Many factors, including palatability, determine the effectiveness and choice of antacid. Although sodium bicarbonate effectively neutralizes acid, it is very water soluble and rapidly absorbed from the stomach, and the alkali and sodium loads may pose a risk for patients with cardiac or renal failure. Depending on particle size and crystal structure, CaCO3 rapidly and effectively neutralizes gastric H+, but the release of CO2 from bicarbonate- and carbonate-containing antacids can cause belching, nausea, abdominal distention, and flatulence. Calcium also may induce rebound acid secretion, necessitating more frequent administration.
Combinations of Mg2+ (rapidly reacting) and Al3+ (slowly reacting) hydroxides provide a relatively balanced and sustained neutralizing capacity and are preferred by most experts. Magaldrate is a hydroxymagnesium aluminate complex that is converted rapidly in gastric acid to Mg(OH)2 and Al(OH)3, which are absorbed poorly and thus provide a sustained antacid effect. Although fixed combinations of magnesium and aluminum theoretically counteract the adverse effects of each other on the bowel (Al3+ can relax gastric smooth muscle, producing delayed gastric emptying and constipation; Mg2+ exerts the opposite effects), such balance is not always achieved in practice.
Simethicone, a surfactant that may decrease foaming and hence esophageal reflux, is included in many antacid preparations. However, other fixed combinations, particularly those with aspirin, that are marketed for "acid indigestion" are irrational choices, are potentially unsafe in patients predisposed to gastroduodenal ulcers, and should not be used.
The relative effectiveness of antacid preparations is expressed as milliequivalents of acid-neutralizing capacity (defined as the quantity of 1N HCl, expressed in milliequivalents, that can be brought to pH 3.5 within 15 minutes); according to FDA requirements, antacids must have a neutralizing capacity of at least 5 mEq per dose. Due to discrepancies between in vitro and in vivo neutralizing capacities, antacid doses in practice are titrated simply to relieve symptoms. For uncomplicated ulcers, antacids are given orally 1 and 3 hours after meals and at bedtime. This regimen, providing ~120 mEq of a Mg-Al combination per dose, may be almost as effective as conventional dosing with an H2 receptor antagonist. For severe symptoms or uncontrolled reflux, antacids can be given as often as every 30-60 minutes. In general, antacids should be administered in suspension form because this probably has a greater neutralizing capacity than powder or tablet dosage forms. If tablets are used, they should be thoroughly chewed for maximum effect.
Antacids are cleared from the empty stomach in ~30 minutes. However, the presence of food is sufficient to elevate gastric pH to ~5 for ~1 hour and to prolong the neutralizing effects of antacids for ~2-3 hours.
Antacids vary in the extent to which they are absorbed, and hence in their systemic effects. In general, most antacids can elevate urinary pH by ~1 pH unit. Antacids that contain Al3+, Ca2+, or Mg2+ are absorbed less completely than are those that contain NaHCO3. With normal renal function, the modest accumulations of Al3+ and Mg2+ do not pose a problem; with renal insufficiency, however, absorbed Al3+ can contribute to osteoporosis, encephalopathy, and proximal myopathy. About 15% of orally administered Ca2+ is absorbed, causing a transient hypercalcemia. Although this is not a problem in normal patients, the hypercalcemia from as little as 3-4 g of CaCO3 per day can be problematic in patients with uremia. In the past, when large doses of NaHCO3 and CaCO3 were administered commonly with milk or cream for the management of peptic ulcer, the milk-alkali syndrome (alkalosis, hypercalcemia, and renal insufficiency) occurred frequently. Today, this syndrome is rare and generally results from the chronic ingestion of large quantities of Ca2+ (five to forty 500-mg tablets per day of calcium carbonate) taken with milk. Patients may be asymptomatic or may present with the insidious onset of hypercalcemia, reduced secretion of parathyroid hormone, retention of phosphate, precipitation of Ca2+ salts in the kidney, and renal insufficiency.
By altering gastric and urinary pH, antacids may affect a number of drugs (e.g., thyroid hormones, allopurinol, and imidazole antifungals, by altering rates of dissolution and absorption, bioavailability, and renal elimination). Al3+ and Mg2+ antacids also are notable for their propensity to chelate other drugs present in the GI tract, forming insoluble complexes that pass through the GI tract without absorption. Thus it generally is prudent to avoid concurrent administration of antacids and drugs intended for systemic absorption. Most interactions can be avoided by taking antacids 2 hours before or after ingestion of other drugs.
Other Acid Suppressants and Cytoprotectants
The M1 muscarinic receptor antagonists pirenzepine and telenzepine (Chapter 9) can reduce basal acid production by 40-50% and long have been used to treat patients with peptic ulcer disease in countries other than the U.S. The ACh receptor on the parietal cell itself is of the M3 subtype, and these drugs are believed to suppress neural stimulation of acid production via actions on M1 receptors of intramural ganglia (Figure 45–1). Because of their relatively poor efficacy, significant and undesirable anticholinergic side effects, and risk of blood disorders (pirenzepine), they rarely are used today.
In the hope of providing more rapid onset of action and sustained acid suppression, reversible inhibitors of the gastric H+, K+-ATPase (e.g., the pyrrolopyridazine derivative AKU517) are being developed for clinical use. Antagonists of the CCK2 gastrin receptor on parietal cells also are under study. The precise role that these agents will play in the therapy of acid-peptic disorders in the future is yet to be determined.
Rebamipide (2-(4-chlorobenzoylamino)-3-[2(1H)-quinolinon-4-yl]-propionic acid) is used for ulcer therapy in parts of Asia. It appears to exert a cytoprotective effect both by increasing prostaglandin generation in gastric mucosa and by scavenging reactive oxygen species. Ecabet (gastrom; 12-sulfodehydroabietic acid monosodium), which appears to increase the formation of PGE2 and PGI2, also is used for ulcer therapy, mostly in Japan. Carbenoxolone, a derivative of glycyrrhizic acid found in licorice root, has been used with modest success for ulcer therapy in Europe. Its exact mechanism of action is not clear, but it may alter the composition and quantity of mucin. Unfortunately, carbenoxolone inhibits the type I isozyme of 11β-hydroxysteroid dehydrogenase, which protects the mineralocorticoid receptor from activation by cortisol in the distal nephron; it therefore causes hypokalemia and hypertension due to excessive mineralocorticoid receptor activation (Chapter 42). Bismuth compounds (Chapter 46) may be as effective as cimetidine in patients with peptic ulcers and are frequently prescribed in combination with antibiotics to eradicate H. pylori and prevent ulcer recurrence. Bismuth compounds bind to the base of the ulcer, promote mucin and bicarbonate production, and have significant antibacterial effects. Bismuth compounds are an important component of many anti-Helicobacter regimens; however, given the availability of more effective drugs, bismuth compounds seldom are used alone as cytoprotective agents.