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Managing Acid-Reflux Disorders


Drugs mentioned:

* Axid (nizatidine) | Lilly
* Pepcid (famotidine) | Merck
* Prilosec (omeprazole) | Astra/Merck
* Prepulsid (cisapride) | Janssen
* Tagamet (cimetidine) | SmithKline Beecham
* Zantac (ranitidine) | Glaxo

Gastroesophageal reflux (acid reflux) is a condition that occurs when transient relaxation of the lower esophageal sphincter permits the reflux of acidic gastric contents into the esophagus. Esophageal peristalsis will remove most of the refluxed bolus of gastric acid, and saliva will neutralize the rest, but the esophageal epithelium is still damaged by the acid. The primary symptom is a characteristic substernal burning sensation that radiates to the neck. Pain is relieved promptly by antacids, but the relief is only transient. In some patients, the refluxed fluid causes chest pain resembling that associated with coronary insufficiency. Acid reflux can also reach the larynx, causing laryngitis, and it can exacerbate asthma and cause other pulmonary symptoms.

The extent of epithelial damage depends on the frequency of reflux episodes, the length of time the refluxed gastric fluid is in contact with the mucosa, the contents of the refluxed fluid, and the intrinsic resistance of the esophageal epithelium to the acid. Acid and pepsin together are more damaging to the esophageal epithelium than either one alone, and the presence of bile salts further increases the damage. Relaxation of the lower esophageal sphincter is more common after meals, and more common after a high-fat meal (fat delays gastric emptying, and fat in the duodenum is also a stimulus for relaxation of the lower esophageal sphincter). A hiatal hernia may play a role in acid-reflux disease; indeed, severe reflux disease is usually associated with a small hernial pouch.

In his comprehensive review of acid-reflux disorders that appeared recently in the New England Journal of Medicine, gastroenterologist Charles Pope (University of Washington School of Medicine) described a diagnostic algorithm that covers most clinical situations. A patient presenting with heartburn is first given conservative therapy. If this solves the problem, the therapy is maintained. If symptoms persist or if the heartburn is associated with bleeding or dysphagia, wrote Pope, endoscopy is indicated, with preliminary barium esophagography performed if an obstruction is suspected (i.e., if the patient needs to regurgitate the bolus of food or saliva). If endoscopy discloses mucosal erosion, a diagnosis of reflux damage can be made. If mucosal erosion is present and the patient is immunocompromised, a biopsy should be performed to identify any pathogen requiring specific therapy. Endoscopy will also demonstrate the presence of Barrett’s epithelium (where normal epithelium is replaced by abnormal metaplastic columnar cells). Barrett’s esophagitis is a consequence of severe acid reflux, and as it is potentially malignant (the risk of esophageal cancer is increased 30- to 50-fold), patients with Barrett’s epithelium require biopsy and further evaluation.

According to Pope, the first step in therapy of acid-reflux disorders is the elevation of the head of the bed, which often reduces or even eliminates the problem. The efficacy of bed elevation approaches that of therapy with H2-receptor blockers. Patients should also be advised to avoid bedtime snacks, eat low-fat foods, quit smoking, reduce alcohol consumption, and use antacids or alginic acid for symptom control. If erosive esophagitis is absent on endoscopy, therapy may be initiated with H2 blockers – cimetidine (Tagamet/SmithKline Beecham), ranitidine (Zantac/Glaxo), famotidine (Pepcid/Merck), nizatidine (Axid/Lilly) – or with omeprazole (Prilosec/Astra, Merck) or cisapride (Propulsid/Janssen). H2 blockers and cisapride provide symptomatic relief in 5% to 75% of patients, whereas omeprazole has a much higher efficacy rate. When erosive esophagitis is present, only those drugs that reduce the output of hydrogen by the parietal cell – namely, H2 blockers and omeprazole – will heal erosions. Omeprazole is usually effective in patients whose erosive esophagitis is resistant to H2 blockers in escalating doses, and the majority of patients will respond as well to 20 mg of omeprazole once daily as to 20 mg twice daily (Pope has found that only about one third of patients require the twice daily regimen).

Cisapride provides symptomatic relief by decreasing the duration of contact between the gastric acid and the esophageal mucosa. It accomplishes this by increasing lower esophageal sphincter pressure and improving esophageal motility. Referred to as a “prokinetic” agent, cisapride acts via serotonin receptors to stimulate the release of acetylcholine from the myenteric plexus, which in turn increases esophageal and GI motility and accelerates gastric emptying. The drug is synergistic with H2 blockers. Controlled trials have found that cisapride 10-20 mg four times daily improved esophagitis (symptomatic and on endoscopy) in 57% to 69% of patients. Antireflux surgery is indicated when medical therapy is ineffective or the patient is noncompliant, or when the patient is young and faced with a lifetime of medical therapy.

Acid in the larynx causes distinct symptoms – hoarseness, chronic nonproductive cough, a sensation of pressure deep in the throat, and a persistent need to clear the throat – often in the absence of heartburn or regurgitation. Endoscopy may show erythema or white plaques on the posterior larynx, a normal larynx, or, in severe cases, ulceration or polyps on the vocal cords. Treatment with omeprazole improves acid laryngitis.

Acid reflux can also contribute to asthma and pulmonary fibrosis. While aspiration of gastric acid directly into the lungs may occur on occasion, the problem is most likely esophageal irritation with resulting vagally induced bronchoconstriction. Also, coughing may promote reflux. Theophylline may also promote reflux by decreasing lower esophageal sphincter pressure. “The only way to establish a causal relation,” wrote Pope, “is to demonstrate that control of acid reflux by medical or surgical means ameliorates asthma.” Medical trials suggest that acid blockade (with H2 blockers or omeprazole) is beneficial in some patients, while antireflux surgery improves symptoms in 30% to 60% of patients. One comparative trial found that cimetidine 300 mg four times a day improved symptoms and pulmonary function, although patients relapsed as soon as the drug was withdrawn. Surgery resulted in lasting improvement (up to 5 years), although a small group of patients with allergic asthma did not benefit from the procedure.

For maintenance therapy of acid-reflux disorders, omeprazole has proved to be efficacious, although there is inadequate information about long-term safety. Cisapride has also been shown to prevent relapse. H2 blockers are not effective. Pope prefers to begin therapy with an eight-week trial of cimetidine (800 mg twice daily) or ranitidine (150 mg twice daily). If clinical results are satisfactory, he continues treatment with the smallest dose of the H2 blocker that will control symptoms. If initial therapy fails, he prescribes omeprazole for 1 month, with the dose increased to 40 mg per day if symptoms persist. Antireflux surgery is offered to patients who are unresponsive, noncompliant, or young (those who would otherwise need medications indefinitely). Patients with acid laryngitis are given a 2- month trial with omeprazole to suppress acid output, with monitoring of clinical response and appearance at laryngoscopy. In conclusion, most acid-reflux disorders can be managed with lifestyle changes and modest drug therapy (using as low a dose as possible), with monitoring to detect side effects and disease recurrence.

Omeprazole in acid-reflux disease

Omeprazole (Prilosec/Merck|Astra) is the first member of a new class of gastric antisecretory agents, the benzimidazoles. Omeprazole acts by irreversibly blocking the hydrogen/potassium ATPase enzyme system (the proton pump) on the secretory surface of the gastric parietal cell. The drug is used for the treatment of gastroesophageal reflux, for which it is much more effective than histamine2-receptor (H2) blockers. It is also used for gastrointestinal hypersecretory disorders and duodenal ulcer. The most common side effects affect the gut (diarrhea, nausea, constipation, abdominal pain, vomiting) and central nervous system (headache, dizziness).

Recently Sivakuma and Dalakas (National Institutes of Neurological Disorders and Stroke) described a lupus-like syndrome in a 63-year-old man who was treated for 2 weeks with omeprazole for severe reflux esophagitis. The GI symptoms resolved, but the fever, malaise, arthralgia, severe erythematous swelling of the metacarpophalangeal joints, Raynaud’s phenomenon, and pitting edema of the feet developed. Hematologic and chemical screening results were normal except for raised erythrocyte sedimentation rate and elevated levels of IgA and autoantibodies (antinuclear, antihistone, and anticardiolipid IgG antibodies). Omeprazole was discontinued, and symptoms resolved over the next 2 months (except for residual swelling of metacarpal joints and feet). Drug-induced lupus erythematosus is thought to be related to alteration of the catabolism of nuclear chromatin or histone by the drug or metabolites. Failure to recognize the altered products as “self” results in an autoimmune attack. Since omeprazole also has an affect on cellular DNA synthesis, it may induce lupus by a similar mechanism.

Immunologic mechanisms are thought to be responsible for other serious side effects associated with omeprazole therapy, including vasculitis, renal and cardiac damage, and possibly blindness and deafness. To date, 19 cases of impaired vision and blindness and four cases of impaired hearing and deafness have been associated with omeprazole administration. While most reports have concerned patients who received the drug by intravenous injection, in some cases the drug was given orally. In the United States, omeprazole is available only in an oral (delayed-release) formulation. In Europe, the drug is available in both oral and injectable formulations, although physicians are advised to give the drug orally whenever possible. When the drug must be used intravenously (IV), physicians are warned to take into account the pharmacokinetic differences between bolus injection and infusion. In Germany, the license for IV omeprazole was suspended in August pending Astra’s completion of additional safety studies. Germany’s Federal Health Agency says that product information should include warnings on blindness and deafness, as well as allergic vasculitis and drug-induced fever.

Originally posted 2010-04-11 05:05:12. Republished by Blog Post Promoter

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