Gastrointestinal Agents
AGENTS FOR GASTROESOPHAGEAL REFLUX DISEASE
What is the main cause of gastroesophageal reflux disease (GERD)?
Decreased lower esophageal sphincter pressure
What complications may arise from GERD?
Strictures; esophagitis; Barrett esophagus (squamocolumnar metaplasia)
What are the drug therapy goals in treating GERD?
To eliminate symptoms; heal esophagitis; prevent the relapse of esophagitis; prevent the development of complications
What types of medications may be useful in the treatment of GERD?
Antacids; H2-receptor antagonists; proton pump inhibitors (PPIs); prokinetic agents (cisapride, metoclopramide, bethanechol); mucosal protectants (sucralfate)
Give the mechanism of action for each of the following drugs or drug classes:
Antacids
Weak bases that increase gastric pH through acid-neutralizing ability to form a salt and water
H2–-receptor antagonists
Competitively antagonize H2 receptors on gastric parietal cells, thereby decreasing acid production
PPIs
Inhibit gastric acid secretion via inhibiting gastric parietal cell H+/K+-ATPase. Restoration of acid secretion requires resynthesis of the H+/K+-ATPase (proton pump).
Cisapride
Increases lower esophageal sphincter pressure; accelerate gastric emptying time; increases amplitude of esophageal contractions; 5-HT4 agonist; 5-HT3antagonist
Metoclopramide
Dopamine (D2) receptor antagonist; increases lower esophageal sphincter pressure; accelerates gastric emptying time
Sucralfate
When exposed to acid, complexes with positively charged proteins to form a viscous coat, thereby protecting gastric lining from gastric acid secretions
What are the adverse effects caused by metoclopramide?
Anxiety; insomnia; extrapyramidal symptoms; increased prolactin levels
What are the adverse effects caused by sucralfate?
Constipation; nausea; abdominal discomfort
What are the possible adverse effects of antacids?
Belching (sodium bicarbonate and calcium carbonate); diarrhea (magnesium salts); constipation (calcium or aluminum salts); acid-base disturbances; bone damage via binding phosphate in the gut (aluminum salts); worsening of hypertension and congestive heart failure (CHF) (sodium salts); decreased absorption of medications via pH alteration or formation of insoluble complexes (tetracycline, fluoroquinolones, isoniazid [INH], ferrous sulfate, ketoconazole, PPIs)
Which antacid(s) can produce a metabolic alkalosis?
Sodium bicarbonate; calcium carbonate
What causes the milk-alkali syndrome?
Ingestion of excessive amounts of calcium and absorbable alkali such as sodium bicarbonate or calcium carbonate
What is a potential complication after discontinuing chronic antacid use?
Acid rebound
List the names of the H2-receptor antagonists:
Cimetidine; famotidine; ranitidine; nizatidine
Which H2-receptor antagonist inhibits hepatic cytochrome P-450 metabolizing enzymes?
Cimetidine
Name at least five drugs showing potential drug interactions with cimetidine:
- Warfarin
- Diazepam
- Phenytoin
- Metronidazole
- Propranolol
- Lidocaine
- Calcium channel blockers (CCBs)
- Theophylline
- Certain tricyclic antidepressants (TCAs); chlordiazepoxide
Which H2-receptor antagonist can cause gynecomastia?
Cimetidine (prolactin-stimulating activity)
Which H2-receptor antagonist has antiandrogenic activity?
Cimetidine
List the names of the PPIs:
Omeprazole; esomeprazole; lansoprazole; rabeprazole; pantoprazole
What are the common side effects of PPIs?
Headache; dizziness; nausea; diarrhea; constipation. Prolonged use can lead to bacterial overgrowth in the GI tract. Note also that a recent analysis revealed that people (age > 50) taking high doses of PPIs for more than a year were 2.6 times as likely to break a hip as were people not taking PPIs. Histamine H2-receptor inhibitors also increased fracture risk, but not to the extent as did PPIs.
What is the most serious side effect of cisapride?
Prolongation of the QT interval
Cisapride should be avoided in which type of patients?
Patients with prolonged QT intervals; patients taking medications that inhibit cytochrome P-ISO 3A4 (fluconazole, ketoconazole, itraconazole, erythromycin, clarithromycin, ritonavir)
What arrhythmia can be caused by prolongation of the QT interval?
Torsades de pointes (a polymorphic ventricular tachycardia)
Which drugs increase cisapride blood levels by inhibiting the cytochrome P-450 3A4 enzymes that metabolize cisapride? (Please mention at least four drugs).
- Erythromycin
- Clarithromycin
- Itraconazole
- Fluconazole
- Ketoconazole
- Indinavir
- Ritonavir
- Class 1A antiarrhythmics
- Class III antiarrhythmics
- Certain TCAs
- Certain antipsychotics
AGENTS FOR PEPTIC ULCER DISEASE
What three mediators can stimulate acid secretion from parietal cells?
- Acetylcholine
- Histamine (via H2 receptor)
- Gastrin
Name three causes of peptic ulcer disease (PUD):
- Helicobacter pylori infection (primary cause)
- Nonsteroidal anti-inflammatory drugs (NSAIDs)
- Extreme physiologic stress (ie, patients in the ICU setting being ventilated, burn patients)
What type of patients do acute peptic ulcers occur in?
Hospitalized patients who are critically ill (stress ulcers)
What is the name of the syndrome that is characterized by hypersecretion of gastric acid secondary to a gastrin-secreting tumor?
Zollinger-Ellison syndrome
Which are the drug therapy goals in treating PUD?
Control H. pylori infection; alleviate symptoms; promote healing; prevent recurrences; prevent complications (eg, hemorrhage)
What types of medications are useful for the treatment of PUD?
Antimicrobial agents; H2-receptor antagonists; PPIs; prostaglandins; antimuscarinic agents; antacids; mucosal protective agents; bismuth salts
How might H. pylori play a role in peptic ulcer development?
Direct mucosal damage; alterations in inflammatory response; induced hypergastrinemia
Meals worsen the pain associated with what type of ulcer?
Gastric ulcer
Meals relieve the pain associated with what type of ulcer?
Duodenal ulcer
What treatment options are available to eradicate H. pylori?
Triple therapy with a PPI added to two antimicrobial agents such as metronidazole, amoxicillin, tetracycline, or clarithromycin; four-drug regimens consisting of triple therapy plus bismuth subsalicylate; (must use triple or quadruple antibiotic therapy to eradicate H. pylori)
Why should you not give bismuth subsalicylate to children?
May be associated with Reye syndrome (contains salicylates)
What is Reye syndrome?
Acute onset encephalopathy and fatty liver formation. Symptoms begin with vomiting, lethargy, and confusion progressing to stupor, respiratory distress, coma, and seizures. Its cause is unknown, but has been found to be associated with aspirin use in young children. Therefore, aspirin administration is to be avoided in pediatric patients.
How do prostaglandins help treat PUD?
Prostaglandins such as PGE2 and PGI2inhibit gastric acid secretion and stimulate secretion of bicarbonate and mucus (cytoprotective activity); used to treat NSAID-induced peptic ulcers
Which prostaglandin analog is commonly used as a cytoprotective agent for the treatment of PUD?
Misoprostol (synthetic PGE1 analog)
Why should misoprostol not be given to a preterm pregnant woman?
Induction of premature uterine contractions (abortifacient properties)
AGENTS FOR INFLAMMATORY BOWEL DISEASE
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