Drugs for Gastric and Duodenal Ulcers

In the area of a gastric or duodenal peptic ulcer, the mucosa has been attacked by digestive juices to such an extent as to expose the subjacent connective tissue layer (submucosa). This “self-digestion” occurs when the equilibrium between the corrosive hydrochloric acid and acid-neutralizing mucus, which forms a protective cover on the mucosal surface, is disturbed. Mucosal damage can be promoted by Helicobacter pylori bacteria that colonize the gastric mucus.

Drugs are employed with the following therapeutic aims: (a) to relieve pain; (b) to accelerate healing; and (c) to prevent ulcer recurrence. Therapeutic approaches are threefold : (I) to reduce aggressive forces by lowering H+ output, (II) to increase protective forces by means of mucoprotectants; and (III) to eradicate Helicobacter pylori.

I. Lowering of Acid Concentration

Ia. Agents for acid neutralization (A). H+- binding groups such as CO32-, HCO3− or OH−, together with their counter ions, are contained in antacid drugs. Neutralization reactions occurring after intake of CaCO3 and NaHCO3, respectively, are shown in (A). With nonabsorbable antacids, the counter ion is dissolved in the acidic gastric juice in the process of neutralization. Upon mixture with the alkaline pancreatic secretion in the duodenum, it is largely precipitated again by basic groups, e.g., as CaCO3 or AlPO4, and excreted in feces. Therefore, systemic absorption of counter ions or basic residues is minor. In the presence of renal insuf ciency, however, absorption of even small amounts may cause an increase in plasma levels of counter ions (e.g., magnesium intoxication with paralysis and cardiac disturbances). Precipitation in the gut lumen is responsible for other side effects, such as reduced absorption of other drugs due to their adsorption to the surface of precipitated antacid; or

phosphate depletion of the body with excessive intake of Al(OH)3.

Na+ ions remain in solution even in the presence ofHCO3−-rich pancreaticsecretions and are subject to absorption, like HCO3−. Because of the uptake of Na+, use of NaHCO3 must be avoided in conditions requiring restriction of NaCl intake, such as hypertension, cardiac failure, and edema.

Since food has a buffering effect, antacids are taken between meals (e.g.,1 and 3 hours after meals and at bedtime). Nonabsorbable antacids are preferred. Because Mg(OH)2 produces a laxative effect (cause: osmotic action, p.174, release of cholecystokinin by Mg2+, or both) and Al(OH)3 produces constipation (cause: astringent action of Al3+, p.180), these two antacids are frequently used in combination (e.g., magaldrate).

Ib. Inhibitors of acid production (B). Acting on their respective receptors,the transmitter acetylcholine, the hormone gastrin, and histamine released intramucosally stimulate the parietal cells of the gastric mucosa to increase output of HCl. Histamine comes from enterochromaf n-like (ECL) cells; its release is stimulated by the vagus nerve (via M1 receptors) and hormonally by gastrin. The effects of acetylcholine and histamine can be abolished by orally applied antagonists that reach parietal cells via the blood. Proton pump inhibitors are drugs of first choice for promoting healing of ulcers. Infection with H. pylori should be treated resolutely (p.172) to lower the risk of ulcer recurrence, chronic gastritis, gastric carcinomas, and gastric lymphomas.

The cholinoceptor antagonist pirenzepine preferentially blocks cholinoceptors of the M1 type; its use in peptic ulcer therapy is now obsolete.

Histamine receptors on the parietal cells belong to the H2 type and are blocked by H2 antihistaminics (p.118). Because histamine plays a pivotal role in the activation of parietal cells, H2 antihistaminics also diminish responsivity to other stimulants, e.g., gastrin (in gastrin-producing pancreatic tumors, Zollinger–Ellison syndrome). The first H2- blocker used clinically, cimetidine, only rarely produces adverse effects (CNS disturbances such as confusion; endocrine effects in the male such as gynecomastia, decreased libido, impotence); however, it inhibits the hepatic biotransformation of many other drugs. The more recently introduced substances ranitidine, nizatidine, and famotidine are effective at lower dosages. Evidently, inhibition of microsomal enzymes decreases with reduced drug load; thus, these substances are less likely to interfere with the therapeutic use of other pharmaceuticals.

Omeprazole (p.171) can cause maximal inhibition of HCl secretion. Given orally in gastric juice-resistant capsules, it reaches parietal cells via the blood. In the acidic milieu of the mucosa, an active metabolite is formed and binds covalently to the ATP-driven proton pump (H+/K+-ATPase) that transports H+ in exchange for K+ into the gastric juice.

Lansoprazole, pantoprazole, and rabeprazole produce analogous effects. Omeprazole is a racemate. With respect to dosage, the now available (S)-omeprazole (esomeprazole) represents the more potent enantiomer, but this offers no therapeutic advantage.

II. Protective Drugs

Sucralfate (A) contains numerous aluminum hydroxide residues. However, it is not an antacid because it fails to lower the overall acidity of gastric juice. After oral intake, sucralfate molecules undergo cross-linking in gastric juice, forming a paste that adheres to mucosal defects and exposed deeper layers. Here sucralfate intercepts H+. Protected from acid, and also from pepsin, trypsin, and bile acids, the mucosal defect can heal more rap-

idly. Sucralfate is taken on an empty stomach (1 hour before meals and at bedtime). It is well tolerated, but released Al3+ ions can cause constipation.

Misoprostol (B) is a semisynthetic prostaglandin derivative with greater stability than natural prostaglandin, permitting absorption after oral administration. Locally released prostaglandins (PGF2α, PGE2) promote mucus production in superficial cells and inhibit acid secretion of parietal cells (B). Inhibition of physiological PG synthesis by drugs (e.g., NSAIDS, p.200) explains the mucosal injury from these pharmaceuticals: protection by the mucus layer is diminished and acid production is enhanced. Misoprostol mimics the action of the prostaglandins on the mucosal tunic and thus can attenuate the adverse effects produced by inhibitors of PG synthesis, at least as regards the gastric mucosa. Additional systemic effects (frequent diarrhea; risk of precipitating contractions of the gravid uterus) significantly restrict its therapeutic utility.

III. Eradication of Helicobacter pylori (C)

This organism plays an important role in the pathogenesis of chronic gastritis and peptic ulcer disease. The combination of antibacterial drugs and omeprazole has proved effective. If amoxicillin (p.272) or clarithromycin (p.278) cannot be tolerated, metronidazole (p.276) may serve as a substitute. Colloidal bismuth compounds are also effective; however, as they entail the problem of heavymetal exposure, this treatment can no longer be recommended.