Gastroduodenal Mucosal Resistance to Injury

Pathophysiology of the Stomach: acid-peptic aggression and mucosal defense with balance favoring mucosal defense

Why doesn’t the stomach digest itself?

Lumenal surface lined by specialized gastric surface mucous cells.

Mucous cells secrete mucus and bicarbonate, under the influence of prostaglandin E.

Mucus and bicarbonate form protective layer on surface, reducing exposure to acid, pepsin, and other injurious agents.

Tight junctions between the cells help resist back diffusion of acid into the epithelium.

Nitric oxide (vasodilators) and endothelins (vasoconstrictors) regulate mucosal blood flow, washing away injurious agents.

Cells resist injury by anti-oxidants, including superoxide dismutate, catalase, glutathione, tocopherol, and ascorbic acid. In an event of injury, cells are quickly replaced (restitution), with prostaglandins and epidermal growth factors probably playing an important role in repair process.

Duodenum: bicarbonate secretion by mucosal Brunner’s glands and by pancreas neutralize acidity.

Colonization of the mucosal surface in the gastric antrum with helicobacter pylori profoundly affects mucosal integrity

Agents and conditions which injure gastric mucosa

Salicylates and NSAIDs (relieve pain and inflammation). Inhibit cyclooxygenase Þ ß prostaglandins (recall: normal fx of prostaglandins is to enhance mucosal resistance by stimulating mucous and bicarbonate secretion, and enhancing mucosal blood flow and epithelial repair). ß prostaglandins Þ ß mucous, ß bicarbonate, ß blood flow, ß repair (side effect: gastoduodenal mucosal injury)

Risk factors: Age, cardiovascular disease, history of ulcers, Ý NSAID doses, co-therapy with corticosteroids.

Prevention: acetaminophen instead of NSAIDs, local instead of systemic treatments, stop smoking and drinking, take Vitamin C, use newer NSAIDs (ASA is the worst! COX-2 inhibitors could be future because don’t work on stomach).

Alcohol. Þ mucosal edema and hemorrhage Þ disruption of over-lying epithelium. How? EtOH causes mediators to be released: histamine, leukotrienes, vasoactive intestinal peptide, endothelin Þ vasodilation Þ granulocyte activation Þ cytotoxic O₂free radicals and other enzymes that injure cells; portal hypertension Þ more susceptible to EtOH damage

Protection: Anti-neutrophil serum protects, blocking O₂-derived free radical formation with allopurinol, enhancement of mucosal glutathione protects against oxidative injury, increasing mucosal prostaglandin E synthesis.

Stress/Ischemia. Physical stresses including trauma, surgery, burns, cardiorespiratory failure, shock (due to sepsis and blood loss) produce gastric ischemia Þ ß ATP (hypoxanthine accumulates), ß prostaglandin E, Ý permeability of acid Þ Ý histamine, Ý leukotrienes into lamina propria Þ mucosal edema and hemorrhage. Note: reperfusion injury may occur because production of O₂ free radicals.

Protection: Allopurinol inhibits xanthine oxidase (converts hypoxanthine to xanthine; produces radicals), Nitric Oxide also helps stop injury.

Smoking. Þ ß prostaglandin production, ß duodenal bicarbonate secretion, ß epithelial repair, Ý reflux of bile and pancreatic enzymes into stomach, Ý prevalence of ulcers, ß ulcer healing rates, Ý ulcer recurrence rates.

Helicobacter pylori. Gram-negative curved rod, adapted to live in gastric mucosa. By age 60, >60% adults have it. Associated with gastritis, focal epithelial cell injury, inflammation in lamina propria, duodenal and gastric ulcers, gastric cancer, gastric lymphoma, and gastric atrophy. Transmission uncertain.

Mechanism: bug produces urease that cleaves urea to ammonia and carbon dioxide. This protects the bug from acidity. Its toxic effects are mediated by a toxin release that inhibits somatostatin D cells whose normal function is to inhibit gastrin cells Þ Ý gastrin Þ ß pH.

Agents and conditions which probably do not injure gastric mucosa

Stress/Psychological. Studies unclear. Psychological stress probably does not have a role in gastric injury.

Spicy Foods. Probably not involved.

Pharmacological agents which enhance mucosal resistance

Prostaglandins (see figure below)

Sucraflate

Bismuth and antibiotics – eradicate H. pylori. Indications for therapy, cost effectiveness, and side effects are under investigation.

Pharmacologic Treatment of Gastric Injury

The end result of stomach secretions (HCl and pepsinogenÞ pepsin) is a strongly acidic, proteolytic solution that initiates breakdown of dietary proteins during gastric mixing of meals. For different reasons this acidic mixture can sometimes cause injury to the stomach wall. The following are pharmacologic treatments for gastric injury (two phases for treatment – initial treatement for healing and maintenance treatment to prevent recurrence):

(1) Sucraflate – no systemic toxicity (poorly absorbed)

Pharmacodynamics: Sucraflate is a mix of sucrose octasulfate and aluminum hydroxide gel. This viscous gel sticks to damaged parts of the stomach lining and protects it from acid. WOA. Blood Al may increase with renal failure on hemodialysis.

Pharmacokinetics: F_o=0. Can be problem when given with WOBs, which will not be absorbed because they bind it. Acid activates sucraflate, so avoid concomitant antacids.

Therapeutic utility: repair ulcers; prevent and treat gastroduodenal injury; promotes healing in the short term. However, relapse is far sooner than with other agents. Doesn’t provide protection between meals or during sleep. No pain relief; healing is similar to H₂ antagonists but maintenance is more effective.

Adverse effects: none in itself; constipation

(2) Antacids: Al(OH)₃, Mg(OH)₃, Ca(CO₃)₂, Ca(OH)₂, NaHCO₃

Pharmacodynamics: Chemical rather than biological action. Directly neutralize stomach acid. Best antacids are mixtures of Mg and Al (Mylanta, Maalox, etc.) because they will only increase gastic pHÞ 4, thus not activating acid secretion (Ca and Na antacids increase pHÞ 7, thus activating further acid secretion). Also, Ca and Na antacids can cause electrolyte imbalances, and are therefore not recommended in treatment of gastric injury; decreased pepsin activation and increased acid secretion as pH increases

Note: some antacids contain Simethicone – breaks up gas bubbles.

Pharmacokinetics: Mg salts are fast acting and cause diarrhea, while Al salts are slow acting and may clear stomach before neutralization occurs. This is another reason to combine Al and Mg antacids. Dosing is 1 hour after mealtime thus taking advantage of food-induced slowing of gastric emptying and also allowing for pepsin activation. Also, because of their affect on acid, antacids may affect drug dissolution, absorption, and bioavailability.

Therapeutic utility: Provide only transient acid neutralization and no nocturnal protection. Not as effective as other treatments. Need to take very large doses. Liquid better than tablets; promotes healing in duodenal but not gastric ulcers.

Adverse effects: Al binds to and precipitates both phosphate and fluoride thus preventing absorption. Can lead to phosphate deficiency. Major adverse effect is on bowel movement. Mg Þ diarrhea. Al Þ constipation.

(3) H⁺, K⁺-ATPase inhibitors: Omeprazole

Pharmacodynamics: Non-competitive inhibitor which blocks acid secretion to any known stimulus. Regardless, does not alter pepsin or intrinsic factor secretion. Does not alter volume of gastric secretions, nor does it alter gastric motility. Does increase gastrin secretion. Omeprazole is a prodrug and requires acid for activation Þ Self-limiting.

Pharmacokinetics: half life ~4 days. Dose is 1/day. Absorbed rapidly but variably. F_o dependent on pH of stomach.

Therapeutic utility: promotes healing in stomach, duodenum, and esophagus. Good when H₂ blockers don’t work or must eliminate all acid from stomach.

Adverse effects: well-tolerated. 3% patients get GI effects. Rarely, skin rash and leukopenia observed.

(4) Prostaglandin (PGE₂) Agonists: Misoprostol Þ important for normal mucosal injury

Pharmacodynamics: PGE₂ blocks acid secretion by all known stimuli. Do this by blocking H₂ receptor pathway, likely by increasing cAMP, mucin, and bicarbonate. Note: administrating misoprostol and NSAIDs together is a problem because NSAIDs block the PGE₂ producing pathway cyclooxygenases. They also inhibit mucin and bicarbonate. Why not just give PGE₂? because has a short half life (~5 minutes; is an autocoid), synthesized and degraded locally. Misoprostol has longer T_½

Pharmacokinetics: Multiple dosing (4x/day) required. Other pharmacokinetics not known.

Therapeutic utility: helps heal gastric but not duodenal ulcers. Stops esophageal reflux and pain associated with ulceration. Currently used to prevent ulceration in patients at risk of ulcers and who take large doses of NSAIDs.

Adverse effects: Well tolerated; diarrhea. Contraindicated in pregnancy because highly teratogenic and can be abortifacient.

(5) Muscarinic Cholinergic Antagonists

Pharmacodynamics: Decrease basal acid secretion (50%), but not stimulated acid secretion as effectively. Also decreases mucin and bicarbonate secretions.

Pharmacokinetics: no special kinetic issues

Therapeutic utility: Enhances healing but not as good as other drugs; almost equal to H₂ blockers in maintenance

Adverse effects: anything atropine will do. Dry mouth, blurred vision, tachycardia, urinary retention; in overdose, delerium, hallucination, sedation Þ coma and lowered temperature

(6) Histamine H₂-receptor Antagonists: Cimetidine, Ranitidine, others

Pharmacodynamics: Drug of choice! Very selective for H₂ receptors only, which almost all located in stomach. Reduce acid secretion and volume of gastric secretions. Inhibit both basal fasting and nocturnal secretion as well as secretion induced by all known stimuli (feeding, sham feeding, gastric distention, increased pH). Secretion of intrinsic factor and pepsin are reduced. Of little consequence because present in excess.

Pharmacokinetics: Rapidly absorbed. Though have short half-life (3 hrs) given in high dose 1/day because have few adverse effects. Cimetidine inhibits metabolism of many drugs in the liver. Could be bad.

Therapeutic utility: used for all gastric and duodenal ulceration. Low replase (1/5 per year).

Adverse effects: well tolerated. Though cimetidine has many interactions it is so widely used that the actual incidence is low. Ranitidine and other new ones do not inhibit drug metabolism in the liver to the same extent. The older agents (including cimetidine) had some endocrine effects including gynecomastia, loss of libido, and impotence, the newer agents do not show any of these.