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 ??
Sucralfate
Cytoprotective agent
Sulfated disaccharide Al+++ salt –> binds necrotic tissue forming protective barrier
Activated by acidic pH – give on empty stomach – 2-4 / day
Not absorbed – few side effects – constipation
Diminishing use
Misoprostol
Cytoprotective agent
Prostaglandin analog - acts on epithelial cell –> decreased H+ secretion - increased mucus-bicarbonate
Indicated for NSAID-induced ulcers
Side effects limit use – diarrhea, uterine cramping, contraindicated in pregnancy
Properties of ideal antacid
- rapidly raise pH of stomach to 4
- should be nonabsorbable (avoid NaHCO3; while Al/Mg/Ca less complete absorp (better))
- long acting (hard to attain)
- no adverse effects, but diarrhea-constipation common
- no DDIs (avoid by spacing dose around other drugs)
Gastric antacids: Calcium
Calcium (carbonate– tums):
Rapid, prolonged neutralization –> rebound secretion
Safe - not for chronic use (but OK as Ca++ supplement)
Constipation - hypercalcemia - renal calculi possible
Aluminum gastric antacid
Widely used, binds phosphate in gut (used in CKD)
Main side effect is constipation
Chronic intake may lead to CNS toxicity
Magnesium gastric antacid
Mild of magnesia (hydroxide)
Osmotic diarrhea – used to counteract Al+++ or Ca++-induced constipation (Maalox, Mylanta)
Avoid if renal disease –> retention of Mg++ ions
Metoclopramide
Prokinetic agent
Dopamine antagonist –> blocks presynaptic inhibition of ACh release
Increase in coordinated contractions –> enhance transit
Approved for not > 12 weeks
Additional benefit of antiemetic effect at chemoreceptor trigger zone (weak 5HT3 antagonist) –> relief of n/v
Somnolence, dystonic reactions, tardive dyskinesias [Boxed warning]
QT prolongation
tegaserod
EPSE
Metoclopramide
