Upper GI drugs

Question 1

Duodenal/gastric ulcers

Answer 1

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.

Question 2

Antibiotic therapy for

Answer 2

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)

Question 3

Proton Pump Inhibitors Pharmacodynamics

Answer 3

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

Question 4

Pharmacokinetics of PPIs

Answer 4

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

Question 5

Clinical uses of PPIs

Answer 5

GERD: most effective agent

Peptic ulcer disease: faster than H2 antag

NSAID-induced ulcers: prevention and treatment

Prevention of stress gastritis

Zollinger-Ellison syndrome

Question 6

Drud-drug interactions with PPIs

Answer 6

Due to actions on CYP450 enzymes: omeprazole may inhibit conversion of antiplatelet agent clopidogrel to active form

Question 7

Adverse effects of PPIs

Answer 7

Overall very safe

Mild side effects (1-5%). Headache, abdominal pain, nausea, constipation, diarrhea

Minor reduction in oral cyanocobalamin (B12) absorption and levels.

Question 8

H2 Receptor Antagonists

Answer 8

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%).

Question 9

Pharmacokinetics of H2 receptor antagonists

Answer 9

All are rapidly absorbed from the GI tract

Elimination: kidney
Dosage reduction required if impaired renal function

Question 10

Clinical uses of H2 receptor antagonists

Answer 10

GERD, Peptic ulcer disease, Stress-related gastritis

Question 11

Drug-drug interactions with H2 receptor antagonists

Answer 11

Cimetidine inhibits cytochrome P450 oxidative metabolism

All antisecretory agents can decrease ketoconazole absorption by causing an increase in gastric pH.

Question 12

Mucosal Protective Agents

Answer 12

Sucralfate

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

Question 13

Prostaglandin (PGE1) analog

Answer 13

Misoprostol

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

Question 14

Gastric Antacids

Answer 14

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

Question 15

Properties of Ideal Antacid

Answer 15

Should rapidly raise pH of stomach contents to 4-5

Should be nonabsorbable

Should be long-acting

Should have no undesirable side effects

Question 16

Side effects of antacids

Answer 16

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.

Question 17

Drug interactions with antacids

Answer 17

General rule is to space drug dosing around antacid dosing to minimize potential for interactions.

Question 18

Primary Neutralizing Ingredients of antacids

Answer 18

Calcium, Aluminum, Magnesium, sodium bicarb

Question 19

Antimuscarinic Agents

Answer 19

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.

Question 20

Prokinetic Agents

Answer 20

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

Question 21

Mechanisms of Promotility Drugs

Answer 21

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.

Question 22

Metoclopramide and side effects

Answer 22

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]

Question 23

Which PPIs are available IV?

Answer 23

Pantoprazole and lansoprazole

Question 24

Which antacids agents cause constipation and which cause diarrhea?

Answer 24

Calcium and aluminum: constipation

Mg: diarrhea

Question 25

Tegaserod - Cisapride

Answer 25

Prokinetics

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

Question 26

Which drug causes increased QT interval

Answer 26

Cisapride