GI Pharmacology - Acid-Peptic Disorders and Prokinetics
- 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
- Antacids neutralize gastric acid, inhibit pepsin activity, and are safe
- 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
- 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
- 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
- Mucosal protection - enhance mucosal defense against acid and digestive enzymes
- Sucralfate, Postaglandins, Bismuth subsalisylate
- 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
- 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
- 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