MUCOSAL PROTECTIVE AGENTS
The gastroduodenal mucosa has evolved a number of defense mechanisms to protect itself against the noxious effects of acid and pepsin. Both mucus and epithelial cell-cell tight junctions restrict back diffusion of acid and pepsin. Epithelial bicarbonate secretion establishes a pH gradient within the mucous layer in which the pH ranges from 7 at the mucosal surface to 1–2 in the gastric lumen. Blood flow carries bicarbonate and vital nutrients to sur-face cells. Areas of injured epithelium are quickly repaired by res-titution, a process in which migration of cells from gland neck cells seals small erosions to reestablish intact epithelium. Mucosal prostaglandins appear to be important in stimulating mucus and bicarbonate secretion and mucosal blood flow. A number of agents that potentiate these mucosal defense mechanisms are available for the prevention and treatment of acid-peptic disorders.
Sucralfate is a salt of sucrose complexed to sulfated aluminum hydroxide. In water or acidic solutions it forms a viscous, tena-cious paste that binds selectively to ulcers or erosions for up to 6 hours. Sucralfate has limited solubility, breaking down into sucrose sulfate (strongly negatively charged) and an aluminum salt. Less than 3% of intact drug and aluminum is absorbed from the intestinal tract; the remainder is excreted in the feces.
A variety of beneficial effects have been attributed to sucralfate, but the precise mechanism of action is unclear. It is believed that the negatively charged sucrose sulfate binds to positively chargedproteins in the base of ulcers or erosion, forming a physical barrier that restricts further caustic damage and stimulates mucosal pros-taglandin and bicarbonate secretion.
Sucralfate is administered in a dosage of 1 g four times daily on an empty stomach (at least 1 hour before meals). At present, its clinical uses are limited. Sucralfate (administered as a slurry through a nasogastric tube) reduces the incidence of clinically significant upper gastrointestinal bleeding in critically ill patients hospitalized in the intensive care unit, although it is slightly less effective than intravenous H2 antagonists. Sucralfate is still used by many clinicians for prevention of stress-related bleeding because of concerns that acid inhibitory therapies (antacids, H2 antagonists, and proton pump inhibitors) may increase the risk of nosocomial pneumonia.
Because it is not absorbed, sucralfate is virtually devoid of systemic adverse effects. Constipation occurs in 2% of patients due to the aluminum salt. Because a small amount of aluminum is absorbed, it should not be used for prolonged periods in patients with renal insufficiency.
Sucralfate may bind to other medications, impairing their absorption.
The human gastrointestinal mucosa synthesizes a number of pros-taglandins ; the primary ones are prostaglandins E and F. Misoprostol, a methyl analog of PGE1, has been approved for gastrointestinal conditions. After oral administration, it is rap-idly absorbed and metabolized to a metabolically active free acid. The serum half-life is less than 30 minutes; hence, it must be administered 3–4 times daily. It is excreted in the urine; however, dose reduction is not needed in patients with renal insufficiency.
Misoprostol has both acid inhibitory and mucosal protective prop-erties. It is believed to stimulate mucus and bicarbonate secretion and enhance mucosal blood flow. In addition, it binds to a prosta-glandin receptor on parietal cells, reducing histamine-stimulated cAMP production and causing modest acid inhibition. Prostaglandins have a variety of other actions, including stimula-tion of intestinal electrolyte and fluid secretion, intestinal motility, and uterine contractions.
Peptic ulcers develop in approximately 10–20% of patients who receive long-term NSAID therapy (see Proton Pump Inhibitors,above). Misoprostol reduces the incidence of NSAID-induced ulcers to less than 3% and the incidence of ulcer complications by 50%. It is approved for prevention of NSAID-induced ulcers in high-risk patients; however, misoprostol has never achieved wide-spread use owing to its high adverse-effect profile and need for multiple daily dosing. As discussed, proton pump inhibitors may be as effective as and better tolerated than misoprostol for this indication. Cyclooxygenase-2-selective NSAIDs, which may have less gastrointestinal toxicity , offer another option for patients at high risk for NSAID-induced complications.
Diarrhea and cramping abdominal pain occur in 10–20% of patients. Because misoprostol stimulates uterine contractions , it should not be used during pregnancy or in women of childbearing potential unless they have a negative serum preg-nancy test and are compliant with effective contraceptive mea-sures. No significant drug interactions are reported.
Two bismuth compounds are available: bismuth subsalicylate, a nonprescription formulation containing bismuth and salicylate, and bismuth subcitrate potassium. In the USA, bismuth subci-trate is available only as a combination prescription product that also contains metronidazole and tetracycline for the treatment of H pylori. Bismuth subsalicylate undergoes rapid dissociationwithin the stomach, allowing absorption of salicylate. Over 99% of the bismuth appears in the stool. Although minimal (< 1%), bismuth is absorbed; it is stored in many tissues and has slow renal excretion. Salicylate (like aspirin) is readily absorbed and excreted in the urine.
The precise mechanisms of action of bismuth are unknown. Bismuth coats ulcers and erosions, creating a protective layer against acid and pepsin. It may also stimulate prostaglandin, mucus, and bicarbonate secretion. Bismuth subsalicylate reduces stool frequency and liquidity in acute infectious diarrhea, due to salicylate inhibition of intestinal prostaglandin and chloride secre-tion. Bismuth has direct antimicrobial effects and binds enterotox-ins, accounting for its benefit in preventing and treating traveler’s diarrhea. Bismuth compounds have direct antimicrobial activity against H pylori.
In spite of the lack of comparative trials, nonprescription bismuth compounds (eg, Pepto-Bismol, Kaopectate) are widely used by patients for the nonspecific treatment of dyspepsia and acute diar-rhea. Bismuth subsalicylate also is used for the prevention of traveler’s diarrhea (30 mL or 2 tablets four times daily).
Bismuth compounds are used in 4-drug regimens for the eradication of H pylori infection. One regimen consists of a proton pump inhibitor twice daily combined with bismuth subsalicylate (2 tablets; 262 mg each), tetracycline (250–500 mg), and metron-idazole (500 mg) four times daily for 10–14 days. Another regi-men consists of a proton pump inhibitor twice daily combined with three capsules of a combination prescription formulation (each capsule containing bismuth subcitrate 140 mg, metronida-zole 125 mg, and tetracycline 125 mg) taken four times daily for 10 days. Although these are effective, standard “triple therapy” regimens (ie, proton pump inhibitor, clarithromycin, and amoxi-cillin or metronidazole twice daily for 14 days) generally are pre-ferred for first-line therapy because of twice-daily dosing and superior compliance. Bismuth-based quadruple therapies are com-monly used as second-line therapies.
All bismuth formulations have excellent safety profiles. Bismuth causes harmless blackening of the stool, which may be confused with gastrointestinal bleeding. Liquid formulations may cause harmless darkening of the tongue. Bismuth agents should be used for short periods only and should be avoided in patients with renal insufficiency. Prolonged usage of some bismuth compounds may rarely lead to bismuth toxicity, resulting in encephalopathy (ataxia, headaches, confusion, seizures). However, such toxicity is not reported with bismuth subsalicylate or bismuth citrate. High dos-ages of bismuth subsalicylate may lead to salicylate toxicity.