Flashcards in Upper GI drugs Deck (26)
85% duodenal due to H pylori
Acid suppression is still the treatment of choice for acute ulcers and given alone these agents will lead to ulcer healing
Antibiotic therapy is necessary to reduce the rate of recurrence of gastric ulcers (50-80% success) and duodenal ulcers (90-95% success) antibiotic therapy is critical.
Antibiotic therapy for
Triple Therapy: Clarithromycin-Amoxicillin or Metronidazole-PPI
Quadruple Therapy: Bismuth subsalicylate-Metronidazole-Tetracycline-PPI or H2 Antagonist
Sequential Therapy: Amoxicillin-PPI (5 days) then Clarithromycin-Tinidazole-PPI (5 days)
Proton Pump Inhibitors Pharmacodynamics
Omeprazole (OTC), Lansoprazole
Administered as prodrug, absorbed into systemic circulation, then diffuses into parietal cells of stomach where proton catalyzed formation of the active sulfenamide “traps” the drug in the acidic secretory canniculi
Covalent linkage of sulfenamide form to sulfhydryl groups of H+-K+-ATPase IRREVERSIBLY inactivates enzyme
Only inactivates active pumps
80-95% reduction in daily acid production
Efficacy of the 5 available PPIs is equivalent at comparable doses
Pharmacokinetics of PPIs
Rapidly absorbed, highly protein bound
Oral bioavailability (40-90%) is improved by administration as enteric-coated preparation or with sodium bicarbonate in capsule admixture to prevent degradation in gastric lumen.
Best to give on empty stomach 1 hour ac (before meals) so peak plasma concentration occurs with maximal proton pump secretion
Dosage reduction if severe hepatic disease – no change if renal disease
Clinical uses of PPIs
GERD: most effective agent
Peptic ulcer disease: faster than H2 antag
NSAID-induced ulcers: prevention and treatment
Prevention of stress gastritis
Drud-drug interactions with PPIs
Due to actions on CYP450 enzymes: omeprazole may inhibit conversion of antiplatelet agent clopidogrel to active form
Adverse effects of PPIs
Overall very safe
Mild side effects (1-5%). Headache, abdominal pain, nausea, constipation, diarrhea
Minor reduction in oral cyanocobalamin (B12) absorption and levels.
H2 Receptor Antagonists
Ranitidine, Cimetidine, Famotidine, Nizatidine
All agents are available OTC for acute gastritis
REVERSIBLE, competitive block at parietal cell H2 receptors on basolateral membrane. Less efficacious than PPIs but still suppress 24 hour acid secretion by 70%.
Better at blocking nocturnal (H2 mediated) acid secretion (90%) than meal-stimulated (ACh- and gastrin-mediated, 60-80%).
Pharmacokinetics of H2 receptor antagonists
All are rapidly absorbed from the GI tract
Dosage reduction required if impaired renal function
Clinical uses of H2 receptor antagonists
GERD, Peptic ulcer disease, Stress-related gastritis
Drug-drug interactions with H2 receptor antagonists
Cimetidine inhibits cytochrome P450 oxidative metabolism
All antisecretory agents can decrease ketoconazole absorption by causing an increase in gastric pH.
Mucosal Protective Agents
When acid-induced damage occurs, pepsin will hydrolyze mucosal proteins causing erosion and ulcerations. This process is inhibited by this sulfated disaccharide aluminum salt that selectively binds to necrotic ulcer tissue to form protective barrier
Diminished clinical use
Prostaglandin (PGE1) analog
decreased H+ secretion (most important clinical effect); they also stimulate acid neutralizing HCO3− formation and cytoprotective mucus formation
Contraindicated during pregnancy because of increase in uterine motility
Major indication is alleviation of NSAID-induced GI ulceration, but rarely used because of 4-time daily dosing and adverse effects
Primary use is pain relief (healing?) due to peptic ulceration and acute gastritis. Largely replaced by more effective and more conveniently administered and dosed drugs
Properties of Ideal Antacid
Should rapidly raise pH of stomach contents to 4-5
Should be nonabsorbable
Should be long-acting
Should have no undesirable side effects
Side effects of antacids
However, constipation (Ca++ and Al+++ antacids) or diarrhea (Mg++ antacids) is common. Fixed combinations of Mg and Al antacids (e.g., Mylanta® and Maalox®) used to theoretically counteract the adverse effects of each other.
Drug interactions with antacids
General rule is to space drug dosing around antacid dosing to minimize potential for interactions.
Primary Neutralizing Ingredients of antacids
Calcium, Aluminum, Magnesium, sodium bicarb
Formerly used as adjunct to H2 blockers, esp. in refractory patients.
The large doses that are required for block of acid secretion (due to low basal parasympathetic muscarinic tone) can cause blurred vision, dry mouth, and urinary hesitation that decrease patient acceptance.
Utilized as empiric and symptoms-based treatment for various disorders of bowel motility [achalasia of esophagus, gastroparesis] and symptom relief of esophagitis associated with gastroesophageal reflux disease (GERD).
Clinical Uses: Diabetic gastroparesis (increase GI motility), gastroesophageal reflux disease (↑ LES pressures), constipation-predominant IBS in women (tegaserod
Mechanisms of Promotility Drugs
These agents directly or indirectly increase agonist activity at smooth muscle M3-receptors.
Direct activation of M3 muscarinic receptors in the gut will increase GI motility BUT will NOT do so in a coordinated manner that will be NO net increase in propulsive activity and will also tend to increase gastric and pancreatic secretions
The mechanism of action common to most prokinetic agents is an “upstream” effect on the motor neuron itself rather than a postsynaptic action. They act to increase gastric motility by increasing release of acetylcholine from cholinergic neurons in the enteric nervous system. This allows maintenance of the coordinated activity among gut segments that is necessary for propulsion of luminal contents.
Metoclopramide and side effects
Dopamine antagonist that blocks presynaptic inhibition of ACh release by dopamine at D2 receptors
Side effects: Somnolence, dystonic reactions, tardive dyskinesias [Boxed warning]
Which PPIs are available IV?
Pantoprazole and lansoprazole
Which antacids agents cause constipation and which cause diarrhea?
Calcium and aluminum: constipation
Tegaserod - Cisapride
5HT4 receptor agonists direct stimulation of ACh release
↑ coordinated contractions-transit in esophagus, stomach
Reduces bloating of irritable bowel syndrome (IBS)
Cisapride life-threatening arrhythmias (↑ QT interval) - restricted
Tegaserod linked to strokes, MI, angina - restricted