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Basic and Clinical Pharmacology > Chapter 62. Drugs Used in the Treatment of Gastrointestinal Diseases >

Case Study

A 21-year-old woman comes with her parents to discuss therapeutic options for Crohn's disease. She was diagnosed with Crohn's disease 2 years ago, and it involves her terminal ileum and proximal colon, as confirmed by colonoscopy and small bowel radiography. She was initially treated with mesalamine and budesonide with good response but over the last 2 months she has had a relapse of symptoms. She is experiencing fatigue, cramping abdominal pains, and nonbloody diarrhea up to 10 times daily, and she has had a 15-lb weight loss.

She has no other significant medical or surgical history. Her current medications are mesalamine 2.4 g/d and budesonide 9 mg/d. She appears thin and tired. Abdominal examination reveals tenderness without guarding in the right lower quadrant; a mass is not palpable. On perianal examination, there is no tenderness, fissure, or fistula. Her laboratory data are notable for anemia and elevated C-reactive protein. What are the options for immediate control of her symptoms and disease? What are the long-term management options?

Drugs Used in the Treatment of Gastrointestinal Diseases: Introduction

Many of the drug groups discussed elsewhere in this book have important applications in the treatment of diseases of the gastrointestinal tract and other organs. Other groups are used almost exclusively for their effects on the gut; these are discussed in the following text according to their therapeutic uses.

Drugs Used in Acid-Peptic Diseases

Acid-peptic diseases include gastroesophageal reflux, peptic ulcer (gastric and duodenal), and stress-related mucosal injury. In all these conditions, mucosal erosions or ulceration arise when the caustic effects of aggressive factors (acid, pepsin, bile) overwhelm the defensive factors of the gastrointestinal mucosa (mucus and bicarbonate secretion, prostaglandins, blood flow, and the processes of restitution and regeneration after cellular injury). Over 90% of peptic ulcers are caused by infection with the bacterium Helicobacter pylori or by use of nonsteroidal anti-inflammatory drugs (NSAIDs). Drugs used in the treatment of acid-peptic disorders may be divided into two classes: agents that reduce intragastric acidity and agents that promote mucosal defense.

Agents that Reduce Intragastric Acidity

Physiology of Acid Secretion

The parietal cell contains receptors for gastrin (CCK-B), histamine (H₂), and acetylcholine (muscarinic, M₃) (Figure 62–1). When acetylcholine (from vagal postganglionic nerves) or gastrin (released from antral G cells into the blood) bind to the parietal cell receptors, they cause an increase in cytosolic calcium, which in turn stimulates protein kinases that stimulate acid secretion from a H⁺,K⁺ ATPase (the proton pump) on the canalicular surface.

Figure 62–1

Schematic model for physiologic control of hydrogen ion (acid) secretion by the parietal cells of the gastric fundic glands. Parietal cells are stimulated to secrete acid (H⁺) by gastrin (acting on gastrin/CCK-B receptor), acetylcholine (M₃ receptor), and histamine (H₂ receptor). Acid is secreted across the parietal cell canalicular membrane by the H⁺,K⁺ ATPase proton pump into the gastric lumen. Gastrin is secreted by antral G cells into blood vessels in response to intraluminal dietary peptides. Within the gastric body, gastrin passes from the blood vessels into the submucosal tissue of the fundic glands, where it binds to gastrin-CCK-B receptors on parietal cells and enterochromaffin-like (ECL) cells. The vagus nerve stimulates postganglionic neurons of the enteric nervous system to release acetylcholine (ACh), which binds to M₃ receptors on parietal cells and ECL cells. Stimulation of ECL cells by gastrin (CCK-B receptor) or acetylcholine (M₃ receptor) stimulates release of histamine. Within the gastric antrum, vagal stimulation of postganglionic enteric neurons enhances gastrin release directly by stimulation of antral G cells (through gastrin-releasing peptide, GRP) and indirectly by inhibition of somatostatin secretion from antral D cells. Acid secretion must eventually be turned off. Antral D cells are stimulated to release somatostatin by the rise in intraluminal H⁺ concentration and by CCK that is released into the bloodstream by duodenal I cells in response to proteins and fats (not shown). Binding of somatostatin to receptors on adjacent antral G cells inhibits further gastrin release. ATPase, H⁺,K⁺ ATPase proton pump; CCK, cholecystokinin; M₃, muscarinic receptors.

In close proximity to the parietal cells are gut endocrine cells called enterochromaffin-like (ECL) cells. ECL cells also have receptors for gastrin and acetylcholine, which stimulate histamine release. Histamine binds to the H₂ receptor on the parietal cell, resulting in activation of adenylyl cyclase, which increases intracellular cyclic adenosine monophosphate (cAMP) and activates protein kinases that stimulate acid secretion by the H⁺,K⁺ ATPase. In humans, it is believed that the major effect of gastrin upon acid secretion is mediated indirectly through the release of histamine from ECL cells rather than through direct parietal cell stimulation. In contrast, acetylcholine provides potent direct parietal cell stimulation.

Antacids

Antacids have been used for centuries in the treatment of patients with dyspepsia and acid-peptic disorders. They were the mainstay of treatment for acid-peptic disorders until the advent of H₂-receptor antagonists and proton pump inhibitors. They continue to be used commonly by patients as nonprescription remedies for the treatment of intermittent heartburn and dyspepsia.

Antacids are weak bases that react with gastric hydrochloric acid to form a salt and water. Their principal mechanism of action is reduction of intragastric acidity. After a meal, approximately 45 mEq/h of hydrochloric acid is secreted. A single dose of 156 mEq of antacid given 1 hour after a meal effectively neutralizes gastric acid for up to 2 hours. However, the acid-neutralization capacity among different proprietary formulations of antacids is highly variable, depending on their rate of dissolution (tablet versus liquid), water solubility, rate of reaction with acid, and rate of gastric emptying.

Sodium bicarbonate (eg, baking soda, Alka Seltzer) reacts rapidly with hydrochloric acid (HCL) to produce carbon dioxide and sodium chloride. Formation of carbon dioxide results in gastric distention and belching. Unreacted alkali is readily absorbed, potentially causing metabolic alkalosis when given in high doses or to patients with renal insufficiency. Sodium chloride absorption may exacerbate fluid retention in patients with heart failure, hypertension, and renal insufficiency. Calcium carbonate (eg, Tums, Os-Cal) is less soluble and reacts more slowly than sodium bicarbonate with HCl to form carbon dioxide and calcium chloride (CaCl₂). Like sodium bicarbonate, calcium carbonate may cause belching or metabolic alkalosis. Calcium carbonate is used for a number of other indications apart from its antacid properties (see Chapter 42). Excessive doses of either sodium bicarbonate or calcium carbonate with calcium-containing dairy products can lead to hypercalcemia, renal insufficiency, and metabolic alkalosis (milk-alkali syndrome).

Formulations containing magnesium hydroxide or aluminum hydroxide react slowly with HCl to form magnesium chloride or aluminum chloride and water. Because no gas is generated, belching does not occur. Metabolic alkalosis is also uncommon because of the efficiency of the neutralization reaction. Because unabsorbed magnesium salts may cause an osmotic diarrhea and aluminum salts may cause constipation, these agents are commonly administered together in proprietary formulations (eg, Gelusil, Maalox, Mylanta) to minimize the impact on bowel function. Both magnesium and aluminum are absorbed and excreted by the kidneys. Hence, patients with renal insufficiency should not take these agents long-term.

All antacids may affect the absorption of other medications by binding the drug (reducing its absorption) or by increasing intragastric pH so that the drug's dissolution or solubility (especially weakly basic or acidic drugs) is altered. Therefore, antacids should not be given within 2 hours of doses of tetracyclines, fluoroquinolones, itraconazole, and iron.

H₂-Receptor Antagonists

From their introduction in the 1970s until the early 1990s, H₂-receptor antagonists (commonly referred to as H₂ blockers) were the most commonly prescribed drugs in the world (see Clinical Uses). With the recognition of the role of H pylori in ulcer disease (which may be treated with appropriate antibacterial therapy) and the advent of proton pump inhibitors, the use of prescription H₂ blockers has declined markedly.

Chemistry & Pharmacokinetics

Four H₂ antagonists are in clinical use: cimetidine, ranitidine, famotidine, and nizatidine. All four agents are rapidly absorbed from the intestine. Cimetidine, ranitidine, and famotidine undergo first-pass hepatic metabolism resulting in a bioavailability of approximately 50%. Nizatidine has little first-pass metabolism. The serum half-lives of the four agents range from 1.1 to 4 hours; however, duration of action depends on the dose given (Table 62–1). H₂ antagonists are cleared by a combination of hepatic metabolism, glomerular filtration, and renal tubular secretion. Dose reduction is required in patients with moderate to severe renal (and possibly severe hepatic) insufficiency. In the elderly, there is a decline of up to 50% in drug clearance as well as a significant reduction in volume of distribution.

Table 62–1 Clinical Comparisons of H₂-Receptor Blockers.

Drug	Relative Potency	Dose to Achieve > 50% Acid Inhibition for 10 Hours	Usual Dose for Acute Duodenal or Gastric Ulcer	Usual Dose for Gastroesophageal Reflux Disease	Usual Dose for Prevention of Stress-Related Bleeding
Cimetidine	1	400–800 mg	800 mg HS or 400 mg bid	800 mg bid	50 mg/h continuous infusion
Ranitidine	4–10	150 mg	300 mg HS or 150 mg bid	150 mg bid	6.25 mg/h continuous infusion or 50 mg IV every 6–8 h
Nizatidine	4–10	150 mg	300 mg HS or 150 mg bid	150 mg bid	Not available
Famotidine	20–50	20 mg	40 mg HS or 20 mg bid	20 mg bid	20 mg IV every 12 h

BID, twice daily; HS, bedtime.

Pharmacodynamics

The H₂ antagonists exhibit competitive inhibition at the parietal cell H₂ receptor and suppress basal and meal-stimulated acid secretion (Figure 62–2) in a linear, dose-dependent manner. They are highly selective and do not affect H₁ or H₃ receptors (see Chapter 16). The volume of gastric secretion and the concentration of pepsin are also reduced.

Figure 62–2

Twenty-four-hour median intragastric acidity pretreatment (red) and after 1 month of treatment with either ranitidine, 150 mg twice daily (blue, H₂ block), or omeprazole, 20 mg once daily (green, PPI). Note that H₂-receptor antagonists have a marked effect on nocturnal acid secretion but only a modest effect on meal-stimulated secretion. Proton pump inhibitors (PPIs) markedly suppress meal-stimulated and nocturnal acid secretion.

(Redrawn from data in Lanzon-Miller S et al: Twenty-four-hour intragastric acidity and plasma gastrin concentration before and during treatment with either ranitidine or omeprazole. Aliment Pharmacol Ther 1987;1:239.)

H₂ antagonists reduce acid secretion stimulated by histamine as well as by gastrin and cholinomimetic agents through two mechanisms. First, histamine released from ECL cells by gastrin or vagal stimulation is blocked from binding to the parietal cell H₂ receptor. Second, direct stimulation of the parietal cell by gastrin or acetylcholine has a diminished effect on acid secretion in the presence of H₂-receptor blockade.

The potencies of the four H₂-receptor antagonists vary over a 50-fold range (Table 62–1). When given in usual prescription doses however, all inhibit 60–70% of total 24-hour acid secretion. H₂ antagonists are especially effective at inhibiting nocturnal acid secretion (which depends largely on histamine), but they have a modest impact on meal-stimulated acid secretion (which is stimulated by gastrin and acetylcholine as well as histamine). Therefore, nocturnal and fasting intragastric pH is raised to 4–5 but the impact on the daytime, meal-stimulated pH profile is less. Recommended prescription doses maintain greater than 50% acid inhibition for 10 hours; hence, these drugs are commonly given twice daily. At doses available in over-the-counter formulations, the duration of acid inhibition is less than 6 hours.

Clinical Uses

H₂-receptor antagonists continue to be prescribed but proton pump inhibitors (see below) are steadily replacing H₂ antagonists for most clinical indications. However, the over-the-counter preparations are heavily used by the public.

Gastroesophageal Reflux Disease (GERD)

Patients with infrequent heartburn or dyspepsia (fewer than 3 times per week) may take either antacids or intermittent H₂ antagonists. Because antacids provide rapid acid neutralization, they afford faster symptom relief than H₂ antagonists. However, the effect of antacids is short-lived (1–2 hours) compared with H₂ antagonists (6–10 hours). H₂ antagonists may be taken prophylactically before meals in an effort to reduce the likelihood of heartburn. Frequent heartburn is better treated with twice-daily H₂ antagonists (Table 62–1) or proton pump inhibitors. In patients with erosive esophagitis (approximately 50% of patients with GERD), H₂ antagonists afford healing in less than 50% of patients; hence proton pump inhibitors are preferred because of their superior acid inhibition.

Peptic Ulcer Disease

Proton pump inhibitors have largely replaced H₂ antagonists in the treatment of acute peptic ulcer disease. Nevertheless, H₂ antagonists are still sometimes used. Nocturnal acid suppression by H₂ antagonists affords effective ulcer healing in most patients with uncomplicated gastric and duodenal ulcers. Hence, all the agents may be administered once daily at bedtime, resulting in ulcer healing rates of more than 80–90% after 6–8 weeks of therapy. For patients with ulcers caused by aspirin or other NSAIDs, the NSAID should be discontinued. If the NSAID must be continued for clinical reasons despite active ulceration, a proton pump inhibitor should be given instead of an H2 antagonist to more reliably promote ulcer healing. For patients with acute peptic ulcers caused by H pylori, H₂ antagonists no longer play a significant therapeutic role. H pylori should be treated with a 10- to 14-day course of therapy including a proton pump inhibitor and two antibiotics (see below). This regimen achieves ulcer healing and eradication of the infection in more than 90% of patients. For the minority of patients in whom H pylori cannot be successfully eradicated, H₂ antagonists may be given daily at bedtime in half of the usual ulcer therapeutic dose to prevent ulcer recurrence (eg, ranitidine, 150 mg; famotidine, 20 mg).

Nonulcer Dyspepsia

H₂ antagonists are commonly used as over-the-counter agents and prescription agents for treatment of intermittent dyspepsia not caused by peptic ulcer. However, benefit compared with placebo has never been convincingly demonstrated.

Prevention of Bleeding from Stress-Related Gastritis

Clinically important bleeding from upper gastrointestinal erosions or ulcers occurs in 1–5% of critically ill patients as a result of impaired mucosal defense mechanisms caused by poor perfusion. Although most critically ill patients have normal or decreased acid secretion, numerous studies have shown that agents that increase intragastric pH (H₂ antagonists or proton pump inhibitors) reduce the incidence of clinically significant bleeding. However, the optimal agent is uncertain at this time. For patients without a nasoenteric tube or with significant ileus, intravenous H₂ antagonists are preferable over intravenous proton pump inhibitors because of their proven efficacy and lower cost. Continuous infusions of H₂ antagonists are generally preferred to bolus infusions because they achieve more consistent, sustained elevation of intragastric pH.

Adverse Effects

H₂ antagonists are extremely safe drugs. Adverse effects occur in less than 3% of patients and include diarrhea, headache, fatigue, myalgias, and constipation. Some studies suggest that intravenous H₂ antagonists (or proton pump inhibitors) may increase the risk of nosocomial pneumonia in critically ill patients.

Mental status changes (confusion, hallucinations, agitation) may occur with administration of intravenous H₂ antagonists, especially in patients in the intensive care unit who are elderly or who have renal or hepatic dysfunction. These events may be more common with cimetidine. Mental status changes rarely occur in ambulatory patients.

Cimetidine inhibits binding of dihydrotestosterone to androgen receptors, inhibits metabolism of estradiol, and increases serum prolactin levels. When used long-term or in high doses, it may cause gynecomastia or impotence in men and galactorrhea in women. These effects are specific to cimetidine and do not occur with the other H₂ antagonists.

Although there are no known harmful effects on the fetus, H₂ antagonists cross the placenta. Therefore, they should not be administered to pregnant women unless absolutely necessary. The H₂ antagonists are secreted into breast milk and may therefore affect nursing infants.

H₂ antagonists may rarely cause blood dyscrasias. Blockade of cardiac H₂ receptors may cause bradycardia, but this is rarely of clinical significance. Rapid intravenous infusion may cause bradycardia and hypotension through blockade of cardiac H₂ receptors; therefore, intravenous injections should be given over 30 minutes. H₂ antagonists rarely cause reversible abnormalities in liver chemistry.

Drug Interactions

Cimetidine interferes with several important hepatic cytochrome P450 drug metabolism pathways, including those catalyzed by CYP1A2, CYP2C9, CYP2D6, and CYP3A4 (see Chapter 4). Hence, the half-lives of drugs metabolized by these pathways may be prolonged. Ranitidine binds 4–10 times less avidly than cimetidine to cytochrome P450. Negligible interaction occurs with nizatidine and famotidine.

H₂ antagonists compete with creatinine and certain drugs (eg, procainamide) for renal tubular secretion. All of these agents except famotidine inhibit gastric first-pass metabolism of ethanol, especially in women. Although the importance of this is debated, increased bioavailability of ethanol could lead to increased blood ethanol levels.

Proton Pump Inhibitors

Since their introduction in the late 1980s, these efficacious acid inhibitory agents have assumed the major role for the treatment of acid-peptic disorders. Proton pump inhibitors (PPIs) are now among the most widely prescribed drugs worldwide due to their outstanding efficacy and safety.

Chemistry & Pharmacokinetics

Five proton pump inhibitors are available for clinical use: omeprazole, lansoprazole, rabeprazole, pantoprazole,  and esomeprazole.  All are substituted benzimidazoles that resemble H₂ antagonists in structure (Figure 62–3) but have a completely different mechanism of action. Omeprazole is a racemic mixture of R- and S-isomers. Esomeprazole is the S-isomer of omeprazole. All are available in oral formulations. Esomeprazole and pantoprazole are also available in intravenous formulations (Table 62–2).

Figure 62–3

Molecular structure of the proton pump inhibitors: omeprazole, lansoprazole, pantoprazole, and the sodium salt of rabeprazole. Omeprazole and esomeprazole have the same chemical structure (see text).

Table 62–2 Pharmacokinetics of Proton Pump Inhibitors.

Drug	pKa	Bioavailability (%)	t1/2 (h)	Tmax (h)	Usual Dosage for Peptic Ulcer or GERD
Omeprazole	4	40–65	0.5–1.5	1–3.5	20–40 mg qd
Esomeprazole	4	> 80	1.2–1.5	1.6	20–40 mg qd
Lansoprazole	4	> 80	1.5	1.7	30 mg qd
Pantoprazole	3.9	77	1.0–1.9	2.5–4.0	40 mg qd
Rabeprazole	5	52	1.0–2.0	2.0–5.0	20 mg qd

GERD, gastroesophageal reflux disease.

Proton pump inhibitors are administered as inactive prodrugs. To protect the acid-labile prodrug from rapid destruction within the gastric lumen, oral products are formulated for delayed release as acid-resistant, enteric-coated capsules or tablets. After passing through the stomach into the alkaline intestinal lumen, the enteric coatings dissolve and the prodrug is absorbed. For children or patients with dysphagia or enteral feeding tubes, capsules may be opened and the microgranules mixed with apple or orange juice or mixed with soft foods (eg, applesauce). Lansoprazole is also available as a tablet formulation that disintegrates in the mouth, or it may be mixed with water and administered via oral syringe or enteral tube. Omeprazole is also available as a powder formulation (capsule or packet) that contains sodium bicarbonate (1100–1680 mg NaHCO3 ; 304–460 mg of sodium) to protect the naked (non–enteric-coated) drug from acid degradation. When administered on an empty stomach by mouth or enteral tube, this "immediate-release" suspension results in rapid omeprazole absorption (T_max < 30 minutes) and onset of acid inhibition.

The proton pump inhibitors are lipophilic weak bases (pK_a 4–5) and after intestinal absorption diffuse readily across lipid membranes into acidified compartments (eg, the parietal cell canaliculus). The prodrug rapidly becomes protonated within the canaliculus and is concentrated more than 1000-fold by Henderson-Hasselbalch trapping (see Chapter 1). There, it rapidly undergoes a molecular conversion to the active form, a reactive thiophilic sulfenamide cation, which forms a covalent disulfide bond with the H⁺,K⁺ ATPase, irreversibly inactivating the enzyme.

The pharmacokinetics of available proton pump inhibitors are shown in Table 62–2. Rabeprazole or immediate-release omeprazole may have a slightly faster onset of acid inhibition than other oral formulations. Although differences in pharmacokinetic profiles may affect speed of onset and duration of acid inhibition in the first few days of therapy, they are of little clinical importance with continued daily administration. The bioavailability of all agents is decreased approximately 50% by food; hence, the drugs should be administered on an empty stomach. In a fasting state, only 10% of proton pumps are actively secreting acid and susceptible to inhibition. Proton pump inhibitors should be administered approximately 1 hour before a meal (usually breakfast), so that the peak serum concentration coincides with the maximal activity of proton pump secretion. The drugs have a short serum half-life of about 1.5 hours, but acid inhibition lasts up to 24 hours owing to the irreversible inactivation of the proton pump. At least 18 hours are required for synthesis of new H⁺,K⁺ ATPase pump molecules. Because not all proton pumps are inactivated with the first dose of medication, up to 3–4 days of daily medication are required before the full acid-inhibiting potential is reached. Similarly, after stopping the drug, it takes 3–4 days for full acid secretion to return.

Proton pump inhibitors undergo rapid first-pass and systemic hepatic metabolism and have negligible renal clearance. Dose reduction is not needed for patients with renal insufficiency or mild to moderate liver disease but should be considered in patients with severe liver impairment. Although other proton pumps exist in the body, the H⁺,K⁺ ATPase appears to exist only in the parietal cell and is distinct structurally and functionally from other H⁺-transporting enzymes.

The intravenous formulations of esomeprazole and pantoprazole have characteristics similar to those of the oral drugs. When given to a fasting patient, they inactivate acid pumps that are actively secreting, but they have no effect on pumps in quiescent, nonsecreting vesicles. Because the half-life of a single injection of the intravenous formulation is short, acid secretion returns several hours later as pumps move from the tubulovesicles to the canalicular surface. Thus, to provide maximal inhibition during the first 24–48 hours of treatment, the intravenous formulations must be given as a continuous infusion or as repeated bolus injections. The optimal dosing of intravenous proton pump inhibitors to achieve maximal blockade in fasting patients is not yet established.

From a pharmacokinetic perspective, proton pump inhibitors are ideal drugs: they have a short serum half-life, they are concentrated and activated near their site of action, and they have a long duration of action.

Pharmacodynamics

In contrast to H₂ antagonists, proton pump inhibitors inhibit both fasting and meal-stimulated secretion because they block the final common pathway of acid secretion, the proton pump. In standard doses, proton pump inhibitors inhibit 90–98% of 24-hour acid secretion (Figure 62–2). When administered at equivalent doses, the different agents show little difference in clinical efficacy. In a crossover study of patients receiving long-term therapy with all five proton pump inhibitors, the mean 24-hour intragastric pH varied from 3.3 (pantoprazole, 40 mg) to 4.0 (esomeprazole, 40 mg) and the mean number of hours the pH was higher than 4 varied from 10.1 (pantoprazole, 40 mg) to 14.0 (esomeprazole, 40 mg).

Clinical Uses

Gastroesophageal Reflux Disease (GERD)

Proton pump inhibitors are the most effective agents for the treatment of nonerosive and erosive reflux disease, esophageal complications of reflux disease (peptic stricture or Barrett's esophagus), and extraesophageal manifestations of reflux disease. Once-daily dosing provides effective symptom relief and tissue healing in 85–90% of patients; up to 15% of patients require twice-daily dosing.

GERD symptoms recur in over 80% of patients within 6 months after discontinuation of a proton pump inhibitor. For patients with erosive esophagitis or esophageal complications, long-term daily maintenance therapy with a full-dose or half-dose proton pump inhibitor is usually needed. Many patients with nonerosive GERD may be treated successfully with intermittent courses of proton pump inhibitors or H₂ antagonists taken as needed ("on demand") for recurrent symptoms.

In current clinical practice, many patients with symptomatic GERD are treated empirically with medications without prior endoscopy, ie, without knowledge of whether the patient has erosive or nonerosive reflux disease. Empiric treatment with proton pump inhibitors provides sustained symptomatic relief in 70–80% of patients, compared with 50–60% with H₂ antagonists. Because of recent cost reductions, proton pump inhibitors are being used increasingly as first-line therapy for patients with symptomatic GERD.

Sustained acid suppression with twice-daily proton pump inhibitors for at least 3 months is used to treat extraesophageal complications of reflux disease (asthma, chronic cough, laryngitis, and noncardiac chest pain).

Peptic Ulcer Disease

Compared with H₂ antagonists, proton pump inhibitors afford more rapid symptom relief and faster ulcer healing for duodenal ulcers and, to a lesser extent, gastric ulcers. All the pump inhibitors heal more than 90% of duodenal ulcers within 4 weeks and a similar percentage of gastric ulcers within 6–8 weeks.

H pylori-Associated Ulcers

For H pylori-associated ulcers, there are two therapeutic goals: to heal the ulcer and to eradicate the organism. The most effective regimens for H pylori eradication are combinations of two antibiotics and a proton pump inhibitor. Proton pump inhibitors promote eradication of H pylori through several mechanisms: direct antimicrobial properties (minor) and—by raising intragastric pH—lowering the minimal inhibitory concentrations of antibiotics against H pylori. The best treatment regimen consists of a 14-day regimen of "triple therapy": a proton pump inhibitor twice daily; clarithromycin, 500 mg twice daily; and either amoxicillin, 1 g twice daily, or metronidazole, 500 mg twice daily. After completion of triple therapy, the proton pump inhibitor should be continued once daily for a total of 4–6 weeks to ensure complete ulcer healing. Recently, 10 days of "sequential treatment" consisting on days 1–5 of a proton pump inhibitor twice daily plus amoxicillin, 1 g twice daily, and followed on days 6–10 by five additional days of a proton pump inhibitor twice daily, plus clarithromycin, 500 mg twice daily, and tinidazole, 500 mg twice daily, has been shown to be a highly effective treatment regimen.

NSAID-Associated Ulcers

For patients with ulcers caused by aspirin or other NSAIDs, either H₂ antagonists or proton pump inhibitors provide rapid ulcer healing so long as the NSAID is discontinued; however continued use of the NSAID impairs ulcer healing. In patients with NSAID-induced ulcers who require continued NSAID therapy, treatment with a once- or twice-daily proton pump inhibitor more reliably promotes ulcer healing.

Asymptomatic peptic ulceration develops in 10–20% of people taking frequent NSAIDs, and ulcer-related complications (bleeding, perforation) develop in 1–2% of persons per year. Proton pump inhibitors taken once daily are effective in reducing the incidence of ulcers and ulcer complications in patients taking aspirin or other NSAIDs.

Prevention of Rebleeding from Peptic Ulcers

In patients with acute gastrointestinal bleeding due to peptic ulcers, the risk of rebleeding from ulcers that have a visible vessel or adherent clot is increased. Rebleeding of this subset of high-risk ulcers is reduced significantly with proton pump inhibitors administered for 3–5 days either as high-dose oral therapy (eg, omeprazole, 40 mg orally twice daily) or as a continuous intravenous infusion. It is believed that an intragastric pH higher than 6 may enhance coagulation and platelet aggregation. The optimal dose of intravenous proton pump inhibitor needed to achieve and maintain this level of near-complete acid inhibition is unknown; however, initial bolus administration (80 mg) followed by constant infusion (8 mg/h) is commonly recommended.

Nonulcer Dyspepsia

Proton pump inhibitors have modest efficacy for treatment of nonulcer dyspepsia, benefiting 10–20% more patients than placebo. Despite their use for this indication, superiority to H₂ antagonists (or even placebo) has not been conclusively demonstrated.

Prevention of Stress-Related Mucosal Bleeding

As discussed previously (see H₂-Receptor Antagonists) proton pump inhibitors (given orally, by nasogastric tube, or by intravenous infusions) may be administered to reduce the risk of clinically significant stress-related mucosal bleeding in critically ill patients. The only proton pump inhibitor approved by the Food and Drug Administration (FDA) for this indication is an oral immediate-release omeprazole formulation, which is administered by nasogastric tube twice daily on the first day, then once daily. For patients with nasoenteric tubes, immediate-release omeprazole may be preferred to intravenous H₂ antagonists or proton pump inhibitors because of comparable efficacy, lower cost, and ease of administration.

For patients without a nasoenteric tube or with significant ileus, intravenous H₂ antagonists are preferred to intravenous proton pump inhibitors because of their proven efficacy and lower cost. Although proton pump inhibitors are increasingly used, there are no controlled trials demonstrating efficacy or optimal dosing.

Gastrinoma and Other Hypersecretory Conditions

Patients with isolated gastrinomas are best treated with surgical resection. In patients with metastatic or unresectable gastrinomas, massive acid hypersecretion results in peptic ulceration, erosive esophagitis, and malabsorption. Previously, these patients required vagotomy and extraordinarily high doses of H₂ antagonists, which still resulted in suboptimal acid suppression. With proton pump inhibitors, excellent acid suppression can be achieved in all patients. Dosage is titrated to reduce basal acid output to less than 5–10 mEq/h. Typical doses of omeprazole are 60–120 mg/d.

Adverse Effects

General

Proton pump inhibitors are extremely safe. Diarrhea, headache, and abdominal pain are reported in 1–5% of patients, although the frequency of these events is only slightly increased compared with placebo. Proton pump inhibitors do not have teratogenicity in animal models; however, safety during pregnancy has not been established.

Nutrition

Acid is important in releasing vitamin B12 from food. A minor reduction in oral cyanocobalamin absorption occurs during proton pump inhibition, potentially leading to subnormal B₁₂ levels with prolonged therapy. Acid also promotes absorption of food-bound minerals (iron, calcium, zinc); however, no mineral deficiencies have been reported with proton pump inhibitor therapy. Recent case-control studies have suggested a modest increase in the risk of hip fracture in patients taking proton pump inhibitors over a long term compared with matched controls. Although a causal relationship is unproven, proton pump inhibitors may reduce calcium absorption or inhibit osteoclast function. Pending further studies, patients who require long-term proton pump inhibitors—especially those with risk factors for osteoporosis—should have monitoring of bone density and should be provided calcium supplements.

Respiratory and Enteric Infections

Gastric acid is an important barrier to colonization and infection of the stomach and intestine from ingested bacteria. Increases in gastric bacterial concentrations are detected in patients taking proton pump inhibitors, which is of unknown clinical significance. Some studies have reported an increased risk of both community-acquired respiratory infections and nosocomial pneumonia among patients taking proton pump inhibitors.

A small increased risk of enteric infections may exist in patients taking proton pump inhibitors, especially when traveling in underdeveloped countries. Hospitalized patients may have an increased risk for Clostridium difficile infection.

Potential Problems Due to Increased Serum Gastrin

Gastrin levels are regulated by intragastric acidity. Acid suppression alters normal feedback inhibition so that median serum gastrin levels rise 1.5- to 2-fold in patients taking proton pump inhibitors. Although gastrin levels remain within normal limits in most patients, they exceed 500 pg/mL (normal, < 100 pg/mL) in 3%. Upon stopping the drug, the levels normalize within 4 weeks.

The rise in serum gastrin levels in patients receiving long-term therapy with proton pump inhibitors raises a theoretical concern because gastrin may stimulate hyperplasia of ECL cells. In female rats given proton pump inhibitors for prolonged periods, gastric carcinoid tumors developed in areas of ECL hyperplasia. Although humans who take proton pump inhibitors for a long time may exhibit ECL hyperplasia in response to hypergastrinemia, carcinoid tumor formation has not been documented. At present, routine monitoring of serum gastrin levels is not recommended in patients receiving prolonged proton pump inhibitor therapy.

Other Potential Problems Due to Decreased Gastric Acidity

Among patients infected with H pylori, long-term acid suppression leads to increased chronic inflammation in the gastric body and decreased inflammation in the antrum. Concerns have been raised that increased gastric inflammation may accelerate gastric gland atrophy (atrophic gastritis) and intestinal metaplasia—known risk factors for gastric adenocarcinoma. A special FDA Gastrointestinal Advisory Committee concluded that there is no evidence that prolonged proton pump inhibitor therapy produces the kind of atrophic gastritis (multifocal atrophic gastritis) or intestinal metaplasia that is associated with increased risk of adenocarcinoma. Routine testing for H pylori is not recommended in patients who require long-term proton pump inhibitor therapy. Long-term proton pump inhibitor therapy is associated with the development of small benign gastric fundic-gland polyps in a small number of patients, which may disappear after stopping the drug and are of uncertain clinical significance.

Drug Interactions

Decreased gastric acidity may alter absorption of drugs for which intragastric acidity affects drug bioavailability, eg, ketoconazole, itraconazole, digoxin, and atazanavir. All proton pump inhibitors are metabolized by hepatic P450 cytochromes, including CYP2C19 and CYP3A4. Because of the short half-lives of proton pump inhibitors, clinically significant drug interactions are rare. Omeprazole may inhibit the metabolism of warfarin, diazepam, and phenytoin. Esomeprazole also may decrease metabolism of diazepam. Lansoprazole may enhance clearance of theophylline. Rabeprazole and pantoprazole have no significant drug interactions.

Mucosal Protective Agents

The gastroduodenal mucosa has evolved a number of defense mechanisms to protect itself against the noxious effects of acid and pepsin. Both mucus and epithelial cell-cell tight junctions restrict back diffusion of acid and pepsin. Epithelial bicarbonate secretion establishes a pH gradient within the mucous layer in which the pH ranges from 7 at the mucosal surface to 1–2 in the gastric lumen. Blood flow carries bicarbonate and vital nutrients to surface cells. Areas of injured epithelium are quickly repaired by restitution, a process in which migration of cells from gland neck cells seals small erosions to reestablish intact epithelium. Mucosal prostaglandins appear to be important in stimulating mucus and bicarbonate secretion and mucosal blood flow. A number of agents that potentiate these mucosal defense mechanisms are available for the prevention and treatment of acid-peptic disorders.

Sucralfate

Chemistry & Pharmacokinetics

Sucralfate is a salt of sucrose complexed to sulfated aluminum hydroxide. In water or acidic solutions it forms a viscous, tenacious paste that binds selectively to ulcers or erosions for up to 6 hours. Sucralfate has limited solubility, breaking down into sucrose sulfate (strongly negatively charged) and an aluminum salt. Less than 3% of intact drug and aluminum is absorbed from the intestinal tract; the remainder is excreted in the feces.

Pharmacodynamics

A variety of beneficial effects have been attributed to sucralfate, but the precise mechanism of action is unclear. It is believed that the negatively charged sucrose sulfate binds to positively charged proteins in the base of ulcers or erosion, forming a physical barrier that restricts further caustic damage and stimulates mucosal prostaglandin and bicarbonate secretion.

Clinical Uses

Sucralfate is administered in a dosage of 1 g four times daily on an empty stomach (at least 1 hour before meals). At present, its clinical uses are limited. Sucralfate (administered as a slurry through a nasogastric tube) reduces the incidence of clinically significant upper gastrointestinal bleeding in critically ill patients hospitalized in the intensive care unit, although it is slightly less effective than intravenous H₂ antagonists. Sucralfate is still used by many clinicians for prevention of stress-related bleeding because of concerns that acid inhibitory therapies (antacids, H₂ antagonists, and proton pump inhibitors) may increase the risk of nosocomial pneumonia.

Adverse Effects

Because it is not absorbed, sucralfate is virtually devoid of systemic adverse effects. Constipation occurs in 2% of patients due to the aluminum salt. Because a small amount of aluminum is absorbed, it should not be used for prolonged periods in patients with renal insufficiency.

Drug Interactions

Sucralfate may bind to other medications, impairing their absorption.

Prostaglandin Analogs

Chemistry & Pharmacokinetics

The human gastrointestinal mucosa synthesizes a number of prostaglandins (see Chapter 18); the primary ones are prostaglandins E and F. Misoprostol, a methyl analog of PGE1 , has been approved for gastrointestinal conditions. After oral administration, it is rapidly absorbed and metabolized to a metabolically active free acid. The serum half-life is less than 30 minutes; hence, it must be administered 3–4 times daily. It is excreted in the urine; however, dose reduction is not needed in patients with renal insufficiency.

Pharmacodynamics

Misoprostol has both acid inhibitory and mucosal protective properties. It is believed to stimulate mucus and bicarbonate secretion and enhance mucosal blood flow. In addition, it binds to a prostaglandin receptor on parietal cells, reducing histamine-stimulated cAMP production and causing modest acid inhibition. Prostaglandins have a variety of other actions, including stimulation of intestinal electrolyte and fluid secretion, intestinal motility, and uterine contractions.

Clinical Uses

Peptic ulcers develop in approximately 10–20% of patients who receive long-term NSAID therapy (see Proton Pump Inhibitors, above). Misoprostol reduces the incidence of NSAID-induced ulcers to less than 3% and the incidence of ulcer complications by 50%. It is approved for prevention of NSAID-induced ulcers in high-risk patients; however, misoprostol has never achieved widespread use owing to its high adverse-effect profile and need for multiple daily dosing. As discussed, proton pump inhibitors may be as effective as and better tolerated than misoprostol for this indication. Cyclooxygenase-2-selective NSAIDs, which may have less gastrointestinal toxicity (see Chapter 36), offer another option for patients at high-risk for NSAID-induced complications.

Adverse Effects & Drug Interactions

Diarrhea and cramping abdominal pain occur in 10–20% of patients. Because misoprostol stimulates uterine contractions (see Chapter 18), it should not be used during pregnancy or in women of childbearing potential unless they have a negative serum pregnancy test and are compliant with effective contraceptive measures. No significant drug interactions are reported.

Bismuth Compounds

Chemistry & Pharmacokinetics

Two bismuth compounds are available: bismuth subsalicylate,  a nonprescription formulation containing bismuth and salicylate, and bismuth subcitrate potassium.  In the USA, bismuth subcitrate is available only as a combination prescription product that also contains metronidazole and tetracycline for the treatment of H pylori. Bismuth subsalicylate undergoes rapid dissociation within the stomach, allowing absorption of salicylate. Over 99% of the bismuth appears in the stool. Although minimal (< 1%), bismuth is absorbed; it is stored in many tissues and has slow renal excretion. Salicylate (like aspirin) is readily absorbed and excreted in the urine.

Pharmacodynamics

The precise mechanisms of action of bismuth are unknown. Bismuth coats ulcers and erosions, creating a protective layer against acid and pepsin. It may also stimulate prostaglandin, mucus, and bicarbonate secretion. Bismuth subsalicylate reduces stool frequency and liquidity in acute infectious diarrhea, due to salicylate inhibition of intestinal prostaglandin and chloride secretion. Bismuth has direct antimicrobial effects and binds enterotoxins, accounting for its benefit in preventing and treating traveler's diarrhea. Bismuth compounds have direct antimicrobial activity against H pylori.

Clinical Uses

In spite of the lack of comparative trials, nonprescription bismuth compounds are widely used by patients for the nonspecific treatment of dyspepsia and acute diarrhea. Bismuth subsalicylate also is used for the prevention of traveler's diarrhea (30 mL or 2 tablets four times daily).

Bismuth compounds are used in 4 drug regimens for the eradication of H pylori infection. One regimen consists of a proton pump inhibitor twice daily combined with bismuth subsalicylate (2 tablets; 262 mg each), tetracycline (250–500 mg), and metronidazole (500 mg) four times daily for 10–14 days. Another regimen consists of a proton pump inhibitor twice daily combined with three capsules of a combination prescription formulation (each capsule containing bismuth subcitrate 140 mg, metronidazole 125 mg, and tetracycline 125 mg) taken four times daily for 10 days. Although these are effective, standard "triple therapy" regimens (ie, proton pump inhibitor, clarithromycin, and amoxicillin or metronidazole twice daily for 14 days) generally are preferred for first-line therapy because of twice-daily dosing and superior compliance. Bismuth-based quadruple therapies commonly are used as second-line therapies.

Adverse Effects

All bismuth formulations have excellent safety profiles. Bismuth causes harmless blackening of the stool, which may be confused with gastrointestinal bleeding. Liquid formulations may cause harmless darkening of the tongue. Bismuth agents should be used for short periods only and should be avoided in patients with renal insufficiency. Prolonged usage of some bismuth compounds may rarely lead to bismuth toxicity, resulting in encephalopathy (ataxia, headaches, confusion, seizures). However, such toxicity is not reported with bismuth subsalicylate or bismuth citrate. High dosages of bismuth subsalicylate may lead to salicylate toxicity.

Drugs Stimulating Gastrointestinal Motility

Drugs that can selectively stimulate gut motor function (prokinetic agents) have significant potential clinical usefulness. Agents that increase lower esophageal sphincter pressures may be useful for GERD. Drugs that improve gastric emptying may be helpful for gastroparesis and postsurgical gastric emptying delay. Agents that stimulate the small intestine may be beneficial for postoperative ileus or chronic intestinal pseudo-obstruction. Finally, agents that enhance colonic transit may be useful in the treatment of constipation. Unfortunately, only a limited number of agents in this group are available for clinical use at this time.

Physiology of the Enteric Nervous System

The enteric nervous system (see also Chapter 6) is composed of interconnected networks of ganglion cells and nerve fibers mainly located in the submucosa (submucosal plexus) and between the circular and longitudinal muscle layers (myenteric plexus). These networks give rise to nerve fibers that connect with the mucosa and muscle. Although extrinsic sympathetic and parasympathetic nerves project onto the submucosal and myenteric plexuses, the enteric nervous system can independently regulate gastrointestinal motility and secretion. Extrinsic primary afferent neurons project via the dorsal root ganglia or vagus nerve to the central nervous system (Figure 62–4). Release of serotonin (5-HT) from intestinal mucosa enterochromaffin (EC) cells stimulates 5-HT₃ receptors on the extrinsic afferent nerves, stimulating nausea, vomiting, or abdominal pain. Serotonin also stimulates submucosal 5-HT_1P receptors of the intrinsic primary afferent nerves (IPANs), which contain calcitoningene-related peptide (CGRP) and acetylcholine and project to myenteric plexus interneurons. 5-HT₄ receptors on the presynaptic terminals of the IPANs appear to enhance release of CGRP or acetylcholine. The myenteric interneurons are important in controlling the peristaltic reflex, promoting release of excitatory mediators proximally and inhibitory mediators distally. Motilin may stimulate excitatory neurons or muscle cells directly. Dopamine acts as an inhibitory neurotransmitter in the gastrointestinal tract, decreasing the intensity of esophageal and gastric contractions.

Figure 62–4

Release of serotonin (5-HT) by enterochromaffin (EC) cells from gut distention stimulates submucosal intrinsic primary afferent neurons (IPANs) via 5-HT_1P receptors and extrinsic primary afferent neurons via 5-HT₃ receptors (5-HT_1PR, 5-HT₃R). Submucosal IPANs activate the enteric neurons responsible for peristaltic and secretory reflex activity. Stimulation of 5-HT₄ receptors (5-HT₄R) on presynaptic terminals of IPANs enhances release of acetylcholine (ACh) and calcitoningene-related peptide (CGRP), promoting reflex activity. CNS, central nervous system; ENS, enteric nervous system.

(Redrawn from Gershon MD: Serotonin and its implication for the management of irritable bowel syndrome. Rev Gastroenterol Dis 2003;3[Suppl 2]:S25.)

Although there are at least 14 serotonin receptor subtypes, 5-HT drug development for gastrointestinal applications to date has focused on 5-HT ₃ receptorantagonists and 5-HT ₄ -receptor agonists. These agents—which have effects on gastrointestinal motility and visceral afferent sensation—are discussed under Drugs Used for the Treatment of Irritable Bowel Syndrome and Antiemetic Agents. Other drugs acting on 5-HT receptors are discussed in Chapters 16, 29, and 30.

Cholinomimetic Agents

Cholinomimetic agonists such as bethanechol stimulate muscarinic M₃ receptors on muscle cells and at myenteric plexus synapses (see Chapter 7). Bethanechol was used in the past for the treatment of GERD and gastroparesis. Owing to multiple cholinergic effects and the advent of less toxic agents, it is now seldom used. The acetylcholinesterase inhibitor neostigmine can enhance gastric, small intestine, and colonic emptying. Intravenous neostigmine has enjoyed a resurgence in clinical usage for the treatment of hospitalized patients with acute large bowel distention (known as acute colonic pseudo-obstruction or Ogilvie's syndrome). Administration of 2 mg results in prompt colonic evacuation of flatus and feces in the majority of patients. Cholinergic effects include excessive salivation, nausea, vomiting, diarrhea, and bradycardia.

Metoclopramide & Domperidone

Metoclopramide and domperidone are dopamine D₂ receptor antagonists. Within the gastrointestinal tract activation of dopamine receptors inhibits cholinergic smooth muscle stimulation; blockade of this effect is believed to be the primary prokinetic mechanism of action of these agents. These agents increase esophageal peristaltic amplitude, increase lower esophageal sphincter pressure, and enhance gastric emptying but have no effect on small intestine or colonic motility. Metoclopramide and domperidone also block dopamine D₂ receptors in the chemoreceptor trigger zone of the medulla (area postrema), resulting in potent antinausea and antiemetic action.

Clinical Uses

Gastroesophageal Reflux Disease

Metoclopramide is available for clinical use in the USA; domperidone is available in many other countries. These agents are sometimes used in the treatment of symptomatic GERD but are not effective in patients with erosive esophagitis. Because of the superior efficacy and safety of antisecretory agents in the treatment of heartburn, prokinetic agents are used mainly in combination with antisecretory agents in patients with regurgitation or refractory heartburn.

Impaired Gastric Emptying

These agents are widely used in the treatment of patients with delayed gastric emptying due to postsurgical disorders (vagotomy, antrectomy) and diabetic gastroparesis. Metoclopramide is sometimes administered in hospitalized patients to promote advancement of nasoenteric feeding tubes from the stomach into the duodenum.

Nonulcer Dyspepsia

These agents lead to symptomatic improvement in a small number of patients with chronic dyspepsia.

Prevention of Vomiting

Because of their potent antiemetic action, metoclopramide and domperidone are used for the prevention and treatment of emesis.

Postpartum Lactation Stimulation

Domperidone is sometimes recommended to promote postpartum lactation (see also Adverse Effects).

Adverse Effects

The most common adverse effects of metoclopramide involve the central nervous system. Restlessness, drowsiness, insomnia, anxiety, and agitation occur in 10–20% of patients, especially the elderly. Extrapyramidal effects (dystonias, akathisia, parkinsonian features) due to central dopamine receptor blockade occur acutely in 25% of patients given high doses and in 5% of patients receiving long-term therapy. Tardivedyskinesia, sometimes irreversible, has developed in patients treated for a prolonged period with metoclopramide. For this reason, long-term use should be avoided unless absolutely necessary, especially in the elderly. Elevated prolactin levels (caused by both metoclopramide and domperidone) can cause galactorrhea, gynecomastia, impotence, and menstrual disorders.

Domperidone is extremely well tolerated. Because it does not cross the blood-brain barrier to a significant degree, neuropsychiatric and extrapyramidal effects are rare.

Macrolides

Macrolide antibiotics such as erythromycin directly stimulate motilin receptors on gastrointestinal smooth muscle and promote the onset of a migrating motor complex. Intravenous erythromycin (3 mg/kg) is beneficial in some patients with gastroparesis; however, tolerance rapidly develops. It may be used in patients with acute upper gastrointestinal hemorrhage to promote gastric emptying of blood before endoscopy.

Laxatives

The overwhelming majority of people do not need laxatives; yet they are self-prescribed by a large portion of the population. For most people, intermittent constipation is best prevented with a high-fiber diet, adequate fluid intake, regular exercise, and the heeding of nature's call. Patients not responding to dietary changes or fiber supplements should undergo medical evaluation before initiating long-term laxative treatment. Laxatives may be classified by their major mechanism of action, but many work through more than one mechanism.

Bulk-Forming Laxatives

Bulk-forming laxatives are indigestible, hydrophilic colloids that absorb water, forming a bulky, emollient gel that distends the colon and promotes peristalsis. Common preparations include natural plant products (psyllium, methylcellulose) and synthetic fibers (polycarbophil). Bacterial digestion of plant fibers within the colon may lead to increased bloating and flatus.

Stool Surfactant Agents (Softeners)

These agents soften stool material, permitting water and lipids to penetrate. They may be administered orally or rectally. Common agents include docusate (oral or enema) and glycerin suppository. In hospitalized patients, docusate is commonly prescribed to prevent constipation and minimize straining. Mineral oil is a clear, viscous oil that lubricates fecal material, retarding water absorption from the stool. It is used to prevent and treat fecal impaction in young children and debilitated adults. It is not palatable but may be mixed with juices. Aspiration can result in a severe lipid pneumonitis. Long-term use can impair absorption of fat-soluble vitamins (A, D, E, K).

Osmotic Laxatives

The colon can neither concentrate nor dilute fecal fluid: fecal water is isotonic throughout the colon. Osmotic laxatives are soluble but nonabsorbable compounds that result in increased stool liquidity due to an obligate increase in fecal fluid.

Nonabsorbable Sugars or Salts

These agents may be used for the treatment of acute constipation or the prevention of chronic constipation. Magnesium hydroxide (milk of magnesia) is a commonly used osmotic laxative. It should not be used for prolonged periods in patients with renal insufficiency due to the risk of hypermagnesemia. Sorbitol and lactulose are nonabsorbable sugars that can be used to prevent or treat chronic constipation. These sugars are metabolized by colonic bacteria, producing severe flatus and cramps.

High doses of osmotically active agents produce prompt bowel evacuation (purgation) within 1–3 hours. The rapid movement of water into the distal small bowel and colon leads to a high volume of liquid stool followed by rapid relief of constipation. The most commonly used purgatives are magnesium citrate and sodium phosphate. Sodium phosphate is available as a nonprescription liquid formulation and by prescription as a tablet formulation. When taking these agents, it is very important that patients maintain adequate hydration by taking increased oral liquids to compensate for fecal fluid loss. Sodium phosphate frequently causes hyperphosphatemia, hypocalcemia, hypernatremia, and hypokalemia. Although these electrolyte abnormalities are clinically insignificant in most patients, they may lead to cardiac arrhythmias or acute renal failure due to tubular deposition of calcium phosphate (nephrocalcinosis). Sodium phosphate preparations should not be used in patients who are frail or elderly, have renal insufficiency, have significant cardiac disease, or are unable to maintain adequate hydration during bowel preparation.

Balanced Polyethylene Glycol

Lavage solutions containing polyethylene glycol (PEG) are used for complete colonic cleansing before gastrointestinal endoscopic procedures. These balanced, isotonic solutions contain an inert, nonabsorbable, osmotically active sugar (PEG) with sodium sulfate, sodium chloride, sodium bicarbonate, and potassium chloride. The solution is designed so that no significant intravascular fluid or electrolyte shifts occur. Therefore, they are safe for all patients. The solution should be ingested rapidly (2–4 L over 2–4 hours) to promote bowel cleansing. For treatment or prevention of chronic constipation, smaller doses of PEG powder may be mixed with water or juices (17 g/8 oz) and ingested daily. In contrast to sorbitol or lactulose, PEG does not produce significant cramps or flatus.

Stimulant Laxatives

Stimulant laxatives (cathartics) induce bowel movements through a number of poorly understood mechanisms. These include direct stimulation of the enteric nervous system and colonic electrolyte and fluid secretion. There has been concern that long-term use of cathartics could lead to dependence and destruction of the myenteric plexus, resulting in colonic atony and dilation. More recent research suggests that long-term use of these agents probably is safe in most patients. Cathartics may be required on a long-term basis, especially in patients who are neurologically impaired and in bed-bound patients in long-term care facilities.

Anthraquinone Derivatives

Aloe, senna, and cascara occur naturally in plants. These laxatives are poorly absorbed and after hydrolysis in the colon, produce a bowel movement in 6–12 hours when given orally and within 2 hours when given rectally. Chronic use leads to a characteristic brown pigmentation of the colon known as "melanosis coli." There has been some concern that these agents may be carcinogenic, but epidemiologic studies do not suggest a relation to colorectal cancer.

Diphenylmethane Derivatives

Bisacodyl is available in tablet and suppository formulations for the treatment of acute and chronic constipation. It also is used in conjunction with PEG solutions for colonic cleansing prior to colonoscopy. It induces a bowel movement within 6–10 hours when given orally and 30–60 minutes when taken rectally. It has minimal systemic absorption and appears to be safe for acute and long-term use. Phenolphthalein, another agent in this class, was removed from the market owing to concerns about possible cardiac toxicity.

Chloride Channel Activator

Lubiprostone is a prostanoic acid derivative labeled for use in chronic constipation and irritable bowel syndrome (IBS) with predominant constipation. It acts by stimulating the type 2 chloride channel (ClC-2) in the small intestine. This increases chloride-rich fluid secretion into the intestine, which stimulates intestinal motility and shortens intestinal transit time. Over 50% of patients experience a bowel movement within 24 hours of taking one dose. There appears to be no loss of efficacy with long-term therapy. After discontinuation of the drug, constipation may return to its pretreatment severity. Lubiprostone has minimal systemic absorption but is designated category C for pregnancy because of increased fetal loss in guinea pigs. Lubiprostone may cause nausea in up to 30% of patients due to delayed gastric emptying.

Opioid Receptor Antagonists

Acute and chronic therapy with opioids may cause constipation by decreasing intestinal motility, which results in prolonged transit time and increased absorption of fecal water (see Chapter 31). Use of opioids after surgery for treatment of pain as well as endogenous opioids also may prolong the duration of postoperative ileus. These effects are mainly mediated through intestinal mu ()-opioid receptors. Two selective antagonists of the -opioid receptor are commercially available: methylnaltrexone bromide and alvimopan. Because these agents do not readily cross the blood-brain barrier, they inhibit peripheral -opioid receptors without impacting analgesic effects within the central nervous system. Methylnaltrexone is approved for the treatment of opioid-induced constipation in patients receiving palliative care for advanced illness who have had inadequate response to other agents. It is administered as a subcutaneous injection (0.15 mg/kg) every 2 days. Alvimopan is approved for short-term use to shorten the period of postoperative ileus in hospitalized patients who have undergone small or large bowel resection. Alvimopan (12 mg capsule) is administered orally within 5 hours before surgery and twice daily after surgery until bowel function has recovered, but for no more than 7 days. Because of possible cardiovascular toxicity, alvimopan currently is restricted to short-term use in hospitalized patients only.

Serotonin 5-HT₄-Receptor Agonists

Stimulation of 5-HT₄ receptors on the presynaptic terminal of submucosal intrinsic primary afferent nerves enhances the release of their neurotransmitters, including calcitoningene-related peptide, which stimulate second-order enteric neurons to promote the peristaltic reflex (Figure 62–4). These enteric neurons stimulate proximal bowel contraction (via acetylcholine and substance P) and distal bowel relaxation (via nitric oxide and vasoactive intestinal peptide).

Tegaserod is a serotonin5-HT₄ partial agonist that has high affinity for 5-HT₄ receptors but no appreciable binding to 5-HT₃ or dopamine receptors. Tegaserod was approved for the treatment of patients with chronic constipation and IBS with predominant constipation. Although tegaserod initially appeared to be extremely safe, it was voluntarily removed from the general market in 2007 because of an increased incidence of serious cardiovascular events. These adverse events have been attributed to inhibition of the 5-HT_1B receptor. Another partial 5-HT₄ agonist, cisapride, was also associated with an increased incidence of cardiovascular events that was attributed to inhibition of cardiac hERG (human ether-a-go-go-related gene) K⁺ channels, which resulted in QT_c prolongation in some patients.

Prucalopride is a high-affinity 5-HT₄ agonist that is in clinical development. In contrast to cisapride and tegaserod, it does not appear to have significant affinities for either hERG channels or 5-HT_1B. In a recent 12-week clinical trial of patients with severe chronic constipation, it resulted in a significant increase in bowel movements compared with placebo. The long-term efficacy and safety of this agent require further study.

Antidiarrheal Agents

Antidiarrheal agents may be used safely in patients with mild to moderate acute diarrhea. However, these agents should not be used in patients with bloody diarrhea, high fever, or systemic toxicity because of the risk of worsening the underlying condition. They should be discontinued in patients whose diarrhea is worsening despite therapy. Antidiarrheals are also used to control chronic diarrhea caused by such conditions as irritable bowel syndrome (IBS) or inflammatory bowel disease (IBD).

Opioid Agonists

As previously noted, opioids have significant constipating effects (see Chapter 31). They increase colonic phasic segmenting activity through inhibition of presynaptic cholinergic nerves in the submucosal and myenteric plexuses and lead to increased colonic transit time and fecal water absorption. They also decrease mass colonic movements and the gastrocolic reflex. Although all opioids have antidiarrheal effects, central nervous system effects and potential for addiction limit the usefulness of most.

Loperamide is a nonprescription opioid agonist that does not cross the blood-brain barrier and has no analgesic properties or potential for addiction. Tolerance to long-term use has not been reported. It is typically administered in doses of 2 mg taken one to four times daily. Diphenoxylate is a prescription opioid agonist that has no analgesic properties in standard doses; however, higher doses have central nervous system effects, and prolonged use can lead to opioid dependence. Commercial preparations commonly contain small amounts of atropine to discourage overdosage (2.5 mg diphenoxylate with 0.025 mg atropine). The anticholinergic properties of atropine may contribute to the antidiarrheal action.

Colloidal Bismuth Compounds

See the section under Mucosal Protective Agents in earlier text.

Kaolin & Pectin

Kaolin is a naturally occurring hydrated magnesium aluminum silicate (attapulgite), and pectin is an indigestible carbohydrate derived from apples. Both appear to act as absorbents of bacterial toxins and fluid, thereby decreasing stool liquidity and number. They may be useful in acute diarrhea but are seldom used on a chronic basis. A common nonprescription preparation is Kaopectate. The usual dosage is 1.2–1.5 g after each loose bowel movement (maximum: 9 g/d). Kaolin-pectin formulations are not absorbed and have no significant adverse effects except constipation. They should not be taken within 2 hours of other medications (which they may bind).

Bile Salt–Binding Resins

Conjugated bile salts are normally absorbed in the terminal ileum. Disease of the terminal ileum (eg, Crohn's disease) or surgical resection leads to malabsorption of bile salts, which may cause colonic secretory diarrhea. The bile salt-binding resins cholestyramine, colestipol, or colesevelam, may decrease diarrhea caused by excess fecal bile acids (see Chapter 35). These products come in a variety of powder and pill formulations that may be taken one to three times daily before meals. Adverse effects include bloating, flatulence, constipation, and fecal impaction. In patients with diminished circulating bile acid pools, further removal of bile acids may lead to an exacerbation of fat malabsorption. Cholestyramine and colestipol bind a number of drugs and reduce their absorption; hence, they should not be given within 2 hours of other drugs. Colesevelam does not appear to have significant effects on absorption of other drugs.

Octreotide

Somatostatin is a 14-amino-acid peptide that is released in the gastrointestinal tract and pancreas from paracrine cells, D cells, and enteric nerves as well as from the hypothalamus (see Chapter 37). Somatostatin is a key regulatory peptide that has many physiologic effects:

1. It inhibits the secretion of numerous hormones and transmitters, including gastrin, cholecystokinin, glucagon, growth hormone, insulin, secretin, pancreatic polypeptide, vasoactive intestinal peptide, and 5-HT.

2. It reduces intestinal fluid secretion and pancreatic secretion.

3. It slows gastrointestinal motility and inhibits gallbladder contraction.

4. It induces direct contraction of vascular smooth muscle, leading to a reduction of portal and splanchnic blood flow.

5. It inhibits secretion of some anterior pituitary hormones.

The clinical usefulness of somatostatin is limited by its short half-life in the circulation (3 minutes) when it is administered by intravenous injection. Octreotide is a synthetic octapeptide with actions similar to somatostatin. When administered intravenously, it has a serum half-life of 1.5 hours. It also may be administered by subcutaneous injection, resulting in a 6- to 12-hour duration of action. A longer-acting formulation is available for once-monthly depot intramuscular injection.

Clinical Uses

Inhibition of Endocrine Tumor Effects

Two gastrointestinal neuroendocrine tumors (carcinoid, VIPoma) cause secretory diarrhea and systemic symptoms such as flushing and wheezing. For patients with advanced symptomatic tumors that cannot be completely removed by surgery, octreotide decreases secretory diarrhea and systemic symptoms through inhibition of hormonal secretion and may slow tumor progression.

Other Causes of Diarrhea

Octreotide inhibits intestinal secretion and has dose-related effects on bowel motility. In low doses (50 mcg subcutaneously), it stimulates motility, whereas at higher doses (eg, 100–250 mcg subcutaneously), it inhibits motility. Octreotide is effective in higher doses for the treatment of diarrhea due to vagotomy or dumping syndrome as well as for diarrhea caused by short bowel syndrome or AIDS. Octreotide has been used in low doses (50 mcg subcutaneously) to stimulate small bowel motility in patients with small bowel bacterial overgrowth or intestinal pseudo-obstruction secondary to scleroderma.

Other Uses

Because it inhibits pancreatic secretion, octreotide may be of value in patients with pancreatic fistula. The role of octreotide in the treatment of pituitary tumors (eg, acromegaly) is discussed in Chapter 37. Octreotide is sometimes used in gastrointestinal bleeding (see below).

Adverse Effects

Impaired pancreatic secretion may cause steatorrhea, which can lead to fat-soluble vitamin deficiency. Alterations in gastrointestinal motility cause nausea, abdominal pain, flatulence, and diarrhea. Because of inhibition of gallbladder contractility and alterations in fat absorption, long-term use of octreotide can cause formation of sludge or gallstones in over 50% of patients, which rarely results in the development of acute cholecystitis. Because octreotide alters the balance among insulin, glucagon, and growth hormone, hyperglycemia or, less frequently, hypoglycemia (usually mild) can occur. Prolonged treatment with octreotide may result in hypothyroidism. Octreotide also can cause bradycardia.

Drugs Used in the Treatment of Irritable Bowel Syndrome

IBS is an idiopathic chronic, relapsing disorder characterized by abdominal discomfort (pain, bloating, distention, or cramps) in association with alterations in bowel habits (diarrhea, constipation, or both). With episodes of abdominal pain or discomfort, patients note a change in the frequency or consistency of their bowel movements.

Pharmacologic therapies for IBS are directed at relieving abdominal pain and discomfort and improving bowel function. For patients with predominant diarrhea, antidiarrheal agents, especially loperamide, are helpful in reducing stool frequency and fecal urgency. For patients with predominant constipation, fiber supplements may lead to softening of stools and reduced straining; however, increased gas production may exacerbate bloating and abdominal discomfort. Consequently, osmotic laxatives, especially milk of magnesia, are commonly used to soften stools and promote increased stool frequency.

For chronic abdominal pain, low doses of tricyclic antidepressants (eg, amitriptyline or desipramine, 10–50 mg/d) appear to be helpful (see Chapter 30). At these doses, these agents have no effect on mood but may alter central processing of visceral afferent information. The anticholinergic properties of these agents also may have effects on gastrointestinal motility and secretion, reducing stool frequency and liquidity. Finally, tricyclic antidepressants may alter receptors for enteric neurotransmitters such as serotonin, affecting visceral afferent sensation.

Several other agents are available that are specifically intended for the treatment of IBS.

Antispasmodics (Anticholinergics)

Some agents are promoted as providing relief of abdominal pain or discomfort through antispasmodic actions. However, small or large bowel spasm has not been found to be an important cause of symptoms in patients with IBS. Antispasmodics work primarily through anticholinergic activities. Commonly used medications in this class include dicyclomine and hyoscyamine (see Chapter 8). These drugs inhibit muscarinic cholinergic receptors in the enteric plexus and on smooth muscle. The efficacy of antispasmodics for relief of abdominal symptoms has never been convincingly demonstrated. At low doses, they have minimal autonomic effects. However, at higher doses they exhibit significant additional anticholinergic effects, including dry mouth, visual disturbances, urinary retention, and constipation. For these reasons, antispasmodics are infrequently used.

Serotonin 5-HT₃-Receptor Antagonists

5-HT₃ receptors in the gastrointestinal tract activate visceral afferent pain sensation via extrinsic sensory neurons from the gut to the spinal cord and central nervous system. Inhibition of afferent gastrointestinal 5-HT₃ receptors may inhibit unpleasant visceral afferent sensation, including nausea, bloating, and pain. Blockade of central 5-HT₃ receptors also reduces the central response to visceral afferent stimulation. In addition, 5-HT₃-receptor blockade on the terminals of enteric cholinergic neurons inhibits colonic motility, especially in the left colon, increasing total colonic transit time.

Alosetron is a 5-HT₃ antagonist that has been approved for the treatment of patients with severe IBS with diarrhea (Figure 62–5). Four other 5-HT₃ antagonists (ondansetron, granisetron, dolasetron, and palonosetron) have been approved for the prevention and treatment of nausea and vomiting (see Antiemetics); however, their efficacy in the treatment of IBS has not been determined. The differences between these 5-HT₃ antagonists that determine their pharmacodynamic effects have not been well studied.

Figure 62–5

Chemical structure of serotonin; the 5-HT₃ antagonists ondansetron, granisetron, dolasetron, and alosetron; and the 5-HT₄ partial agonist tegaserod.

Pharmacokinetics & Pharmacodynamics

Alosetron is a highly potent and selective antagonist of the 5-HT₃ receptor. It is rapidly absorbed from the gastrointestinal tract with a bioavailability of 50–60% and has a plasma half-life of 1.5 hours but a much longer duration of effect. It undergoes extensive hepatic cytochrome P450 metabolism with renal excretion of most metabolites. Alosetron binds with higher affinity and dissociates more slowly from 5-HT₃ receptors than other 5-HT₃ antagonists, which may account for its long duration of action.

Clinical Uses

Alosetron is approved for the treatment of women with severe IBS in whom diarrhea is the predominant symptom ("diarrhea-predominant IBS"). Its efficacy in men has not been established. In a dosage of 1 mg once or twice daily, it reduces IBS-related lower abdominal pain, cramps, urgency, and diarrhea. Approximately 50–60% of patients report adequate relief of pain and discomfort with alosetron compared with 30–40% of patients treated with placebo. It also leads to a reduction in the mean number of bowel movements per day and improvement in stool consistency. Alosetron has not been evaluated for the treatment of other causes of diarrhea.

Adverse Events

In contrast to the excellent safety profile of other 5-HT₃-receptor antagonists, alosetron is associated with rare but serious gastrointestinal toxicity. Constipation occurs in up to 30% of patients with diarrhea-predominant IBS, requiring discontinuation of the drug in 10%. Serious complications of constipation requiring hospitalization or surgery have occurred in 1 of every 1000 patients. Episodes of ischemic colitis—some fatal—have been reported in up to 3 per 1000 patients. Given the seriousness of these adverse events, alosetron is restricted to women with severe diarrhea-predominant IBS who have not responded to conventional therapies and who have been educated about the relative risks and benefits.

Drug Interactions

Despite being metabolized by a number of CYP enzymes, alosetron does not appear to have clinically significant interactions with other drugs.

Serotonin 5-HT₄-Receptor Agonists

The pharmacology of tegaserod was discussed previously under Laxatives. This agent was approved for the short-term treatment of women with IBS who had predominant constipation. Controlled studies demonstrated a modest improvement (approximately 15%) in patient global satisfaction and a reduction in severity of pain and bloating in patients treated with tegaserod, 6 mg twice daily, compared with placebo. Owing to an increased number of cardiovascular deaths observed in post-marketing studies in patients taking tegaserod, it was voluntarily removed from the market and is no longer clinically available.

Chloride Channel Activator

As discussed previously, lubiprostone is a prostanoic acid derivative that stimulates the type 2 chloride channel (ClC-2) in the small intestine and is used in the treatment of chronic constipation. Lubiprostone recently was approved for the treatment of women with IBS with predominant constipation. Its efficacy for men with IBS is unproven. The approved dose for IBS is 8 mcg twice daily (compared with 24 mcg twice daily for chronic constipation). Lubiprostone has not been compared with other less expensive laxatives (eg, milk of magnesia). Lubiprostone is listed as category C for pregnancy and should be avoided in women of childbearing age.

Antiemetic Agents

Nausea and vomiting may be manifestations of a wide variety of conditions, including adverse effects from medications; systemic disorders or infections; pregnancy; vestibular dysfunction; central nervous system infection or increased pressure; peritonitis; hepatobiliary disorders; radiation or chemotherapy; and gastrointestinal obstruction, dysmotility, or infections.

Pathophysiology

The brain stem "vomiting center" is a loosely organized neuronal region within the lateral medullary reticular formation and coordinates the complex act of vomiting through interactions with cranial nerves VIII and X and neural networks in the nucleus tractus solitarius that control respiratory, salivatory, and vasomotor centers. High concentrations of muscarinic M₁, histamine H₁, neurokinin 1 (NK₁), and serotonin5-HT₃ receptors have been identified in the vomiting center (Figure 62–6).

Figure 62–6

Neurologic pathways involved in pathogenesis of nausea and vomiting (see text). (Modified and reproduced, with permission, from Krakauer EL et al: Case records of the Massachusetts General Hospital. N Engl J Med 2005;352:817.)

There are four important sources of afferent input to the vomiting center:

1. The "chemoreceptor trigger zone" or area postrema is located at the caudal end of the fourth ventricle. This is outside the blood-brain barrier but is accessible to emetogenic stimuli in the blood or cerebrospinal fluid. The chemoreceptor trigger zone is rich in dopamine D₂ receptors and opioid receptors, and possibly serotonin5-HT₃ receptors and NK₁ receptors.

2. The vestibular system is important in motion sickness via cranial nerve VIII. It is rich in muscarinic M₁ and histamine H₁ receptors.

3. Vagal and spinal afferent nerves from the gastrointestinal tract are rich in 5-HT₃ receptors. Irritation of the gastrointestinal mucosa by chemotherapy, radiation therapy, distention, or acute infectious gastroenteritis leads to release of mucosal serotonin and activation of these receptors, which stimulate vagal afferent input to the vomiting center and chemoreceptor trigger zone.

4. The central nervous system plays a role in vomiting due to psychiatric disorders, stress, and anticipatory vomiting prior to cancer chemotherapy.

Identification of the different neurotransmitters involved with emesis has allowed development of a diverse group of antiemetic agents that have affinity for various receptors. Combinations of antiemetic agents with different mechanisms of action are often used, especially in patients with vomiting due to chemotherapeutic agents.

Serotonin 5-HT₃ Antagonists

Pharmacokinetics & Pharmacodynamics

Selective 5-HT₃-receptor antagonists have potent antiemetic properties that are mediated in part through central 5-HT₃-receptor blockade in the vomiting center and chemoreceptor trigger zone but mainly through blockade of peripheral 5-HT₃ receptors on extrinsic intestinal vagal and spinal afferent nerves. The antiemetic action of these agents is restricted to emesis attributable to vagal stimulation (eg, postoperative) and chemotherapy; other emetic stimuli such as motion sickness are poorly controlled.

Four agents are available in the USA: ondansetron, granisetron, dolasetron, and palonosetron. (Tropisetron is another agent available outside the USA.) The first three agents (ondansetron, granisetron, and dolasetron, Figure 62–5) have a serum half-life of 4–9 hours and may be administered once daily by oral or intravenous routes. All three drugs have comparable efficacy and tolerability when administered at equipotent doses. Palonosetron is a newer intravenous agent that has greater affinity for the 5-HT₃ receptor and a long serum half-life of 40 hours. All four drugs undergo extensive hepatic metabolism and are eliminated by renal and hepatic excretion. However, dose reduction is not required in geriatric patients or patients with renal insufficiency. For patients with hepatic insufficiency, dose reduction may be required with ondansetron.

5-HT₃-receptor antagonists do not inhibit dopamine or muscarinic receptors. They do not have effects on esophageal or gastric motility but may slow colonic transit.

Clinical Uses

Chemotherapy-Induced Nausea and Vomiting

5-HT₃-receptor antagonists are the primary agents for the prevention of acute chemotherapy-induced nausea and emesis. When used alone, these drugs have little or no efficacy for the prevention of delayed nausea and vomiting (ie, occurring > 24 hours after chemotherapy). The drugs are most effective when given as a single dose by intravenous injection 30 minutes prior to administration of chemotherapy in the following doses: ondansetron, 8 mg or 0.15 mg/kg; granisetron, 1 mg; dolasetron, 100 mg; or palonosetron, 0.25 mg. A single oral dose given 1 hour before chemotherapy may be equally effective in the following regimens: ondansetron 8 mg twice daily or 24 mg once; granisetron, 2 mg; dolasetron, 100 mg. Although 5-HT₃-receptor antagonists are effective as single agents for the prevention of chemotherapy-induced nausea and vomiting, their efficacy is enhanced by combination therapy with a corticosteroid (dexamethasone) and NK₁-receptor antagonist (see below).

Postoperative and Postradiation Nausea and Vomiting

5-HT₃-receptor antagonists are used to prevent or treat postoperative nausea and vomiting. Because of adverse effects and increased restrictions on the use of other antiemetic agents, 5-HT₃-receptor antagonists are increasingly used for this indication. They are also effective in the prevention and treatment of nausea and vomiting in patients undergoing radiation therapy to the whole body or abdomen.

Adverse Effects

The 5-HT₃-receptor antagonists are well-tolerated agents with excellent safety profiles. The most commonly reported adverse effects are headache, dizziness, and constipation. All four agents cause a small but statistically significant prolongation of the QT interval, but this is most pronounced with dolasetron. Although cardiac arrhythmias have not been linked to dolasetron, it should not be administered to patients with prolonged QT or in conjunction with other medications that may prolong the QT interval (see Chapter 14).

Drug Interactions

No significant drug interactions have been reported with 5-HT₃-receptor antagonists. All four agents undergo some metabolism by the hepatic cytochrome P450 system but they do not appear to affect the metabolism of other drugs. However, other drugs may reduce hepatic clearance of the 5-HT₃-receptor antagonists, altering their half-life.

Corticosteroids

Corticosteroids (dexamethasone, methylprednisolone) have antiemetic properties, but the basis for these effects is unknown. The pharmacology of this class of drugs is discussed in Chapter 39. These agents appear to enhance the efficacy of 5-HT₃-receptor antagonists for prevention of acute and delayed nausea and vomiting in patients receiving moderately to highly emetogenic chemotherapy regimens. Although a number of corticosteroids have been used, dexamethasone, 8–20 mg intravenously before chemotherapy, followed by 8 mg/d orally for 2–4 days, is commonly administered.

Neurokinin Receptor Antagonists

Neurokinin 1 (NK₁)-receptor antagonists have antiemetic properties that are mediated through central blockade in the area postrema. Aprepitant (an oral formulation) is a highly selective NK₁-receptor antagonist that crosses the blood-brain barrier and occupies brain NK₁ receptors. It has no affinity for serotonin, dopamine, or corticosteroid receptors. Fosaprepitant is an intravenous formulation that is converted within 30 minutes after infusion to aprepitant.

Pharmacokinetics

The oral bioavailability of aprepitant is 65%, and the serum half-life is 12 hours. Aprepitant is metabolized by the liver, primarily by the CYP3A4 pathway.

Clinical Uses

Aprepitant is used in combination with 5-HT₃-receptor antagonists and corticosteroids for the prevention of acute and delayed nausea and vomiting from highly emetogenic chemotherapeutic regimens. Combined therapy with aprepitant, a 5-HT₃-receptor antagonist, and dexamethasone prevents acute emesis in 80–90% of patients compared with less than 70% treated without aprepitant. Prevention of delayed emesis occurs in more than 70% of patients receiving combined therapy versus 30–50% treated without aprepitant. NK₁-receptor antagonists may be administered for 3 days as follows: oral aprepitant 125 mg or intravenous fosaprepitant 115 mg given 1 hour before chemotherapy, followed by oral aprepitant 80 mg/d for 2 days after chemotherapy.

Adverse Effects & Drug Interactions

Aprepitant may be associated with fatigue, dizziness, and diarrhea. The drug is metabolized by CYP3A4 and may inhibit the metabolism of other drugs metabolized by the CYP3A4 pathway. Several chemotherapeutic agents are metabolized by CYP3A4, including docetaxel, paclitaxel, etoposide, irinotecan, imatinib, vinblastine, and vincristine. Drugs that inhibit CYP3A4 metabolism may significantly increase aprepitant plasma levels (eg, ketoconazole, ciprofloxacin, clarithromycin, nefazodone, ritonavir, nelfinavir, verapamil, and quinidine). Aprepitant decreases the international normalized ratio (INR) in patients taking warfarin.

Phenothiazines & Butyrophenones

Phenothiazines are antipsychotic agents that can be used for their potent antiemetic and sedative properties (see Chapter 29). The antiemetic properties of phenothiazines are mediated through inhibition of dopamine and muscarinic receptors. Sedative properties are due to their antihistamine activity. The agents most commonly used as antiemetics are prochlorperazine, promethazine, and thiethylperazine.

Antipsychotic butyrophenones also possess antiemetic properties due to their central dopaminergic blockade (see Chapter 29). The main agent used is droperidol, which can be given by intramuscular or intravenous injection. In antiemetic doses, droperidol is extremely sedating. Until recently, it was used extensively for postoperative nausea and vomiting, in conjunction with opiates and benzodiazepines for sedation for surgical and endoscopic procedures, for neuroleptanalgesia, and for induction and maintenance of general anesthesia. Extrapyramidal effects and hypotension may occur. Droperidol may prolong the QT interval, rarely resulting in fatal episodes of ventricular tachycardia including torsade de pointes. Therefore, droperidol should not be used in patients with QT prolongation and should be used only in patients who have not responded adequately to alternative agents.

Substituted Benzamides

Substituted benzamides include metoclopramide (discussed previously) and trimethobenzamide. Their primary mechanism of antiemetic action is believed to be dopamine-receptor blockade. Trimethobenzamide also has weak antihistaminic activity. For prevention and treatment of nausea and vomiting, metoclopramide may be given in the relatively high dosage of 10–20 mg orally or intravenously every 6 hours. The usual dose of trimethobenzamide is 250 mg orally, 200 mg rectally, or 200 mg by intramuscular injection. The principal adverse effects of these central dopamine antagonists are extrapyramidal: restlessness, dystonias, and parkinsonian symptoms.

H₁ Antihistamines & Anticholinergic Drugs

The pharmacology of anticholinergic agents is discussed in Chapter 8 and that of H₁ antihistaminic agents in Chapter 16. As single agents, these drugs have weak antiemetic activity, although they are particularly useful for the prevention or treatment of motion sickness. Their use may be limited by dizziness, sedation, confusion, dry mouth, cycloplegia, and urinary retention. Diphenhydramine and one of its salts, dimenhydrinate, are first-generation histamine H₁ antagonists that also have significant anticholinergic properties. Because of its sedating properties, diphenhydramine is commonly used in conjunction with other antiemetics for treatment of emesis due to chemotherapy. Meclizine is an H₁ antihistaminic agent with minimal anticholinergic properties that also causes less sedation. It is used for the prevention of motion sickness and the treatment of vertigo due to labyrinth dysfunction.

Hyoscine (scopolamine), a prototypic muscarinic receptor antagonist, is one of the best agents for the prevention of motion sickness. However, it has a very high incidence of anticholinergic effects when given orally or parenterally. It is better tolerated as a transdermal patch. Superiority to dimenhydrinate has not been proved.

Benzodiazepines

Benzodiazepines such as lorazepam or diazepam are used before the initiation of chemotherapy to reduce anticipatory vomiting or vomiting caused by anxiety. The pharmacology of these agents is presented in Chapter 22.

Cannabinoids

Dronabinol is ⁹-tetrahydrocannabinol (THC), the major psychoactive chemical in marijuana (see Chapter 32). After oral ingestion, the drug is almost completely absorbed but undergoes significant first-pass hepatic metabolism. Its metabolites are excreted slowly over days to weeks in the feces and urine. Like crude marijuana, dronabinol is a psychoactive agent that is used medically as an appetite stimulant and as an antiemetic, but the mechanisms for these effects are not understood. Because of the availability of more effective agents, dronabinol now is uncommonly used for the prevention of chemotherapy-induced nausea and vomiting. Combination therapy with phenothiazines provides synergistic antiemetic action and appears to attenuate the adverse effects of both agents. Dronabinol is usually administered in a dosage of 5 mg/m² just prior to chemotherapy and every 2–4 hours as needed. Adverse effects include euphoria, dysphoria, sedation, hallucinations, dry mouth, and increased appetite. It has some autonomic effects that may result in tachycardia, conjunctival injection, and orthostatic hypotension. Dronabinol has no significant drug-drug interactions but may potentiate the clinical effects of other psychoactive agents.

Nabilone is a closely related THC analog that has been available in other countries and is now approved for use in the USA.

Drugs Used to Treat Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) comprises two distinct disorders: ulcerative colitis and Crohn's disease. The etiology and pathogenesis of these disorders remains unknown. For this reason, pharmacologic treatment of inflammatory bowel disorders often involves drugs that belong to different therapeutic classes and have different but nonspecific mechanisms of anti-inflammatory action. Drugs used in inflammatory bowel disease are chosen on the basis of disease severity, responsiveness, and drug toxicity (Figure 62–7).

Figure 62–7

Therapeutic pyramid approach to inflammatory bowel diseases. Treatment choice is predicated on both the severity of the illness and the responsiveness to therapy. Agents at the bottom of the pyramid are less efficacious but carry a lower risk of serious adverse effects. Drugs may be used alone or in various combinations. Patients with mild disease may be treated with 5-aminosalicylates (with ulcerative colitis or Crohn's colitis), topical corticosteroids (ulcerative colitis), antibiotics (Crohn's colitis or Crohn's perianal disease), or budesonide (Crohn's ileitis). Patients with moderate disease or patients who fail initial therapy for mild disease may be treated with oral corticosteroids to promote disease remission; immunomodulators (azathioprine, mercaptopurine, methotrexate) to promote or maintain disease remission; or anti-TNF antibodies. Patients with moderate disease who fail other therapies or patients with severe disease may require intravenous corticosteroids, anti-TNF antibodies, or surgery. Natalizumab is reserved for patients with severe Crohn's disease who have failed immunomodulators and TNF antagonists. Cyclosporine is used primarily for patients with severe ulcerative colitis who have failed a course of intravenous corticosteroids. TNF, tumor necrosis factor.

Aminosalicylates

Chemistry & Formulations

Drugs that contain 5-aminosalicylic acid (5-ASA) have been used successfully for decades in the treatment of inflammatory bowel diseases (Figure 62–8). 5-ASA differs from salicylic acid only by the addition of an amino group at the 5 (meta) position. Aminosalicylates are believed to work topically (not systemically) in areas of diseased gastrointestinal mucosa. Up to 80% of unformulated, aqueous 5-ASA is absorbed from the small intestine and does not reach the distal small bowel or colon in appreciable quantities. To overcome the rapid absorption of 5-ASA from the proximal small intestine, a number of formulations have been designed to deliver 5-ASA to various distal segments of the small bowel or the colon. These include sulfasalazine, olsalazine, balsalazide, and various forms of mesalamine.

Figure 62–8

Chemical structures and metabolism of aminosalicylates. Azo compounds (balsalazide, olsalazine, sulfasalazine) are converted by bacterial azoreductase to 5-aminosalicylic acid (mesalamine), the active therapeutic moiety.

Azo Compounds

Sulfasalazine, balsalazide, and olsalazine contain 5-ASA bound by an azo (N=N) bond to an inert compound or to another 5-ASA molecule (Figure 62–8). In sulfasalazine, 5-ASA is bound to sulfapyridine; in balsalazide, 5-ASA is bound to 4-aminobenzoyl--alanine; and in olsalazine, two 5-ASA molecules are bound together. The azo structure markedly reduces absorption of the parent drug from the small intestine. In the terminal ileum and colon, resident bacteria cleave the azo bond by means of an azoreductase enzyme, releasing the active 5-ASA. Consequently, high concentrations of active drug are made available in the terminal ileum or colon.

Mesalamine Compounds

Other proprietary formulations have been designed that package 5-ASA itself in various ways to deliver it to different segments of the small or large bowel. These 5-ASA formulations are known generically as mesalamine. Pentasa is a mesalamine formulation that contains timed-release microgranules that release 5-ASA throughout the small intestine (Figure 62–9). Asacol has 5-ASA coated in a pH-sensitive resin that dissolves at pH 7 (the pH of the distal ileum and proximal colon). Lialda also uses a pH-dependent resin that encases a multimatrix core. On dissolution of the pH-sensitive resin in the colon, water slowly penetrates its hydrophilic and lipophilic core, leading to slow release of mesalamine throughout the colon. 5-ASA also may be delivered in high concentrations to the rectum and sigmoid colon by means of enema formulations (Rowasa) or suppositories (Canasa).

Figure 62–9

Sites of 5-aminosalicylic acid (5-ASA) release from different formulations in the small and large intestines.

Pharmacokinetics & Pharmacodynamics

Although unformulated 5-ASA is readily absorbed from the small intestine, absorption of 5-ASA from the colon is extremely low. In contrast, approximately 20–30% of 5-ASA from current oral mesalamine formulations is systemically absorbed in the small intestine. Absorbed 5-ASA undergoes N-acetylation in the gut epithelium and liver to a metabolite that does not possess significant anti-inflammatory activity. The acetylated metabolite is excreted by the kidneys.

Of the azo compounds, 10% of sulfasalazine and less than 1% of balsalazide are absorbed as native compounds. After azoreductase breakdown of sulfasalazine, over 85% of the carrier molecule sulfapyridine is absorbed from the colon. Sulfapyridine undergoes hepatic metabolism (including acetylation) followed by renal excretion. By contrast, after azoreductase breakdown of balsalazide, over 70% of the carrier peptide is recovered intact in the feces and only a small amount of systemic absorption occurs.

The mechanism of action of 5-ASA is not certain. The primary action of salicylate and other NSAIDs is due to blockade of prostaglandin synthesis by inhibition of cyclooxygenase. However, the aminosalicylates have variable effects on prostaglandin production. It is thought that 5-ASA modulates inflammatory mediators derived from both the cyclooxygenase and lipoxygenase pathways. Other potential mechanisms of action of the 5-ASA drugs relate to their ability to interfere with the production of inflammatory cytokines. 5-ASA inhibits the activity of nuclear factor-B (NF-B), an important transcription factor for proinflammatory cytokines. 5-ASA may also inhibit cellular functions of natural killer cells, mucosal lymphocytes, and macrophages, and it may scavenge reactive oxygen metabolites.

Clinical Uses

5-ASA drugs induce and maintain remission in ulcerative colitis and are considered to be the first-line agents for treatment of mild to moderate active ulcerative colitis. Their efficacy in Crohn's disease is unproven, although many clinicians use 5-ASA agents as first-line therapy for mild to moderate disease involving the colon or distal ileum.

The effectiveness of 5-ASA therapy depends in part on achieving high drug concentration at the site of active disease. Thus, 5-ASA suppositories or enemas are useful in patients with ulcerative colitis or Crohn's disease confined to the rectum (proctitis) or distal colon (proctosigmoiditis). In patients with ulcerative colitis or Crohn's colitis that extends to the proximal colon, both the azo compounds and mesalamine formulations are useful. For the treatment of Crohn's disease involving the small bowel, mesalamine compounds, which release 5-ASA in the small intestine, have a theoretic advantage over the azo compounds.

Adverse Effects

Sulfasalazine has a high incidence of adverse effects, most of which are attributable to systemic effects of the sulfapyridine molecule. Slow acetylators of sulfapyridine have more frequent and more severe adverse effects than fast acetylators. Up to 40% of patients cannot tolerate therapeutic doses of sulfasalazine. The most common problems are dose-related and include nausea, gastrointestinal upset, headaches, arthralgias, myalgias, bone marrow suppression, and malaise. Hypersensitivity to sulfapyridine (or, rarely, 5-ASA) can result in fever, exfoliative dermatitis, pancreatitis, pneumonitis, hemolytic anemia, pericarditis, or hepatitis. Sulfasalazine has also been associated with oligospermia, which reverses upon discontinuation of the drug. Sulfasalazine impairs folate absorption and processing; hence, dietary supplementation with 1 mg/d folic acid is recommended.

In contrast to sulfasalazine, other aminosalicylate formulations are well tolerated. In most clinical trials, the frequency of drug adverse events is similar to that in patients treated with placebo. For unclear reasons, olsalazine may stimulate a secretory diarrhea—which should not be confused with active inflammatory bowel disease—in 10% of patients. Rare hypersensitivity reactions may occur with all aminosalicylates but are much less common than with sulfasalazine. Careful studies have documented subtle changes indicative of renal tubular damage in patients receiving high doses of aminosalicylates. Rare cases of interstitial nephritis are reported, particularly in association with high doses of mesalamine formulations; this may be attributable to the higher serum 5-ASA levels attained with these drugs. Sulfasalazine and other aminosalicylates rarely cause worsening of colitis, which may be misinterpreted as refractory colitis.

Glucocorticoids

Pharmacokinetics & Pharmacodynamics

In gastrointestinal practice, prednisone and prednisolone are the most commonly used oral glucocorticoids. These drugs have an intermediate duration of biologic activity allowing once-daily dosing.

Hydrocortisone enemas, foam, or suppositories are used to maximize colonic tissue effects and minimize systemic absorption via topical treatment of active inflammatory bowel disease in the rectum and sigmoid colon. Absorption of hydrocortisone is reduced with rectal administration, although 15–30% of the administered dosage is still absorbed.

Budesonide is a potent synthetic analog of prednisolone that has high affinity for the glucocorticoid receptor but is subject to rapid first-pass hepatic metabolism (in part by CYP3A4), resulting in low oral bioavailability. A controlled-release oral formulation of budesonide (Entocort) is available that releases the drug in the distal ileum and colon, where it is absorbed. The bioavailability of controlled-release budesonide capsules is approximately 10%.

As in other tissues, glucocorticoids inhibit production of inflammatory cytokines (TNF-, IL-1) and chemokines (IL-8); reduce expression of inflammatory cell adhesion molecules; and inhibit gene transcription of nitric oxide synthase, phospholipase A₂, cyclooxygenase-2, and NF-B.

Clinical Uses

Glucocorticoids are commonly used in the treatment of patients with moderate to severe active inflammatory bowel disease. Active disease is commonly treated with an initial oral dosage of 40–60 mg/d of prednisone or prednisolone. Higher doses have not been shown to be more efficacious but have significantly greater adverse effects. Once a patient responds to initial therapy (usually within 1–2 weeks), the dosage is tapered to minimize development of adverse effects. In severely ill patients, the drugs are usually administered intravenously.

For the treatment of inflammatory bowel disease involving the rectum or sigmoid colon, rectally administered glucocorticoids are preferred because of their lower systemic absorption.

Oral controlled-release budesonide (9 mg/d) is commonly used in the treatment of mild to moderate Crohn's disease involving the ileum and proximal colon. It appears to be slightly less effective than prednisolone in achieving clinical remission, but has significantly less adverse systemic effects.

Corticosteroids are not useful for maintaining disease remission. Other medications such as aminosalicylates or immunosuppressive agents should be used for this purpose.

Adverse Effects

Adverse effects of glucocorticoids are reviewed in Chapter 39.

Purine Analogs: Azathioprine & 6-Mercaptopurine

Pharmacokinetics & Pharmacodynamics

Azathioprine and 6-mercaptopurine (6-MP) are purine antimetabolites that have immunosuppressive properties (see Chapters 54 and 55).

The bioavailability of azathioprine (80%) is superior to 6-MP (50%). After absorption azathioprine is rapidly converted by a nonenzymatic process to 6-MP. 6-Mercaptopurine subsequently undergoes a complex biotransformation via competing catabolic enzymes (xanthine oxidase and thiopurine methyltransferase) that produce inactive metabolites and anabolic pathways that produce active thioguanine nucleotides. Azathioprine and 6-MP have a serum half-life of less than 2 hours; however, the active 6-thioguanine nucleotides are concentrated in cells resulting in a prolonged half-life of days. The prolonged kinetics of 6-thioguanine nucleotide results in a median delay of 17 weeks before onset of therapeutic benefit from oral azathioprine or 6-MP is observed in patients with inflammatory bowel disease.

Clinical Uses

Azathioprine and 6-MP are important agents in the induction and maintenance of remission of ulcerative colitis and Crohn's disease. Although the optimal dose is uncertain, most patients with normal thiopurine-S-methyltransferase (TPMT) activity (see below) are treated with 6-MP, 1–1.5 mg/kg/d, or azathioprine, 2–2.5 mg/kg/d. After 3–6 months of treatment, 50–60% of patients with active disease achieve remission. These agents help maintain remission in up to 80% of patients. Among patients who depend on long-term glucocorticoid therapy to control active disease, purine analogs allow dose reduction or elimination of steroids in the majority.

Adverse Effects

Dose-related toxicities of azathioprine or 6-MP include nausea, vomiting, bone marrow depression (leading to leukopenia, macrocytosis, anemia, or thrombocytopenia), and hepatic toxicity. Routine laboratory monitoring with complete blood count and liver function tests is required in all patients. Leukopenia or elevations in liver chemistries usually respond to medication dose reduction. Severe leukopenia may predispose to opportunistic infections; leukopenia may respond to therapy with granulocyte stimulating factor. Catabolism of 6-MP by TPMT is low in 11% and absent in 0.3% of the population, leading to increased production of active 6-thioguanine metabolites and increased risk of bone marrow depression. TPMT levels can be measured before initiating therapy. These drugs should not be administered to patients with no TPMT activity and should be initiated at lower doses in patients with intermediate activity. Hypersensitivity reactions to azathioprine or 6-MP occur in 5% of patients. These include fever, rash, pancreatitis, diarrhea, and hepatitis.

Although transplant recipients receiving long-term 6-MP or azathioprine therapy appear to have an increased risk of lymphoma, it is unclear whether the risk is increased among patients with inflammatory bowel disease. These drugs cross the placenta; however, there are many reports of successful pregnancies in women taking these agents, and the risk of teratogenicity appears to be small.

Drug Interactions

Allopurinol markedly reduces xanthine oxide catabolism of the purine analogs, potentially increasing active 6-thioguanine nucleotides that may lead to severe leukopenia. The dose of 6-MP or azathioprine should be reduced by at least half in patients taking allopurinol.

Methotrexate

Pharmacokinetics & Pharmacodynamics

Methotrexate is another antimetabolite that has beneficial effects in a number of chronic inflammatory diseases, including Crohn's disease and rheumatoid arthritis (see Chapter 36), and in cancer (see Chapter 54). Methotrexate may be given orally, subcutaneously, or intramuscularly. Reported oral bioavailability is 50–90% at doses used in chronic inflammatory diseases. Intramuscular and subcutaneous methotrexate exhibit nearly complete bioavailability.

The principal mechanism of action is inhibition of dihydrofolate reductase, an enzyme important in the production of thymidine and purines. At the high doses used for chemotherapy, methotrexate inhibits cellular proliferation. However, at the low doses used in the treatment of inflammatory bowel disease (12–25 mg/wk), the antiproliferative effects may not be evident. Methotrexate may interfere with the inflammatory actions of interleukin-1. It may also stimulate increased release of adenosine, an endogenous anti-inflammatory autacoid. Methotrexate may also stimulate apoptosis and death of activated T lymphocytes.

Clinical Uses

Methotrexate is used to induce and maintain remission in patients with Crohn's disease. Its efficacy in ulcerative colitis is uncertain. To induce remission, patients are treated with 15–25 mg of methotrexate once weekly by subcutaneous injection. If a satisfactory response is achieved within 8–12 weeks, the dose is reduced to 15 mg/wk.

Adverse Effects

At higher dosage, methotrexate may cause bone marrow depression, megaloblastic anemia, alopecia, and mucositis. At the doses used in the treatment of inflammatory bowel disease, these events are uncommon but warrant dose reduction if they do occur. Folate supplementation reduces the risk of these events without impairing the anti-inflammatory action.

In patients with psoriasis treated with methotrexate, hepatic damage is common; however, among patients with inflammatory bowel disease and rheumatoid arthritis, the risk is significantly lower. Renal insufficiency may increase risk of hepatic accumulation and toxicity.

Anti-Tumor Necrosis Factor Therapy

Pharmacokinetics & Pharmacodynamics

A dysregulation of the helper T cell type 1 (TH1) response and regulatory T cells (Tregs) is present in inflammatory bowel disease, especially Crohn's disease. One of the key proinflammatory cytokines in inflammatory bowel disease is tumor necrosis factor (TNF). TNF is produced by the innate immune system (eg, dendritic cells, macrophages), the adaptive immune system (especially TH1 cells), and nonimmune cells (fibroblasts, smooth muscle cells). TNF exists in two biologically active forms: soluble TNF and membrane-bound TNF. The biologic activity of soluble and membrane-bound TNF is mediated by binding to TNF receptors (TNFR) that are present on some cells (especially TH1 cells, innate immune cells, and fibroblasts). Binding of TNF to TNFR initially activates components including NF-B that stimulate transcription, growth, and expansion. Biologic actions ascribed to TNFR activation include release of proinflammatory cytokines from macrophages, T-cell activation and proliferation, fibroblast collagen production, up-regulation of endothelial adhesion molecules responsible for leukocyte migration, and stimulation of hepatic acute phase reactants. Activation of TNFR may later lead to apoptosis (programmed cell death) of activated cells.

Three monoclonal antibodies to human TNF are approved for the treatment of inflammatory bowel disease: infliximab, adalimumab, and certolizumab (Table 62–3). Infliximab and adalimumab are antibodies of the IgG₁ subclass. Certolizumab is a recombinant antibody that contains an Fab fragment that is conjugated to polyethylene glycol (PEG) but lacks an Fc portion. The Fab portions of infliximab and certolizumab are chimeric mouse-human antibodies but adalimumab is fully humanized. Infliximab is administered as an intravenous infusion. At therapeutic doses of 5–10 mg/kg, the half-life of infliximab is approximately 8–10 days, resulting in plasma disappearance of antibodies over 8–12 weeks. Adalimumab and certolizumab are administered by subcutaneous injection. The half-life for both is approximately 2 weeks.

Table 62–3 Anti-TNF Antibodies Used in Inflammatory Bowel Disease.

	Infliximab	Adalimumab	Certolizumab
Class	Monoclonal antibody	Monoclonal antibody	Monoclonal antibody
% Human	75%	100%	95%
Structure	IgG1	IgG1	Fab fragment attached to PEG (lacks Fc portion)
Route of administration	Intravenous	Subcutaneous	Subcutaneous
Half-life	8–10 days	10–20 days	14 days
Neutralizes soluble TNF	Yes	Yes	Yes
Neutralizes membrane-bound TNF	Yes	Yes	Yes
Induces apoptosis of cells expressing membrane-bound TNF	Yes	Yes	No
Complement-mediated cytotoxicity of cells expressing membrane-bound TNF	Yes	Yes	No
Induction dose	5 mg/kg at 0, 2, and 6 weeks	160 mg, 80 mg, and 40 mg at 0, 2, and 4 weeks	400 mg at 0, 2, and 4 weeks
Maintenance dose	5 mg/kg every 8 weeks	40 mg every 2 weeks	400 mg every 4 weeks

TNF, tumor necrosis factor.

All three agents bind to soluble and membrane-bound TNF with high affinity, preventing the cytokine from binding to its receptors. Binding of all three antibodies to membrane-bound TNF also causes reverse signaling that suppresses cytokine release. When infliximab or adalimumab bind to membrane-bound TNF, the Fc portion of the human IgG₁ region promotes antibody-mediated apoptosis, complement activation, and cellular cytotoxicity of activated T lymphocytes and macrophages. Certolizumab, without an Fc portion, lacks these properties.

Clinical Uses

All three agents are approved for the acute and chronic treatment of patients with moderate to severe Crohn's disease who have had an inadequate response to conventional therapies. Infliximab also is approved for the acute and chronic treatment of moderate to severe ulcerative colitis. With induction therapy, all three agents lead to symptomatic improvement in 60% and disease remission in 30% of patients with moderate to severe Crohn's disease, including patients who have been dependent on glucocorticoids or who have not responded to 6-MP or methotrexate. The median time to clinical response is 2 weeks. Induction therapy is generally given as follows: infliximab 5 mg/kg intravenous infusion at 0, 2, and 6 weeks; adalimumab 160 mg (in divided doses) initially and 80 mg subcutaneous injection at 2 weeks; and certolizumab 400 mg subcutaneous injection at 0, 2, and 4 weeks. Patients who respond may be treated with chronic maintenance therapy, as follows: infliximab 5 mg/kg intravenous infusion every 8 weeks; adalimumab 40 mg subcutaneous injection every 2 weeks; certolizumab 400 mg subcutaneous injection every 4 weeks. With chronic, regularly scheduled therapy, clinical response is maintained in more than 60% of patients and disease remission in 40%. However, one-third of patients eventually lose response despite higher doses or more frequent injections. Loss of response in many patients may be due to the development of antibodies to the TNF antibody or to other mechanisms.

Infliximab is approved for the treatment of patients with moderate to severe ulcerative colitis who have had inadequate response to mesalamine or corticosteroids. After induction therapy of 5–10 mg/wk at 0, 2, and 6 weeks, 70% of patients have a clinical response and one third achieve a clinical remission. With continued maintenance infusions every 8 weeks, approximately 50% of patients have continued clinical response.

Adverse Effects

Serious adverse events occur in up to 6% of patients with anti-TNF therapy. The most important adverse effect of these drugs is infection due to suppression of the TH1 inflammatory response. This may lead to serious infections such as bacterial sepsis, tuberculosis, invasive fungal organisms, reactivation of hepatitis B, listeriosis, and other opportunistic infections. Reactivation of latent tuberculosis, with dissemination, has occurred. Before administering anti-TNF therapy, all patients must undergo purified protein derivative (PPD) testing; prophylactic therapy for tuberculosis is warranted for patients with positive test results. More common but usually less serious infections include upper respiratory infections (sinusitis, bronchitis, and pneumonia) and cellulitis. The risk of serious infections is increased markedly in patients taking concomitant corticosteroids.

Antibodies to the antibody (ATA) may develop with all three agents. These antibodies may attenuate or eliminate the clinical response and increase the likelihood of developing acute or delayed infusion or injection reactions. Antibody formation is much more likely in patients given episodic anti-TNF therapy than regular scheduled injections. In patients on chronic maintenance therapy, the prevalence of ATA with infliximab is 10%, certolizumab 8%, and adalimumab 3%. Antibody development also is less likely in patients who receive concomitant therapy with immunomodulators (ie, 6-MP or methotrexate). However, there are increasing concerns that concomitant treatment with anti-TNF agents and immunomodulators may increase the risk of lymphoma.

Infliximab intravenous infusions result in acute adverse infusion reactions in up to 10% of patients, but discontinuation of the infusion for severe reactions is required in less than 2%. Infusion reactions are more common with the second or subsequent infusions than with the first. Early mild reactions include fever, headache, dizziness, urticaria, or mild cardiopulmonary symptoms that include chest pain, dyspnea, or hemodynamic instability. Reactions to subsequent infusions may be reduced with prophylactic administration of acetaminophen, diphenhydramine, or corticosteroids. Severe acute reactions include significant hypotension, shortness of breath, muscle spasms, and chest discomfort; such reactions may require treatment with oxygen, epinephrine, and corticosteroids.

A delayed serum sickness-like reaction may occur 1–2 weeks after anti-TNF therapy in 1% of patients. These reactions consist of myalgia, arthralgia, jaw tightness, fever, rash, urticaria, and edema and usually require discontinuation of that agent. Positive antinuclear antibodies and anti-double-stranded DNA develop in a small number of patients. Development of a lupus-like syndrome is rare and resolves after discontinuation of the drug.

Rare but serious adverse effects of all anti-TNF agents also include severe hepatic reactions leading to acute hepatic failure, demyelinating disorders, hematologic reactions, and new or worsened congestive heart failure in patients with underlying heart disease.

Lymphoma appears to be increased in patients with untreated inflammatory bowel disease. Anti-TNF agents may further increase the risk of lymphoma in this population, although the relative risk is uncertain. An increased number of cases of hepatosplenic T-cell lymphoma, a rare but usually fatal disease, have been noted in children and young adults, virtually all of whom have been on combined therapy with immunomodulators, anti-TNF agents, or corticosteroids.

Anti-Integrin Therapy

Integrins are a family of adhesion molecules on the surface of leukocytes that may interact with another class of adhesion molecules on the surface of the vascular endothelium known as selectins, allowing circulating leukocytes to adhere to the vascular endothelium and subsequently move through the vessel wall into the tissue. Integrins consist of heterodimers that contain two subunits, (alpha) and (beta). Natalizumab is a humanized IgG₄ monoclonal antibody targeted against the 4 subunit, which thereby blocks several integrins on circulating inflammatory cells and thus prevents binding to the vascular adhesion molecules and subsequent migration into surrounding tissues.

Natalizumab has shown significant efficacy for a subset of patients with moderate to severe Crohn's disease. Unfortunately, in initial clinical trials of patients with Crohn's disease and multiple sclerosis, 3 of 3100 patients treated with natalizumab developed progressive multifocal leukoencephalopathy due to reactivation of a human polyomavirus (JC virus), which is present in latent form in over 80% of adults. All three patients were receiving concomitant therapy with other immunomodulators. After voluntary withdrawal and review of the drug by the manufacturer in 2005, it was approved by the FDA in 2008 for patients with moderate to severe Crohn's disease who have failed other therapies through a carefully restricted program. The approved dosage is 300 mg every 4 weeks by intravenous infusion, and patients should not be on other immune suppressant agents. Approximately 50% of patients respond to initial therapy with natalizumab. Of patients with an initial response, long-term response is maintained in 60% and remission in over 40%. Other adverse effects include acute infusion reactions and a small risk of opportunistic infections.

Pancreatic Enzyme Supplements

Exocrine pancreatic insufficiency is most commonly caused by cystic fibrosis, chronic pancreatitis, or pancreatic resection. When secretion of pancreatic enzymes falls below 10% of normal, fat and protein digestion is impaired and can lead to steatorrhea, azotorrhea, vitamin malabsorption, and weight loss. Pancreatic enzyme supplements, which contain a mixture of amylase, lipase, and proteases, are the mainstay of treatment for pancreatic enzyme insufficiency. Two major types of preparations in use are pancreatin and pancrelipase. Pancreatin is an alcohol-derived extract of hog pancreas with relatively low concentrations of lipase and proteolytic enzymes, whereas pancrelipase is an enriched preparation. On a per-weight basis, pancrelipase has approximately 12 times the lipolytic activity and more than 4 times the proteolytic activity of pancreatin. Consequently, pancreatin is no longer in common clinical use. Only pancrelipase is discussed here.

Pancrelipase is available in both non–enteric-coated and enteric-coated preparations. Pancrelipase enzymes are rapidly and permanently inactivated by gastric acids. Therefore, non–enteric-coated preparations (eg, Viokase tablets or powder) should be given concomitantly with acid suppression therapy (proton pump inhibitor or H2 antagonist) to reduce acid-mediated destruction within the stomach. Encapsulated formulations contain acid-resistant microspheres (Creon) or microtablets (Pancrease, Ultrase). Enteric-coated formulations are more commonly used because they do not require concomitant acid suppression therapy.

Pancrelipase preparations are administered with each meal and snack. Formulations are available in sizes containing varying amounts of lipase, amylase, and protease. However, manufacturers' listings of enzyme content do not always reflect true enzymatic activity. Enzyme activity may be listed in international units (IU) or USP units. One IU is equal to 2–3 USP units. Dosing should be individualized according to the age and weight of the patient, the degree of pancreatic insufficiency, and the amount of dietary fat intake. Therapy is initiated at a dose that provides 30,000 IUs (60,000–90,000 USP) of lipase activity in the prandial and postprandial period—a level that is sufficient to reduce steatorrhea to a clinically insignificant level in most cases. Suboptimal response to enteric-coated formulations may be due to poor mixing of granules with food or slow dissolution and release of enzymes. Gradual increase of dose, change to a different formulation, or addition of acid suppression therapy may improve response. For patients with feeding tubes, powder formulations (Viokase), or microspheres may be mixed with enteral feeding prior to administration.

Pancreatic enzyme supplements are well tolerated. The capsules should be swallowed, not chewed, because pancreatic enzymes may cause oropharyngeal mucositis. Excessive doses may cause diarrhea and abdominal pain. The high purine content of pancreas extracts may lead to hyperuricosuria and renal stones. Several cases of colonic strictures were reported in patients with cystic fibrosis who received high doses of pancrelipase with high lipase activity. These high-dose formulations have since been removed from the market.

Bile Acid Therapy for Gallstones

Ursodiol (ursodeoxycholic acid) is a naturally occurring bile acid that makes up less than 5% of the circulating bile salt pool in humans and a much higher percentage in bears. After oral administration, it is absorbed, conjugated in the liver with glycine or taurine, and excreted in the bile. Conjugated ursodiol undergoes extensive enterohepatic recirculation. The serum half-life is approximately 100 hours. With long-term daily administration, ursodiol constitutes 30–50% of the circulating bile acid pool. A small amount of unabsorbed conjugated or unconjugated ursodiol passes into the colon, where it is either excreted or undergoes dehydroxylation by colonic bacteria to lithocholic acid, a substance with potential hepatic toxicity.

Pharmacodynamics

The solubility of cholesterol in bile is determined by the relative proportions of bile acids, lecithin, and cholesterol. Although prolonged ursodiol therapy expands the bile acid pool, this does not appear to be the principal mechanism of action for dissolution of gallstones. Ursodiol decreases the cholesterol content of bile by reducing hepatic cholesterol secretion. Ursodiol also appears to stabilize hepatocyte canalicular membranes, possibly through a reduction in the concentration of other endogenous bile acids or through inhibition of immune-mediated hepatocyte destruction.

Clinical Use

Ursodiol is used for dissolution of small cholesterol gallstones in patients with symptomatic gallbladder disease who refuse cholecystectomy or who are poor surgical candidates. At a dosage of 10 mg/kg/d for 12–24 months, dissolution occurs in up to 50% of patients with small (< 5–10 mm) noncalcified gallstones. It is also effective for the prevention of gallstones in obese patients undergoing rapid weight loss therapy. Several trials demonstrate that ursodiol 13–15 mg/kg/d is helpful for patients with early-stage primary biliary cirrhosis, reducing liver function abnormalities and improving liver histology.

Adverse Effects

Ursodiol is practically free of serious adverse effects. Bile salt-induced diarrhea is uncommon. Unlike its predecessor, chenodeoxycholate, ursodiol has not been associated with hepatotoxicity.

Drugs Used to Treat Variceal Hemorrhage

Portal hypertension most commonly occurs as a consequence of chronic liver disease. Portal hypertension is caused by increased blood flow within the portal venous system and increased resistance to portal flow within the liver. Splanchnic blood flow is increased in patients with cirrhosis due to low arteriolar resistance that is mediated by increased circulating vasodilators and decreased vascular sensitivity to vasoconstrictors. Intrahepatic vascular resistance is increased in cirrhosis due to fixed fibrosis within the spaces of Disse and hepatic veins as well as reversible vasoconstriction of hepatic sinusoids and venules. Among the consequences of portal hypertension are ascites, hepatic encephalopathy, and the development of portosystemic collaterals—especially gastric or esophageal varices. Varices can rupture, leading to massive upper gastrointestinal bleeding.

Several drugs are available that reduce portal pressures. These may be used in the short term for the treatment of active variceal hemorrhage or long term to reduce the risk of hemorrhage.

Somatostatin & Octreotide

The pharmacology of octreotide is discussed above under Antidiarrheal Agents. In patients with cirrhosis and portal hypertension, intravenous somatostatin (250 mcg/h) or octreotide (50 mcg/h) reduces portal blood flow and variceal pressures; however, the mechanism by which they do so is poorly understood. They do not appear to induce direct contraction of vascular smooth muscle. Their activity may be mediated through inhibition of release of glucagon and other gut peptides that alter mesenteric blood flow. Although data from clinical trials are conflicting, these agents are probably effective in promoting initial hemostasis from bleeding esophageal varices. They are generally administered for 3–5 days.

Vasopressin & Terlipressin

Vasopressin (antidiuretic hormone) is a polypeptide hormone secreted by the hypothalamus and stored in the posterior pituitary. Its pharmacology is discussed in Chapters 17 and 37. Although its primary physiologic role is to maintain serum osmolality, it is also a potent arterial vasoconstrictor. When administered intravenously by continuous infusion, vasopressin causes splanchnic arterial vasoconstriction that leads to reduced splanchnic perfusion and lowered portal venous pressures. Before the advent of octreotide, vasopressin was commonly used to treat acute variceal hemorrhage. However, because of its high adverse-effect profile, it is no longer used for this purpose. In contrast, for patients with acute gastrointestinal bleeding from small bowel or large bowel vascular ectasias or diverticulosis, vasopressin may be infused—to promote vasospasm—into one of the branches of the superior or inferior mesenteric artery through an angiographically placed catheter. Adverse effects with systemic vasopressin are common. Systemic and peripheral vasoconstriction can lead to hypertension, myocardial ischemia or infarction, or mesenteric infarction. These effects may be reduced by coadministration of nitroglycerin, which may further reduce portal venous pressures (by reducing portohepatic vascular resistance) and may also reduce the coronary and peripheral vascular vasospasm caused by vasopressin. Other common adverse effects are nausea, abdominal cramps, and diarrhea (due to intestinal hyperactivity). Furthermore, the antidiuretic effects of vasopressin promote retention of free water, which can lead to hyponatremia, fluid retention, and pulmonary edema.

Terlipressin is a vasopressin analog that appears to have similar efficacy to vasopressin with fewer adverse effects. Although this agent is available in other countries, it has never been approved for use in the USA.

Beta-Receptor–Blocking Drugs

The pharmacology of -receptor–blocking agents is discussed in Chapter 10. Beta-receptor antagonists reduce portal venous pressures via a decrease in portal venous inflow. This decrease is due to a decrease in cardiac output (₁ blockade) and to splanchnic vasoconstriction (₂ blockade) caused by the unopposed effect of systemic catecholamines on receptors. Thus, nonselective blockers such as propranolol and nadolol are more effective than selective ₁ blockers in reducing portal pressures. Among patients with cirrhosis and esophageal varices who have not previously had an episode of variceal hemorrhage, the incidence of bleeding among patient treated with nonselective blockers is 15% compared with 25% in control groups. Among patients with a history of variceal hemorrhage, the likelihood of recurrent hemorrhage is 80% within 2 years. Nonselective blockers significantly reduce the rate of recurrent bleeding, although a reduction in mortality is unproved.

Summary: Drugs Used Primarily for Gastrointestinal Conditions

Drugs Used Primarily for Gastrointestinal Conditions

Subclass	Mechanism of Action	Effects	Clinical Applications	Pharmacokinetics, Toxicities, Interactions
Drugs used in acid-peptic diseases
Proton pump inhibitors (PPIs), eg, omeprazole, lansoprazole	Irreversible blockade of H^+,K^+-ATPase pump in active parietal cells of stomach	Long-lasting reduction of stimulated and nocturnal acid secretion	Peptic ulcer, gastroesophageal reflux disease, erosive gastritis	Half-lives much shorter than duration of action low toxicity reduction of stomach acid may reduce absorption of some drugs and increase that of others
H2-receptor blockers, eg, cimetidine: Effective reduction of nocturnal acid but less effective against stimulated secretion; very safe, available over the counter (OTC). Cimetidine, but not other H2 blockers, is a weak antiandrogenic agent and a potent CYP enzyme inhibitor
Sucralfate: Polymerizes at site of tissue damage (ulcer bed) and protects against further damage; very insoluble with no systemic effects; must be given four times daily
Antacids: Popular OTC medication for symptomatic relief of heartburn; not as useful as PPI and H2 blockers in peptic diseases
Drugs stimulating motility
Metoclopramide	D2-receptor blocker removes inhibition of acetylcholine neurons in enteric nervous system	Increases gastric emptying and intestinal motility	Gastric paresis (eg, in diabetes) antiemetic (see below)	Parkinsonian symptoms due to block of central nervous system (CNS) D2 receptors
Domperidone: Like metoclopramide, but less CNS effect; not available in USA
Cholinomimetics: Neostigmine often used for colonic pseudo-obstruction in hospitalized patients
Macrolides: Erythromycin useful in diabetic gastroparesis but tolerance develops
Laxatives
Magnesium hydroxide, other nonabsorbable salts and sugars	Osmotic agents increase water content of stool	Usually causes evacuation within 4–6 h, sooner in large doses	Simple constipation; bowel prep for endoscopy (especially PEG solutions)	Magnesium may be absorbed and cause toxicity in renal impairment
Bulk-forming laxatives: Methylcellulose, psyllium, etc: increase volume of colon, stimulate evacuation
Stimulants: senna, cascara; stimulate activity; may cause cramping
Stool surfactants: Docusate, mineral oil; lubricate stool, ease passage
Chloride channel activator: Lubiprostone, prostanoic acid derivative, stimulates chloride secretion into intestine, increasing fluid content
Opioid receptor antagonists: Alvimopan, methylnaltrexone; block intestinal -opioid receptors but do not enter CNS, so analgesia is maintained
5-HT 4 agonists: Tegaserod; activates enteric 5-HT4 receptors and increases intestinal motility
Antidiarrheal drugs
Loperamide	Activates -opioid receptors in enteric nervous system	Slows motility in gut with negligible CNS effects	Nonspecific, noninfectious diarrhea	Mild cramping but little or no CNS toxicity
Diphenoxylate: Similar to loperamide, but high doses can cause CNS opioid effects and toxicity
Colloidal bismuth compounds: Subsalicylate and citrate salts available. OTC preparations popular and have some value in travelers' diarrhea due to adsorption of toxins
Kaolin + pectin: Adsorbent compounds available OTC
Drugs for irritable bowel syndrome (IBS)
Alosetron	5-HT3 antagonist of high potency and duration of binding	Reduces smooth muscle activity in gut	Approved for severe diarrhea-predominant IBS in women	Rare but serious constipation ischemic colitis infarction
Anticholinergics: Nonselective action on gut activity, usually associated with typical antimuscarinic toxicity
Chloride channel activator: Lubiprostone (see above); useful in constipation-predominant IBS in women
Antiemetic drugs
Ondansetron, other 5-HT3 antagonists	5-HT3 blockade in gut and CNS with shorter duration of binding than alosetron	Extremely effective in preventing chemotherapy-induced and postoperative nausea and vomiting	First-line agents in cancer chemotherapy; also useful for postop emesis	Usually given IV but orally active in prophylaxis. 4–9 h duration of action very low toxicity but may slow colonic transit
Aprepitant	NK1-receptor blocker in CNS	Interferes with vomiting reflex no effect on 5-HT, dopamine, or steroid receptors	Effective in reducing both early and delayed emesis in cancer chemotherapy	Given orally IV fosaprepitant available fatigue, dizziness, diarrhea CYP interactions
Corticosteroids: Mechanism not known but useful in antiemetic IV cocktails
Antimuscarinics (scopolamine): Effective in emesis due to motion sickness; not other types
Antihistaminics: Moderate efficacy in motion sickness and chemotherapy-induced emesis
Phenothiazines: Act primarily through block of D 2 and muscarinic receptors
Cannabinoids: Dronabinol is available for use in chemotherapy-induced nausea and vomiting, but is associated with CNS marijuana effects
Drugs used in inflammatory bowel disease (IBD)
5-Aminosalicylates, eg, mesalamine in many formulations	Mechanism uncertain may be inhibition of eicosanoid inflammatory mediators	Topical therapeutic action systemic absorption may cause toxicity	Mild to moderately severe Crohn's disease and ulcerative colitis	Sulfasalazine causes sulfonamide toxicity and may cause GI upset, myalgias, arthralgias, myelosuppression other aminosalicylates much less toxic
Sulfasalazine
Purine analogs and antimetabolites, eg, 6-mercaptopurine, methotrexate	Mechanism uncertain may promote apoptosis of immune cells	Generalized suppression of immune processes	Moderately severe to severe Crohn's disease and ulcerative colitis	GI upset, mucositis myelosuppression purine analogs may cause hepatotoxicity, but rare with methotrexate at the low doses used
	Methotrexate blocks dihydrofolate reductase
Anti-TNF antibodies, eg, infliximab, others	Bind tumor necrosis factor and prevent it from binding to its receptors	Suppression of several aspects of immune function, especially TH1 lymphocytes	Infliximab: Moderately severe to severe Crohn's disease and ulcerative colitis others approved in Crohn's disease	Infusion reactions reactivation of latent tuberculosis increased risk of dangerous systemic fungal and bacterial infections
Corticosteroids: Generalized anti-inflammatory effect; see Chapter 39
Pancreatic supplements
Pancrelipase	Replacement enzymes from animal pancreatic extracts	Improves digestion of dietary fat, protein, and carbohydrate	Pancreatic insufficiency due to cystic fibrosis, pancreatitis, pancreatectomy	Taken with every meal may increase incidence of gout
Pancreatin: Similar pancreatic extracts but much lower potency; rarely used
Bile acid therapy for gallstones
Ursodiol	Reduces cholesterol secretion into bile	Dissolves gallstones	Gallstones in patients refusing or not eligible for surgery	May cause diarrhea
Drugs used to treat variceal hemorrhage
Octreotide	Somatostatin analog mechanism not certain	May alter portal blood flow and variceal pressures	Patients with bleeding varices or at high risk of repeat bleeding	Reduced endocrine and exocrine pancreatic activity other endocrine abnormalities GI upset
Blockers: Reduce cardiac output and splanchnic vascular resistance; see Chapter 10

Preparations Available

Antacids

Aluminum hydroxide gel* (AlternaGEL, others)

Oral: 300, 500, 600 mg tablets; 400, 500 mg capsules; 320, 450, 675 mg/5 mL suspension

Calcium carbonate* (Tums, others)

Oral: 350, 420, 500, 600, 650, 750, 1000, 1250 mg chewable tablets; 1250 mg/5 mL suspension

Combination aluminum hydroxide and magnesium hydroxide preparations* (Maalox, Mylanta, Gaviscon, Gelusil, others)

Oral: 400 to 800 mg combined hydroxides per tablet, capsule, or 5 mL suspension

H₂ Histamine Receptor Blockers

Cimetidine (generic, Tagamet, Tagamet HB*)

Oral: 200*, 300, 400, 800 mg tablets; 300 mg/5 mL liquid

Parenteral: 300 mg/2 mL, 300 mg/50 mL for injection

Famotidine (generic, Pepcid, Pepcid AC,* Pepcid Complete*)

Oral: 10 mg tablets,* gelcaps*; powder to reconstitute for 40 mg/5 mL suspension

Parenteral: 10 mg/mL for injection

Nizatidine (generic, Axid, Axid AR*)

Oral: 75 mg tablets*; 150, 300 mg capsules

Ranitidine (generic, Zantac, Zantac 75*)

Oral: 75,* 150, 300 mg tablets

Parenteral: 1, 25 mg/mL for injection

Selected Anticholinergic Drugs

Atropine (generic)

Oral: 0.4 mg tablets

Parenteral: 0.05, 0.1, 0.3, 0.4, 0.5, 0.8, 1 mg/mL for injection

Belladonna alkaloids tincture (generic)

Oral: 0.27–0.33 mg/mL liquid

Dicyclomine (generic, Bentyl, others)

Oral: 10, 20 mg capsules; 20 mg tablets; 10 mg/5 mL syrup

Parenteral: 10 mg/mL for injection

Glycopyrrolate (generic, Robinul)

Oral: 1, 2 mg tablets

Parenteral: 0.2 mg/mL for injection

Hyoscyamine (Anaspaz, Levsin, others)

Oral: 0.125, 0.15 mg tablets; 0.375 mg timed release capsules; 0.125 mg/5 mL oral elixir and solution

Parenteral: 0.5 mg/mL for injection

Scopolamine (generic, Transderm Scop)

Oral: 0.4 mg tablets

Transdermal patch: 1.5 mg/2.5 cm²

Parenteral: 0.4, 1 mg/mL for injection

Proton Pump Inhibitors

Esomeprazole (Nexium)

Oral: 20, 40 mg delayed-release capsules

Parenteral: 20, 40 mg vial powder for IV injection

Omeprazole (Prilosec, Prilosec OTC,* Zegerid)

Oral: 10, 20, 40 mg delayed-release capsules; 20 mg delayed-release tablet*

Lansoprazole (Prevacid)

Oral: 15, 30 mg delayed-release capsules; 15, 30 mg orally disintegrating tablet containing delayed-release granules; 15, 30 mg delayed-release granules for oral suspension

Parenteral: 30 mg powder for injection

Pantoprazole (Protonix)

Oral: 20, 40 mg delayed release tablets; 40 mg delayed-release granules for oral suspension

Parenteral: 40 mg/vial powder for IV injection

Rabeprazole (Aciphex)

Oral: 20 mg delayed-release tablets

Mucosal Protective Agents

Misoprostol (Cytotec)

Oral: 100, 200 mcg tablets

Sucralfate (generic, Carafate)

Oral: 1 g tablets; 1 g/10 mL suspension

Digestive Enzymes

Pancrelipase (Creon, Lipram, Pancrease MT, Ultrase MT, Viokase)

Oral: Tablets, powder, or delayed-release capsules containing varying amounts of lipase, protease, and amylase activity. See manufacturers' literature for details.

Drugs for Motility Disorders & Selected Antiemetics

5-HT ₃-Receptor Antagonists

Alosetron (Lotronex)

Oral: 0.5, 1 mg tablets

Dolasetron (Anzemet)

Oral: 50, 100 mg tablets

Parenteral: 20 mg/mL for injection

Granisetron (generic, Kytril)

Oral: 1 mg tablets; 2 mg/10 mL oral solution

Parenteral: 0.1, 1 mg/mL for injection

Ondansetron (generic, Zofran)

Oral: 4, 8, 16, 24 mg tablets; 4, 8 mg orally disintegrating tablets; 4 mg/5 mL oral solution

Parenteral: 2 mg/mL, 32 mg/50 mL for IV injection

Palonosetron (Aloxi)

Oral: 0.5 mg capsules

Parenteral: 0.05 mg/mL for injection

Other Motility and Antiemetic Agents

Aprepitant (Emend)

Oral: 80, 125 mg capsules

Fosaprepitant (Emend)

Parenteral: 115 mg/10 mL for IV injection

Dronabinol (Marinol)

Oral: 2.5, 5, 10 mg capsules

Metoclopramide (generic, Reglan, others)

Oral: 5, 10 mg tablets; 5 mg/5 mL syrup, 10 mg/mL concentrated solution

Parenteral: 5 mg/mL for injection

Nabilone (Cesamet)

Oral: 1 mg tablets

Prochlorperazine (Compazine)

Oral: 5, 10, 25 mg tablets; 10, 15, 30 mg capsules; 1 mg/mL solution

Rectal: 2.5, 5, 25 mg suppositories

Parenteral: 5 mg/mL for injection

Promethazine (generic, Phenergan, others)

Oral: 10, 13.2, 25, 50 mg tablets; 5, 6.25, 10 mg/5 mL syrup

Rectal: 10, 12.5, 25, 50 mg suppositories

Parenteral: 25, 50 mg/mL for IM or IV injection

Scopolamine (Transderm Scop)

Transdermal patch: 1.5 mg/2.5 cm²

Tegaserod (Zelnorm)

Oral: 2, 6 mg tablets

Trimethobenzamide (generic, Tigan, others)

Oral: 250, 300 mg capsules

Rectal: 100, 200 mg suppository

Parenteral: 100 mg/mL for injection

Selected Anti-Inflammatory Drugs Used in Gastrointestinal Disease (see also Chapter 55)

Balsalazide (Colazal)

Oral: 750 mg capsules

Budesonide (Entocort)

Oral: 3 mg capsules

Hydrocortisone (Proctofoam-HC, Cortifoam)

Rectal: 100 mg/60 mL unit retention enema; 90 mg/applicatorful intrarectal foam

Mesalamine (5-ASA)

Oral: Asacol: 400 mg delayed-release tablets; Pentasa: 250 mg controlled-release capsules

Rectal: Rowasa: 4 g/60 mL suspension

Canasa: 500, 1000 mg suppositories

Methylprednisolone (Medrol Enpack)

Rectal: 40 mg/bottle retention enema

Olsalazine (Dipentum)

Oral: 250 mg capsules

Sulfasalazine (generic, Azulfidine)

Oral: 500 mg tablets and delayed-release enteric-coated tablets

Infliximab (Remicade)

Parenteral: 100 mg powder for intravenous injection

Adalimumab (Humira)

Parenteral: 40 mg/0.8 mL for subcutaneous injection by syringe or auto-pen

Certolizumab (Cimzia)

Parenteral: 200 mg powder (reconstituted with 1 mL) for subcutaneous injection

Selected Antidiarrheal Drugs

Bismuth subsalicylate* (Pepto-Bismol, others)

Oral: 262 mg caplets, chewable tablets; 130, 262, 524 mg/15 mL suspension

Difenoxin (Motofen)

Oral: 1 mg (with 0.025 mg atropine sulfate) tablets

Diphenoxylate (generic, Lomotil, others)

Oral: 2.5 mg (with 0.025 mg atropine sulfate) tablets and liquid

Loperamide* (generic, Imodium)

Oral: 2 mg tablets, capsules; 1 mg/5 mL liquid

Bulk-Forming Laxatives*

Methylcellulose (generic, Citrucel)

Oral: bulk powder, capsules

Psyllium (generic, Serutan, Metamucil, others)

Oral: granules, bulk powder, wafer

Other Selected Laxative Drugs

Alvimopan (Entereg)

Oral: 12 mg capsules

Bisacodyl* (generic, Dulcolax, others)

Oral: 5 mg enteric-coated tablets

Rectal: 5 mg, 10 mg suppositories

Cascara sagrada* (generic)

Oral: 325 mg tablets; 5 mL per dose fluid extract (approximately 18% alcohol)

Docusate* (generic, Colace, others)

Oral: 50, 100, 250 mg capsules; 100 mg tablets; 20, 50, 60, 150 mg/15 mL syrup

Lactulose (Chronulac, Cephulac)

Oral: 10 g/15 mL syrup

Lubiprostone (Amitiza)

Oral: 8, 24 mcg capsules

Magnesium hydroxide [milk of magnesia, Epsom Salt]* (generic)

Oral: 400, 800 mg/5 mL aqueous suspension

Methylnaltrexone bromide (Relistor)

Parenteral: 12 mg/0.6 mL

Polycarbophil* (Equalactin, Mitrolan, FiberCon, Fiber-Lax)

Oral: 500, 625 mg tablets; 500 mg chewable tablets

Polyethylene glycol electrolyte solution (Co-Lyte, GoLYTELY, HalfLytely, Moviprep, others)

Oral: Powder for oral solution, makes 2L or 4L

Senna* (Senokot, ExLax, others)

Oral: 8.6, 15, 17, 25 mg tablets; 8.8, 15 mg/mL liquid

Sodium Phosphate (Fleets Phospho-soda, OsmoPrep, Visicol)

Oral: 1.5 g tablets; 10 g/15 mL liquid

Drugs That Dissolve Gallstones

Ursodiol (generic, Actigall, URSO)

Oral: 250, 500 mg tablets; 300 mg capsules

*Over-the-counter formulations.

References

Acid-Peptic Diseases

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Motility Disorders

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Laxatives

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Antidiarrheal Agents

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Drugs Used for Irritable Bowel Syndrome

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Antiemetic Agents

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Pancreatic Enzyme Supplements

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Bile Acids for Gallstone Therapy

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Drugs for Portal Hypertension

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