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

H_2–-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:

1. Warfarin
   
2. Diazepam
   
3. Phenytoin
   
4. Metronidazole
   
5. Propranolol
   
6. Lidocaine
   
7. Calcium channel blockers (CCBs)
   
8. Theophylline
   
9. 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).

1. Erythromycin
   
2. Clarithromycin
   
3. Itraconazole
   
4. Fluconazole
   
5. Ketoconazole
   
6. Indinavir
   
7. Ritonavir
   
8. Class 1A antiarrhythmics
   
9. Class III antiarrhythmics
   
10. Certain TCAs
    
11. Certain antipsychotics

AGENTS FOR PEPTIC ULCER DISEASE

What three mediators can stimulate acid secretion from parietal cells?

1. Acetylcholine
   
2. Histamine (via H₂ receptor)
   
3. Gastrin

Name three causes of peptic ulcer disease (PUD):

1. Helicobacter pylori infection (primary cause)
   
2. Nonsteroidal anti-inflammatory drugs (NSAIDs)
   
3. 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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