GI Pharmacology - Acid-Peptic Disorders and Prokinetics



  1. Dyspepsia - indigestion
    • Can be caused by GERD or Peptic Ulcer disease
    • Peptic ulcer disease is gastric and duodenal, and can be stress-induced
    • Dyspepsia is alleviated by reducing gastric acid
  2. Antacids neutralize gastric acid, inhibit pepsin activity, and are safe
  3. Antacids are composed of an acid and a weak base
    • Sodium bicarbonate
    • Calcium carbonate (Tums) can cause hypercalcemia with excessive use
    • Calcium can be beneficial (osteoporisis) or detrimental - may increase risk of MI and kidney stones
    • Aluminum hydroxide - no CO2, so doesn't cause belching, but is constipating
    • Magesium hydroxide - no CO2, can promote diarrhea
    • Fewer problems with hydroxide due to less alkalinization
    • Antacids can slow absorption of other drugs through chelation - sodium bicarbonate does not do this
    • Use of antacids with other drugs should be separated by 2 hours
    • Impaired renal function can decrease excretion of absorbed metals
  4. Reducing Gastric Acid - H2 antagonists
    • -tidine family - Cimetidine, Ranitidine, Famotidine, etc. ("to dine")
    • H2 histamine receptor selectivity, antagonism is reversible
    • Rapid intestinal absorption, all have first pass metabolism (except Nizatidine)
    • Liver metabolism and urinary excretion are important for elimination
    • Ranitidine removed from marketing over concern of NMDA carcinogen contamination, drug itself was safe
    • Cimetidine inhibits CYP450 1A2, 2D6, 3A4, increasing blood levels of Warfarin, Phenytoin, Theophylline, and CCBs
    • H2 antagonists are particularly effective at blocking nocturnal acid secretion
  5. Proton Pump Inhibitors - the "prazole" family
    • All are "prodrugs" - usually administered orally in enteric-coated capsule
    • Food reduces absorption
    • Dissolution occurs in intestines
    • Compounds are lipophilic weak bases
    • Diffuse to acidic parietal cells and protonate, trapping the weak base
    • Converted into reactive intermediate which covalently binds to ATPase, takes a dase for effects to show
    • Short half life but irreversible inhibition
    • QD dosing for Peptic ulcer, BID for GERD
    • Helicobacter pylori can cause a rapid relapse, usually in cases of peptic ulcer - treat with two drug antibiotic therapy
    • Reduced vitamin/mineral absorption - B12 and Mg
    • Changes normal flora - increases susceptibility to enteric infection
    • Increased gastrin signaling - elevated pH, positive feedback, increases number of ECL cells, possibly carcinogenic
    • Reduces clopidogrel efficacy through CYP2C19 inhibiton - Clopidogrel is a prodrug
    • PPIs can increase risk of Clostridium difficule infection, bone fractures (Mg++ malabsorption), community-acquired pneumonia in elderly patients
  6. Mucosal protection - enhance mucosal defense against acid and digestive enzymes
  7. Sucralfate, Postaglandins, Bismuth subsalisylate
  8. Sucralfate forms a viscous paste, creating a barrier to acid and digestive enzymes ("stick" to gastric lesions)
    • Stimulates prostaglandin release, bicarbonate secretion
    • Safe and effective - little absorbed, can cause constipation
  9. Misoprostil
    • PGE1 analog with short half life
    • Stimulates intestinal contractions, mucosal blood flow, bicarbonate secretion
    • Inhibits cAMP accumulation in parietal cells
    • Used for prophylaxis of NSAID ulcers
    • Contraindicated in pregnancy
  10. Bismuth Subsalisylate
    • Dissociates in stomatch, salisylate is absorbed for renal excretion, bismuth coats lesion and eliminated fecally
    • Salisylate inhibits prostaglandin release and is bacteriocidal
    • Bismuth binds enterotoxins, useful in diarrhea caused by microbes
    • Can cause black tongue and stool, constipation, salicylate toxicity