H2RAs: H2RAs competitively block histaminergic activity at the gastric parietal cells, thereby preventing acid secretion. All drugs in this class (ranitidine, cimetidine, nizatidine, and famotidine) achieve similar efficacy at appropriate dosages. Tolerance can develop with H2RA use, making this a significant limiting factor for long-term use. Studies indicate that high-dose H2RAs (or twice-daily therapy), but not low-dose H2RAs or once-daily therapy, are effective for treating and reducing NSAID-related ulcers. H2RAs may be substituted in patients who are unable to tolerate PPIs. The most common adverse effects of H2RAs are headache (≤16% with nizatidine) and diarrhea (<10% with all agents).Cimetidine can inhibit CYP450; therefore, monitoring of medications such as warfarin, theophylline, and phenytoin may be necessary. Cimetidine also can cause gynecomastia (4%).
PPIs: PPIs bind and irreversibly inhibit hydrogen-potassium adenosine triphosphatase and are considered the most potent of the acid-suppressive therapies.PPIs are preferred for healing H pylori– and NSAID-induced ulcers because they provide more effective symptom relief and promote healing of the ulcer. Omeprazole, esomeprazole, lansoprazole, and rabeprazole are comparable in the treatment of H pylori.In the treatment of H pylori, PPIs should be dosed twice daily rather than once daily, for improved efficacy and increased eradication rates. Esomeprazole, lansoprazole, omeprazole, and rabeprazole are indicated for H pylori–induced ulcers and gastric ulcers related to NSAID use.
Generally, all PPIs have been used as preventive therapy for NSAID-induced ulcers. In a randomized, controlled trial comparing omeprazole with miso-prostol, omeprazole was as effective as misoprostol for preventing gastric ulcers and more effective for preventing duodenal ulcers. Owing to their relatively lower adverse-effect profile and convenient dosing, PPIs are often preferred for the prevention and treatment of NSAID-induced ulcers. The most common adverse effects of PPIs are abdominal pain (2%-5%), diarrhea (4%-9%), nausea (3%-4%), and headache (2%-10%).Potential adverse effects with long-term use include osteoporosis, magnesium deficiency, and increased risk of pneumonia and Clostridium difficile infections. Following the initial 10 to 14 days of therapy for H pylori eradication, maintenance therapy with a PPI is continued for an additional 6 to 8 weeks.
Mucosal Protective Agents
Bismuth: The mechanism of bismuth-containing products in ulcer healing is not clear, but these products have antacid properties.The two most common formulations for treatment of PUD are bismuth subcitrate and bismuth subsalicylate. The most common effects with bismuth products are black stools and darkening of the tongue, which are temporary and typically harmless. These products may also cause GI distress such as constipation. Children and adolescents with current viral infections or chickenpox should not take bismuth-containing products owing to risk of Reye syndrome. Neurotoxicity is a rare yet serious concern with large doses taken for a long period. Bismuth subsalicylate contains a salicylate similar to that found in aspirin. Bismuth-containing products are approved, in combination with PPIs and antibiotics, for the treatment of H pylori eradication.
Misoprostol: Prostaglandin analogues play an important role in mucosal repair. Misoprostol has gastric acid antisecretory properties, as well as the ability to enhance natural mucosal defense.Misoprostol is more effective than sucralfate and H2RAs for preventing NSAID-induced ulcers. In a randomized, controlled trial of misoprostol compared with lansoprazole, both agents prevented gastric ulcers at a similar rate. Misoprostol has been shown to reduce serious upper-GI bleeding complications in elderly patients taking prostaglandin analogues. Its use is primarily limited by the adverse effects of stomach cramping (7%-20%) and diarrhea (13%-40%). The drug is contraindicated in women who may be pregnant, and women of childbearing potential should be warned about the risk of birth defects, premature birth, and spontaneous abortion.Misoprostol is approved for the treatment of NSAID-induced ulcers.
Sucralfate: Sucralfate, which is approved for the treatment of duodenal ulcers and for maintenance after the ulcer has healed, is a complex sucrose compound that is insoluble in water and forms a viscous paste in the stomach and duodenum. This compound binds to the site of the ulcer, providing a protective barrier and enhancing prostaglandin synthesis and mucosal repair. Constipation is the most common adverse effect (2%). Patients with renal insufficiency should avoid sucralfate because of the risk of aluminum toxicity. Patients who are predisposed to impaired gastric motility are at increased risk for bezoar formation. Symptom relief may begin in the first two weeks of use, but treatment should continue for 4 to 8 weeks or until the ulcer is healed.
Antibiotics: As part of the extended-spectrum penicillins, amoxicillin maintains bactericidal activity toward gram-positive organisms similar to penicillin’s, but has increased activity toward gram-negative organisms. Amoxicillin is generally well tolerated, and the most common adverse effects are nausea and vomiting (>1%), headache (6%-7%), and diarrhea (7%-8%). There is a serious risk of pseudomembranous colitis (1%-2%) or antibiotic-associated diarrhea with its use. Because penicillins are cross-reacting and cross-sensitizing, hypersensitivity can be a serious concern; therefore, individuals with a previous true and serious allergy to previous penicillins or cephalosporins should avoid this medication.
Clarithromycin, a derivative of erythromycin, inhibits bacterial RNA-dependent protein synthesis, but given its longer half-life, it needs only twice-daily dosing, unlike erythromycin. Diarrhea (2%-15%), abdominal pain (1%-7.5%), altered taste (1%-19%), nausea (3%-28%), vomiting (1%-24.5%), and headache (<9%) are among the most common adverse effects associated with clarithromycin.Patients with a history of QT prolongation or ventricular arrhythmias should avoid this medication. Because clarithromycin is a strong CYP3A4 inhibitor, medications that are metabolized primarily through CYP3A4 should be avoided (i.e., simvastatin and lovastatin). Clarithromycin may need to be discontinued if C difficile–associated diarrhea is a concern. A portion of the drug is excreted in the urine, and dosage adjustments are needed in severe renal impairment.
Metronidazole is an antiprotozoal agent that is cytotoxic to anaerobic bacteria. The most common adverse effects associated with its use are abdominal discomfort (4%-7%), altered taste (2%-9%), nausea (4%-10%), headache (<18%), and vaginitis (<15%). Alcohol should be avoided with metronidazole owing to the disulfiram-like reaction.
Tetracycline is a broad-spectrum antibiotic with bacteriostatic activity toward gram-positive and gram-negative organisms. Photosensitivity and GI upset are common effects of tetracycline, whereas hypersensitivity reactions are less common. Tetracycline binds to calcium deposits in newly formed bone or teeth, which can result in discoloration or cause bone deformity; therefore, tetracycline should be avoided in children younger than 8 years.
ROLE OF THE PHARMACIST
The pharmacist has a unique opportunity to assist in the clinical management of PUD. In addition to providing effective medication counseling, the pharmacist can ensure that the regimen used to treat PUD is of the appropriate indication and duration. The pharmacist can serve as the last line in the dispensing process, reviewing H pylori regimens for potential drug allergies, especially with antibiotics, and recommending appropriate alternatives. Most of the medications reviewed are available OTC, and the pharmacist can help identify the most cost-effective therapy. Many of these medications have the potential to cause drug and disease interactions, and the pharmacist is in a unique position to obtain the most comprehensive medication history and resolve any medication-related problems.
Pharmacists are playing an increasing role in disease-state management. Specifically for PUD, the pharmacist can conduct smoking-cessation visits and review appropriate long-term NSAID safety concerns to reduce the risk of PUD in the general population.
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