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Flashcards in Upper GI drugs Deck (26)

Duodenal/gastric ulcers

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

Zollinger-Ellison syndrome


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

Elimination: kidney
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


Gastric Antacids

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


Antimuscarinic Agents

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.


Prokinetic Agents

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

Prokinetic drug

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
Mg: diarrhea


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


Which drug causes increased QT interval