Antisecretory Agents for PUD and GERD Flashcards
Antibacterial agents
critical role in eradicating H. pylori infection (85% of duodenal ulcers involve H pylori, less w/ gastric ulcers)
Tx for acute ulcers
acid suppression
Triple therapy
Clarithromycin-Amoxicillin {or Metronidazole}-PPI
Quadruple therapy
Bismuth subsalicylate-Metronidazole-Tetracycline-PPI or H2 Antagonist
eradication greater w/ quadruple/sequential than with triple therapy
Sequential therapy
Amoxicillin-PPI (5 days) then Clarithromycin-Tinidazole/Metronidazole-PPI (5 days)
PPIs
Omeprazole, Lansoprazole
Admin as prodrug, systemic circ, parietal cells, activated by canaliculi to sulfenamide, “traps” the drug in the acidic secretory canniculi
-covalent linkage of sulfenamide form to sulfhydryl groups of H/K-ATPase IRREVERSIBLY inactivates enzyme
80-95% reduction in acid production despite short half life of 0.5-2hrs (acid supp >18 hrs)
may take 2-5 days to reach steady state level (bc only inactivates active pumps)
Rapidly absorbed, highly protein bound
Oral bioavail improved w/ enteric coatin or w/ sodium bicarb
IV formulations: Pantoprazole and lansoprazole
When should PPIs be administered?
on empty stomach 1 hour before meals (ac)
peak plasma level coincides w/ maximal pump secretion
Metabolism of PPI
rapid first pass metab w/ CYP450 enzymes
dosage reduction if SEVERE hepatic disease
Clinical uses of PPIs
GERD
PUD (PPI faster sx relief/ healing than H2 antag)
NSAID induced ulcers (tx or prevention of ulcers)
Prevention of stress gastritis
Zollinger-Ellison Syndrome (higher doses, complete sx relief, and healing)
Adverse effects of PPIs
Very safe
mild SE: Headache, abdominal pain, nausea, constipation, diarrhea
Hypergastrinemia from chronic use does not result in tolerance, but acid rebound if d/c
Chronic use (>1 y– erosive esophagitis): increased fracture risk, decreased Mg absorption
DDI: omeprazole may inhibit conversion of antiplatelet drug clopidogrel to active form (CYP2C19)
tNSAID SE GI tract
Interfere with gastric cytoprotection by inhibition of COX-1 PGE synthesis –> dyspepsia and gastric ulceration
Relative contraindication in patients at high risk for PUD
(GI Risk: COX1 inhib >COX2)
Lowest risk w/ ibuprofen, highest w/ naproxen
CV risk: COX2 inhib >COX1
Naproxen safest
H2 receptor antagonists Mechanism
cimetidine, famotidine, and ranitidine
Competitive reversible block of H2 receptors – basolateral membrane
Less efficacious than PPIs – generally requires bid dosing
More rapid onset of action than PPIs in acute gastritis
Better at block of nocturnal (H2) than meal-stimulated (ACh-gastrin) acid secretion
Pharmacokinetics of H2 antag
rapidly absorbed (good for acute gastritis)
- elim: renal
- dosage reduction in renal dysfunction (esp elderly)
H2 receptor antag Uses
GERD:
infrequent? manage with antacids, prn H2 antagonists
frequent? bid H2 antag
Severe erosive esophagitis? PPIs
PUD: largely replaced by PPIs
Stress related gastritis: IV H2 antag
H2A Adverse effects/DDIs
Generally well tolerated – available OTC
CNS dysfunction – mental status change: Seen with cimetidine, or high doses, or elderly with renal dysfunction
Endocrine effects – gynecomastia with chronic high dose cimetidine
DDI: Cimetidine inhibition of CYP450 metabolism
Tolerance with continued use ??
