Relationship between parietal cells and enterochromaffin-like (ECL) cells

ACID-PEPTIC DISEASE AND TREATMENT

Introduction -

A. Acid peptic includes:

1.Peptic ulcers (stomach and duodenal)

2.Gastroesophageal reflux disorders (GERD)

3.Zollinger-Ellison syndrome

B.Acid secretion is controlled by:

1.Histamine

2.Acetylcholine

3.Gastrin

Classes of acid-peptic diseases

Stomach

Duodenum

Common denominator for all three mechanisms

Peptic Ulcer Disease

•Imbalance between defenses and aggressive factors

•Defensive factors:

–Defensive factors the stomach and duodenum from self-digestion

–Mucus: continually secreted, protective effect

–Bicarbonate: secreted from endothelial cells

–Blood flow: proper blood flow maintains mucosal integrity

–Prostaglandins: stimulate secretion of bicarbonate and mucus,promote blood flow, suppress secretion of gastric acid

• Aggressive factors:

–Helicobacter pylori: gram negative bacteria, can live in stomach andduodenum.

The development of peptic ulcers may involvealterations in:

Goals of treatment in peptic ulcer disease:

•Pain relief

•Ulcer healing

•Prevention of complications and ulcerrecurrence

Drugs available for the treatment of acid pepticdiseases act by:

•Neutralizing gastric acid

•Reduce gastric acid secretion

•Enhance mucosal defenses “cytoprotectants”

•Antimicrobial activity against H. pylori

Antacids

•Simply work by neutralizing hydrochloric acid

•They are weak bases that react with hydrochloricacid to form salts and water

•By increasing the pH of the stomach, antacids alsoinactivate the action of pepsin; pepsin is know tocontribute to ulcer formation by digesting proteins inthe wall of the stomach

•At pH above 4, pepsin activity is significantly reduced

Common antacids contain

•Aluminum hydroxide

•Magnesium hydroxide

•Calcium carbonate

•Sodium bicarbonate

H2 receptor antagonists

•Introduced in the 1970’s; became a very popularmedication for the treatment of peptic acid diseases

–Cimetidine (Tagamet)

–Ranitidine (Zantac)

–Famotidine (Pepcid)

–Nizatidine (Axid)

•These drugs are competitive inhibitors of the H2receptor in parietal cells

•H2 blockers also decrease (indirectly) gastrin- andacetylcholine-induced gastric acid secretion

Anticholinergic agents

•Dicyclomine (Bentyl) antagonizes the muscarinic Achreceptors on parietal cells thereby decreasing gastric acidsecretion.

•They are seldom used in the treatment of ulcers because theyare less effective than H2 blockers and proton pumpinhibitors.

•Incidence of adverse effects, such as dry mouth , blurredvision, cardiac arrhythmias and urinary retention makesanticholinergic drugs less desirable for use in the treatment ofpeptic acid diseases.

Proton Pump Inhibitors

•The ultimate mediator of gastric acid secretion is theproton pump in parietal cells.

•A family of substituded benzimidazoles have beenspecifically developed to block the activity of thistransport protein for proton (H+) molecules.

•This pump is unique to the parietal cells.

•The pH of the stomach facilitates the mode of actionof this class of drugs.

•Omeprazole is the prototype proton pump inhibitor.

Specific agents

1.Omeprazole (Prilosec)

2.Lanzopresole (Prevacid)

3.Rabeprazole (Aciphex)

4.Pantoprazole (Protonix)

5.Esomeprazole (Nexium)

All PPIs have similar rates of absorption and oral bio-

Availability. Rabeprazole and lansoprazole appear to

have a significant faster onset of action than omeprazole

and pantropazole. Comparisons of effectiveness suggest

that esomeprazole inhibits acid secretion more effectively

than other proton pump inhibitors at therapeutic doses.

PPIs

•Drugs are inactive at neutral pH, but since they are weakbases, they are activated in the acidic stomach milieu.

•PPIs need to pass intact through the stomach into theintestines where the drug is released from its enteric coatingformulation for absorption into the blood.

•The pro-drug reaches the parietal cells via blood and thenpasses through the luminal side luminal side where the lowpH activates the drug.

•Irreversibly inhibit the H+/K+ ATPase in gastric parietal cells

•Because the drug irreversibly inhibits the proton pump, itproduces a dose-dependent inhibition of gastric acid secretionthat persists even after the drug disappears from plasma.

PPIs adverse effects

•PPIs are generally are well tolerated.

•A potential concern is that the large increase in gastrinproduction associated with PPI could have a trophic effectresulting in hyperplasia of parietal cells.

•In fact long-term treatment of rats with omeprazole (highdoses) develop gastric carcinoid tumors.

•Concerns about infection of the stomach withopportunistic/nosocomial bacterial (e.g., Pneumonmia by C.difficile, enteric infections by Salmonella and E. coli).

•Drug-drug interactions by competition for CYP2C19 (e.g.,clopidrogel).

Mucosal protective agents

•Mucosal erosion and ulceration is characteristic of peptic aciddiseases resulting from pepsin-mediated hydrolysis ofmucosal proteins.

•Mucosal protective agents create a barrier in stomach andintestinal mucosa that prevents the damaging effects ofhydrochloric acid and pepsin.

•The also bind pepsin and bile salts.

•Bismuth is known to have bactericidal activity.

Mucosal protective agents

•Colloidal Bismuth compounds

–Coating agent used in peptic ulcer disease

–Bismuth salts combine with mucus glycoproteins to form abarrier that protects the ulcer from further damage by acidand pepsin.

– Bismuth is also known to stimulate secretion ofbicarbonate, PG and mucus

–Colloidal bismuth has been shown to impede the growthof H. pylori.

–Used in combination with antimicrobial agents and PPIs inpatients that are H. pylori positive.

Mucosal protective agents

•Misoprostol

–prostaglandin E1 analog (PG stimulate mucus and bicarbonateproduction)

–used when treatment with NSAIDs inhibits endogenous PG synthesis

•Sucralfate

–complex of aluminum hydroxide and sulfated sucrose

–Undergoes polymerization and cross linking at low pH of stomach

–Binds tightly to the necrotic/ulcerated tissue

Helicobacter pylori

•Introduction:

–Gram-negative, spiral shaped bacterium.

–Most common cause of non-NSAID-associated peptic ulcerdiseases.

–Can be found in the antrum of the stomach of a significantnumber of patients with duodenal and gastric ulcers.

–Colonizes the epithelium of the gastric mucosa and lives inthe acidic environment of the stomach.

–H. pylori infection is know to be a causative agent forulcers.

H. Pylori Epidemiology (cont.)

H. Pylori Epidemiology

•Prevalence of H. pylori infection correlates best withsocio-economic status rather than race.

•In the United States, probability of being infected isgreater for older persons (>50 years = >50%),minorities (African Americans 40-50%) andimmigrants from developing countries (Latino > 60%,Eastern Europeans > 50%).

•The infection is less common in more affluentCaucasians ( < 40 years = 20%).

Helicobacter pylori (cont.)

–H. pylori penetrate the mucus layer of host stomach andadhere the surface of gastric mucosal epithelial cells.

–H. pylori is capable of living in the harsh acidic conditionsof the stomach because it produces ammonia from urea bythe enzyme urease.

–The ammonia neutralizes the gastric acid and allows thebacteria to escape from elimination.

–H. pylori then proliferates, migrates, and finally forms theinfectious focus.

–Ulcers developed by destruction of mucosa and immune-mediated inflammation and mucosal cell death.

Treatment options for H. Pylori

•Antibiotics

•Antisecretory agents

•Mucosal protectants

•Antisecretory agents that enhance mucosaldefenses

•Antacids