THE APhA COMPLETE REVIEW FOR PHARMACY, 7th Ed

21. Gastrointestinal Diseases - Christa M. George, PharmD, BCPS, CDE

21-1. Peptic Ulcer Disease

Definition and Incidence

Peptic ulcer disease (PUD) is a group of disorders of the upper gastrointestinal (GI) tract characterized by ulcerative lesions that depend on acid and pepsin for their formation.

Approximately 1.5 million to 2 million Americans have an active ulcer at any given time. Annually in the United States, 500,000 new cases are diagnosed.

The U.S. lifetime prevalence of PUD ranges from 11% to 20% for men and from 8% to 11% for women. PUD has been estimated to cost $10 billion per year in the United States.

Classification

Ulcers are either duodenal or gastric in nature. Duodenal ulcers are more common.

Duodenal and gastric ulcers are classified as Helicobacter pylori related, nonsteroidal anti-inflammatory drug (NSAID) related, non-H. pylori related, non-NSAID related, or stress related.

Clinical Presentation

Epigastric pain occurring 1-3 hours after meals that is relieved by ingestion of food or antacids is the classic presentation of PUD. Pain typically occurs in episodes lasting weeks to months and may be followed by variable periods of spontaneous remission and recurrence.

Ten percent of patients with PUD present with complications and have no prior history of pain.

Pathophysiology

Duodenal ulcers result from the imbalance between duodenal acid load and the acid-buffering capacity of the duodenum. Duodenal ulcers are more frequently associated with an antrum-predominant gastritis.

H. pylori is a gram-negative microaerophilic bacterium that inhabits the area between the stomach's mucosal layer and epithelial cells. The bacteria can be found anywhere gastric epithelium is present.

Over 50% of the world's population is colonized by H. pylori, but only 15% of colonized individuals develop clinical symptoms of PUD. The prevalence of H. pylori is decreasing in developed countries. It has been estimated that 30-40% of the U.S. population is infected with H. pylori.

H. pylori causes duodenal inflammation, increases duodenal acid load, and impairs duodenal bicarbonate secretion, which leads to duodenal ulcers. It causes inflammation of gastric epithelium, particularly in the antrum-corpus area. The inflammation disrupts mucosal defense, which also leads to gastric ulcers.

NSAIDs are the leading cause of PUD in patients negative for H. pylori infection. They are directly toxic to gastric epithelium and inhibit the synthesis of prostaglandins.

Inhibition of prostaglandin synthesis leads to decreased secretion of bicarbonate and mucus, decreased mucosal perfusion, decreased epithelial proliferation, and decreased mucosal resistance to injury.

NSAIDs may cause gastric or duodenal ulcers (more frequently gastric). Gastric ulcers are associated with a corpus-predominant (i.e., diffuse-predominant) gastritis. This pattern of gastritis is associated with low acid output, gastric atrophy, and adenocarcinoma.

Diagnostic Criteria

Upper GI endoscopy is used to diagnose PUD. The procedure is usually reserved for patients with symptoms of PUD who are over 55 years of age or who have alarm symptoms (bleeding, anemia, early satiety, unexplained weight loss, progressive dysphagia, odynophagia, recurrent vomiting, family history of GI cancer, previous esophagogastric cancer).

Patients with symptoms of PUD who are under 55 years of age and have no alarm symptoms may be tested for the presence of H. pylori and treated with eradication therapy if results are positive.

Available tests for H. pylori are divided into two groups: those that require endoscopy and those that do not.

• Histology and rapid urease testing may be performed on biopsy samples taken during endoscopy.

• Rapid urease testing may be performed in patients who have not taken a proton pump inhibitor (PPI) within 1-2 weeks or an antibiotic or bismuth within 4 weeks of the endoscopy. Histology should be performed on patients who have recently taken PPIs, antibiotics, or bismuth.

• Culture and polymerase chain reaction testing are not yet widely available for clinical use and are thus not routinely recommended.

• Antibody testing, urea breath tests, and fecal antigen tests do not require endoscopy.

• Antibody testing should be avoided in populations with a low prevalence of H. pylori because of the low positive predictive value in these populations.

• Urea breath tests and fecal antigen tests may be used to confirm eradication of H. pylori no sooner than 4 weeks after completion of the treatment regimen.

Treatment Principles and Goals

The goals of PUD therapy include healing the ulcer and eliminating its cause. Additional considerations include preventing complications and relieving symptoms.

Use of PPIs is associated with faster healing rates and symptom relief than treatment with histamine 2-receptor antagonists (H2RAs). (Note: H2RAs are less expensive.)

Choice of PUD therapy is based on the etiology of the case. For H. pylori-related PUD, antibacterial therapy is used with antisecretory therapy.

• Eradication of H. pylori reduces the recurrence of PUD and is of prime importance.

• The American College of Gastroenterology treatment guidelines for H. pylori eradication in PUD recommend initial triple therapy with a PPI, clarithromycin, and either amoxicillin or metronidazole for 14 days or quadruple therapy with bismuth, metronidazole, tetracycline, and either an H2RA or a PPI for 10-14 days.

• Sequential therapy starting with a PPI and amoxicillin for 5 days followed by a PPI and clarithromycin for an additional 5 days requires further study.

• The eradication of H. pylori should be confirmed with urea breath testing or fecal antigen testing no sooner than 4 weeks after completing eradication therapy.

• If a patient has persistent H. pylori infection after the initial eradication therapy regimen, salvage therapy with bismuth quadruple therapy for 7-14 days should be administered.

For NSAID-related PUD, discontinuation of the offending agent is imperative.

• Antisecretory therapy with a PPI or an H2RA should be administered for 4 weeks to promote healing and to relieve symptoms.

• If H. pylori is also present, antibacterial therapy should be initiated. Eradication of H. pylori does not prevent NSAID-related complications or recurrence.

• PPIs, H2RAs, or misoprostol should be used to prevent PUD in patients who require chronic NSAIDs and who are at risk of developing PUD (e.g., patients who are elderly or who have concomitant cardiovascular disease, patients with a history of PUD, patients using high-dose NSAID therapy, and patients who concomitantly use corticosteroids or anticoagulants).

Sucralfate may also be used to aid in ulcer healing, but it requires multiple daily dosing and is associated with many significant drug interactions.

Non-H. pylori, non-NSAID-related PUD should be treated with antisecretory therapy.

Drug Therapy

Mechanism of action

PPIs suppress gastric acid secretion specifically by inhibiting the H+-K+-ATPase enzyme system of the secretory surface of the gastric parietal cell.

H2RAs suppress gastric acid secretion by reversibly blocking histamine-2 receptors on the surface of the gastric parietal cell.

Clarithromycin, amoxicillin, metronidazole, tetracycline, bismuth subsalicylate, and furazolidone exhibit antibacterial effects against H. pylori.

When exposed to gastric acid, sucralfate forms a viscous adhesive that binds positively charged protein molecules in the ulcer crater, thus forming a protective barrier that protects against back-diffusion of hydrogen ions.

See

Table 21-1 for selected medications.

Patient counseling

Educate patients about the importance of completing the entire course of therapy to ensure the eradication of H. pylori and to avoid bacterial resistance.

PPIs are best taken before eating. Lansoprazole and dexlansoprazole granules may be sprinkled onto applesauce for patients who have trouble swallowing pills. Lansoprazole orally disintegrating tablets should not be crushed or chewed. Omeprazole capsules should be swallowed whole. Omeprazole over-the-counter (OTC) tablets should not be crushed or chewed. Omeprazole-sodium bicarbonate capsules should be swallowed whole.

If antacids are being used to control breakthrough symptoms, the dose should be taken no less than 1-2 hours before or after an H2RA is taken. H2RAs may be taken without regard to meals.

Amoxicillin, clarithromycin, and metronidazole may be taken without regard to meals; however, taking clarithromycin and metronidazole with meals often reduces the incidence of stomach upset.

Tetracycline is best taken on an empty stomach. Antacids, dairy products, or iron-containing products should be taken 2 hours before or after tetracycline.

Sucralfate should be taken 1 hour before meals and at bedtime.

Adverse drug effects

• Side effects occur in 15-20% of patients, but they are usually minor.

• PPIs and H2RAs are generally well tolerated, but headache, diarrhea, and nausea have been reported.

[Table 21-1. Selected Medications Used in Peptic Ulcer Disease]

• Antibiotics may cause diarrhea, nausea, dysgeusia, rash, and monilial vaginitis.

• Bismuth subsalicylate may cause black, tarry stools.

• Constipation is the most common side effect of sucralfate.

Drug interactions

• Omeprazole inhibits the cytochrome P450 (CYP450) enzyme system, which decreases the elimination of warfarin, phenytoin, diazepam, and cyclosporine. Lansoprazole has been reported to increase theophylline clearance by approximately 10%.

• PPIs and H2RAs may alter the bioavailability of drugs that require an acidic environment for absorption (e.g., ketoconazole, digoxin, and iron).

• Cimetidine is a potent inhibitor of the CYP450 enzyme system, which decreases the elimination of numerous drugs (e.g., warfarin, theophylline, and phenytoin).

• Amoxicillin and tetracycline may decrease the effectiveness of oral contraceptives.

• Clarithromycin is a potent inhibitor of the CYP450 enzyme system, which decreases the elimination of warfarin, digoxin, cyclosporine, carbamazepine, theophylline, and cisapride (no longer on the market).

• Tetracycline may decrease the effectiveness of oral contraceptives. Antacids, iron products, and dairy products bind to tetracycline, decreasing its effectiveness. Tetracycline can also increase the therapeutic effect of warfarin. Tetracycline can increase or decrease lithium levels.

• Metronidazole produces a disulfiram-like reaction when ingested with alcohol and increases the therapeutic effect of warfarin and lithium.

• Sucralfate leads to the absorption of small amounts of aluminum, which may accumulate if given to patients with renal insufficiency (especially when combined with aluminum-containing antacids).

• Sucralfate alters the absorption of numerous drugs, including warfarin, digoxin, phenytoin, ketoconazole, quinidine, and quinolones.

• Disulfiram-like reactions have been reported with the concurrent ingestion of alcohol and furazolidone.

Monitoring parameters

Patients should monitor for the return of PUD symptoms and for the side effects of medications, as discussed in the earlier sections.

Pharmacokinetics

Several medications are substrates for or have effects on the CYP450 enzyme system in the liver, as discussed in the drug interactions section.

Nondrug Therapy and Complications

Patients should be counseled to decrease psychological stress and to discontinue smoking and drinking alcohol, taking NSAIDs, and ingesting food or beverages that may exacerbate PUD symptoms.

Major complications occur in approximately 25% of patients with PUD (hemorrhage, perforation, penetration, and obstruction):

• Patients with active bleeding who are hemodynamically stable should receive intravenous PPI therapy and undergo endoscopy to evaluate the risk of bleeding recurrence.

• Patients with active bleeding who are hemodynamically unstable should receive intravenous fluids and blood transfusions. They should undergo emergency endoscopy for coagulation of bleeding sites. Various modalities may be used to achieve bleeding-site coagulation.

• As soon as patients tolerate oral intake, intravenous PPI therapy should be changed to oral therapy.

• Surgery is reserved for those patients who have refractory ulcers, recurrent bleeding, or a perforated ulcer.

21-2. Gastroesophageal Reflux Disease

Definition and Incidence

Gastroesophageal reflux disease (GERD) is a condition that develops when the reflux of stomach contents causes troublesome symptoms or complications.

The prevalence of GERD is highest in Western countries. It occurs equally in men and women, except that its incidence is higher in pregnant women. The incidence of GERD is higher and more frequently severe in Caucasians than in African Americans. Obesity has been strongly correlated to the incidence of GERD. GERD may also occur in children. The risk of experiencing complications from GERD increases with age.

Approximately 20% of the U.S. population experiences heartburn or regurgitation of gastric acid weekly.

Approximately 30-50% of pregnant women have symptomatic esophageal reflux; 50% experience heartburn daily.

Classification

The manifestations of GERD are divided into esophageal and extraesophageal syndromes.

Esophageal syndromes

Esophageal syndromes comprise those that are only symptomatic in nature and those that are symptomatic with esophageal injury on endoscopy. Symptomatic syndromes include the typical reflux syndrome and the reflux chest pain syndrome:

• The typical reflux syndrome is defined by the presence of troublesome heartburn, regurgitation, or both. Patients may have other symptoms, such as epigastric pain or sleep disturbance.

• The reflux chest pain syndrome occurs when GERD causes chest pain that is similar to ischemic cardiac pain. This pain can occur without concurrent heartburn or regurgitation.

Symptomatic syndromes with esophageal injury include GERD complications such as reflux esophagitis, reflux stricture, Barrett's esophagus, and esophageal adenocarcinoma.

• Reflux esophagitis is characterized by visible breaks in the distal esophageal mucosa.

• A reflux stricture is defined as a persistent luminal narrowing of the esophagus caused by GERD.

• Barrett's esophagus occurs when esophageal squamous epithelium from the gastroesophageal junction is replaced with metaplastic columnar epithelium. It is a risk factor for the development of esophageal adenocarcinoma.

Extraesophageal syndromes

Extraesophageal syndromes include those syndromes that have established associations with GERD and those with proposed associations with GERD.

Esophageal syndromes that have established associations with GERD include reflux cough syndrome, reflux laryngitis syndrome, reflux asthma syndrome, and reflux dental erosion syndrome.

Esophageal syndromes that have proposed associations with GERD include pharyngitis, sinusitis, idiopathic pulmonary fibrosis, and recurrent otitis media.

Clinical Presentation

Heartburn and regurgitation are the common characteristic symptoms of the typical reflux syndrome. Heartburn is defined as a burning sensation in the retrosternal area. Regurgitation is defined as the perception of flow of refluxed gastric content into the mouth or hypopharynx.

Symptoms usually occur shortly after having a meal, when reclining after a meal, or on lying down at bedtime. Symptoms often awaken patients from sleep.

Symptoms are exacerbated by eating a large meal (especially a high-fat meal), by bending over, and occasionally by exercising.

Symptoms suggestive of complications from GERD include continuous pain, dysphagia, odynophagia, bleeding, unexplained weight loss, and choking.

Symptom severity does not correlate with the degree of esophagitis present on endoscopy, but severity usually does correlate with the duration of reflux.

Pathophysiology

The effortless movement of gastric contents into the esophagus is a physiologic process that occurs numerous times daily throughout life and does not produce symptoms. It occurs more frequently in patients with GERD.

The pathophysiology of GERD involves the prolonged contact of esophageal epithelium with refluxed gastric contents containing acid and pepsin. Prolonged contact between esophageal epithelium and gastric contents can overwhelm esophageal defense mechanisms and produce symptoms.

Higher-potency gastric refluxate may produce symptoms during times of esophageal contact of normal duration. The presence of refluxate in an esophagus with impaired defense mechanisms may also produce symptoms.

Esophageal defenses consist of the antireflux barrier, luminal clearance mechanisms, and tissue resistance.

• Components of the antireflux barrier are the lower esophageal sphincter (LES) and the diaphragm. The LES is a thickened ring of circular smooth muscle localized to the distal 2-3 cm of the esophagus. It is contracted at rest, thereby serving as a barrier to refluxate. The diaphragm encircles the LES and acts as a mechanical support, especially during physical exertion.

• Luminal clearance factors include gravity, esophageal peristalsis, and salivary and esophageal gland secretions (which contain acid-neutralizing bicarbonate).

• The three areas of tissue resistance are preepithelial, epithelial, and postepithelial defense. Preepithelial and epithelial tissues limit the rate of diffusion of H+ between cell membranes. Postepithelial defense is provided by the blood supply, which removes HCl and supplies oxygen, nutrients, and bicarbonate.

Diagnostic Criteria

For patients who present with troublesome symptoms of GERD, a trial of empiric therapy is appropriate. A diagnosis of GERD may be assumed for patients who respond to empiric treatment.

Diagnostic testing with endoscopy should be performed in patients who present with troublesome GERD symptoms and dysphagia, weight loss, or epigastric mass on physical examination. It should also be performed on patients who do not respond to empiric treatment.

• Endoscopy is the preferred method for evaluating the esophageal mucosa for esophagitis and for evaluating for the presence of complications. It is a highly specific test, but it is not extremely sensitive. Patients with symptoms may have normal esophageal mucosa.

• Esophageal manometry may be performed in patients with persistent symptoms despite an empiric trial of twice-daily PPI therapy with normal esophageal mucosa on endoscopy. It consists of passing a tube into the stomach and subsequently measuring pressures as the tube is pulled back across the LES, esophagus, and pharynx. Esophageal manometry is often performed to facilitate placement of ambulatory pH probes. It is always performed to aid in determining the best procedure in antireflux surgery candidates.

• Ambulatory pH monitoring may be used to confirm the diagnosis of GERD in patients with persistent GERD symptoms despite an empiric trial of PPI therapy, with normal esophageal mucosa on endoscopy, and no abnormalities on esophageal manometry testing. It is performed by passing a small electrode to measure pH intranasally to the level of 5 cm above the LES. This test allows patient symptoms to be correlated with the timing of episodes of decreased pH levels in the esophagus. It may not be available at all institutions.

Treatment Principles and Goals

Goals of therapy are to alleviate or eliminate symptoms, decrease frequency and duration of reflux, promote healing of the injured mucosa, and prevent the development of complications.

Therapy is directed at increasing lower esophageal pressure, improving esophageal acid clearance and gastric emptying, protecting esophageal mucosa, decreasing the acidity of refluxate, and decreasing the amount of gastric contents being refluxed.

Acid suppression is the mainstay of therapy for patients with esophageal GERD syndromes. GERD is considered a chronic condition, and most patients will require chronic therapy. Chronic therapy should be titrated down to the lowest effective dose.

PPIs provide faster symptomatic relief and heal esophagitis more effectively than H2RAs. H2RAs are more effective than placebo.

Antacids are appropriate self-treatment for patients with symptoms of GERD that are not troublesome to the patient.

An empiric trial of once-daily PPI therapy is appropriate for patients with troublesome GERD symptoms. If patients do not respond to once-daily therapy, twice-daily therapy may be used.

Patients with esophageal GERD syndromes and troublesome dysphagia should undergo endoscopy to evaluate for the presence of reflux esophagitis, reflux stricture, Barrett's esophagus, or esophageal adenocarcinoma.

An empirical trial of twice-daily PPI therapy may be used for patients with suspected reflux chest pain syndrome after cardiac causes have been thoroughly considered.

Acute or maintenance therapy with once- or twice-daily PPIs may be used in patients with a suspected extraesophageal GERD syndrome who also have esophageal GERD syndrome.

Antireflux surgery may be performed when a patient is responsive to, but intolerant of, acid suppressive therapy or has persistent troublesome symptoms of GERD.

Drug Therapy

Mechanism of action

For information on H2RAs and PPIs, see the section on PUD.

Antacids neutralize gastric acid (which increases LES tone) and inhibit the conversion of pepsinogen to pepsin, thus raising the pH of gastric contents.

Alginic acid reacts with sodium bicarbonate in saliva to form sodium alginate viscous solution, which floats on the surface of gastric contents. The solution acts as a barrier to protect the esophagus from the corrosive effects of gastric reflux.

See

Table 21-2 for selected medications.

[Table 21-2. Selected Antacids and Absorbents]

Patient counseling

For information on H2RAs and PPIs, see the section on PUD.

Antacids and alginic acid are appropriate for the initial management of symptoms of GERD that are not troublesome to the patient. Symptoms persisting longer than 2 weeks require further evaluation and treatment with prescription medications.

Refrigeration of liquid antacids may aid in palatability. Chewable tablets may be more effective than liquids because of increased adherence of antacid and saliva to the distal esophagus. Antacids must be taken at least 2 hours apart from tetracyclines, iron, and digoxin. Antacids and quinolones should be taken 4-6 hours apart.

Alginic acid is effective for the relief of GERD symptoms, but no data indicate esophageal healing on endoscopy. Alginic acid is ineffective if the patient is in the supine position and must not be taken at bedtime.

Adverse drug effects

For information on H2RAs and PPIs, see the section on PUD.

Magnesium-containing antacids frequently cause diarrhea. Aluminum-containing antacids frequently cause constipation and bind to phosphate in the gut, which can lead to bone demineralization. Antacids may also cause acid-base disturbances.

Magnesium and aluminum toxicity may occur when used chronically in patients with renal insufficiency. Sodium bicarbonate may cause sodium overload, particularly in patients with hypertension, congestive heart failure, and chronic renal failure. It may also lead to systemic alkalosis. It should be used on a short-term basis, if at all.

Drug interactions

For information on H2RAs and PPIs, see the section on PUD.

When taken with antacids, the absorption and effectiveness of tetracycline, ferrous sulfate, and quinolones are reduced because the antacids form chelates with them. Antacids decrease the absorption of azoles and sucralfate by increasing gastric pH. Antacids increase urine pH, which decreases the renal clearance of quinidine. Antacids decrease the systemic absorption of digoxin and H2RAs when taken concomitantly with them. Large doses of antacid may decrease the absorption of phenytoin.

Digoxin and phenytoin levels should be monitored frequently when antacids are used concomitantly. Suspected adverse effects of antacids should be reported to a health care provider.

Monitoring parameters

Patients should monitor for the return of GERD symptoms and for the side effects of medications as discussed in the previous section.

Pharmacokinetics

Several medications are substrates for or have effects on the CYP450 enzyme system in the liver. See the discussion under drug interactions in Section 21-1.

Nondrug Therapy

• Lifestyle modifications alone are unlikely to control GERD symptoms. Lifestyle modifications should be tailored to the circumstances of the individual patient.

• Weight loss should be recommended for overweight or obese patients with esophageal GERD syndromes.

• Patients who experience GERD symptoms when recumbent should be advised to elevate the head of the bed.

• Patients should be advised to avoid foods that exacerbate GERD symptoms (alcohol, coffee, chocolate, high-fat foods, spicy foods, acidic foods, and carbonated drinks).

• Patients should be advised to adopt behaviors that reduce esophageal acid exposure, such as to stop smoking, to avoid lying down for 2-3 hours after meals, and to eat smaller meals.

• Calcium channel blockers, β-blockers, nitrates, barbiturates, anticholinergics, and theophylline decrease LES pressure. Tetracyclines, NSAIDs, aspirin, bisphosphonates, iron, quinidine, and potassium chloride have direct irritant effects on the esophageal mucosa.

21-3. Inflammatory Bowel Disease

Definition and Incidence

Idiopathic inflammatory bowel disease (IBD) is divided into two major types:

• Ulcerative colitis (UC) is defined as a chronic mucosal inflammatory condition confined to the rectum and colon.

• Crohn's disease (CD) is defined as a transmural inflammation of the GI tract that can affect any part of the GI tract from mouth to anus.

The prevalence of UC is approximately 37.5-229.0 cases per 100,000 persons. The prevalence of CD is approximately 50 cases per 100,000 persons.

Approximately 500,000 persons have CD and 500,000 persons have UC in the United States. UC is slightly predominant in men; CD is predominant in women. The overall incidence of IBD is similar between men and women.

North America, Scandinavia, and Great Britain have the highest incidence rates for IBD.

UC typically occurs in persons between 30 and 40 years of age. CD typically occurs between ages 20 and 30. Both may be diagnosed at any stage in life, but of all cases of IBD, 10-15% are diagnosed before adulthood.

The incidence of IBD is low for Hispanics and Asian Americans. Its incidence in African Americans has increased and is equal to that of Caucasians. In addition, its incidence rate is high among the Jewish population in North America, Europe, and Israel.

Classification

The two major types of IBD are ulcerative colitis and Crohn's disease. Clinical presentation and diagnostic tests help distinguish one form from the other.

Clinical Presentation

IBD is characterized by acute exacerbations of symptoms followed by periods of remission that are spontaneous or secondary to changes in medical therapy.

Ulcerative colitis

The hallmark clinical symptom of UC is bloody diarrhea, which is often accompanied by rectal urgency and tenesmus.

The extent and severity of UC are characterized by clinical and endoscopic findings. Clinical symptoms are categorized as mild, moderate, severe, and fulminant. Endoscopic findings are categorized as distal (limited to below the splenic flexure) or extensive (extending proximal to the splenic flexure).

• Mild UC is characterized by fewer than four stools per day with or without blood, without systemic disturbance and with a normal erythrocyte sedimentation rate (ESR).

• Moderate UC is characterized by more than four stools per day with minimal signs of toxicity.

• Severe UC is characterized by more than six stools per day with blood; systemic disturbance (e.g., fever, tachycardia, anemia); and ESR greater than 30.

• Fulminant UC is characterized by more than 10 bowel movements per day, continuous bleeding, toxicity, abdominal tenderness and distension, blood transfusion requirement, and colonic dilation on abdominal plain films.

Crohn's disease

The presentation of CD is variable and its onset is often insidious. Typical symptoms include chronic or nocturnal diarrhea and abdominal pain. Additional typical symptoms include weight loss, fever, and rectal bleeding.

Clinical signs may include pallor, abdominal mass or tenderness, cachexia, perianal fissure, fistula, or abscess.

Extraintestinal symptoms include inflammation of the skin, joints, and eyes.

Symptoms differ depending on the site and severity of inflammation:

• Mild to moderate: Patients are ambulatory and tolerate oral alimentation without dehydration; toxicity (fever, rigors, or prostration); abdominal tenderness; painful mass or obstruction; or weight loss > 10%.

• Moderate to severe: Patients fail to respond to treatment for mild to moderate disease or have fever, weight loss, abdominal pain, nausea, vomiting (without obstruction), or anemia.

• Severe to fulminant: Patients have persistent symptoms despite the use of steroids or biologic agents as outpatients, or individuals present with high fever, persistent vomiting, evidence of obstruction, rebound tenderness, cachexia, or abscess.

Symptomatic remission occurs when a patient is asymptomatic or without any symptomatic inflammatory sequelae.

The ileum and colon are the most commonly affected sites. Ileitis may mimic appendicitis. Intestinal obstruction and inflammatory masses or abscesses may also develop. Patients with colonic CD commonly have rectal bleeding, perianal lesions, and extraintestinal manifestations (e.g., spondylarthritis, peripheral arthritis, erythema nodosum, pyoderma gangrenosum, uveitis, fatty liver, chronic active hepatitis, cirrhosis, primary sclerosing cholangitis, gallstones, cholangio-carcinoma, and hypercoagulability).

Oral CD is characterized by lesions ranging from a few aphthous ulcers to deep linear ulcers with edema and induration. Gastroduodenal involvement may mimic PUD.

Pathophysiology

The etiology of UC and CD is unclear, but similar factors may contribute to both diseases. These factors include infectious agents, genetics, environmental factors, immune deficits, and psychological factors. Major etiologic theories involve a combination of infectious and immunologic factors.

UC is confined to the rectum and colon and affects only the mucosa and submucosa. The primary lesion of UC is a crypt abscess, which forms in the crypts of the mucosa. CD most commonly affects the terminal ileum and involves extensive damage to the bowel wall.

UC and CD complications can be local or systemic. Local complications of UC include hemorrhoids, anal fissures, and perirectal abscesses. Toxic megacolon can lead to perforation and is a major complication that affects 1-3% of patients with UC or CD. Colonic strictures and hemorrhage may also occur. Small bowel strictures, obstruction, and fistulae are common in CD. Systemic complications (extraintestinal) can occur with UC and CD.

Diagnostic Criteria

UC is diagnosed on the basis of clinical symptoms, proctosigmoidoscopy or colonoscopy, tissue biopsy, and bacteria-negative stool studies. CD is diagnosed on the basis of clinical symptoms, contrast radiography or endoscopy, tissue biopsy, and bacteria-negative stool studies. Abdominal ultrasonography, computed tomography, and magnetic resonance imaging aid in the identification of masses, abscesses, and perianal complications in UC and CD.

Treatment Principles and Goals

Treatment of IBD involves medications that target inflammatory mediators and alter immuno-inflammatory processes. These medications include anti-inflammatory, immunosuppressive, and biologic agents.

Nutritional considerations are also important because many patients with IBD may be malnourished.

Goals of therapy for UC and CD include induction and maintenance of remission of symptoms, induction and maintenance of mucosal healing, improved quality of life, resolution of complications and systemic symptoms, and prevention of future complications. For patients with CD, remission means that patients are asymptomatic or without inflammatory sequelae, including patients who have responded to medical intervention. Patients who require steroids to maintain their condition are considered steroid dependent, not in remission.

In UC patients, remission is likely to last at least 1 year with medical therapy. Without medical therapy, up to two-thirds of patients will relapse within 9 months. For mild CD, up to 40% of patients improve in 3-4 months with observation alone. Most will remain in remission for prolonged periods without medical therapy.

The treatment of choice for distal UC that involves only the rectum (proctitis) is topical therapy with aminosalicylates:

• Treatment is initiated with a nightly suppository or enema. Improvement usually occurs within 2-3 weeks. Most patients will require maintenance therapy with topical aminosalicylates to remain in remission.

• Rectally administered steroids may be used in combination with aminosalicylates when patients do not respond to aminosalicylates alone.

• For patients who do not respond to or who cannot tolerate topical therapy, oral therapy with steroids or aminosalicylates is necessary.

Mild to moderate distal colitis may be treated with oral aminosalicylates, topical mesalamine, or topical steroids; however, topical aminosalicylates are more effective than topical steroids or oral aminosalicylates.

• Combining oral and topical aminosalicylates is more effective than using them individually.

• Patients who are refractory to maximum doses of these agents may require oral steroid treatment.

• For the maintenance of remission, mesalamine enemas may be used every 1-2 days. Oral aminosalicylates are also effective for maintaining remission. Combining oral and topical aminosalicylates is more effective at maintaining remission than using them individually. Topical steroids are not effective at maintaining remission.

For moderate to severe distal colitis, twice-daily enemas are required. Combining oral and topical aminosalicylates may also be required.

For severe distal colitis, combining oral and topical aminosalicylates is required.

• Oral corticosteroids are reserved for patients who fail initial aminosalicylate therapy.

• Corticosteroids are tapered after remission is achieved, and topical and oral aminosalicylates are continued as maintenance therapy.

Extensive UC (pancolitis) requires oral therapy; however, topical therapy is still a useful adjunct in controlling rectal disease.

For mild to moderate extensive UC, oral aminosalicylates are first-line therapy.

• Patients who fail to respond require the addition of high-dose oral corticosteroid therapy.

• Azathioprine and 6-mercaptopurine may be used in patients who do not respond to, or cannot be weaned from, corticosteroids. These drugs may also be used to maintain remission.

• Corticosteroid tapering should begin only when complete remission is achieved.

• Corticosteroids do not have a role in maintenance therapy; aminosalicylates are usually effective at maintaining remission.

• For patients who fail oral therapy, hospitalization and intravenous steroid therapy is necessary.

For moderate to severe UC refractory to conventional therapy, infliximab may be used to avoid or reduce corticosteroid use and to induce remission.

For severe or fulminant colitis, hospitalization and complete bowel rest are required.

• Intravenous (IV) steroids are the mainstays of therapy.

• Topical therapy may be added for patients with significant rectal symptoms.

• In patients who do not respond to 7 days of IV steroids, surgery or IV cyclosporine should be considered. Patients who respond to IV cyclosporine are converted to oral cyclosporine and a steroid taper.

• Azathioprine may be added to maintain remission.

Abdominal x-ray should be performed to exclude toxic megacolon. Surgery is often required for patients with toxic megacolon, and preoperative antibiotics are recommended to reduce the chance of septic complications.

For CD, clinical improvement should be evident within 2-4 weeks. Maximal clinical improvement should occur within 12-16 weeks. Treatment for acute disease should be continued until remission is achieved or the patient's symptoms fail to improve.

For mild to moderate CD localized to the ileum or right colon, controlled-release oral budesonide is appropriate initial therapy.

• Controlled-release oral budesonide is more effective than oral mesalamine and placebo. It has similar efficacy to conventional oral corticosteroids.

• Oral mesalamine has been used as first-line therapy; however, new evidence indicates that it is only minimally more effective than placebo and less effective than corticosteroids.

• Oral sulfasalazine is more effective than placebo but less effective than corticosteroids for ileocolonic and colonic CD.

• Rectal aminosalicylates are often used to treat distal colonic CD; however, controlled studies showing efficacy are lacking.

• Although metronidazole and ciprofloxacin are widely used in the treatment of CD, clinical trials have not consistently demonstrated efficacy.

• No controlled data exist regarding the treatment of mild to moderate oral CD. Lidocaine lozenges may provide symptomatic relief. Lesions will respond to systemic steroids or azathioprine in 50% of patients.

• For CD of the stomach, esophagus, duodenum, and jejunum, PPIs, oral corticosteroids, mercaptopurine, azathioprine, methotrexate, infliximab, adalimumab, and certolizumab pegol have improved symptoms in uncontrolled trials.

• When remission is achieved, maintenance therapy should be initiated. For patients who do not respond, treatment with alternative agents for mild to moderate disease may be initiated or the treatment may be advanced to agents used for moderate to severe disease.

For patients with moderate to severe disease, oral corticosteroids are the mainstay of therapy.

• Prednisone 40-60 mg daily should be given until symptoms resolve and weight gain resumes. Steroids are not appropriate maintenance therapy.

• Infections or abscesses should be treated with appropriate antibiotics or surgical drainage.

• Azathioprine and 6-mercaptopurine may be added to oral corticosteroids to maintain a steroid-induced remission. They are also effective for steroid-dependent or steroid-refractory patients.

• Parenteral methotrexate is effective for inducing remission and allowing steroid dose reduction in patients with steroid-dependent and steroid-refractory CD.

• Infliximab, adalimumab, and certolizumab pegol may be used in patients who do not respond to oral corticosteroids or immunosuppressive agents. They may also be used as an alternative to oral corticosteroids when the side effects of oral corticosteroids need to be avoided.

• Natalizumab may be used when patients are intolerant or unresponsive to oral corticosteroids, immunosuppressants, and biologic therapies.

• Enteral nutrition should be used to support the patient's overall nutrition status, not to induce remission of CD.

• When remission is achieved, maintenance therapy should be initiated.

For severe to fulminant CD, hospitalization for intravenous steroids and hydration is required.

• Intravenous steroids equivalent to 40-60 mg/day of prednisone should be administered.

• Parenteral fluid and electrolyte therapy should be administered to restore hydration.

• Parenteral or enteral nutrition support should be administered after 5-7 days if the patient cannot meet adequate nutritional requirements.

• Anemic patients may require blood transfusions.

• Intestinal obstructions related to adhesions should be managed with bowel rest and nasogastric tube suctioning. Obstructions related to inflammatory strictures require antibiotic therapy and IV steroids. Surgery should be considered if obstructive symptoms do not respond to therapy.

• Abscesses should be drained and appropriate antibiotic therapy instituted.

• High-dose metronidazole or ciprofloxacin may be used in the management of fistulas. Chronic therapy may be required to prevent recurrent drainage.

• Azathioprine, 6-mercaptopurine, and infliximab may also be used in the management of fistulas.

• If patients do not respond to IV steroids after 5-7 days of therapy, cyclosporine or tacrolimus therapy may be instituted.

• When symptoms respond to initial treatment, the patient should be converted to an equivalent oral corticosteroid regimen.

• Patients who do not respond to therapy require surgical intervention.

Maintenance therapy should be initiated when remission is achieved.

• Corticosteroids should not be used as long-term maintenance therapy.

• Sulfasalazine and mesalamine have not shown consistent benefit as maintenance therapy.

• Azathioprine, 6-mercaptopurine, and methotrexate have shown benefit as maintenance therapy.

• Azathioprine may be used as maintenance therapy in steroid-naive patients who achieved remission with infliximab.

• Infliximab, adalimumab, and certolizumab pegol are effective maintenance therapies.

• Natalizumab may be used for maintenance therapy after it has been successfully used to induce remission.

Drug Therapy

See

Table 21-3 for selected medications used in IBD.

Mechanism of action

Sulfasalazine is cleaved to sulfapyridine (excreted in the urine) by bacteria in the gut and mesalamine (the

[Table 21-3. Selected Medications Used in Inflammatory Bowel Disease]

active component). The sulfapyridine molecule is responsible for the many side effects associated with sulfasalazine.

Mesalamine's mechanism of action is poorly understood. Mesalamine inhibits cyclooxygenase and may also inhibit production of cyclooxygenase, thromboxane synthetase, platelet-activating factor synthetase, and interleukin-1 in macrophages. It may also act as a superoxide free-radical scavenger.

Corticosteroids have immunomodulatory effects and inhibit the production of cytokines and other inflammatory mediators.

Corticosteroids, azathioprine, 6-mercaptopurine, cyclosporine, and tacrolimus are immunosuppressive agents. For full discussion of their mechanism of action, patient counseling, side effects, drug interactions, and pharmacokinetics, see Chapter 20 on transplantation.

The exact mechanism of action of metronidazole and ciprofloxacin in IBD is not known. One theory suggests that antibacterials interrupt the role of bacteria in the inflammatory process.

Methotrexate inhibits dihydrofolate reductase and purine synthesis, reduces the production of leukotriene-B4 and interleukin-1 and -2, and may induce T-cell apoptosis.

Infliximab is a chimeric monoclonal antibody that inhibits human tumor necrosis factor, which inhibits subsequent cytokine-triggered inflammatory processes.

Adalimumab is a recombinant monoclonal antibody that inhibits human tumor necrosis factor, which inhibits subsequent cytokine-triggered inflammatory processes.

Certolizumab pegol is a pegylated humanized antibody Fab fragment of tumor necrosis factor monoclonal antibody. It inhibits human tumor necrosis factor activity, which inhibits subsequent cytokine-triggered inflammatory processes. Pegylation delays elimination and prolongs the half-life of the drug.

Natalizumab is a monoclonal antibody against the alpha-4 subunit of integrin molecules. It blocks the association of integrin with vascular receptors, which limits adhesion and transmigration of leukocytes.

Patient counseling

Sulfasalazine should be taken after meals. Patients should avoid sun exposure while taking it. Folic acid supplementation should be given during sulfasalazine treatment to avoid anemia. Sulfasalazine may cause orange discoloration of urine and skin.

Mesalamine tablets should be swallowed whole. Suppositories should not be handled excessively and foil wrappers should be removed before insertion. Suspension enemas should be shaken well before use.

Antacids and ciprofloxacin should be taken 4-6 hours apart. Iron- or zinc-containing products should be taken 4 hours before or 2 hours after taking ciprofloxacin. Patients should avoid excessive exposure to sunlight.

Patients taking methotrexate should avoid alcohol, salicylates, and prolonged exposure to sunlight. Female patients of childbearing age should be counseled on appropriate contraceptive measures during methotrexate therapy.

Patients receiving therapy with infliximab should be counseled on the possibility of infusion reactions, delayed hypersensitivity reactions, and increased risk of infections. Live vaccines should not be administered to patients taking infliximab.

Patients taking adalimumab should be counseled on the increased risk of infections and to report any symptoms of infection to their physician immediately. They should also be counseled on the potential for injection site reactions and be taught proper injection technique and proper sharps disposal. Live vaccines should not be administered to patients taking adalimumab.

Patients taking certolizumab pegol should be counseled on the increased risk of infections and to report any symptoms of infection to their physician immediately. They should also be counseled on the potential for injection-site reactions and be taught proper injection technique and sharps disposal. Live vaccines should not be administered to patients taking certolizumab pegol.

Patients taking natalizumab should be counseled on the risk of acute hypersensitivity infusion reactions. They should also be counseled on the increased risk of infections, particularly progressive multifocal leukoencephalopathy. Patients should report symptoms of infection to their physician immediately.

Adverse drug effects

Sulfasalazine may cause nausea, vomiting, anorexia, and headaches. The sulfapyridine moiety leads to hypersensitivity reactions (e.g., rash, fever, agranulocytosis, pancreatitis, nephritis, and hepatitis) and altered spermatogenesis in males.

Mesalamine is better tolerated than sulfasalazine. Olsalazine may cause self-limited watery diarrhea. Balsalazide causes abdominal pain in 10% of patients.

Ciprofloxacin may cause nausea, diarrhea, headache, and vaginal candidiasis.

Methotrexate frequently causes nausea and leukopenia. Asymptomatic elevations in liver function tests may occur.

Infliximab may cause infusion-related reactions, upper respiratory infections, headache, rash, cough, and stomach pain. Allergic reactions have been reported. Infliximab increases the risk of serious infections (bacterial, viral, and fungal infections; tuberculosis) and certain types of cancer. New onset or exacerbation of preexisting heart failure, hepatotoxicity, neuropathy, anemia, and lupus-like syndrome have also been reported.

Adalimumab may cause injection-site reactions, upper respiratory infections, headaches, rash, and nausea. Allergic reactions have been reported. Adalimumab increases the risk of serious infections (bacterial, viral, and fungal infections; tuberculosis) and certain types of cancer. New onset or exacerbation of preexisting heart failure, neuropathy, anemia, and lupus-like syndrome have also been reported.

Certolizumab pegol may cause injection-site reactions, upper respiratory tract infections, rash, and urinary tract infections. Allergic reactions have been reported. Certolizumab increases the risk of serious infections (bacterial, viral, and fungal infections; tuberculosis) and certain types of cancer. New onset or exacerbation of preexisting heart failure, neuropathy, anemia, and lupus-like syndrome have also been reported.

Natalizumab increases the risk of developing progressive multifocal leukoencephalopathy. Serious allergic reactions (usually within 2 hours of infusion) and hepatotoxicity have been reported. Natalizumab increases the risk of serious infections (bacterial, viral, and fungal infections; tuberculosis).

Drug interactions

Sulfasalazine may decrease the bioavailability of digoxin by inhibiting its absorption.

Azathioprine is converted into 6-mercaptopurine in vivo; 6-mercaptopurine then undergoes hepatic first-pass metabolism, which is catalyzed by xanthene oxidase. By inhibiting xanthene oxidase, allopurinol increases the bioavailability of azathioprine. The azathioprine dose should be lowered by 25-50% when the two agents are used concurrently.

Ciprofloxacin binds with antacids, zinc, and iron products. It also increases the therapeutic effects of warfarin, cyclosporine, and theophylline.

Corticosteroids should not be administered with natalizumab because of the increased risk of serious infections.

The use of methotrexate and concurrent NSAIDs has caused fatal interactions. Methotrexate may increase levels of 6-mercaptopurine.

Infliximab should not be administered with etanercept or anakinra because of the increased risk of serious infections. Live vaccines should not be administered to patients taking infliximab. The herbal supplement echinacea may decrease the effectiveness of infliximab.

Adalimumab should not be administered with anakinra because of the increased risk of serious infections. Live vaccines should not be administered to patients taking adalimumab. The herbal supplement echinacea may decrease the effectiveness of adalimumab. Methotrexate may decrease the clearance of adalimumab; however, this effect has not been shown to be clinically significant.

Certolizumab pegol should not be administered with anakinra, abatacept, rituximab, or natalizumab because of the increased risk of serious infections. Live vaccines should not be administered to patients taking certolizumab. The herbal supplement echinacea may decrease the effectiveness of certolizumab. Certolizumab may falsely elevate the activated partial thromboplastin time and the lupus anticoagulant assays.

Natalizumab should not be administered with other immunosuppressants, such as 6-mercaptopurine, azathioprine, cyclosporine, and methotrexate, or with tumor necrosis factor inhibitors because of the increased risk of progressive multifocal leukoencephalopathy. The herbal supplement echinacea may decrease the effectiveness of natalizumab.

Monitoring parameters

Serum chemistries, complete blood counts, liver function tests, blood glucose concentrations, ESR, response to therapy, and the presence of adverse effects should be monitored. Tuberculosis skin testing should be performed before administering biologic agents.

Pharmacokinetics

• Sulfasalazine is metabolized by intestinal flora to sulfapyridine and 5-aminosalicylic acid. Unchanged drug and metabolites are excreted in the urine.

• Mesalamine is metabolized in the liver and gut to 5-aminosalicylic acid. The metabolite is eliminated via the urine and feces.

• Azathioprine is thought to be hepatically metabolized to 6-mercaptopurine by glutathione S-transferase; 6-mercaptopurine is further metabolized by hypoxanthine guanine phosphoribosyltransferase, xanthene oxidase, and thiopurine methyltransferase. Metabolites are excreted in the urine.

• Ciprofloxacin is partially metabolized in the liver. Unchanged drug and metabolites are excreted in the urine and feces.

• Metronidazole is metabolized in the liver and is excreted in the urine and feces.

• Prednisone is metabolized in the liver and excreted in the urine.

• Methotrexate is primarily eliminated by the kidneys.

Nondrug Therapy

Patients with UC and CD are often malnourished because of malabsorption or maldigestion caused by chronic bowel inflammation, "short gut" syndrome from multiple bowel surgeries, or bile salt deficiency in the gut. The catabolic effects of the disease process can also lead to malnutrition.

Individuals should eliminate foods that exacerbate symptoms. Patients with lactase deficiency should avoid dairy products or take lactase supplements to avoid symptoms.

Enteral or parenteral supplementation may be used in patients with severe UC or CD to maintain adequate nutritional status.

Surgery may be necessary for patients with severe UC or CD. Surgery involves removing diseased segments of bowel, repairing fistulas, and draining abscesses.

• In UC, surgery is indicated for patients who fail maximum medical therapy to correct complications (perforation, strictures, obstruction, hemorrhage, toxic megacolon). It is also used as prophylaxis against the development of cancer (in patients with long-standing UC) and in patients with premalignant changes found on bowel biopsies.

• In CD, surgery is indicated for neoplastic or preneoplastic lesions, obstructing stenoses, suppurative complications, or CD that does not respond to pharmacotherapy. Smoking cessation should be encouraged to reduce the risk of recurrence of CD after surgery (as well as for overall health benefits).

21-4. Irritable Bowel Syndrome

Definition and Incidence

Irritable bowel syndrome (IBS) is defined as abdominal pain or discomfort that occurs in association with altered bowel habits over a period of 3 months.

IBS is a prevalent and expensive condition. It significantly impairs health-related quality of life and leads to reduced work productivity.

IBS patients visit physicians more frequently, have more diagnostic tests performed, take more medications, miss more workdays, show lower work productivity, are hospitalized more frequently, and consume more direct health care costs than patients without IBS.

The worldwide prevalence of IBS is 7-10%. Most cases of IBS are diagnosed before age 50. IBS is 1.5 times more common in women than in men. It is also more common in patients from lower socioeconomic groups.

Classifications

No symptom-based diagnostic criteria have ideal accuracy for diagnosing IBS. Traditional criteria (Kruis, Manning) are at least as accurate as the more recent Rome I criteria. Rome II and III criteria have been proposed, but their accuracy has not been evaluated.

Because of the lack of ideal accuracy of symptom-based diagnostic criteria, the American College of Gastroenterology proposed a new definition of IBS (see previous section).

Once the diagnosis is made, IBS may be classified according to its predominant symptom: diarrhea predominant, constipation predominant, or mixed (symptoms may alternate). Symptoms may also be further categorized as mild, moderate, or severe.

Clinical Presentation

IBS is a heterogeneous disorder with various clinical presentations:

• Abdominal pain is generally described as crampy or achy, and the intensity and location are highly variable. Pain may be exacerbated by meals and may last from 1 to 3 hours. Stress and emotional turmoil can also exacerbate pain.

• Patients typically present with diarrhea, constipation, or alternating periods of both.

• Upper GI symptoms occur more frequently in patients with constipation (heartburn, dyspepsia, early satiety, and nausea). Women experience abdominal distention, bloating, and nausea more often than men.

• Extraintestinal symptoms are common. They include genitourinary symptoms (e.g., pelvic pain, dysmenorrhea, dyspareunia, urinary frequency, nocturia, and sensation of incomplete bladder evacuation); impaired sexual function (e.g., decreased libido); and musculoskeletal complaints (e.g., lower back pain, headaches, and chronic fatigue).

• Alarm features include rectal bleeding, weight loss, iron deficiency anemia, nocturnal symptoms, family history of colorectal cancer, IBD, or celiac sprue. These symptoms may indicate the presence of an organic disease.

Pathophysiology

The pathogenesis is multifactorial and includes abnormal gut sensorimotor activity, central nervous system (CNS) dysfunction, psychological disturbances, genetic predisposition, enteric infection, and other luminal factors:

• Colonic motor abnormalities commonly occur in IBS. Patients with IBS may exhibit an exaggerated gastrocolonic response lasting up to 3 hours.

• Small intestinal motor patterns are frequently disturbed in patients with IBS. Small intestinal transit is delayed in constipation-predominant IBS and is accelerated in diarrhea-predominant IBS.

• Bloating may be the result of abnormal retrograde reflux of intestinal gas, enhanced perception of the presence of intestinal gas, or obstructive intestinal motor patterns.

• Motor dysfunction of other smooth muscles may occur in IBS. The following abnormalities may also be found: lowered LES sphincter pressures, abnormal esophageal body peristalsis, gastric slow-wave dysrhythmias, delayed gastric and gallbladder emptying, and dysfunction of the sphincter of Oddi.

• It is theorized that IBS results from sensitization of visceral afferent fibers, which causes normal physiologic events to be perceived as painful. It is unknown if sensorineural dysfunction is generalized or localized to the gut afferent fibers.

• It is unknown whether IBS is primarily a CNS disorder with centrally directed changes in gut sensorimotor function or primarily a gut disorder with inappropriate CNS input. Further investigation is needed in this area.

• Eighty percent of patients with IBS exhibit psychiatric disturbances. The onset of psychiatric disturbances usually predates or occurs concurrently with the onset of IBS. Psychological stress triggers symptoms in many patients. IBS is also associated with a history of sexual abuse.

• Other factors that may contribute to IBS are alterations in gut flora (controversial), antecedent GI infection, carbohydrate malabsorption, food allergies, neurohumoral disturbances, genetic factors, and abnormal stool characteristics (low concentrations of bile or short-chain fatty acids).

Relief of pain with defecation, looser stool with pain onset, more frequent stools with pain onset, and abdominal distention are significantly more common in IBS than in organic disease.

Diagnostic Criteria

• Physical examination is usually normal.

• Routine diagnostic testing with complete blood count, serum chemistries, thyroid function tests, stool for ova and parasites, and abdominal imaging are not recommended in patients with typical IBS symptoms and no alarm symptoms because of the low probability of diagnosing organic disease.

• Serologic screening for celiac sprue should be pursued in patients with diarrhea-predominant or mixed-symptom IBS.

• Lactose breath testing may be considered when lactose intolerance is suspected after dietary modification.

• Colonoscopy should be performed in patients with IBS with alarm symptoms to rule out CD, ulcerative colitis, and colorectal cancer.

• Colonoscopy should be performed in patients with IBS over the age of 50 to rule out colon cancer.

Treatment Principles and Goals

Treatment should be offered to patients seeking medical care if the patient and physician believe that the IBS symptoms decrease the patient's quality of life. Goals of therapy include improving IBS symptoms and improving patient quality of life.

Evidence from small clinical trials is inconsistent regarding the effectiveness of anticholinergic and antimuscarinic agents (dicyclomine and hyoscyamine) in the management of IBS; however, they are often used as first-line therapy in patients with mild symptoms. They may provide short-term relief of abdominal pain and discomfort. They should be used with caution in patients with constipation.

Psyllium has been shown to be moderately effective for IBS, although the evidence is weak.

Calcium polycarbophil was shown to improve symptoms in one small study. Polyethylene glycol was shown to improve stool frequency, but not abdominal pain, in a small study of adolescents with constipation-predominant IBS. It may be used as adjunctive therapy in patients with constipation-predominant IBS.

Loperamide significantly improves stool consistency and decreases stool frequency in patients with diarrhea-predominant IBS. It has no effect on abdominal pain or global IBS symptoms.

Tegaserod improves global IBS symptoms, bloating, abdominal pain, and altered bowel habits in patients with constipation-predominant IBS. It was withdrawn from the U.S. market in March 2007 because of an increased incidence (0.11%) of cardiovascular events in patients taking the drug. It is available only through the U.S. Food and Drug Administration (FDA) under an emergency investigational drug protocol.

Tricyclic antidepressants (TCAs) improve abdominal pain in patients with IBS. They also improve global IBS symptoms in patients with diarrhea-predominant IBS but not constipation-predominant IBS.

Selective serotonin reuptake inhibitors (SSRIs) improve abdominal pain in patients with IBS and are also effective in the treatment of comorbid psychiatric disorders in patients with IBS. SSRIs are recommended for patients with moderate to severe abdominal pain or those with psychiatric comorbidities. Several types of psychological counseling and therapy are effective in some patients with IBS.

Alosetron improves global IBS symptoms, abdominal discomfort, stool consistency, and stool frequency in women with diarrhea-predominant IBS. Because of the incidence of colon ischemia and complicated constipation, alosetron is available only through a prescribing program regulated by the FDA and administered by the drug's manufacturer. It is approved only for use in women with chronic, severe, diarrhea-predominant IBS who do not respond to other therapies.

Lubiprostone has been shown to relieve global IBS symptoms in women with constipation-predominant IBS.

Drug Therapy

Table 21-4 shows selected medications used to treat IBS.

Mechanism of action

The antispasmodic agent dicyclomine decreases GI motility by relaxing smooth muscle in the gut.

Hyoscyamine is an anticholinergic agent that decreases GI motility by decreasing smooth muscle tone through antimuscarinic activity in the gut.

Tricyclic antidepressants, such as amitriptyline, delay intestinal transit and may blunt perception of visceral distention. The effect of TCAs on the cerebral processing of visceral pain is unknown.

Tegaserod maleate, a partial 5-HT4 agonist that stimulates the peristaltic reflex and intestinal secretion, inhibits visceral sensitivity by binding to 5-HT4 receptors in the gut.

Lactulose, milk of magnesia, and polyethylene glycol solutions are osmotic laxatives that aid in the treatment of IBS patients with constipation.

Fiber supplements (bulk laxatives) increase stool bulk and water content.

Loperamide inhibits peristalsis by directly affecting the circular and longitudinal muscles of the intestinal wall.

Diphenoxylate is a meperidine congener that directly affects the circular smooth muscle in the gut, which slows GI transit time.

Alosetron is a selective 5-HT3 receptor antagonist that inhibits activation of nonselective cation channels in the gut, thereby modulating the enteric nervous system.

[Table 21-4. Selected Medications Used in Irritable Bowel Syndrome]

SSRIs inhibit the neuronal uptake of serotonin in the CNS. Citalopram has peripheral effects on colonic tone and sensitivity. Paroxetine has potent anticholinergic effects.

Lubiprostone is the only C-2 chloride channel activator available. By activating C-2 chloride channels in the gut, lubiprostone increases secretion of saltwater into the intestinal lumen. It is approved only for women with constipation-dependent IBS.

Patient counseling

Antispasmodics and anticholinergic agents are best used on an as-needed basis up to three times per day during acute attacks or before meals when postprandial symptoms are present.

Patients taking a TCA should avoid prolonged exposure to sunlight and avoid concurrent use of CNS depressants.

Tegaserod should be taken 30 minutes before meals and should not be initiated during an acute exacerbation of IBS. It is available only through an emergency investigational drug protocol from the FDA.

Osmotic laxatives should be used on an as-needed basis. Lactulose may be mixed with water or juice to increase palatability. Patients should drink plenty of water.

Patients must be enrolled in the manufacturer's prescribing program to receive alosetron. Patients should not initiate therapy with alosetron if they are currently constipated. Alosetron should be discontinued if no improvement in symptoms is seen after 4 weeks of therapy.

See Chapter 25 on psychiatric disease for a full discussion of SSRIs.

Lubiprostone should be taken with food and water. Softgel capsules should be swallowed whole.

Adverse drug effects

Dicyclomine, hyoscyamine, and TCAs may cause anticholinergic side effects (CNS depression, dry mouth, urinary retention, constipation, and decreased sweating).

Tegaserod may cause diarrhea, nausea, headache, and abdominal pain. It was associated with an increased risk of cardiovascular events in clinical trials.

Osmotic laxatives may cause abdominal pain and cramping.

Alosetron may cause constipation, abdominal pain, and nausea. Intestinal obstruction, perforation, toxic megacolon, ischemic colitis, and death have occurred.

See Chapter 25 on psychiatric disease for a full discussion of SSRIs.

Lubiprostone's most common side effects are nausea, diarrhea, and headache. Allergic reactions and dyspnea within 1 hour of the first dose have also been reported. Though dyspnea may recur with repeated doses, it usually resolves within 3 hours.

Drug interactions

Anticholinergics and antispasmodics may decrease the effectiveness of antipsychotic medications. Side effects from anticholinergics are increased when they are given concurrently with a TCA.

TCA concentrations may be increased or decreased by medications that induce or inhibit the activity of the CYP450 enzyme system in the liver. TCAs should not be given concurrently with monoamine oxidase inhibitors or sympathomimetic agents.

No significant drug interactions with tegaserod have been reported.

Other medications should not be taken within 1 hour of the start of therapy with osmotic laxatives.

The levels of alosetron may be decreased by concurrent administration of rifamycin derivatives.

There are no known drug interactions with lubiprostone.

Monitoring parameters

Patients should monitor for the presence of IBS symptoms and for the side effects of medications, as discussed in the section on adverse drug effects.

Pharmacokinetics

Dicyclomine, hyoscyamine, amitriptyline, paroxetine, tegaserod, alosetron, loperamide, and diphenoxylate/atropine undergo hepatic metabolism.

Lubiprostone is metabolized in the stomach and small intestine.

Nondrug Therapy

An effective physician-patient relationship is necessary for successful treatment. Education should be provided regarding disease pathophysiology and treatment and reassurance that the symptoms are real.

Although evidence supporting exclusion diets is lacking, patients may be counseled to avoid foods that exacerbate IBS symptoms. Foods commonly implicated are fatty foods, beans, gas-producing foods, alcohol, caffeine, lactose (in lactase-deficient individuals), and occasionally excess fiber.

Cognitive behavioral therapy, dynamic psychotherapy, and hypnotherapy are more effective than usual care in relieving global symptoms of IBS. Although the quality of the evidence regarding such therapy is low, the potential benefit outweighs the potential risks.

21-5. Key Points

Peptic Ulcer Disease

• PUD is a group of disorders of the upper GI tract characterized by ulcerative lesions that require acid and pepsin for their formation.

• Duodenal and gastric ulcers are classified as Helicobacter pylori related, NSAID related, non-H. pylori related, non-NSAID related, or stress related.

• Epigastric pain occurring 1-3 hours after meals that is relieved by ingestion of food or antacids is the classic symptom of PUD.

• H. pylori is a gram-negative microaerophilic bacterium inhabiting the area between the mucous layer and epithelial cells in the stomach. It can be found anywhere gastric epithelium is present.

• NSAIDs are the leading cause of PUD in patients who are negative for H. pylori infection.

• NSAIDs are directly toxic to gastric epithelium and inhibit the synthesis of prostaglandins.

• The goals of PUD therapy are ulcer healing and eliminating the cause. Additional considerations are prevention of complications and relief of symptoms.

• Upper GI endoscopy is used to diagnose PUD. The procedure is usually reserved for patients with symptoms of PUD who are over 55 years of age or who have alarm symptoms (bleeding, anemia, early satiety, unexplained weight loss, progressive dysphagia, odynophagia, recurrent vomiting, family history of gastrointestinal cancer, or previous esophagogastric cancer).

• Patients with symptoms of PUD who are less than 55 years of age and have no alarm symptoms may be tested for the presence of H. pylori and treated with eradication therapy if results are positive.

• Histology and rapid urease testing may be performed on biopsy samples obtained during endoscopy to test for H. pylori.

• Serum antibody tests, urea breath tests, and fecal antibody testing do not require endoscopy to test for H. pylori.

• The American College of Gastroenterology treatment guidelines for H. pylori eradication in PUD recommend initial triple therapy with a PPI, clarithromycin, and either amoxicillin or metronidazole for 14 days or quadruple therapy with bismuth, metronidazole, tetracycline, and either an H2RA or a PPI for 10-14 days.

• NSAID-related PUD treatment consists of discontinuing the offending agent and issuing antisecretory therapy for symptom relief.

• Antisecretory therapy with a PPI or an H2RA should be administered for 4 weeks to promote healing and to relieve symptoms.

• Patients with active bleeding who are hemodynamically stable should receive intravenous PPI therapy and undergo endoscopy to evaluate the risk of bleeding recurrence.

• Patients with active bleeding who are hemodynamically unstable should receive intravenous fluids and blood transfusions. They should undergo emergency endoscopy for coagulation of bleeding sites. Various modalities may be used to achieve bleeding-site coagulation.

• Surgery is reserved for patients who have refractory ulcers, recurrent bleeding, or a perforated ulcer.

• Patients should be counseled on the importance of adherence to treatment regimens, proper dosing, and the side effects of medications.

• Patients should be counseled to decrease psychological stress, to discontinue smoking and drinking alcohol, to stop using NSAIDs, and to avoid food or beverages that exacerbate PUD symptoms.

Gastroesophageal Reflux Disease

• GERD is a condition that develops when the reflux of stomach contents causes troublesome symptoms or complications.

• Approximately 20% of the U.S. population experiences heartburn or regurgitation of gastric acid weekly.

• The manifestations of GERD are divided into esophageal and extraesophageal syndromes.

• Esophageal syndromes consist of those that are only symptomatic in nature and those that are symptomatic with esophageal injury on endoscopy. Symptomatic syndromes include the typical reflux syndrome and the reflux chest pain syndrome.

• The typical reflux syndrome is defined by the presence of troublesome heartburn or regurgitation. Patients may also have other symptoms, such as epigastric pain or sleep disturbance.

• The pathophysiology of GERD involves the prolonged contact of esophageal epithelium with refluxed gastric contents that contain acid and pepsin.

• Esophageal defenses consist of the antireflux barrier, luminal clearance mechanisms, and tissue resistance. Increased contact time of refluxate and esophageal mucosa or impaired defense mechanisms can lead to the symptoms of GERD.

• For patients who present with troublesome symptoms of GERD, a trial of empiric therapy is appropriate. A diagnosis of GERD may be assumed for patients who respond to empiric treatment.

• Diagnostic testing with endoscopy should be performed in patients who present with troublesome GERD symptoms and dysphagia, weight loss, or epigastric mass on physical examination. It should also be performed on patients who do not respond to empiric treatment.

• Goals of therapy are to alleviate or eliminate symptoms, decrease frequency and duration of reflux, promote healing of the injured mucosa, and prevent the development of complications.

• An empiric trial of once-daily PPI therapy is appropriate for patients with troublesome GERD symptoms. If patients do not respond to once-daily therapy, twice-daily therapy may be used.

• Antireflux surgery may be performed when a patient is responsive to, but intolerant of, acid suppressive therapy or has persistent troublesome symptoms of GERD.

• Patients should be counseled on medication dosing and administration, side effects, drug interactions, monitoring of GERD symptoms, and lifestyle modifications.

• Lifestyle modifications alone are unlikely to control GERD symptoms. Lifestyle modifications should be tailored to the circumstances of the individual patient.

• GERD is considered a chronic condition, and most patients will require chronic therapy with antisecretory agents. Antisecretory therapy should be titrated to the lowest effective dose.

Inflammatory Bowel Disease

• Idiopathic IBD is divided into two major types: (1) ulcerative colitis and (2) Crohn's disease.

• UC is a mucosal inflammatory condition confined to the rectum and colon.

• CD is a transmural inflammation of the GI tract that can affect any part (mouth to anus).

• The hallmark clinical symptom of UC is bloody diarrhea, often with rectal urgency and tenesmus.

• Clinical symptoms are categorized as mild, moderate, or severe. Endoscopic findings are categorized as distal (limited to below the splenic flexure) or extensive (extending proximal to the splenic flexure).

• Typical symptoms of CD include chronic or nocturnal diarrhea and abdominal pain. Additional typical symptoms include weight loss, fever, and rectal bleeding.

• Symptoms differ depending on the site of inflammation and are categorized as mild, moderate, or severe.

• The etiology of IBD is unclear, but similar factors may contribute to both UC and CD. The diagnosis of IBD is made on the basis of negative stool evaluation for infectious causes.

• Treatment of IBD involves medications that target inflammatory mediators and alter immuno-inflammatory processes. These medications include anti-inflammatory agents, immunosuppressive agents, and biologic agents.

• Goals of therapy for UC and CD include inducing and maintaining remission of symptoms, improving quality of life, resolving complications and systemic symptoms, and preventing future complications.

• Patients should be counseled on medication dosing and administration, side effects, drug interactions, monitoring of IBD symptoms, and proper nutrition.

• Patients with IBD are often malnourished because of malabsorption or maldigestion caused by chronic bowel inflammation, "short gut" syndrome from multiple bowel surgeries, or bile salt deficiency in the gut.

• Surgery may be necessary for patients with severe UC or CD. Surgery (proctocolectomy) is curative for UC but not for CD.

Irritable Bowel Syndrome

• IBS is abdominal pain or discomfort that occurs in association with altered bowel habits over a period of 3 months.

• IBS is a prevalent and expensive condition. It significantly impairs health-related quality of life and leads to reduced work productivity.

• IBS is a heterogeneous disorder with various clinical presentations. Common symptoms include abdominal pain, diarrhea, and constipation.

• The pathogenesis is multifactorial, including abnormal gut sensorimotor activity, CNS dysfunction, psychological disturbances, genetic predisposition, enteric infection, and other luminal factors.

• No symptom-based diagnostic criteria have ideal accuracy for diagnosing IBS. Traditional criteria (Kruis, Manning) are at least as accurate as the more recent Rome I criteria. Rome II and III criteria have been proposed, but their accuracy has not been evaluated.

• Alarm features include rectal bleeding, weight loss, iron-deficiency anemia, nocturnal symptoms, family history of colorectal cancer, IBD, or celiac sprue. These symptoms may indicate the presence of an organic disease.

• Treatment should be offered to patients seeking medical care if the patient and physician believe that the IBS symptoms decrease the patient's quality of life.

• Goals of therapy include improving IBS symptoms and patient quality of life.

• Anticholinergic and antimuscarinic agents provide short-term relief of abdominal pain and discomfort. Psyllium has been shown to be moderately effective for IBS. Calcium polycarbophil was shown to improve symptoms in one small study. Polyethylene glycol was shown to improve stool frequency. Loperamide decreases stool frequency in patients with diarrhea-predominant IBS. TCAs improve abdominal pain in IBS patients. SSRIs are recommended for patients with moderate to severe abdominal pain or psychiatric comorbidities. Tegaserod improves global IBS symptoms, bloating, abdominal pain, and altered bowel habits in patients with constipation-predominant IBS. Alosetron improves global IBS symptoms, abdominal discomfort, stool consistency, and stool frequency in women with diarrhea-predominant IBS. Lubiprostone has been shown to relieve global IBS symptoms in women with constipation-predominant IBS.

• Patients should be counseled on medication dosing and administration, side effects, drug interactions, and monitoring of IBS symptoms.

• An effective physician-patient relationship is necessary for successful treatment.

• Education regarding disease pathophysiology and treatment, and reassurance that the symptoms are real should be provided.

• Patients should be counseled to avoid foods that exacerbate symptoms.

• Cognitive behavioral therapy, dynamic psychotherapy, and hypnotherapy are more effective than usual care in relieving global symptoms of IBS.

21-6. Questions

1.

H. B. is a 59-year-old black male recently diagnosed with PUD on endoscopy. Tissue biopsy is positive for H. pylori. H. B. has no known drug allergies. Which of the following is the ideal therapeutic regimen for H. pylori-related PUD in H. B.?

A. PPI, clarithromycin, amoxicillin

B. PPI, bismuth, metronidazole, tetracycline

C. Omeprazole, amoxicillin

D. Omeprazole, bismuth, clarithromycin, furazolidone

E. Omeprazole, sucralfate, clarithromycin, furazolidone

 

2.

If H. B. were allergic to penicillin, which treatment recommendation would you choose?

A. PPI, clarithromycin, amoxicillin

B. PPI, bismuth, metronidazole, tetracycline

C. Omeprazole, metronidazole

D. Clarithromycin, metronidazole, tetracycline

E. Clarithromycin, metronidazole, furazolidone

 

3.

Which one of the following is the leading cause of PUD in H. pylori-negative patients?

A. Mineralocorticoids

B. NSAIDs

C. DMARDs

D. Antibiotics

E. Corticosteroids

 

4.

Which of the following are true of NSAIDs?

I. They inhibit production of prostaglandins.

II. They are directly toxic to gastroduodenal epithelium.

III. They require dose adjustments in renal insufficiency.

IV. They cause only gastric ulcers.

V. They allow healing of PUD during continued therapy.

A. I, II, and III only

B. I and III only

C. II and IV only

D. V only

E. All are correct.

 

5.

Which of the following are goals of therapy for PUD?

I. Reduce episodes of diarrhea.

II. Eliminate symptoms.

III. Reduce risk of gastric cancer.

IV. Heal ulcerations.

V. Avoid spreading H. pylori.

A. I, II, and III only

B. I and III only

C. II and IV only

D. V only

E. All are correct.

 

6.

Which of the following tests do not require endoscopy to test for H. pylori infection?

I. Serum antibody test

II. Fecal antigen test

III. Urea breath test

IV. Histology test

V. Rapid urease test

A. I, II, and III only

B. I and III only

C. II and IV only

D. V only

E. All are correct.

 

7.

A. B. is a 45-year-old white female with a past medical history significant only for seizure disorder. She has experienced heartburn after meals intermittently for the past 2 weeks. It becomes worse when she is reclining at bedtime. Her medications include phenytoin 300 mg hs. A. B. says her symptoms are not troublesome and she is going to self-treat with over-the-counter medications. Which one of the following should not be recommended to A. B.?

A. Aluminum hydroxide

B. Cimetidine

C. Famotidine

D. Ranitidine

E. Magnesium hydroxide

 

8.

A. B.'s symptoms are not relieved after 2 weeks of OTC treatment with famotidine and lifestyle modifications. A. B. states her symptoms are becoming "troublesome." Which of the following is the best choice?

A. Add the prokinetic agent metoclopramide to famotidine.

B. Endoscopy should be performed because A. B. has symptoms suggestive of complications from GERD.

C. Add alginic acid 2 tablets qhs to famotidine.

D. Discontinue current therapy and initiate therapy with omeprazole 20 mg daily.

E. Continue famotidine for 1 more week to achieve maximum effectiveness.

 

9.

Which of the following are the most common symptoms of esophageal GERD syndromes?

I. Heartburn

II. Belching

III. Regurgitation

IV. Hypersalivation

V. Hoarseness

A. I, II, and III only

B. I and III only

C. II and IV only

D. V only

E. All are correct.

 

10.

Which of the following diagnoses carries an increased risk for developing esophageal adenocarcinoma?

I. Typical reflux syndrome

II. Reflux cough syndrome

III. Reflux laryngitis

IV. Nontroublesome symptoms of GERD

V. Barrett's esophagus

A. I, II, and III only

B. I and III only

C. II and IV only

D. V only

E. All are correct.

 

11.

Which of the following may exacerbate GERD symptoms by lowering the LES pressure?

A. Quinidine

B. Iron

C. Potassium chloride

D. Diltiazem

E. Tetracycline

 

12.

Which of the following is the best choice for the initial treatment of troublesome symptoms of the typical reflux syndrome?

A. Nizatidine 75 mg qd

B. Pantoprazole 40 mg qd

C. Metoclopramide 10 mg qid

D. A 3-month trial of lifestyle modifications

E. Pantoprazole 40 mg qd with metoclopramide 10 mg qid

 

13.

A. Y. is a 32-year-old white male who presents with bloody diarrhea (less than four stools per day) for 2 days. Complete blood counts and ESR are normal. Physical exam is normal. Colonoscopy reveals distal colitis. Which of the following is the best choice for initial therapy for A. Y.?

A. Prednisone 40 mg po qd

B. Sulfasalazine 4-6 g po qd

C. Mesalamine 1-4 g PR qhs

D. Mesalamine 4-6 g po qd

E. Methylprednisolone 16 mg IV q8h

 

14.

A. Y. continues to have bloody diarrhea (without systemic disturbances). Which one of the following is the best choice?

A. Add prednisone 40 mg po qd and discontinue enema.

B. Add mesalamine 2-4 g po qd and continue enema.

C. Add methylprednisolone 16 mg IV q8h until remission is achieved.

D. Add mesalamine 2-4 g po qd and discontinue enema.

E. Add azathioprine 1.0-2.5 mg/kg per day and discontinue enema.

 

15.

Which of the following are true for UC?

I. Aminosalicylates are the drugs of choice for maintenance therapy.

II. Oral corticosteroids are the drugs of choice for maintenance therapy.

III. Azathioprine often allows reduction in corticosteroid dose.

IV. Topical aminosalicylates are the drugs of choice for severe or fulminant disease.

V. Ciprofloxacin is alternative first-line therapy for mild to moderate disease.

A. I, II, and III only

B. I and III only

C. II and IV only

D. V only

E. All are correct.

 

16.

Which of the following is true for CD?

I. Infliximab is the drug of choice for mild to moderate disease.

II. Oral corticosteroids are the drugs of choice for maintenance therapy.

III. Topical aminosalicylates are the drugs of choice for mild to moderate disease.

IV. Oral cyclosporine is the drug of choice for maintenance therapy.

V. Budesonide should be used as initial therapy for CD of the ileum and right colon.

A. I, II, and III only

B. I and III only

C. II and IV only

D. V only

E. All are correct.

 

17.

Which of the following is true for moderate to severe CD?

A. Azathioprine is the drug of choice for initial therapy.

B. Budesonide is appropriate maintenance therapy.

C. Oral corticosteroids are the drugs of choice for initial therapy.

D. Methotrexate has no role in CD therapy.

E. Topical aminosalicylates are appropriate maintenance therapy.

 

18.

Which of the following is associated with the development of progressive multifocal leukoencephalopathy?

A. Prednisone

B. Sulfasalazine

C. Mesalamine

D. Methotrexate

E. Natalizumab

 

19.

J. J. is a 39-year-old female who presents with mild abdominal pain and diarrhea for 12 weeks. J. J. has no significant past medical history and occasionally misses days from her full-time job. Her symptoms are worse after meals. Which of the following is the best choice for initial therapy?

I. Paroxetine 10 mg qd

II. Amitriptyline 10 mg hs

III. Tegaserod 6 mg bid

IV. Alosetron 1 mg qd

V. Dicyclomine 10 mg qid after meals

A. I, II, and III only

B. I and III only

C. II and IV only

D. V only

E. All are correct.

 

20.

J. J.'s symptoms are controlled for several months until she loses her job. Her abdominal pain then returns. She has five episodes of diarrhea per day and complains of fatigue and insomnia. Which of the following are the most appropriate for J. J.?

I. Initiate psychological counseling.

II. Prescribe amitriptyline 10-50 mg hs.

III. Add loperamide 2 mg after each loose stool (16 mg/d maximum).

IV. Add alosetron 1 mg qd.

V. Start tegaserod 6 mg bid.

A. I, II, and III only

B. I and II only

C. II and IV only

D. V only

E. All are correct.

 

21.

Which of the following is indicated for constipation-predominant IBS?

A. Tegaserod 6 mg bid

B. Alosetron 1 mg bid

C. Loperamide 2-16 mg/d

D. Paroxetine 10-40 mg qd

E. Diphenoxylate + atropine 2 tabs qid

 

22.

Which of the following is affected by medications that induce or inhibit the cytochrome P450 enzyme system?

A. Tegaserod

B. Alosetron

C. Fibercon

D. Polyethylene glycol

E. Amitriptyline

 

23.

Which life-threatening complication caused the restriction of alosetron?

A. Stevens-Johnson syndrome

B. Toxic epidermal necrolysis

C. Aplastic anemia

D. Ischemic colitis

E. Chronic diarrhea

 

24.

Alosetron is indicated for which group of IBS patients?

A. Women with diarrhea-predominant IBS

B. Men with diarrhea-predominant IBS

C. Women with constipation-predominant IBS

D. Men with constipation-predominant IBS

E. Children with diarrhea-predominant IBS

 

21-7. Answers

1.

A. Triple-drug therapy with a PPI, clarithromycin, and amoxicillin is recommended by the American Gastroenterological Association as initial therapy for H. pylori. Quadruple therapy with a bismuth-based regimen is less convenient but may be used first line in patients who are penicillin allergic. Two-drug regimens are less effective and are not recommended. Furazolidone is unavailable in the United States.

 

2.

B. The patient is allergic to penicillin; therefore, amoxicillin cannot be used. Two-drug regimens are less effective and not recommended. Antisecretory therapy is an integral part of H. pylori regimens to promote ulcer healing. Furazolidone is unavailable in the United States.

 

3.

B. NSAIDs are the leading cause of PUD in patients who are negative for H. pylori infection.

 

4.

A. NSAIDs inhibit production of prostaglandins and are directly toxic to gastroduodenal epithelium. NSAIDs require dose adjustments in renal insufficiency. NSAIDs may cause gastric or duodenal ulcers and must be discontinued to allow for ulcer healing.

 

5.

C. Elimination of symptoms and healing of ulcerations are goals of therapy for PUD.

 

6.

A. The serum antibody test, fecal antigen test, and urea breath test do not require endoscopy.

 

7.

B. Cimetidine is a potent inhibitor of the cytochrome P450 enzyme system and will increase serum concentrations of phenytoin in A. B.

 

8.

D. Prokinetic agents are useful mainly in patients with concurrent gastric motility disorders and are not routinely recommended. A. B. does not currently exhibit symptoms of GERD complications. Alginic acid is ineffective when the patient is lying in the supine position and should not be given at bedtime. Nonprescription medications for GERD should be discontinued if symptoms are not relieved after a 2-week trial.

 

9.

B. Heartburn and regurgitation are the most common symptoms of the typical reflux syndrome.

 

10.

D. Patients with Barrett's esophagus have an increased risk of developing esophageal adenocarcinoma.

 

11.

D. Calcium channel blockers decrease LES pressure. Quinidine, iron, potassium chloride, and tetracycline have direct irritant effects on the esophageal mucosa.

 

12.

B. The correct dose of nizatidine (prescription strength) would be 150 mg bid. Metoclopramide is not routinely recommended for the treatment of the typical reflux syndrome. When patients find their symptoms "troublesome," pharmacologic therapy should be initiated.

 

13.

C. Topical aminosalicylates (answer C) are more effective than oral aminosalicylates (answer B) and topical steroids for mild distal UC (although oral aminosalicylates or topical steroids may be used first line if the patient prefers). Oral and IV steroids (answers A and E) are reserved for more severe cases of UC or cases that do not respond to oral and topical aminosalicylates. The oral dose of mesalamine in answer D is incorrect.

 

14.

B. Oral aminosalicylates should be added if no response is achieved with topical aminosalicylates. Oral and IV steroids are reserved for moderate to severe UC or for patients with systemic disturbances. Azathioprine may be added if UC is refractory to aminosalicylates and to allow corticosteroid dose reduction.

 

15.

B. Aminosalicylates are the drugs of choice for maintenance therapy of UC, not corticosteroids. Azathioprine often allows a reduction in dose of corticosteroids in the management of active UC. Severe or fulminant UC requires oral, not topical, therapy. Ciprofloxacin may be used as an alternative first-line therapy in the treatment of mild to moderate CD, not UC.

 

16.

D. Budesonide is the treatment of choice for mild to moderate CD of the ileum and right colon. Infliximab is reserved for moderate to severe disease in patients who do not respond to oral corticosteroids or immunosuppressive agents. It may also be used in patients in whom side effects from oral corticosteroids must be avoided. Oral corticosteroids should not be used for long-term maintenance therapy. Oral budesonide is the drug of choice for mild to moderate CD, not topical corticosteroids. Oral cyclosporine has no role in CD; IV cyclosporine may be used in severe or fulminant CD that does not respond to 5-7 days of IV corticosteroids.

 

17.

C. Moderate to severe disease initially requires oral corticosteroid therapy. Corticosteroids have no role in maintenance therapy. Topical aminosalicylates may be used as adjuncts in colonic CD. Methotrexate is used as maintenance therapy for moderate to severe CD.

 

18.

E. Natalizumab has been associated with the development of progressive multifocal leukoencephalopathy.

 

19.

D. J. J. has mild, diarrhea-predominant IBS. Symptomatic treatment with dicyclomine is appropriate initial therapy, especially since her symptoms are meal related. A TCA may be added to dicyclomine if needed. Tegaserod is indicated for constipation-predominant IBS. Alosetron is reserved for patients with severe, diarrhea-predominant disease who have failed other therapies. Paroxetine may be added if initial therapies are ineffective or if J. J. develops severe abdominal pain or psychiatric comorbidities.

 

20.

A. Alosetron is reserved for patients with severe, diarrhea-predominant disease who have failed other therapies. Several types of psychotherapy have been shown to be more effective than usual care in IBS. TCAs improve abdominal pain in IBS and may also help with insomnia. Loperamide may be used on an as-needed basis for diarrhea. Tegaserod is indicated for constipation-predominant IBS.

 

21.

A. Alosetron is approved for restricted use in diarrhea-predominant IBS. Loperamide and diphenoxylate + atropine are antidiarrheal medications that will exacerbate constipation. Paroxetine is an SSRI with potent anticholinergic effects, which could worsen constipation. Another drug should be chosen if an SSRI is needed for depression.

 

22.

E. TCA serum concentrations are affected by drugs that alter cytochrome P450 activity.

 

23.

D. Severe constipation, ischemic colitis, and death have been reported with alosetron.

 

24.

A. Alosetron is approved for women with diarrhea-predominant IBS. It was not found to be effective in men and is not approved for use in children.

 

21-8. References

Peptic Ulcer Disease

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Chey WD, Wong BC. American College of Gastroenterology guideline on the management of Helicobacter pylori infection. Am J Gastroenterol. 2007; 102:1808-25.

Del Valle, J. Peptic ulcer disease and related disorders. In: Fauci AS, Braunwald E, Kasper DL, et al., eds. Harrison's Principles of Internal Medicine. 17th ed. New York: McGraw-Hill; 2008.

Malfertheiner P, Megraud F, O'Morain C, et al. Current concepts in the management of Helicobacter pylori infection: The Maastricht III Consensus Report. Gut. 2007;56:772-81.

NIH Consensus Conference. Helicobacter pylori in peptic ulcer diseases: NIH Consensus Development Panel on Helicobacter Pylori in Peptic Ulcer Disease. JAMA. 1994;272:65-69.

Ramakrishnan K, Salinas RC. Peptic ulcer disease. Am Fam Physician. 2007;76:1005-12.

Rokkas T, Sechopoulos P, Robotis I, et al. Cumulative H. pylori eradication rates in clinical practice by adopting first- and second-line regimens proposed by the Maastrict III consensus and a third-line empirical regimen. Am J Gastroenterol. 2009;104: 21-25.

Shiotani A, Graham DY. Pathogenesis and therapy of gastric and duodenal ulcer disease. Med Clin North Am. 2002;86:1447-66.

Singh G, Triadafilopoulos G. Epidemiology of NSAID-induced GI complications. J Rheumatol. 1999; 26(suppl 26):18-24.

Vakil, N. H. pylori treatment: New wine in old bottles? Am J Gastroenterol. 2009;104:26-30.

Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal toxicity of nonsteroidal anti-inflammatory drugs. N Engl J Med. 1999;340:1888-89.

Gastroesophageal Reflux Disease

Cappell MS. Clinical presentation, diagnosis, and management of gastroesophageal reflux disease. Med Clin North Am. 2005;89:243-91.

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Goyal RK. Diseases of the esophagus. In: Fauci AS, Braunwald E, Kasper DL, et al., eds. Harrison's Principles of Internal Medicine. 17th ed. New York: McGraw-Hill; 2008.

Kahrilas PJ, Shaheen NJ, Vaezi MF. American Gastroenterological Association institute technical review on the management of gastroesophageal reflux disease. Gastroenterol. 2008;135:1392-413.

Kahrilas PJ, Shaheen NJ, Vaezi MF, et al. American Gastroenterological Association medical position statement on the management of gastroesophageal reflux disease. Gastroenterol. 2008;135:1383-91.

Locke GR, Talley NH, Fett SL, et al. Prevalence and clinical spectrum of gastroesophageal reflux: A population-based study in Olmstead county. Gastroenterol. 1997;112:1448-56.

Vakil N, van Zanten SV, Kahrilas P, et al. The Montreal definition and classification of gastroesophageal reflux disease: A global, evidence-based consensus. Am J Gastroenterol. 2006;101:1900-20.

Williams DB, Schade RR. Gastroesophageal reflux disease. In: Dipiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach. 7th ed. New York: McGraw-Hill; 2008:555-67.

Inflammatory Bowel Disease

Ardizzone S, Porro GB. Inflammatory bowel disease: New insights into pathogenesis and treatment. J Intern Med. 2002;252:475-96.

Banerjee S, Peppercorn MA. Inflammatory bowel disease: Medical therapy for specific clinical presentations. Gastroenterol Clin North Am. 2002; 31:185-202.

Drug therapy for ulcerative colitis. Pharmacist's/Prescriber's Letter. 2007;23:230308.

Friedman S, Blumberg RS. Inflammatory bowel disease. In: Fauci AS, Braunwald E, Kasper DL, et al., eds. Harrison's Principles of Internal Medicine. 17th ed. New York: McGraw-Hill; 2008.

Hemstreet BA, DiPiro JT. Inflammatory bowel disease. In: Dipiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach. 7th ed. New York: McGraw-Hill; 2008:589-605.

Kornbluth A, Sachar DB. Ulcerative colitis practice guidelines in adults (update): American College of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol. 2004;99:1371-85.

Lichtenstein GR, Hanauer SB, Sandborn WJ, et al. Management of Crohn's disease in adults: American College of Gastroenterology Practice guidelines. Am J Gastroenterol. 2009;104:465-83.

Rutgeerts P, Vermeire S, Van Assche, G. Biological therapies for inflammatory bowel diseases. Gastroenterol. 2009;136:1182-97.

Irritable Bowel Syndrome

Brandt LJ, Chey WD, Foxx-Orenstein AE, et al. An evidence-based position statement on the management of irritable bowel syndrome. Am J Gastroenterol. 2009;104(suppl 1): S1-7.

Brandt LJ, Chey WD, Foxx-Orenstein AE, et al. An evidence-based systematic review on the management of irritable bowel syndrome. Am J Gastroenterol. 2009;104(suppl 1):S8-S35.

Drossman DA, Camilleri M, Mayer EA, Whitehead WE. AGA technical review on irritable bowel syndrome. Gastroenterol. 2002;123:2108-31.

Owyang C. Irritable bowel syndrome. In: Fauci AS, Braunwald E, Kasper DL, et al., eds. Harrison's Principles of Internal Medicine. 17th ed. New York: McGraw-Hill; 2008.

Palsson OS, Drossman DA. Psychiatric and psychological dysfunction in irritable bowel syndrome and the role of psychological treatments. Gastroenterol Clin North Am. 2005;34:281-303.

Spruill WJ, Wade WE. Diarrhea, constipation, and irritable bowel syndrome. In: Dipiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach. 7th ed. New York: McGraw-Hill; 2008:617-32.