Gastric Mucosal Barrier and Peptic Ulcer Disease

Question 1

The Gastric Mucosal Barrier

Answer 1

• The gastric mucosal barrier is critical for protection against HCl induced ulceration.
• The barrier is dependent on surface epithelial cells connected by tight junctions, and covered with a mucus barrier trapping an alkaline fluid at the cell surface.
• The high pH of the fluid surrounding the mucosal apical membrane is dependent on secreted HCO3 - covered by mucus both produced by the surface epithelial cells.
• Prostaglandins (most potently PGE2) stimulate these secretory processes, as well as the formation of tight junctions, and therefore play an important role in the maintenance of the mucosal barrier function.
• The hormones Gastrin and CCK via their effects on cell growth and turnover also facilitate maintenance of the functional barrier.
• Finally, it is clear that regulation of blood flow to the submucosa, and afferent neural signaling also contribute to maintenance of barrier integrity.

Question 2

Primary Mechanisms for Inhibitng HCl Release from Oxyntic Cells

Answer 2

• somatostain inhibiting gastrin
• Prostaglandins (E₂ and I₂ )
• signals originating from the duodenum
• GI hormones Secretin, CCK and GIP

Question 3

Answer 3

Question 4

Answer 4

Question 5

Peptic Ulcer

Answer 5

• A benign lesion of gastric or duodenal mucosa occurring at a site where the mucosal epithelium is damaged by acid and pepsin.
• Excess acid production or an intrinsic defect in the mucosal defense barrier can result in formation of an ulcer.

Question 6

Upper GI Ulcerations

Answer 6

•Esophageal

-Acid Reflux; GERD

•Duodenal

-Acid Dumping

•Gastric

-Failure of the Protective Barrier

*exogenous factors: NSAIDs (nhibit PG production), ethanol, smoking, bacteria (H.pylori - 85%)

*endogenous factors: bile, lysolecithin

Question 7

H. pylori and Peptic Ulcers

Answer 7

•Most ulcers are the result of infection with H. pylori 80-85% of cases; nearly 100% of Gastric Ulcers

– Not all of those infected with H. pylori develop ulcers.

– H. pylori MAY result in weakening of the mucosal defense systems, allowing for development of ulcer subsequent to acid/pepsin aggression

Question 8

Other Causes of Peptic Ulcers

Answer 8

• NSAIDs ~ 15% of all Ulcers – Long term use of nonsteroidal anti-inflammatory drugs is the second most common cause of ulcers. NSAIDs block COX enzymes decreasing prostaglandin synthesis (PGs). PGs are important in decreasing acid production and stimulating mucus production and the integrity of the epithelial protective layer.
• Gastrinoma (Zollinger-Ellison Syndrome): Gastrinoma

– Patients typically have tumors of the duodenum or pancreas and secrete abnormally high amounts of gastrin which stimulates gastric gland proliferation and acid production. Patients almost always develop a duodenal ulcer.

• Stress ulcers

• Result of physical trauma (i.e., burn patients). ‘Long term sympathetic stress’

Question 9

Therapeutic Strategies for Ulcers

Answer 9

• Old Therapeutic Strategy:

– “no acid, no ulcer”.

– Accomplished by reduction of acid production OR improvement of the integrity of the mucosal barrier, :: Recurrent Ulcerations

• Current Therapeutic Strategy:

– “no NSAID damage, no Zollinger Ellison syndrome (Gastrinoma), no H. pylori, no ulcer”.

– Accomplished by eradication of H. pylori with antibiotic therapy and inhibition of acid secretion.

Question 10

Ulcer Treatment Approaches

Answer 10

Eradication of Helicobacter pylori Antibiotic therapy Inhibition of Acid

– Proton Pump Inhibitors (Omeprazole)*

– Histamine (H2) Receptor Antagonists (Cimetidine, Ranitidine)

– Antacids

– Prostaglandin Agonists (Misoprostol -prototype)

Question 11

First Line Triple Therapy

Answer 11

Administration of: omeprazole 20 mg and clarithromycin 250 mg & amoxicillin 1000 mg, each for 10-14 days.

: limited studies suggest approximately a 90% effectiveness for eradication.

Question 12

H+ Pump Inhibitors

Answer 12

Omeprazole and its Derivatives: Prilosec, Nexium, Prevecid, Protonix

:: Covalently blocks the Proton ATPase

• Recovery requires translation and transcription of new proton pumps after dosing.
• Requires an Acidic Environment to become Activated

Question 13

Histamine H₂ Receptor Antagonists

Answer 13

Cimetidine and its Derivatives

Tagamet, Zantac, Pepcid and Axid

Tagamet: Short duration, inhibits hepatic cytochrome P-450 slowing clearance of many drugs, and exhibits some antiandrogenic effects

Derivatives: longer duration of action do not possess anti-androgenic properties or interfere significantly with drug metabolism.

:: Primarily Used for Treatment of GERD

Question 14

Antacids

Answer 14

• Antacids have been useful adjuncts to therapy with H2 histamine receptor antagonists and for management of gastroesophageal reflux (“heartburn”) or occasional dyspepsia.
• They are important in that patients will self-medicate without serious consideration of these agents as real drugs.
• Antacids are weak bases that neutralize acid (HCl) in the stomach; acid + base = salt + water. Antacids thus do not decrease secretion of acid. In fact they can sometimes increase acid production by the oxyntic cells.
• They instead neutralize acid in the lumen of the stomach to produce two desirable therapeutic goals: total acid load delivered to the duodenum is decreased and activity of pepsin is inhibited
• systemic and nonsystemic

Question 15

Systemic Antacids

Answer 15

• Systemic antacids are those that are absorbed into the bloodstream, can increase blood pH, and alkalinize the urine.
• The classic example of a systemic antacid is sodium bicarbonate (“baking soda”).
• For occasional, intermittent therapy, a systemic antacid poses no hazard. When used regularly for days or weeks, however, a systemic antacid is undesirable and a non-systemic antacid is required.

Question 16

Nonsystemic Antacids

Answer 16

•Nonsystemic antacids are primarily Carbonates and Hydroxides that contain a cation (usually calcium, magnesium or aluminum) that is poorly absorbed from the small intestine, does not alter blood pH, and therefore does not alkalinize the urine.

Question 17

Answer 17

• Sodium and potassium salts generally have a fast onset of action (almost immediate neutralization) and can briefly raise intragastric pH to 5-7 or higher. However, the neutralizing effect is short and, as acid secretion continues, the pH soon creeps down to pH 2-3.
• In contrast, most calcium salts have both a fairly rapid onset of action and the pH remains elevated as long as calcium is present in the stomach.
• Magnesium and aluminum salts: both magnesium trisilicate and aluminum oxide neutralize acid slowly, so these salts have a slow (minutes) onset of action. However, total neutralizing capacity is adequate to maintain pH at desirable levels as long as they are present in the stomach.

-Magnesium hydroxide (milk of magnesia) has a more rapid onset of neutralizing action and can raise intragastric pH to 8-9 for short periods.

Question 18

Antacid Problems

Answer 18

• The most common problems encountered with antacids as therapy for peptic ulcer are constipation and diarrhea.
• Magnesium is a laxative and aluminum (similar to Calcium) is constipating due to changes in motility.
• An acceptable balance in stool frequency and consistency can be achieved by mixtures of Mg2+ and Al3+ salts or by alternating doses of Mg2+ and Al3+ containing antacids. 
• Antacids are generally prepared from natural deposits and may contain large amounts of sodium. Because patients may consume vast quantities of antacid, a high sodium content may exacerbate existing heart and circulatory problems and hypertension associated with renal disease

Question 19

Pentgastrin

Answer 19

The agent of choice for stimulation of gastric secretion is pentagastrin (Pentavlon®), a synthetic pentapeptide containing the carboxy-terminal pentapeptide fragment of gastrin. Pentagastrin retains the secretory activity of gastrin, the natural circulating secretory stimulant, and has virtually no other effect in the doses used.