GI Lect II

• Oxyntic or parietal cells
• Peptic or chief cells
• Mucous neck cells

G and D cells

• 1. Cephalic phase
• 2. Gastric phase
• 3. Intestinal phase

• Produced by enterochromaffin-like (ECL) cells
• Induces gastric acid secretion
• Paracrine mediator = Works on parietal cells, where it activates H2 receptors

• Produced by antral G cells
• Most potent inducer of gastric acid secretion
• Endocrine mediator
• Gastrin released by CNS activation, local distention, and chemicals in the gastric contents
• Gastrin can stimulate acid secretion indirectly by inducing the release of histamine by ECL cells

• Produced by antral D cells
• Inhibits gastric acid secretion
• Acidification of the gastric luminal pH to <3 stimulates SST release
• Direct suppression of gastrin release
• Inhibition of histamine release

• Causes secretion of fluid and HCO₃^-
• Duodenum triggers: acid from stomach
• Absorbed into bloodstream

• Causes secretion of digestive enzymes
• Contracts the gall bladder, triggering release of bile into duodenum
• Duodenum release triggers: fats and amino acids
• Absorbed into bloodstream

• Reducing basal and stimulated gastric acid secretion
• Enhancing epithelial cell bicarbonate secretion, mucus production, cell turnover, and local blood flow
• Drugs that inhibit prostaglandin formation (e.g., NSAIDs, ethanol) decrease mucus secretion

• Risk factors include cigarette smoking, caffeine ingestion, alcoholic cirrhosis, glucocorticoids, genetics, and psychological stress
• Causes include H. pylori infection, NSAIDs, and acid hypersecretion (Zollinger-Ellison syndrome and Cushing’s ulcers)

1. Systemic Injury: Inhibits COX, thus less prostaglandins; AND Increases expression of intracellular adhesion molecules in gastric vascular endothelium, thus more neutrophil adherence.

2. Topical Injury: Drug enters gastric epithelial cell, becomes ionized and trapped in neutral pH, then charged molecule causes cell damage.

• Suppress somatostatin: Inflammatory mediators from H. pylori inhibit somatostatin secretion by D cells in stomach antrum
• Increase gastrin: Ammonium hydroxide produced by H. pylori-derived urease increases gastric pH, which in turn stimulates gastrin secretion; also conveniently makes alkaline protective cloud around bacteria

• Condition associated with one or more tumors in the duodenum or the pancreas (aka gastrinomas) and secrete the hormone gastrin in large amounts.
• This hormone leads to extreme production of acid in the stomach eventually causing peptic ulcers. There usually are many ulcers in the area affected.

• 1. H₂ antagonists
• 2. Proton pump inhibitors
• 3. Prostaglandins
• 4. Muscarinic antagonists

• 1. Sucralfate
• 2. Prostaglandin analogs

• 1. Clarithromycin
• 2. Amoxicillin
• 3. Metronidazole
• 4. Bismuth

• H+/K+ ATPase pump
• Apical membrane of oxyntic cells along canaliculi
• Inhibition blocks both basal and stimulated acid secretion

• Most potent suppressors of gastric acid secretion
• Diminish the daily production of acid (basal and stimulated) by 80-95%
• PK: Enteric coated or given with sodium bicarbonate; (also comes IV)
• Give 30 min prior to meals
• Hepatic metabolism (CYP2C19 and CYP3A4) so reduce dose if hepatic dysfunction
• DDIs: warfarin, diazepam, cyclosporine, disulfiram, phenytoin, clopidogrel, imipramine, tacrine, theophylline
• ADEs: Nausea, GI disturb, bone fracture risk, risk of infection (C.diff), hypergastrinemia (may promote GI tumors)

• Most potent suppressors of gastric acid secretion
• Diminish the daily production of acid (basal and stimulated) by 80-95%
• Prodrugs that require activation in acid environment
• Absorbed into systemic circulation and diffuse into parietal cells and accumulates in acidic secretory canaliculi
• Activation by proton-catalyzed formation of tetracyclic sulfenamide trapping the drug
• Activated form binds covalently with –SH groups of cysteines on proton pump causing irreversible inactivation

• MoA: reversibly compete with histamine at H2 receptors on the basolateral membrane of parietal cells, thus inhibiting basal acid secretion
• Tx: GI ulcers, uncomplicated GERD, preventing stress ulcers
• ADME: Renal adjust, but some is hepatically metabolized
• ADEs: mostly minor (diarrhea, constipation, muscular pain), except long-term cimetidine (decreases testosterone binding to cause galactorrhea in women and gynecomastia + impotence in men)
• DDIs: Cimetidine inhibits CYPs, Ranitidine 10% inhib CYPs
• Examples in order of increasing half-life: cimetidine, ranitidine, famotidine, nizatidine (?)

• For relief of osteoarthritis and rheumatoid arthritis
• Prevention of NSAID ulcers

• For relief of osteoarthritis and rheumatoid arthritis
• Prevention of NSAID ulcers

• Synthetic PGE₁ analog (mimics PGE₂ and PGI₂)
• MoA: binds to EP₃ receptor on parietal cells to decrease cAMP and thus decrease gastric acid secretion.  Also stimulates mucin, bicarbonate secretions + blood flow in epithelial cells
• Tx: NSAID-induced mucosal injury
• PK: qid dosing
• ADEs: diarrhea, Contraindicated in pregnancy

• Acidic activation: pH<4, cross-linking forms a viscous sticky polymer that coats ulcers for up to 6 hours
• MoA: Inhibits hydrolysis of mucosal proteins by pepsin. Stimulates production of prostaglandins and EGFs.
• Dose: 1 hr before meals, 1 g qid
• ADEs: constipation, drug adsorption (digoxin, phenytoin, fluoroquinolones), bezoars in pts w/ gastroparesis

• Preferred antacids (inactivate pepsin)
• Mg²⁺ rapidly reacts
• Al³⁺ slowly reacts
• ADEs: Al³⁺ (constipation) w/ Mg²⁺ (diarrhea); electrolyte disturbances (esp Al³⁺); avoid in renal failure; DDIs w/ thyroid hormones, allopurinol, imidazole antifungals, and more via chelation

• Antacid (inactivates pepsin)
• Water soluble
• Avoid in cardiac or renal failure
• ADEs: CO₂ = gassy GI

• Antacid (inactivates pepsin)
• ADEs: CO2 = gassy GI; transient hypercalcemia (milk-alkali syndrome, reduced PTH secretion, retention of phosphate); DDIs due to chelation (tetracycline, quinolones, digoxin, phenytoin, levodopa)

• M1 Receptor Antagonist (outside US)
• May suppress neural stimulation of acid production via actions on M1 receptors of intramural ganglia
• Because of relatively poor efficacy, significant anticholinergic side effects, and risk of blood disorders, it is rarely used today

• Stage I: < 2-3/week
• Stage II: > 2-3/week +/- esophagitis
• Stage III: chronic symptoms, stricture, Barrett's metaplasia