Pharmacology of Drugs for Peptic Ulcer

Introduction/Overview

Peptic ulcer disease (PUD) represents a common clinical condition characterized by a breach in the mucosal lining of the stomach or duodenum, extending through the muscularis mucosa. The pathophysiology involves an imbalance between aggressive factors, primarily gastric acid and pepsin, and defensive mucosal mechanisms. The pharmacological management of PUD has evolved significantly, shifting from a primary focus on acid suppression to a more nuanced approach that includes eradication of Helicobacter pylori and enhancement of mucosal defense. This chapter provides a systematic examination of the pharmacological agents used in the treatment and prevention of peptic ulcers, detailing their mechanisms, clinical applications, and associated considerations.

The clinical relevance of these therapeutic agents is substantial, given the prevalence of PUD and its associated complications, including hemorrhage, perforation, and gastric outlet obstruction. Effective pharmacotherapy not only promotes ulcer healing but also prevents recurrence and manages symptoms, thereby reducing morbidity and healthcare utilization. An understanding of the pharmacology underlying these drugs is essential for rational therapeutic decision-making.

Learning Objectives

• Classify the major drug categories used in the management of peptic ulcer disease and describe their primary sites of action.
• Explain the molecular and cellular mechanisms of action for acid-suppressive agents, mucosal protectants, and anti-H. pylori therapies.
• Analyze the pharmacokinetic profiles of these drug classes and relate them to dosing regimens and therapeutic outcomes.
• Evaluate the spectrum of adverse effects, significant drug interactions, and special population considerations for peptic ulcer drugs.
• Formulate appropriate therapeutic strategies for common clinical scenarios in PUD, integrating knowledge of efficacy and safety profiles.

Classification

Drugs employed in the management of peptic ulcer disease can be systematically classified based on their primary mechanism of action. This classification provides a framework for understanding therapeutic strategies.

Acid-Suppressing Agents

This category comprises drugs that directly or indirectly reduce the secretion of gastric hydrochloric acid.

• Proton Pump Inhibitors (PPIs): Omeprazole, Esomeprazole, Lansoprazole, Pantoprazole, Rabeprazole, Dexlansoprazole. These are substituted benzimidazoles that covalently inhibit the H⁺/K⁺-ATPase pump.
• Histamine H₂-Receptor Antagonists (H2RAs): Cimetidine, Ranitidine, Famotidine, Nizatidine. These agents competitively inhibit histamine binding at parietal cell H₂ receptors.
• Anticholinergics: Pirenzepine, Telenzepine (M₁-selective muscarinic antagonists). Their use is now largely historical in PUD.
• Prostaglandin Analogues: Misoprostol. This agent inhibits acid secretion via a receptor-mediated mechanism and enhances mucosal defense.

Mucosal Protectants and Cytoprotective Agents

These drugs do not significantly reduce acid secretion but strengthen the gastric mucosal barrier.

• Sucralfate: A complex salt of sucrose octasulfate and aluminum hydroxide.
• Colloidal Bismuth Compounds: Bismuth subsalicylate, Bismuth subcitrate.
• Prostaglandin Analogues: Misoprostol (also has acid-suppressive effects).

Antimicrobial Agents for Helicobacter pylori Eradication

H. pylori infection is a major etiological factor in PUD. Eradication requires combination therapy, typically consisting of:

• First-Line Regimens: A PPI or bismuth compound combined with two antibiotics. Common antibiotics include Clarithromycin, Amoxicillin, Metronidazole, Tetracycline, and Levofloxacin.

Antacids

These are basic compounds that neutralize secreted gastric acid, providing rapid symptomatic relief but poor ulcer healing efficacy when used alone.

• Systemic: Sodium bicarbonate (largely obsolete).
• Non-systemic: Aluminum hydroxide, Magnesium hydroxide, Calcium carbonate.

Mechanism of Action

The pharmacodynamic actions of peptic ulcer drugs are directed at various points in the physiological pathways of acid secretion and mucosal integrity.

Proton Pump Inhibitors (PPIs)

PPIs are prodrugs that require activation in an acidic environment. They are weak bases (pK_a ≈ 4.0) that accumulate selectively in the acidic secretory canaliculi of parietal cells. Within this compartment, they undergo protonation to form reactive sulfenamide or sulfenic acid intermediates. These activated forms covalently bind to cysteine residues on the extracellular domain of the H⁺/K⁺-ATPase (proton pump), irreversibly inhibiting its function. This enzyme is the final common pathway for gastric acid secretion, responsible for exchanging intracellular H⁺ for extracellular K⁺. Inhibition is non-competitive and prolonged, as recovery of acid secretion requires synthesis of new pumps, with a typical turnover time of about 24-48 hours. The degree of inhibition is dose-dependent and correlates with the area under the plasma concentration-time curve (AUC) rather than peak plasma concentration (C_max).

Histamine H₂-Receptor Antagonists (H2RAs)

H2RAs competitively and reversibly antagonize histamine binding at the H₂ receptor on the basolateral membrane of parietal cells. Histamine, released from enterochromaffin-like (ECL) cells, is the primary physiological stimulant of acid secretion. By blocking this receptor, H2RAs inhibit the cAMP-mediated pathway that activates the proton pump. They reduce basal (fasting) acid secretion by approximately 90% and nocturnal secretion effectively, but are less potent than PPIs against meal-stimulated or gastrin-mediated secretion. Their effect is surmountable by high concentrations of agonist.

Antacids

Antacids are simple bases that directly neutralize secreted hydrochloric acid in the gastric lumen via a straightforward chemical reaction (e.g., Mg(OH)₂ + 2HCl → MgCl₂ + 2H₂O). This raises intragastric pH, providing rapid symptom relief. They also may exert minor secondary effects, such as inhibition of pepsin activity (which is pH-dependent) and stimulation of mucosal prostaglandin synthesis. Their duration of action is short, typically 1-2 hours, depending on gastric emptying.

Sucralfate

Sucralfate’s mechanism is primarily topical and multifactorial. In the acidic gastric environment, it undergoes polymerization and cross-linking to form a viscous, adhesive gel that binds selectively to ulcerated tissue, creating a protective barrier against acid, pepsin, and bile salts. It may also stimulate local synthesis of prostaglandins and growth factors, increase mucosal bicarbonate secretion, and bind epidermal growth factor, concentrating it at the ulcer site. Its actions are essentially limited to the gastrointestinal lumen with minimal systemic absorption.

Bismuth Compounds

Colloidal bismuth subcitrate and bismuth subsalicylate have complex actions. They exert direct bactericidal activity against H. pylori by disrupting bacterial cell wall integrity and inhibiting enzymes such as urease and ATPase. Bismuth also forms a protective coating over ulcer craters, similar to sucralfate, and may stimulate prostaglandin and bicarbonate secretion. Furthermore, bismuth ions can bind to sulfhydryl groups of pepsin, inhibiting its proteolytic activity.

Misoprostol

Misoprostol is a synthetic prostaglandin E₁ analogue. It exerts its effects by binding to prostaglandin EP₃ receptors on parietal cells, which are coupled to inhibitory G-proteins (G_i), leading to a decrease in intracellular cAMP and subsequent inhibition of acid secretion. Its more prominent cytoprotective action is mediated through stimulation of mucus and bicarbonate secretion, enhancement of mucosal blood flow, and reinforcement of the hydrophobic phospholipid layer of the mucosa. These actions collectively strengthen mucosal defense mechanisms.

Pharmacokinetics

The pharmacokinetic properties of peptic ulcer drugs significantly influence their dosing schedules, onset of action, and therapeutic utility.

Proton Pump Inhibitors

All PPIs are administered orally as enteric-coated formulations to prevent degradation by gastric acid. Absorption occurs in the small intestine, with time to C_max (t_max) ranging from 1 to 5 hours. Their bioavailability is variable and often incomplete (50-80%) due to first-pass metabolism and acid degradation; it may increase with repeated dosing. PPIs are highly protein-bound (>95%) and have a relatively small volume of distribution. They are extensively metabolized in the liver by the cytochrome P450 system, primarily CYP2C19 and CYP3A4. Genetic polymorphisms in CYP2C19 can lead to significant inter-individual variability in plasma levels, with “poor metabolizers” achieving higher AUCs. The plasma elimination half-life (t_1/2) is short (1-2 hours), but the pharmacological effect lasts much longer due to irreversible pump inhibition. Excretion is primarily renal as inactive metabolites. For optimal efficacy, PPIs should be administered 30-60 minutes before the first meal of the day to coincide with activation of proton pumps.

Histamine H₂-Receptor Antagonists

H2RAs are well absorbed after oral administration, with bioavailability ranging from 40% (cimetidine) to over 90% (famotidine, nizatidine). Food may delay absorption but does not significantly reduce overall bioavailability. They achieve peak plasma concentrations within 1-3 hours. Distribution is widespread, with some crossing the blood-brain barrier. Metabolism occurs in the liver: cimetidine and ranitidine undergo significant hepatic metabolism via CYP450, while famotidine and nizatidine undergo minimal metabolism. Renal excretion of unchanged drug or metabolites is the primary route of elimination, with t_1/2 values between 2-4 hours, necessitating multiple daily doses or higher single bedtime doses for nocturnal acid suppression. Dose adjustment is required in renal impairment.

Antacids

Antacids are not absorbed to a clinically significant degree, with the exception of a small fraction of their cationic components (Al³⁺, Mg²⁺, Ca²⁺). Their action is entirely intraluminal and begins within minutes of ingestion. Duration of effect is brief (1-2 hours), determined by gastric emptying time. Systemic absorption of cations can occur with large or chronic use, potentially leading to electrolyte disturbances.

Sucralfate

Sucralfate is minimally absorbed from the gastrointestinal tract (<5% as sucrose sulfate). Its action is entirely local. The small absorbed fraction is excreted unchanged in the urine. It requires an acidic environment (pH < 4) for activation, which can be compromised by concurrent use of potent acid suppressants. Administration is typically four times daily on an empty stomach.

Bismuth Compounds

Bismuth is poorly absorbed from the GI tract (<1% of an oral dose). The absorbed fraction is primarily excreted in urine, with a renal t_1/2 of approximately 20-30 days. The unabsorbed majority is excreted in feces, often turning stools black. Salicylate from bismuth subsalicylate is well absorbed and follows the pharmacokinetics of aspirin.

Misoprostol

Misoprostol is rapidly absorbed and extensively de-esterified to its active metabolite, misoprostol acid. The t_max for the active acid is about 15-30 minutes. It is highly protein-bound (>80%) and undergoes extensive beta-oxidation in the liver. The terminal t_1/2 of the active metabolite is approximately 20-40 minutes. Excretion is primarily renal, with about 80% of an administered dose recovered in urine within 24 hours.

Therapeutic Uses/Clinical Applications

The clinical application of these agents is guided by the etiology of the ulcer, desired speed of healing, need for symptom control, and goals of prevention.

Peptic Ulcer Disease Healing and Symptom Relief

PPIs are considered first-line therapy for active duodenal and gastric ulcers due to their superior acid suppression and faster healing rates compared to H2RAs. A typical course for a duodenal ulcer is 4-8 weeks of therapy, while gastric ulcers may require 8-12 weeks. H2RAs remain effective, particularly for nocturnal acid suppression and maintenance therapy, and may be used in patients with milder disease or contraindications to PPIs. Antacids are used adjunctively for immediate symptom relief but are not adequate as monotherapy for ulcer healing.

Helicobacter pylori Eradication

Eradication of H. pylori is indicated in all patients with PUD who test positive for the infection. Standard first-line regimens include triple therapy (PPI + clarithromycin + amoxicillin or metronidazole) for 10-14 days or bismuth-based quadruple therapy (PPI + bismuth + tetracycline + metronidazole). The PPI component raises intragastric pH, enhancing the stability and antimicrobial efficacy of the co-administered antibiotics. Sequential and concomitant regimens are also employed, particularly in regions with high clarithromycin resistance.

Prevention of Ulcer Recurrence

Maintenance therapy with a reduced dose of a PPI or a full dose of an H2RA may be indicated for patients with a history of complicated ulcers (e.g., bleeding, perforation), those who require continued use of ulcerogenic drugs like NSAIDs, or those with frequent recurrent ulcers not associated with H. pylori.

Prevention of NSAID-Induced Ulcers

For patients at high risk (e.g., history of ulcer, advanced age, concomitant corticosteroid or anticoagulant use) who require chronic NSAID therapy, co-therapy with a PPI or misoprostol is recommended for ulcer prophylaxis. PPIs are generally preferred over misoprostol due to better tolerability. The COX-2 selective NSAIDs also carry a lower risk of ulcerogenesis.

Stress Ulcer Prophylaxis

In critically ill patients (e.g., those on mechanical ventilation, with coagulopathy, or severe trauma), PPIs or H2RAs are used to prevent stress-related mucosal damage and bleeding. This is a prophylactic, not therapeutic, indication.

Gastroesophageal Reflux Disease (GERD)

Although not strictly an ulcerative condition, PPIs and H2RAs are the mainstay of pharmacological treatment for GERD and erosive esophagitis, which share the pathophysiological element of acid exposure.

Adverse Effects

The adverse effect profiles of these drug classes vary widely, from generally benign to potentially serious.

Proton Pump Inhibitors

PPIs are generally well-tolerated. Common adverse effects (1-3% incidence) include headache, diarrhea, nausea, abdominal pain, and flatulence. Long-term use has been associated with several concerns:

• Nutritional Deficiencies: Chronic profound acid suppression may impair absorption of vitamin B₁₂, iron (which requires acid for conversion to the absorbable ferrous form), and possibly magnesium (leading to hypomagnesemia).
• Infections: Increased risk of community-acquired pneumonia, Clostridioides difficile-associated diarrhea, and other enteric infections due to alteration of gastric flora.
• Bone Health: Some observational studies suggest a potential increased risk of osteoporosis-related fractures with long-term, high-dose use, possibly related to impaired calcium absorption (calcium carbonate requires acid for solubilization).
• Renal Effects: Associations with acute interstitial nephritis and chronic kidney disease have been reported.
• Others: Potential drug-induced lupus, hypomagnesemia, and fundic gland polyps.

Histamine H₂-Receptor Antagonists

Adverse effects are generally mild and infrequent. Diarrhea, dizziness, somnolence, and headache may occur. Cimetidine has unique effects due to its imidazole ring structure: it inhibits cytochrome P450 enzymes (notably CYP1A2, CYP2C9, CYP2D6, CYP3A4), leading to numerous drug interactions. It also has weak anti-androgenic effects, which can cause gynecomastia and impotence with prolonged high-dose use. Ranitidine, previously widely used, was found to contain low levels of N-nitrosodimethylamine (NDMA), a probable carcinogen, leading to its withdrawal from many markets. CNS effects like confusion, particularly in the elderly or those with renal impairment, are a class effect.

Antacids

Adverse effects are primarily related to the cationic components and depend on the specific formulation.

• Aluminum-containing: Can cause constipation and, with chronic use in renal failure, aluminum toxicity (osteomalacia, encephalopathy).
• Magnesium-containing: Can cause diarrhea and, in renal impairment, hypermagnesemia.
• Calcium carbonate: Can cause constipation, rebound acid secretion (“acid rebound”), and hypercalcemia with excessive intake (milk-alkali syndrome).
• Sodium bicarbonate: Can cause systemic alkalosis, sodium overload, and “rebound” acidosis.

Sucralfate

The most common adverse effect is constipation (2-3%). Due to its aluminum content, chronic use in renal impairment carries a risk of aluminum accumulation. It can cause bezoar formation in patients with gastroparesis. Hypophosphatemia has been reported rarely.

Bismuth Compounds

Bismuth subsalicylate carries the risk of salicylate toxicity (tinnitus, vertigo) if taken in large doses. Both compounds darken stools and may darken the tongue. Neurotoxicity (encephalopathy) is a rare but serious risk with high doses or prolonged use, particularly with older, poorly absorbed bismuth salts.

Misoprostol

The most frequent and dose-limiting adverse effects are gastrointestinal, including diarrhea (10-30%), abdominal pain, and flatulence. These are often transient. Due to its uterotonic properties, it is a potent abortifacient and is absolutely contraindicated in pregnancy. Uterine bleeding and cramping may occur in women of childbearing potential.

Drug Interactions

Significant drug interactions can alter the efficacy or safety of peptic ulcer drugs and co-administered medications.

Proton Pump Inhibitors

By raising gastric pH, PPIs can alter the absorption of drugs that require an acidic environment for optimal bioavailability. Key interactions include:

• Atazanavir, Rilpivirine (HIV medications): Absorption is significantly decreased, contraindicating co-administration.
• Ketoconazole, Itraconazole, Posaconazole (oral): Reduced absorption of these weak-base antifungals.
• Clopidogrel: Some PPIs (especially omeprazole and esomeprazole) inhibit CYP2C19, the enzyme required to activate clopidogrel. This may theoretically reduce clopidogrel’s antiplatelet effect, though the clinical significance is debated. Pantoprazole and rabeprazole have weaker CYP2C19 inhibition.
• Methotrexate: PPIs may reduce renal clearance of methotrexate, increasing toxicity risk.
• Digoxin, Warfarin: Potential for increased levels due to metabolic inhibition (varies by specific PPI).

Histamine H₂-Receptor Antagonists

Cimetidine is the most notable for interactions due to its potent inhibition of multiple CYP450 isoenzymes and inhibition of renal tubular secretion. It can increase levels of warfarin, theophylline, phenytoin, lidocaine, tricyclic antidepressants, and many benzodiazepines. Ranitidine has a much weaker inhibitory effect. All H2RAs, by altering gastric pH, can affect absorption of pH-dependent drugs similarly to PPIs, though usually to a lesser extent.

Antacids

Antacids can form insoluble complexes with numerous drugs in the GI tract, impairing their absorption. Administration should be separated by 2-4 hours from:

• Tetracyclines, Fluoroquinolones: Chelation with polyvalent cations (Al³⁺, Mg²⁺, Ca²⁺).
• Iron supplements, Levothyroxine, Digoxin, Isoniazid: Adsorption or complexation.

Sucralfate

Sucralfate can bind to and decrease the absorption of several drugs, including warfarin, digoxin, levothyroxine, phenytoin, and fluoroquinolone antibiotics. Dosing should be separated by at least 2 hours. Its requirement for an acidic environment means its efficacy may be reduced by concurrent acid-suppressive therapy.

Bismuth Subsalicylate

It carries the drug interaction profile of salicylates, including increased risk of bleeding with anticoagulants and potentiation of hypoglycemics. It may also reduce absorption of tetracyclines.

Special Considerations

The use of peptic ulcer drugs requires careful adjustment in specific patient populations due to altered pharmacokinetics, pharmacodynamics, or unique risks.

Pregnancy and Lactation

Pregnancy: Antacids (particularly calcium carbonate and magnesium hydroxide) and sucralfate are generally considered safe for short-term use. H2RAs (Category B: famotidine, ranitidine) are often used when stronger acid suppression is needed. PPIs (mostly Category B: omeprazole, pantoprazole, lansoprazole) may be used if clearly indicated, though long-term safety data are limited. Misoprostol is absolutely contraindicated (Category X) due to its abortifacient properties and association with birth defects.
Lactation: Most agents are excreted in breast milk in small amounts. Antacids and sucralfate are considered compatible. H2RAs (famotidine preferred) and PPIs are likely safe, though monitoring the infant for GI effects is prudent.

Pediatric Considerations

PPIs and H2RAs are used in children, with dosing adjusted by weight. Liquid formulations are available for many. Long-term safety profiles in children are less established than in adults. Sucralfate is rarely used. The need for H. pylori testing and treatment in children is more selective than in adults.

Geriatric Considerations

Elderly patients often have multiple comorbidities and polypharmacy, increasing the risk of drug interactions. Age-related decline in renal function necessitates dose adjustment for renally excreted drugs like H2RAs. They are more susceptible to CNS adverse effects from H2RAs (confusion, dizziness) and to the consequences of long-term PPI use (fracture risk, C. difficile infection, nutritional deficiencies). The lowest effective dose for the shortest duration should be employed.

Renal Impairment

Dose reduction is required for H2RAs, as they are primarily renally excreted. Cimetidine also inhibits renal tubular secretion of other drugs. PPIs generally do not require dose adjustment, though some caution is advised with severe impairment. Sucralfate and aluminum-containing antacids should be used with extreme caution or avoided due to the risk of aluminum accumulation and toxicity. Magnesium-containing antacids are contraindicated due to risk of hypermagnesemia.

Hepatic Impairment

PPIs are metabolized hepatically; dose reduction may be considered in severe liver cirrhosis, though they are generally well-tolerated. H2RAs that undergo significant hepatic metabolism (cimetidine, ranitidine) may require dose adjustment. Monitoring for signs of CNS toxicity is important.

Summary/Key Points

The pharmacology of peptic ulcer drugs encompasses a range of agents targeting acid secretion, mucosal defense, and bacterial eradication.

• Proton Pump Inhibitors (PPIs) are the most potent acid-suppressive agents, providing irreversible inhibition of the H⁺/K⁺-ATPase pump. They are first-line for active ulcer healing and H. pylori eradication regimens.
• Histamine H₂-Receptor Antagonists (H2RAs) provide reversible, competitive inhibition of acid secretion and remain useful for nocturnal acid suppression and maintenance therapy.
• Antacids offer rapid, short-term neutralization of gastric acid for symptomatic relief but are inadequate for ulcer healing as monotherapy.
• Sucralfate and Bismuth Compounds act as topical mucosal protectants, with bismuth also possessing anti-H. pylori activity.
• Misoprostol, a prostaglandin analogue, inhibits acid and enhances mucosal defense but is limited by gastrointestinal side effects and is contraindicated in pregnancy.
• H. pylori eradication is a cornerstone of ulcer therapy and typically involves a PPI combined with two or more antibiotics, with or without bismuth.
• Long-term use of PPIs, while generally safe, is associated with potential risks including nutritional deficiencies, infections, and bone health concerns, necessitating periodic re-evaluation of therapy.
• Significant drug interactions occur via pH-dependent absorption effects (PPIs, H2RAs, antacids), CYP450 inhibition (cimetidine, some PPIs), and chelation (antacids, sucralfate).
• Dosing and agent selection must be carefully considered in special populations, particularly those with renal/hepatic impairment, the elderly, and pregnant patients.

Clinical Pearls

• For optimal effect, PPIs should be administered 30-60 minutes before the first meal of the day to coincide with activation of proton pumps.
• When testing for H. pylori via urea breath test or stool antigen test, PPIs should be discontinued for 2 weeks and H2RAs for 1-2 days prior to avoid false-negative results.
• In patients requiring both a PPI and clopidogrel, consider using pantoprazole or rabeprazole, which have the weakest CYP2C19 interaction, and monitor for cardiovascular events.
• The “on-demand” or intermittent PPI therapy is a viable strategy for many patients with non-erosive GERD or mild PUD to minimize long-term exposure.
• Always consider and attempt to discontinue ulcerogenic medications (e.g., NSAIDs, aspirin) as part of the comprehensive management of peptic ulcer disease.

References

1. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
2. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.
3. Katzung BG, Vanderah TW. Basic & Clinical Pharmacology. 15th ed. New York: McGraw-Hill Education; 2021.
4. Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 14th ed. New York: McGraw-Hill Education; 2023.
5. Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor's Pharmacology: Examination & Board Review. 13th ed. New York: McGraw-Hill Education; 2022.
6. Golan DE, Armstrong EJ, Armstrong AW. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. 4th ed. Philadelphia: Wolters Kluwer; 2017.
7. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
8. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.