SPECIFIC ACID – PEPTIC DISORDERS AND THERAPEUTIC STRATEGIES

Peptic Ulcer Disease
The pathophysiology of peptic ulcer disease is best viewed as an imbalance between mucosal defense factors (bicarbonate, mucin, prostaglandin, nitric oxide, and other peptides and growth factors) and injurious factors (acid and pepsin). H.pylori and exogenous agent such as nonsteroidal anti-inflammatory drugs (NSAIDs) interact in complex ways to cause an ulcer. Up to 60% of peptic ulcers are associated with H.pylori infection of the stomach. This infection may lead to impaired production of somatostatin by D cells of the pancreas, and in time, decreased inhibition of gastrin production, resulting in increased acid production and reduced duodenal bicarbonate production.           
H.pylori has been associated with gastritis and the subsequent development of gastric and duodenal ulcers, gastric adenocarcinoma, and gastric B- cell lymphoma. Because of the critical role of H.pylori in the pathogenesis of peptic ulcers, to eradicate this infection is standard care in patients with gastric and duodenal ulcers. Provided that patients are not taking NSAIDs, this strategy almost completely eliminates the risk of ulcer recurrence. NSAIDs also are very frequently associated with peptic ulcers (in up to 60% of patients, particularly those with complications such as bleeding). The effects of these drugs are mediated systemically; the critical element is suppression of the constitutive form of cyclooxygenase-1 (COX-1) in the mucosa and decreased production of cytoprotective prostaglandins PGE2 and PGI2.
            Table 1 summarizes current recommendations for drug therapy of gastroduodenal ulcers. Proton pump inhibitors relieve symptoms of duodenal ulcers and promote healing more rapidly than do H2 receptor antagonists, although both classes of drugs are very effective in this setting. Peptic ulcer represents a chronic disease and recurrence within 1 year is expected in the majority of patients who do not receive prophylactic acid suppression. With the appreciation that H.pylori plays a major etiopathogenic role in the majority of peptic ulcers, prevention of relapse is focused on eliminating this organism from the stomach. Chronic acid suppression, once the mainstay of ulcer prevention, now is used mainly in patients who are H.pylori- negative or, in some cases, for maximum prevention of recurrence in patients who have had life-threatening complications.
            Intravenous pantoprazole or lansoprazole clearly is the preferred therapy in patients with acute bleeding ulcers. The theoretical benefit of maximal acid suppression in this setting is to accelerate healing of the underlying ulcer. In addition, a higher gastric pH enhances clot formation and retards clot dissolution.

Table 1
Recommendations for Treatment of Gastroduodenal Ulcers                                                

                                   
DU, duodenal ulcer; GU, gastric ulcer. *Only misoprostol 800µg/day has been directly shown to reduce the risk of ulcer complications such as perforation, hemorrhage, or obstruction.

Treatment of Helicobacter pylori infection
Many regimens for H. pylori eradication have been proposed. Five important considerations influence the selection of an eradication regimen (Table 2). First, single- antibiotic regimens are ineffective in eradicating H. pylori infection and lead to microbial resistance. Combination therapy with two or three antibiotics (plus acid- suppressive therapy) is associated with the highest rate of H. pyroli eradication. Second, a proton pump inhibitor or H2 receptor antagonist significantly enhances the effectiveness of H. pylori antibiotic regimens containing amoxicillin or clarithromycin. Third, a regimen of 10 to 14 days of treatment appears to be better than shorter treatment regimens. Fourth, poor patient compliance is linked to the medication- related side effects experienced by as many as half of patients taking triple- agent regimens administered several times per day. Packaging that combines the daily doses into one convenient unit is available and may improve patient compliance (Table 2). Finally, the emergence of resistance to clarithromycin and metronidazole increasingly is recognized as an important factor in the failure to eradicate H. pylori. In the presence of in vitro evidence of resistance to metronidazole, amoxicillin should be used instead. In areas with a high frequency of resistance to clarithromycin and metronidazole, a 14- day, quadruple- drug regimen (three antibiotics combined with a proton pump inhibitor) generally is effective.

Table 2
Therapy of Helicobacter pylori Infection
Triple therapy×14 days: [Proton pump inhibitor + clarithromycin 500mg + (metronidazole 500mg or amoxicillin 1 g)] twice a day. (Tetracycline 500mg can be substituted for amoxicillin or metronidazole.)
Quadruple therapy ×14 days: Proton pump inhibitor twice a day + metronidazole 500mg three times daily + (bismuth subsalicylate 525mg + tetracycline 500mg four times daily)
Or
H2 receptor antagonist twice a day + (bismuth subsalicylate 525mg + metronidazole 250mg + tetracycline 500mg) four times daily

Dosages:
Proton pump inhibitors:                      H2 receptor antagonists:
Omeprazole: 20mg                              Cimetidine: 400mg
Lansoprazole: 30mg                            Famotidine: 20mg
Rabeprazole: 20mg                             Nizatidine: 150mg
Pantoprazole: 40mg                            Ranitidine: 150mg
Esomeprazole: 40mg

NSAID-Related Ulcers
Chronic NSAID users have a 2% to 4% of developing a symptomatic ulcer, gastrointestinal bleeding, or perforation. Ideally, NSAIDs should be discontinued in patients with ulcer if at all possible. If continued therapy is needed, selected COX-2 inhibitors may be considered, although this does not eliminate the risk of subsequent ulcer formation and the possible association of these drugs with adverse cardiovascular events mandate caution. Healing of ulcers despite continued NSAID use is possible with the use of acid-suppressant agents, usually at higher doses and for a considerably longer duration than standard regiments (e.g., 8 weeks or longer). Again, proton pump inhibitors are superior to H2 receptor antagonists and misoprostol promoting the healing of active ulcers (healing rates of 80% to 90% for proton pump inhibitors versus 60% to 75% for the H2 receptor antagonists), and in preventing recurrence of gastric and duodenal ulcers in the setting of continued NSAID administration.

Stress-Related Ulcers
Stress ulcers are ulcers of the stomach or duodenum that occur in the context of a profound illness or trauma requiring intensive care. The etiology of stress-related ulcers differs somewhat from that of other peptic ulcers, involving acid and mucosal ischemia. Because of limitations on the oral administration of drugs in many patients with stress-related ulcers, intravenous preparations of proton pump inhibitors are available; it is likely that they will prove to be equally beneficial.

Gastroesophageal Reflux Disease
Patients with gastroesophageal reflux disease (GERD) has symptoms of heartburn or gastroesophageal regurgitation. Although most cases follow a relatively benign course, GERD in some individuals can cause severe erosive esophagitis, stricture formation and Barrett’s metaplasia (replacement of squamous by intestinal columnar epithelium), which, in turn, is associated with a small but significant risk of adenocarcinoma. Most of the symptoms of GERD reflect injurious effects of the refluxed acid-peptic content on the esophageal epithelium. The goals of GERD therapy are complete resolution of symptoms and healing of esophagitis. Proton pump inhibitors clearly are more effective than H2 receptor antagonists in achieving these goals.
*Healing rates after 4 weeks and 8 weeks of therapy with proton pump inhibitors are approximately 80% and 90%, respectively, while the corresponding healing rates with H2 receptor antagonists are 50% and 75%, respectively.
Because of the wide clinical spectrum associated with GERD, the therapeutic approach is best tailored to the level of severity in the individual patient (Table 3). In general, the optimal dose for each patient is determined based upon symptom control, and routine measurement of esophageal pH to guide dosing is not recommended.

Table 3.  General guidelines for the medical management of gastroesophageal reflux disease (GERD). Only medications that suppress acid production or that neutralize acid are shown.

            Regiments for the treatment of GERD with proton pump inhibitors and histamine H2 receptor antagonists are listed in Table 4. Although some patients with mild GERD symptoms may be managed by nocturnal doses of H2 receptor antagonists, twice-daily dosing usually is required. Antacids are recommended only for the patient with mild, infrequent episodes of heartburn.

Table 4 Antisecretory Drug Regimens for Treatment and Maintenance of GERD

            GERD is a chronic disorder that requires long-term therapy. Some experts advocate “step-down” approaches that attempt to maintain symptomatic remission by either decreasing the dose of the proton pump inhibitor or switching to an H2 receptor antagonist. Other experts have advocated intermittent, “on-demand” therapy with proton pump inhibitors for symptomatic relief in patients who have responded initially but continue to have symptoms. Several studies suggest that these drugs are better than H2 receptor antagonists for maintaining remission in GERD.

Therapy for Extraintestinal Manifestations of GERD
 With varying levels of evidence, acid reflux has been implicated in a variety of atypical symptoms, including non cardiac chest pain, asthma, laryngitis, chronic cough, and other ear, nose, and throat conditions. Proton pump inhibitors have been used with some success in certain patients with these disorders, generally in higher doses and for longer periods of time than those used for patients with more classic symptoms of GERD.
GERD and Pregnancy
Heartburn is estimated to occur in 30% to 50% of pregnancies, with an incidence approaching 80% in some populations. In the vast majority of cases, GERD ends soon after delivery and thus does not represent an exacerbation of a preexisting condition. Nevertheless, because of its high prevalence and the fact that it can contribute to the nausea of pregnancy, treatment often is required. Treatment choice in this setting is complicated by paucity of data for the most commonly used drugs. In general, most drugs used to treat GERD fall in FDA Category B, with the exception of omeprazole (FDA Category C).
            Mild cases of GERD during pregnancy should be treated conservatively; antacids or sucralfate are considered the first-line drugs. If symptoms persist, H2 receptor antagonists can be used, with ranitidine having the most established track record in this setting. Proton pump inhibitors are reserved for women with intractable symptoms or complicated reflux disease. In these situations, lansoprazole is considered the preferred choice among the proton pump inhibitors, based on animal data and available experience in pregnant women.