizziness, constipation, or diarrhea. Cimetidine is associated with hepatotoxicity, interstitial nephritis, and gynecomastia due to hormonal interference. Ranitidine has been linked to immunologic reactions and, more recently, to contamination with N‑nitrosodimethylamine, prompting market withdrawals. Famotidine and nizatidine generally exhibit favorable safety profiles.

3. Proton‑Pump Inhibitors

PPIs may cause abdominal bloating, flatulence, diarrhea, and nausea. Long‑term therapy has been associated with increased risks of Clostridioides difficile infection, community‑acquired pneumonia, and low‑grade hypomagnesemia. Osteoporotic fractures have emerged as a concern with chronic PPI use, potentially mediated by impaired calcium absorption. Rarely, interstitial nephritis or acute interstitial lung disease may occur.

4. Sucralfate

Gastrointestinal discomfort, constipation, or diarrhea may arise. Rarely, hypersensitivity reactions or dysphagia have been reported. Given its limited systemic absorption, severe adverse reactions are uncommon.

5. Antibiotic Regimens

Clarithromycin may induce dysgeusia, nausea, diarrhea, and QT prolongation. Amoxicillin can cause rash, gastrointestinal upset, and, rarely, anaphylaxis. Metronidazole is associated with metallic taste, neuropathy, and, at high doses, hepatotoxicity. Bismuth compounds may lead to black stools, constipation, and, rarely, neurotoxicity. Resistance patterns and patient comorbidities dictate the risk profile of each regimen.

Drug Interactions

1. Antacids

Antacids can impair the absorption of concomitant medications such as ketoconazole, fluconazole, tetracyclines, and iron supplements by forming insoluble complexes. Timing of administration should be spaced at least 2 h apart to mitigate interaction risk.

2. H₂‑Receptor Antagonists

Cimetidine is a potent inhibitor of CYP1A2 and CYP3A4, reducing clearance of drugs like clozapine, theophylline, and cyclosporine. Famotidine and ranitidine exhibit negligible enzymatic inhibition. Nizatidine may inhibit CYP2D6, impacting metabolism of selective serotonin reuptake inhibitors.

3. Proton‑Pump Inhibitors

PPIs inhibit CYP2C19 and CYP3A4, thereby increasing plasma concentrations of drugs such as clopidogrel, phenytoin, and theophylline. Omeprazole and esomeprazole may potentiate the anticoagulant effect of warfarin by displacing it from plasma proteins. Grapefruit juice can further inhibit CYP3A4, intensifying interaction potential.

4. Sucralfate

Sucralfate can reduce the absorption of oral antibiotics, anti‑epileptics, and thyroxine. It is recommended that sucralfate be administered at least 2 h before or after these agents.

5. Antibiotic Regimens

Clarithromycin may inhibit CYP3A4, enhancing levels of statins, benzodiazepines, and macrolides. Metronidazole can potentiate the central nervous system effects of alcohol and benzodiazepines. Amoxicillin has minimal interaction potential but may interfere with the absorption of tetracyclines and fluoroquinolones.

Special Considerations

1. Pregnancy and Lactation

Antacids are generally considered safe in pregnancy (Category B). H₂RAs have limited data but are often used when benefits outweigh risks. PPIs are classified as Category B or C depending on the agent; omeprazole has been associated with rare congenital anomalies in animal studies, necessitating cautious use. Sucralfate is Category C, with animal studies indicating potential fetal toxicity. Antibiotic regimens for H. pylori eradication should avoid clarithromycin and tetracycline during pregnancy; alternative regimens using amoxicillin and metronidazole are preferred. Lactation safety is variable; most antacids and PPIs are excreted in minimal amounts into breast milk, but caution is advised with clarithromycin and sucralfate.

2. Pediatric Considerations

Children with peptic ulcer disease often present with dyspepsia or abdominal pain. Antacid dosing is weight‑based, with careful monitoring for electrolyte disturbances. H₂RAs are frequently used in pediatric NSAID‑induced ulcer prophylaxis, with famotidine being the most studied. PPIs are licensed for pediatric use in certain age groups; esomeprazole and omeprazole are commonly prescribed. Sucralfate is approved for children older than 2 years for ulcer healing. Antibiotic regimens for H. pylori eradication require pediatric formulations and dosing adjustments; amoxicillin and clarithromycin are commonly employed.

3. Geriatric Considerations

Older adults are at increased risk of PUD and medication interactions due to polypharmacy. Dose adjustments for PPIs or H₂RAs may be necessary in the presence of hepatic or renal impairment. Monitoring for hypomagnesemia, bone density loss, and infection risk is advisable. Sucralfate is often well tolerated but may cause constipation in this population.

4. Renal Impairment

Famotidine and ranitidine require dose reduction in reduced glomerular filtration rate (GFR) <30 mL/min, whereas cimetidine clearance is markedly impaired, necessitating significant dose adjustment. PPIs are primarily hepatically metabolized, but omeprazole and esomeprazole may accumulate in severe renal dysfunction. Sucralfate is renally excreted in minimal amounts, making it suitable for patients with renal failure. Antibiotic regimens necessitate adjustment of amoxicillin dosing in renal insufficiency; clarithromycin and metronidazole are less affected.

5. Hepatic Impairment

PPIs undergo hepatic metabolism; severe hepatic dysfunction may prolong half‑life, particularly for omeprazole and esomeprazole. H₂RAs such as ranitidine are minimally metabolized and can be used with caution. Sucralfate is not hepatically metabolized, rendering it safe in liver disease. Antibiotic regimens may require dose modification for clarithromycin and metronidazole, which are metabolized by hepatic enzymes.

Summary / Key Points

• Peptic ulcer pharmacotherapy encompasses acid‐neutralizing agents (antacids), receptor antagonists (H₂RAs), potent acid suppressors (PPIs), mucosal protectants (sucralfate), and H. pylori eradication antibiotics.
• PPIs provide the most profound and sustained acid suppression, making them the preferred first‑line option for ulcer healing and prevention of recurrence.
• Drug–drug interactions are frequent, especially with cytochrome P450 inhibitors; staggered dosing and monitoring are essential strategies.
• Special patient populations—including pregnant, lactating, pediatric, geriatric, renal, and hepatic patients—require individualized dosing and vigilant assessment of safety profiles.
• Long‑term PPI therapy may carry risks of hypomagnesemia, bone loss, and infection; periodic evaluation of necessity and lowest effective dose is recommended.

• Clinical pearls: Administer antacids at least 2 h before PPIs or antibiotics to avoid absorption interference; monitor serum magnesium in patients on chronic PPIs or antacids containing magnesium; consider CYP2C19 genotyping to predict PPI metabolism and guide dosing.

References

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