Pharmacology of Drugs for Peptic Ulcer

Introduction / Overview

Peptic ulcer disease (PUD) remains a significant clinical problem worldwide, contributing to morbidity through pain, bleeding, perforation, and gastric outlet obstruction. The therapeutic armamentarium for PUD has evolved from simple antacids to sophisticated acid-suppressive agents that target specific components of gastric acid secretion. Understanding the pharmacology of these agents is essential for optimizing treatment, anticipating adverse events, and managing drug interactions in diverse patient populations.

Learning objectives for this monograph include:

• Recognize the major pharmacologic classes employed in PUD management and their chemical characteristics.
• Elucidate the mechanisms of action of antacids, H₂ receptor antagonists, proton pump inhibitors, and other emerging agents.
• Describe key pharmacokinetic parameters that influence dosing regimens and therapeutic monitoring.
• Identify common therapeutic indications, off‑label uses, and evidence‑based recommendations.
• Appraise adverse effect profiles, drug‑drug interactions, and special population considerations.

Classification

Drug Classes and Categories

Therapeutic agents for PUD can be categorized into four principal classes based on their primary mechanism of acid suppression or mucosal protection:

• Antacids – neutralizing agents that raise intragastric pH.
• H₂ receptor antagonists – competitive inhibitors of histamine H₂ receptors on parietal cells.
• Proton pump inhibitors (PPIs) – irreversible blockers of the H⁺/K⁺ ATPase.
• Other agents – including sucralfate, cytoprotective agents, and investigational therapies (e.g., potassium-competitive acid blockers).

Chemical Classification

Within each class, agents exhibit distinct chemical frameworks that influence their pharmacodynamic and pharmacokinetic behavior:

• Antacids: inorganic salts (magnesium hydroxide, aluminum hydroxide), organic bases (aluminum hydroxide–magnesium hydroxide combinations).
• H₂ antagonists: 1,3‑pyrimidinyl‑piperazine derivatives (famotidine), imidazole-based compounds (cimetidine).
• PPIs: substituted benzimidazole and thiazole derivatives (omeprazole, esomeprazole, pantoprazole).
• Other agents: sulfonated polysaccharides (sucralfate), mucosal protective agents (sucralfate, misoprostol), and novel potassium‑competitive acid blockers (vonoprazan).

Mechanism of Action

Antacids

Antacids act by directly neutralizing gastric hydrochloric acid through ionic exchange reactions. Calcium carbonate releases Ca²⁺ and CO₃²⁻ ions, which combine with H⁺ to form insoluble salts. The resulting rise in intragastric pH reduces ulcerogenic irritation and promotes mucosal healing. Antacids do not inhibit acid production but provide rapid symptomatic relief; their action is short‑lived and is influenced by gastric emptying dynamics.

H₂ Receptor Antagonists

H₂ antagonists competitively inhibit histamine binding to H₂ receptors on the gastric parietal cell surface. This blockade reduces cyclic AMP production, thereby decreasing H⁺/K⁺ ATPase activity and acid secretion. The effect is reversible and dose‑dependent, with maximal suppression achieved at therapeutic concentrations. Cimetidine, for instance, also inhibits cytochrome P450 enzymes, accounting for its extensive interaction profile.

Proton Pump Inhibitors

PPIs irreversibly bind to the catalytic site of the H⁺/K⁺ ATPase, the final step in gastric acid secretion. Covalent modification of cysteine residues prevents proton translocation, leading to sustained acid suppression for up to 24 hours. Activation in the acidic parietal cell canaliculus converts the prodrug to its active sulfenamide form, which then covalently attaches to the pump. PPIs exhibit high potency and a prolonged duration of action relative to H₂ antagonists.

Other Agents

Sucralfate forms a viscous, adhesive matrix that adheres to ulcerated mucosa, shielding it from gastric acid and pepsin. Misoprostol, a synthetic prostaglandin E₁ analogue, promotes mucus and bicarbonate secretion, enhances mucosal blood flow, and inhibits acid secretion. Vonoprazan, a potassium‑competitive acid blocker, binds reversibly to the ATPase, displacing potassium and inhibiting proton transport; it offers rapid onset and sustained suppression with a distinct safety profile.

Pharmacokinetics

Absorption

Antacids are absorbed minimally, exerting their effect locally. H₂ antagonists achieve high oral bioavailability (≈70–80%) with peak plasma concentrations reached within 1–3 hours. PPIs display variable absorption; for example, omeprazole bioavailability is approximately 40% and is highly influenced by gastric pH. Vonoprazan has a bioavailability of ~60% and is less affected by gastric acidity.

Distribution

H₂ antagonists are widely distributed, with a volume of distribution (V_d) ranging from 0.3 to 0.5 L/kg. PPIs are largely plasma protein bound (≈90%) and distribute predominantly to the gastric mucosa. Sucralfate remains largely confined to the gastrointestinal lumen due to its high molecular weight and low permeability.

Metabolism

H₂ antagonists undergo extensive hepatic metabolism via cytochrome P450 isoenzymes; cimetidine is metabolized by CYP2D6 and CYP3A4, whereas famotidine is predominantly renally excreted. PPIs are metabolized primarily by CYP2C19 and CYP3A4. Metabolites are often inactive, but polymorphisms in CYP2C19 can significantly alter drug exposure. Vonoprazan is metabolized by CYP3A4, yielding metabolites with similar acid‑suppressive activity.

Excretion

Renal excretion dominates for most agents. Famotidine is eliminated unchanged via glomerular filtration, necessitating dose adjustment in renal impairment. PPIs are excreted as metabolites in urine and feces, with a negligible amount of unchanged drug. Sucralfate is excreted largely unchanged in feces.

Half‑Life and Dosing Considerations

Antacids provide immediate but short‑term relief; dosing is typically repeated every 4–6 hours as needed. H₂ antagonists have half‑lives of 2–4 hours; standard dosing involves twice‑daily administration. PPIs possess a half‑life of 1–1.5 hours, but their effect persists for >24 hours; once‑daily dosing at bedtime is common. Vonoprazan’s half‑life is ~3–4 hours, with a dosing interval of once daily. In patients with hepatic or renal impairment, dose adjustments or alternative agents may be necessary to avoid accumulation or subtherapeutic exposure.

Therapeutic Uses / Clinical Applications

Approved Indications

All classes are approved for the treatment of erosive esophagitis, duodenal ulcers, gastric ulcers, and reflux‑associated symptoms. PPIs are first‑line therapy for Helicobacter pylori eradication regimens, often combined with a clarithromycin‑based triple therapy or a bismuth quadruple regimen. Sucralfate is used for mucosal protection in patients on nonsteroidal anti‑inflammatory drugs (NSAIDs). Misoprostol is indicated for NSAID‑induced ulcer prevention in high‑risk patients.

Off‑Label Uses and Emerging Evidence

Antacids are frequently employed for symptomatic relief of dyspepsia and heartburn in primary care settings. H₂ antagonists are occasionally used as rescue therapy in patients with refractory acid‑related symptoms. Vonoprazan has shown efficacy in healing refractory GERD and may serve as an alternative to PPIs in patients with poor CYP2C19 metabolism. Experimental agents, such as potassium‑competitive acid blockers, are under investigation for chronic ulcer disease and functional dyspepsia.

Adverse Effects

Common Side Effects

• Antacids: dyspepsia, constipation (aluminum hydroxide), diarrhea (magnesium hydroxide).
• H₂ antagonists: headache, dizziness, diarrhea, constipation.
• PPIs: abdominal pain, constipation, nausea, headache, flatulence.
• Sucralfate: constipation, abdominal fullness.
• Misoprostol: diarrhea, abdominal cramps, nausea.

Serious or Rare Adverse Reactions

Long‑term PPI use has been associated with an increased risk of Clostridioides difficile infection, enteric bacterial infections, and potential bone mineral density loss leading to fractures. H₂ antagonists may cause hypomagnesemia, particularly with chronic cimetidine use. Sucralfate can cause hypochlorhydria and, rarely, allergic reactions. Misoprostol carries a risk of severe diarrhea and emesis, especially in patients with gastrointestinal disorders.

Black Box Warnings

PPIs bear a black box warning regarding the risk of serious infections and potential bone fracture with prolonged use. Misoprostol’s black box warning highlights the risk of serious, potentially life‑threatening gastrointestinal side effects.

Drug Interactions

Major Drug‑Drug Interactions

• PPIs → decreased absorption of drugs requiring an acidic environment (e.g., ketoconazole, atazanavir, clopidogrel).
• H₂ antagonists (cimetidine) inhibit CYP2D6 and CYP3A4, augmenting plasma concentrations of drugs metabolized by these enzymes (e.g., phenytoin, warfarin).
• PPIs (omeprazole, esomeprazole) inhibit CYP2C19, potentially increasing levels of drugs like clopidogrel and diazepam.
• Sucralfate binds to and reduces absorption of various oral medications, including levothyroxine, calcium supplements, and aminoglycosides.

Contraindications

Antacids are contraindicated in patients with acute gastric obstruction or perforation. H₂ antagonists should be avoided in patients on drugs that rely on acidic pH for absorption. PPIs are contraindicated in patients with known hypersensitivity to any component. Misoprostol is contraindicated in patients with active peptic ulcer disease or gastrointestinal obstruction.

Special Considerations

Pregnancy and Lactation

Antacids are generally considered safe during pregnancy and lactation. PPIs exhibit low teratogenic risk in animal studies; however, limited human data necessitate cautious use, typically reserved for severe disease. H₂ antagonists (famotidine) have a favorable safety profile in pregnancy, whereas cimetidine is less well studied. Misoprostol is contraindicated due to its uterotonic properties. Lactation: most agents have minimal excretion into breast milk, but monitoring is advised.

Pediatric and Geriatric Considerations

In pediatric patients, dosing is weight‑based; antacids are often used for symptomatic relief, while PPIs and H₂ antagonists are reserved for ulcer or GERD management. Geriatric patients often exhibit altered pharmacokinetics, increased sensitivity to adverse effects, and higher prevalence of comorbidities; dose adjustments and monitoring for drug interactions are essential.

Renal and Hepatic Impairment

Famotidine requires dose reduction in patients with creatinine clearance <30 mL/min. PPIs undergo hepatic metabolism; patients with severe hepatic impairment may experience elevated drug levels, particularly with omeprazole. Vonoprazan, with relatively fewer hepatic interactions, may be preferable in hepatic disease. Sucralfate and misoprostol are largely unaffected by renal function.

Summary / Key Points

• Antacids provide rapid, short‑term symptom relief through neutralization of gastric acid.
• H₂ antagonists competitively block histamine‑mediated acid secretion, offering moderate potency.
• PPIs irreversibly inhibit the H⁺/K⁺ ATPase, producing sustained acid suppression and high healing rates.
• Vonoprazan and other potassium‑competitive acid blockers represent promising alternatives with distinct pharmacologic profiles.
• Adverse event risks, particularly with long‑term PPI use, warrant careful patient selection and monitoring.
• Drug interactions are common, especially with PPIs and H₂ antagonists; clinicians should review concomitant medications regularly.
• Special populations—pregnant, lactating, pediatric, geriatric, and those with organ impairment—require individualized dosing and safety considerations.

Comprehensive understanding of the pharmacologic nuances of peptic ulcer drugs enables clinicians to tailor therapy, mitigate risks, and achieve optimal clinical outcomes in diverse patient populations.

References

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