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Oxyntic glands
- Oxyntic or parietal cells
- Peptic or chief cells
- Mucous neck cells
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Pyloric glands
G and D cells
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3 Phases of Gastric Secretions
- 1. Cephalic phase
- 2. Gastric phase
- 3. Intestinal phase
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Histamine
- Produced by enterochromaffin-like (ECL) cells
- Induces gastric acid secretion
- Paracrine mediator = Works on parietal cells, where it activates H2 receptors
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Gastrin
- 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
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Somatostatin (SST)
- 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
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Pancreatic Secretions: Secretin
- Causes secretion of fluid and HCO3-
Duodenum triggers: acid from stomach - Absorbed into bloodstream
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Pancreatic Secretions: Cholecystokinin
- 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
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Prostaglandins (PGE2 and PGI2)
- 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
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Peptic Ulcer Disease (PUD)
- 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)
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NSAID-Induced PUD
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.
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H. pylori PUD Mechanisms
- 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
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Zollinger-Ellison Syndrome
- 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.
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Drug classes that inhibit acid secretion
- 1. H2 antagonists
- 2. Proton pump inhibitors
- 3. Prostaglandins
- 4. Muscarinic antagonists
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Drug classes that prevent contact with acid
- 1. Sucralfate
- 2. Prostaglandin analogs
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Antibiotics against H. pylori
- 1. Clarithromycin
- 2. Amoxicillin
- 3. Metronidazole
- 4. Bismuth
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Proton pump
- H+/K+ ATPase pump
- Apical membrane of oxyntic cells along canaliculi
- Inhibition blocks both basal and stimulated acid secretion
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Proton Pump Inhibitors "-prazoles"
- 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)
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PPIs MoA
- 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
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H2 Receptor Antagonists "-tidines"
- 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 (?)
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Duexis (ibuprofen + famotidine)
- For relief of osteoarthritis and rheumatoid arthritis
- Prevention of NSAID ulcers
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Vimovo (naproxen + esomeprazole)
- For relief of osteoarthritis and rheumatoid arthritis
- Prevention of NSAID ulcers
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Misoprostal (Cytotec)
- 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
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Sucralfate (Carafate)
- 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
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Mg2+ and Al3+ Hydroxide Combo
- 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
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Sodium Bicarbonate
- Antacid (inactivates pepsin)
- Water soluble
- Avoid in cardiac or renal failure
- ADEs: CO2 = gassy GI
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Calcium carbonate
- 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)
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Pirenzepine (Gastrozepin)
- 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
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GERD Stages
- Stage I: < 2-3/week
- Stage II: > 2-3/week +/- esophagitis
- Stage III: chronic symptoms, stricture, Barrett's metaplasia
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