GI Lect II

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  1. Oxyntic glands
    • Oxyntic or parietal cells
    • Peptic or chief cells
    • Mucous neck cells
  2. Pyloric glands
    G and D cells
  3. 3 Phases of Gastric Secretions
    • 1. Cephalic phase
    • 2. Gastric phase
    • 3. Intestinal phase
  4. Histamine
    • Produced by enterochromaffin-like (ECL) cells
    • Induces gastric acid secretion
    • Paracrine mediator = Works on parietal cells, where it activates H2 receptors
  5. 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
  6. 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
  7. Pancreatic Secretions: Secretin
    • Causes secretion of fluid and HCO3-
    • Duodenum triggers: acid from stomach
    • Absorbed into bloodstream
  8. 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
  9. 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
  10. 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)
  11. 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.
  12. 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
  13. 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.
  14. Drug classes that inhibit acid secretion
    • 1. H2 antagonists
    • 2. Proton pump inhibitors
    • 3. Prostaglandins
    • 4. Muscarinic antagonists
  15. Drug classes that prevent contact with acid
    • 1. Sucralfate
    • 2. Prostaglandin analogs
  16. Antibiotics against H. pylori
    • 1. Clarithromycin
    • 2. Amoxicillin
    • 3. Metronidazole
    • 4. Bismuth
  17. Proton pump
    • H+/K+ ATPase pump
    • Apical membrane of oxyntic cells along canaliculi
    • Inhibition blocks both basal and stimulated acid secretion
  18. 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)
  19. 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
  20. 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 (?)
  21. Duexis (ibuprofen + famotidine)
    • For relief of osteoarthritis and rheumatoid arthritis
    • Prevention of NSAID ulcers
  22. Vimovo (naproxen + esomeprazole)
    • For relief of osteoarthritis and rheumatoid arthritis
    • Prevention of NSAID ulcers
  23. 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
  24. 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
  25. 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
  26. Sodium Bicarbonate
    • Antacid (inactivates pepsin)
    • Water soluble
    • Avoid in cardiac or renal failure
    • ADEs: CO2 = gassy GI
  27. 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)
  28. 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
  29. GERD Stages
    • Stage I: < 2-3/week
    • Stage II: > 2-3/week +/- esophagitis
    • Stage III: chronic symptoms, stricture, Barrett's metaplasia
Card Set:
GI Lect II
2013-04-01 15:44:46
Pharmacology II Rutgers Antiacids

For Rutgers P2 students
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