Mucosal protective agents Domina Petric, MD

Introduction 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: pH 7 at the mucosal surface, pH 1-2 in the gastric lumen.

Introduction Blood flow carries bicarbonate and vital nutrients to surface cells. Areas of injured epithelium are quickly repaired by restitution: migration of cells from gland neck cells seals small erosions to reestablish intact epithelium. Mucosal prostaglandins are important in stimulating secretion of mucus and bicarbonate. Mucosal prostaglandins also stimulate mucosal blood flow.

Mucosal protective agents Sucralfate Prostaglandin analogs Bismuth compounds

Sucralfate Sucralfate is a salt of sucrose complexed to sulfated aluminium hydroxide. In water or acidic solutions it forms a viscous, tenacious paste that binds selectively to ulcers or erosions for up to 6 hours.

Sucralfate Sucralfate has limited solubility. It breaks down into sucrose sulfate (strongly negatively charged) and an aluminium salt. Less than 3% of intact drug and aluminium is absorbed from the intestinal tract. The remainder is excreted in the feces.

Pharmacodynamics Negatively charged sucrose sulfate binds to positively charged proteins in the base of ulcers or erosions. A physical barrier is formed. Barrier restricts further caustic damage and stimulates mucosal prostaglandin and bicarbonate secretion.

Clinical use Sucralfate is administered in a dose of 1 g 4 times daily on an empty stomach (at least 1 hour before meal). Sucralfate, administered as a slurry through a nasogastric tube, reduces the incidence of clinically significant upper gastrointestinal bleeding in critically ill patients.

Clinical use Sucralfate is still used for prevention of stress-related bleeding. There is concern that acid inhibitory therapies (antacids, H2 antagonists, PPIs) may increase the risk of nosocomial pneumonia.

Adverse effects Constipation occurs in 2% of patients due to the aluminium salt. Small amount of aluminium is absorbed. Sucralfate should not be used for prolonged periods in patients with renal insufficiency. Sucralfate may bind to other medicinations, impairing their absorption.

Prostaglandin analogs The human gastrointestinal mucosa synthesizes a number of prostaglandins. The primary ones are prostaglandins E and F. Misoprostol (methyl analog of PGE1) is approved for gastrointestinal conditions.

Prostaglandin analogs After oral administration, misoprostol is rapidly absorbed and metabolized to a metabolically active free acid. The serum half-life is less than 30 minutes. It must be administered 3-4 times daily. It is excreted in the urine, but dose reduction is not needed in patients with renal insufficiency.

Pharmacodynamics Misoprostol has both acid inhibitory and mucosal protective properties. It stimulates mucus and bicarbonate secretion, and enhances mucosal blood flow. It binds to a prostaglandin receptor on parietal cells, reducing histamine-stimulated cAMP production with modest acid inhibition.

Clinical use Peptic ulcers develop in approximately 10-20% of patients who receive long-term NSAID therapy. Misoprostol reduces the incidence of NSAID-induced ulcers to less than 3% and the incidence of ulcer complications by 50%.

Adverse effects Diarrhea and cramping abdominal pain occur in 10-20% of patients. Misoprostol stimulates uterine contractions. It should not be used during pregnancy or in women of childbearing potential that do not use contraception. No significant drug interactions.

Bismuth compounds Bismuth subsalicylate and bismuth subcitrate potassium! Bismuth subsalicylate undergoes rapid dissociation within the stomach, allowing absorption of salicylate. Over 99% of the bismuth appears in the stool.

Bismuth compounds Minimal bismuth is absorbed (1%), but it is stored in many tissues and has slow renal excretion. Salicylate is readily absorbed and excreted in the urine. Bismuth subcitrate potassium is usually used in combination with metronidazole, tetracycline and IPP as quadruple therapy for H. pylori.

Pharmacodynamics Bismuth coats ulcers and erosions. It creates protective layer against acid and pepsin. It may also stimulate prostaglandin, mucus and bicarbonate secretion.

Pharmacodynamics Bismuth subsalicylate reduces stool frequency and liquidity in acute infectious diarrhea due to salicylate inhibition of intestinal prostaglandin and chloride secretion.

Bismuth has direct antimicrobial effects and binds enterotoxins. Pharmacodynamics Bismuth has direct antimicrobial effects and binds enterotoxins. Bismuth compounds have direct antimicrobial activity against H. pylori.

Clinical use Nonprescription bismuth compounds are widely used by patients for the nonspecific treatment of dyspepsia and acute diarrhea. Bismuth subsalicylate is used for the prevention of traveler´s diarrhea: 30 mL or 2 tablets 4 times daily.

Clinical use Bismuth compounds are used in four drug regimen for the eradication of H. pylori infection during 10-14 days: PPI twice daily bismuth subsalicylate 2 tablets (262 mg each) 4 times daily tetracycline 250-500 mg 4 times daily metronidazole 500 mg 4 times daily

Clinical use Another regime for H. pylori during 10 days: PPI twice daily bismuth subcitrate 140 mg 4 times daily metronidazole 125 mg 4 times daily tetracycline 125 mg 4 times daily

Adverse effects 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.

Adverse effects Prolonged usage of some bismuth compounds, but not bismuth subsalicylate and citrate, may rarely lead to bismuth toxicity. Toxicity results in encephalopathy: ataxia, headaches, confusion, seizures. High dosages of bismuth subsalicylate may lead to salicylate toxicity.

Literature Katzung, Masters, Trevor. Basic and clinical pharmacology.