Basic & Clinical Pharmacology, 10th Edition

63. Drugs Used in the Treatment of Gastrointestinal Diseases - Kenneth R. McQuaid, MD

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 below according to their therapeutic uses.

I. DRUGS USED IN ACID-PEPTIC DISEASES

INTRODUCTION

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 99% 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, histamine (H₂), and acetylcholine (muscarinic, M₃) (Figure 63-1). When acetylcholine or gastrin 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.

In close proximity to the parietal cells are gut endocrine cells called enterochromaffin-like (ECL) cells. ECL cells have receptors for gastrin and acetylcholine and are the major source for 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). cAMP 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.

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. Although their principal mechanism of action is reduction of intragastric acidity, they may also promote mucosal defense mechanisms through stimulation of mucosal prostaglandin production. 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 the rate of gastric emptying.

Sodium bicarbonate (eg, baking soda, Alka Seltzer) reacts rapidly with HCl to produce carbon dioxide and NaCl. 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 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 upon 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

Introduction

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 (Figure 63-2). 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 and a bioavailability of almost 100%. The serum half-lives of the four agents range from 1.1-4 hours; however, duration of action depends on the dose given (Table 63-1). 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.

Pharmacodynamics

The H₂ antagonists exhibit competitive inhibition at the parietal cell H₂ receptor and suppress basal and meal-stimulated acid secretion in a linear, dose-dependent manner (Figure 63-3). They are highly selective and do not affect H₁ or H₃ receptors. The volume of gastric secretion and the concentration of pepsin are also reduced.

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 results in diminished acid secretion in the presence of H₂-receptor blockade. It appears that reduced parietal cell cAMP levels attenuate the intracellular activation of protein kinases by gastrin or acetylcholine.

The potencies of the four H₂-receptor antagonists vary over a 50-fold range (Table 63-1). When given in usual prescription doses however, all of the H₂ antagonists 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 have a modest impact on meal-stimulated acid secretion (which is stimulated by gastrin and acetylcholine as well as histamine). Thus, they block more than 90% of nocturnal acid but only 60-80% of daytime acid secretion. Therefore, nocturnal and fasting intragastric pH is raised to 4-5 but the impact upon 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 commonly. However, due to their superior acid inhibition and safety profile, proton pump inhibitors (see below) are steadily replacing H₂ antagonists for most clinical indications.

A. 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). H₂antagonists 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; this regimen provides effective symptom control in 50-75% of people (Table 63-1). In patients with erosive esophagitis (approximately half of patients with GERD), H₂ antagonists afford healing in less than 50% of patients. Although higher doses of H₂ antagonists increase healing rates, proton pump inhibitors are preferred.

B. PEPTIC ULCER DISEASE
Proton pump inhibitors have largely replaced H₂ antagonists in the treatment of peptic ulcer disease. Nocturnal acid suppression by either drug group affords effective ulcer healing in the majority of patients with uncomplicated gastric and duodenal ulcers. Hence, all the agents may be administered once daily at bedtime for acute, uncomplicated ulcers, resulting in ulcer healing rates greater than 80-90% after 6-8 weeks of therapy. For patients with acute peptic ulcers caused by H pylori, H₂ antagonists no longer play a significant therapeutic role. 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). For patients with ulcers caused by aspirin or other NSAIDs, H₂ antagonists provide rapid ulcer healing so long as the NSAID is discontinued. If the NSAID must be continued for clinical reasons despite active ulceration, a proton pump inhibitor should be given to promote ulcer healing.

C. 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.

D. PREVENTION OF BLEEDING FROM STRESS-RELATED GASTRITIS
H₂-receptor antagonists significantly reduce the incidence of bleeding from stress-related gastritis in seriously ill patients in the intensive care unit. H₂ antagonists are given intravenously, either as intermittent injections or continuous infusions. For maximal efficacy, the pH of gastric aspirates should be measured and the doses titrated to achieve a gastric pH higher than 4.

Adverse Effects

H₂ antagonists are extremely safe drugs. Adverse effects occur in fewer than 3% of patients and include diarrhea, headache, fatigue, myalgias, and constipation.

A. CENTRAL NERVOUS SYSTEM
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.

B. ENDOCRINE EFFECTS
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.

C. PREGNANCY AND NURSING MOTHERS
Although there are no known harmful effects on the fetus, these agents 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.

D. OTHER EFFECTS
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 injection 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 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 (PPI)

Introduction

Since their introduction in the late 1980s, these efficacious acid inhibitory agents have rapidly assumed the major role for the treatment of acid-peptic disorders. They are now among the most widely selling 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 63-4) 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, lansoprazole, and pantoprazole are also available in intravenous formulations (Table 63-2).

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 capsule or tablet formulations. 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 may be mixed with water and administered via oral syringe or enteral tube. Omeprazole is also available as a non-enteric-coated powder that contains sodium bicarbonate (1680 mg NaHCO₃; 460 mg of sodium) to protect the naked (nonenteric coated) drug from acid degradation. When mixed with water and 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 (such as the parietal cell canaliculus). Within the acidified compartment the prodrug rapidly becomes protonated and is concentrated more than 1000-fold within the parietal cell canaliculus by Henderson-Hasselbalch trapping (see Chapter 1). There, it rapidly undergoes a molecular conversion to the active, reactive thiophilic sulfonamide cation. The sulfonamide reacts with the H⁺/K⁺ATPase, forms a covalent disulfide linkage, and irreversibly inactivates the enzyme. The rate of conversion is inversely proportional to the pK_a of the drug.

The pharmacokinetics of available proton pump inhibitors are shown in Table 63-2. Rabeprazole (due to its higher pK_a) or immediate-release omeprazole (due to its rapid release and absorption) 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 or dinner), 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; however, the duration of acid inhibition lasts up to 24 hours due 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, lansoprazole, and pantoprazole have similar characteristics to the oral drugs. When given to a fasting patient, they inactivate acid pumps that are actively secreting but 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 tubulo-vesicles to the canalicular surface. Thus, in order 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 63-3). Among commercially available formulations, 40 mg of esomeprazole achieves slightly greater 24-hour gastric acid suppression compared with standard doses of other delayed-release oral proton pump inhibitors (lansoprazole, 30 mg; rabeprazole, 20 mg; omeprazole, 20-40 mg; or pantoprazole 40 mg); however, when administered at equivalent doses there is little difference in clinical efficacy among the different agents. 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

A. 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 H₂antagonists. Due to recent cost reductions, proton pump inhibitors are increasingly being used 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).

B. 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 of the pump inhibitors heal more than 90% of duodenal ulcers within 4 weeks and a similar percentage of gastric ulcers within 6-8 weeks.

1. H pylori-associated ulcers¾ For H pylori-associated ulcers, there are two therapeutic goals: heal the ulcer and 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) and¾by raising intragastric pH¾lowering the minimal inhibitory concentrations of antibiotics against H pylori. The best treatment regimen consists of a 10-14 day regimen of "triple therapy": a proton pump inhibitor twice daily; clarithromycin, 500 mg twice daily; and amoxicillin, 1 g twice daily. For patients who are allergic to penicillin, metronidazole, 500 mg twice daily, should be substituted for amoxicillin. 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.

2. NSAID-associated ulcers¾ 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; continued use of the NSAID impairs ulcer healing. Treatment with a once-daily proton pump inhibitor promotes ulcer healing despite continued NSAID therapy.

Proton pump inhibitors are also given to prevent ulcer complications from NSAIDs. 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.

3. Prevention of rebleeding from peptic ulcers¾ 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 in this subset of high-risk ulcers is reduced significantly with use of 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 (60-80 mg) followed by constant infusion (8 mg/h) commonly is recommended.

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

D. PREVENTION OF STRESS-RELATED MUCOSAL BLEEDING
Clinically important bleeding from upper gastrointestinal erosions or ulcers occurs in 1-5% of critically ill patients due to mucosal ischemia. Although most critically ill patients have normal or decreased acid secretion, numerous studies have shown that maintaining intragastric pH higher than 4 reduces the incidence of clinically significant bleeding. The only proton pump inhibitor approved by the Food and Drug Administration for reduction of stress-related mucosal bleeding is an oral immediate-release omeprazole formulation, which is administered by nasogastric tube twice daily on the first day, then once daily. In a large controlled trial, nasogastric immediate-release omeprazole had similar efficacy to a continuous intravenous infusion of an H₂ antagonist (cimetidine) in the prevention of stress-related bleeding and superior inhibition of gastric acidity (median pH > 6).

At this time, the optimal agent for the reduction of stress-related mucosal bleeding is uncertain. For patients with nasoenteric tubes, immediate-release omeprazole may be preferred to intravenous H₂ antagonists because of comparable efficacy, lower cost, and ease of administration. For patients without a nasoenteric tube or with significant ileus, intravenous H₂antagonists are the preferred agents because of their proven efficacy. Although proton pump inhibitors are increasingly used, there are no controlled trials demonstrating efficacy or optimal dosing.

E. 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 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

A. 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.

B. 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 B₁₂levels 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.

C. 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 unclear 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.

D. POTENTIAL PROBLEMS DUE TO INCREASED SERUM GASTRIN
Gastrin levels are regulated by intragastric acidity. Acid suppression alters normal feedback inhibition so that median 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 has raised two theoretical concerns. First, gastrin is a trophic hormone that stimulates 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. Second, hypergastrinemia increases the proliferative rate of colonic mucosa, potentially promoting carcinogenesis. In humans, hypergastrinemia caused by vagotomy, atrophic gastritis, or Zollinger-Ellison syndrome has not been associated with increased colon cancer risk. At present, routine monitoring of serum gastrin levels is not recommended in patients receiving prolonged proton pump inhibitor therapy.

E. 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 metaplasia¾known risk factors for gastric adenocarcinoma. A special US 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 no longer 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 and digoxin. All proton pump inhibitors are metabolized by hepatic P450 cytochromes, including CYP2C19 and CYP3A4. Due to their short-half lives, clinically significant drug interactions are rare. Omeprazole may inhibit the metabolism of coumadin, 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

INTRODUCTION

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, or 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. Following 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, it has never achieved widespread use due 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 occurs 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.

COLLOIDAL BISMUTH COMPOUNDS

Chemistry & Pharmacokinetics

The only bismuth compound available in the USA is bismuth subsalicylate, a nonprescription formulation containing bismuth and salicylate. In other countries, bismuth subcitrate and bismuth dinitrate are also available. 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

Like sucralfate, bismuth probably 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 have been used in multidrug regimens for the eradication of H pylori infection. In the USA, a "triple therapy" regimen has been used, consisting of bismuth subsalicylate (2 tablets; 262 mg each), tetracycline (500 mg), and metronidazole (250 mg), each taken four times daily for 14 days. Because of the need for four-times daily dosing and the high adverse effect profile, this regimen is no longer used as first-line therapy for H pylori eradication (see Proton Pump Inhibitors above). For patients with resistant infections, "quadruple therapy" consisting of a proton pump inhibitor twice daily in addition to the three-drug bismuth-based regimen four times daily for 14 days is highly effective. In Europe, bismuth subcitrate is used instead of bismuth subsalicylate, and treatment for 7-10 days may be sufficient.

Adverse Effects

All bismuth formulations have an excellent safety profile. Bismuth causes 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.

II. DRUGS STIMULATING GASTROINTESTINAL MOTILITY

INTRODUCTION

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 deep 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 63-5). 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 calcitonin gene-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.

Although there are at least 14 serotonin receptor subtypes, 5-HT drug development for gastrointestinal applications to date has focused on 5-HT₃-receptor antagonists and 5-HT₄-receptor agonists. These agents¾which have effects upon gastrointestinal motility and visceral afferent sensation¾are discussed below 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. Due 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

Introduction

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 upon small intestine or colonic motility. Metoclopramide and domperidone also block dopamine D₂receptors in the chemoreceptor trigger zone of the medulla (area postrema), resulting in potent antinausea and antiemetic action.

Clinical Uses

A. GASTROESOPHAGEAL REFLUX DISEASE (GERD)
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. Due to 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.

B. 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.

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

D. PREVENTION OF VOMITING
Due to their potent antiemetic action, metoclopramide and domperidone are used for the prevention and treatment of emesis (see page 1027).

E. 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. Tardive dyskinesia, 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 prior to endoscopy.

CHLORIDE CHANNEL ACTIVATOR

Lubiprostone is a recently approved prostanoic acid derivative labeled for use in chronic constipation. It is reported to act by stimulating chloride channel opening in the intestine. This increases liquid secretion into the intestine and shortens intestinal transit time. The drug also delays gastric emptying, which may cause nausea. No comparative studies with other drugs are available.

III. LAXATIVES

INTRODUCTION

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 prior to the initiation of 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) or 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

Introduction

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 oxide (milk of magnesia) is a commonly used osmotic laxative. It should not be used for prolonged periods in patients with renal insufficiency due to 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. These hyperosmolar agents may lead to intravascular volume depletion and electrolyte fluctuations; hence they should not be used in patients who are frail, elderly, have renal insufficiency, or have significant cardiac disease.

Balanced Polyethylene Glycol

Lavage solutions containing polyethylene glycol (PEG) are used for complete colonic cleansing prior to 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 (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

Introduction

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 relationship to colorectal cancer.

Diphenylmethane Derivatives

Due to concerns about possible cardiac toxicity, these agents (eg, phenolphthalein) were removed from the market.

Castor Oil

This oil is a potent stimulant laxative. It is hydrolyzed in the upper small intestine to ricinoleic acid, a local irritant that stimulates intestinal motility. Formerly used as a purgative to clean the colon before procedures, it is now seldom used.

SEROTONIN 5-HT₄-RECEPTOR AGONISTS

Pharmacokinetics & Pharmacodynamics

Tegaserod is a serotonin 5-HT₄ partial agonist that resembles serotonin in structure. It has high affinity for 5-HT₄ receptors but no appreciable binding to 5-HT₃ or dopamine receptors. As discussed earlier, stimulation of 5-HT₄ receptors on the presynaptic terminal of submucosal intrinsic primary afferent nerves enhances the release of their neurotransmitters, including calcitonin gene-related peptide, that stimulate second-order enteric neurons to promote the peristaltic reflex (Figure 63-5). These enteric neurons stimulate proximal bowel contraction (via acetylcholine and substance P) and distal bowel relaxation (via nitric oxide and vasoactive intestinal peptide). Tegaserod promotes gastric emptying and enhances small and large bowel transit but has no effect upon esophageal motility. Stimulation of 5-HT₄ receptors also activates cAMP-dependent chloride secretion from the colon, leading to increased stool liquidity.

Tegaserod has a bioavailability of only 10%. It should be taken before meals because food further reduces bioavailability by 50%. The drug is metabolized both by gastric acid-catalyzed hydrolysis and hepatic glucuronidation. Approximately 66% of drug is excreted unchanged in the feces and 33% as a metabolite in the urine. It should not be given to patients with severe hepatic or renal impairment.

Clinical Uses

A. CHRONIC CONSTIPATION
Tegaserod is approved for the treatment of patients with chronic constipation. In controlled trials, 40% of patients treated with tegaserod, 2-6 mg twice daily, had a significant increase in the number of spontaneous bowel movements compared with 25% receiving placebo. Responders also reported reduced bloating, straining, and stool hardness, and enhanced satisfaction. The effect of tegaserod on bowel activity is usually noted within 48 hours. Given its high cost, tegaserod should be reserved for patients with chronic constipation who have failed or are intolerant of other less expensive therapies.

B. OTHER USES
The role of tegaserod in the treatment of other gastrointestinal motility disorders, such as nonulcer dyspepsia, gastroparesis, and chronic constipation, is under investigation. The use of tegaserod in the treatment of irritable bowel syndrome is discussed later in the chapter.

Adverse Effects

Tegaserod appears to be an extremely safe agent. Diarrhea occurs in 9% of patients within the first few days of treatment but resolves in the majority of patients. Less than 2% of patients discontinue the drug because of diarrhea. Although it is stated that the drug does not cross the blood-brain barrier (and does not affect central serotonin receptors), headache may occur.

Drug Interactions

Tegaserod has no known effects on cytochrome P450 enzymes and no reported drug interactions.

IV. ANTIDIARRHEAL AGENTS

INTRODUCTION

Antidiarrheal agents may be used safely in patients with mild to moderate acute diarrhea. However, they 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

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 another 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 on page 1018 .

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 bacteria, 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 commercial preparation is Kaopectate. The usual dose 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 or colestipol may decrease diarrhea caused by excess fecal bile acids (see Chapter 35). The usual dose is 4-5 g 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. These agents bind a number of drugs and reduce their absorption; hence, they should not be given within 2 hours of other drugs.

OCTREOTIDE

Introduction

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). It 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

A. 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.

B. OTHER CAUSES OF DIARRHEA
Octreotide inhibits intestinal secretion and has dose-related affects 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.

C. 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. Due to inhibition of gallbladder contractility and alterations in fat absorption, long-term use can cause formation of sludge or gallstones in over half of patients, which rarely results in the development of acute cholecystitis. Because octreotide alters the balance between 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.

V. DRUGS USED IN THE TREATMENT OF IRRITABLE BOWEL SYNDROME

INTRODUCTION

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 irritable bowel syndrome 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 the treatment of 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 of stools. 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 irritable bowel syndrome.

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 irritable bowel syndrome. These agents work primarily through anticholinergic activities. Commonly used medications in this class include dicyclomine and hyoscyamine. These drugs inhibit muscarinic cholinergic receptors in the enteric plexus and on smooth muscle. Efficacy of these agents 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, these drugs are infrequently used.

SEROTONIN 5-HT₃-RECEPTOR ANTAGONISTS

Introduction

As discussed earlier, 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-HT₃receptors 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 irritable bowel syndrome with diarrhea (Figure 63-6). 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 irritable bowel syndrome has not been determined. The differences between these 5-HT₃ antagonists that determine their pharmacodynamic effects have not been well studied.

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 currently is approved for the treatment of women with severe irritable bowel syndrome in whom diarrhea is the predominant symptom ("diarrhea-predominant IBS"). 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 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. This agent 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 colitis¾some fatal¾have 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 is discussed under Laxatives, above. This agent is approved for the short-term treatment of women with irritable bowel syndrome who have predominant constipation. Controlled studies have 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. Tegaserod also increases the number of bowel movements per week and reduces the hardness of stools. Given the expense of this agent, it should be reserved for patients with moderate to severe symptoms who have failed to respond to standard therapies (ie, fiber supplementation, laxatives). Although its use is approved for up to 12 weeks, long-term therapy may be considered for patients who demonstrate a good response.

VI. ANTIEMETIC AGENTS

INTRODUCTION

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 brainstem vomiting center is located in 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, and serotonin 5-HT₃receptors have been identified in the vomiting center.

There are five sources of afferent input to the vomiting center:

1. The chemoreceptor trigger zone is located in the fourth ventricle in the area postrema. This is outside the blood-brain barrier and is accessible to emetogenic stimuli in the blood or cerebrospinal fluid. The chemoreceptor trigger zone is rich in dopamine D₂ receptors, serotonin 5-HT₃ receptors, neurokinin 1 (NK₁), and opioid receptors.
2. The vestibular system is important in motion sickness via cranial nerve VIII. It is rich in muscarinic and histamine H₁ receptors.
3. Irritation of the pharynx, innervated by the vagus nerve, provokes a prominent gag and retch response.
4. 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.
5. 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 mainly through central 5-HT₃-receptor blockade in the vomiting center and chemoreceptor trigger zone and 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: ondansetron, granisetron, dolasetron, and palonosetron. The first three agents (ondansetron, granisetron, and dolasetron, Figure 63-6) 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.

These agents do not inhibit dopamine or muscarinic receptors. They do not have effects on esophageal or gastric motility but may slow colonic transit.

Clinical Uses

A. 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, 24-32 mg; 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: granisetron, 2 mg; dolasetron, 100 mg. Ondansetron may be given as a single oral dose (16-24 mg) or as 8 mg every 8-12 hours for 1-2 days. 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).

B. POSTOPERATIVE AND POSTRADIATION NAUSEA AND VOMITING
5-HT₃-receptor antagonists are used to prevent or treat postoperative nausea and vomiting. Due to adverse effects and increased restrictions on 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.

C. OTHER INDICATIONS
The efficacy of 5-HT₃-receptor antagonists in the treatment of nausea and vomiting due to acute or chronic medical illness or acute gastroenteritis has not been evaluated.

Adverse Effects

These 5-HT₃-receptor antagonists are well-tolerated agents with excellent safety profiles. The most commonly reported adverse effects are headache, dizziness, and constipation. All three 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 use of dolasetron, it should not be administered to patients with prolonged QT or in conjunction with other medications that may prolong the QT interval.

Drug Interactions

No significant drug interactions have been reported. All four agents undergo some metabolism by the hepatic cytochrome P450 system but they do not appear to affect the metabolism of other drugs metabolized by these enzyme systems. 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

Introduction

Neurokinin 1 (NK₁) receptor antagonists have antiemetic properties that are mediated through central blockade in the area postrema. Aprepitant 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.

Pharmacokinetics & Pharmacodynamics

The oral bioavailability 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. Aprepitant is administered orally for 3 days as follows: 125 mg given 1 hour prior to chemotherapy, followed by 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, potentially increasing their levels, effects, and toxicity. 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 only be used in patients who have not responded adequately to alternative agents.

SUBSTITUTED BENZAMIDES

Substituted benzamides include metoclopramide 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. As discussed previously, the principal adverse effects of these central dopamine antagonists are extrapyramidal: restlessness, dystonias, and parkinsonian symptoms.

H₁ ANTIHISTAMINES & ANTICHOLINERGICS

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 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 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 prior to 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 D⁹ -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, this drug 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 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 approved for use in the USA.

VII. DRUGS USED TO TREAT INFLAMMATORY BOWEL DISEASE

INTRODUCTION

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.

AMINOSALICYLATES

Chemistry & Formulations

Drugs that contain 5-aminosalicylic acid (5-ASA) have been used successfully for decades in the treatment of inflammatory bowel diseases. 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.

A. 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 63-7). In sulfasalazine, 5-ASA is bound to sulfapyridine; in balsalazide, 5-ASA is bound to 4-aminobenzoyl-b-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.

B. MESALAMINE COMPOUNDS
Other proprietary formulations have been designed that package 5-ASA itself in various ways in order 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 time-release microgranules that release 5-ASA throughout the small intestine. Asacol has 5-ASA coated in a pH-sensitive resin that dissolves at pH 7 (the pH of the distal ileum and proximal 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).

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 systemically 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-kB (NF-kB), 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 not as well established, 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 diarrhea¾which should not be confused with active inflammatory bowel disease¾in 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 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-a, 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-kB.

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 to maintain 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 55 and 56).

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.

The molecular basis for the therapeutic effects of the purine analogs is unknown. Intracellular 6-thioguanine causes inhibition of purine nucleotide metabolism and DNA synthesis and repair, resulting in inhibition of cell division and proliferation, and may promote T-lymphocyte apoptosis.

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 prior to initiating therapy. These drugs should not be administered to patients with absent 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 there appears to be an increased risk of lymphoma in transplant recipients receiving long-term 6-MP or azathioprine therapy, 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 55). 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 T helper cell type 1 (TH1) response is present in inflammatory bowel disease, especially Crohn's disease. One of the key proinflammatory cytokines in the TH1 response is tumor necrosis factor-a (TNF-a). Infliximab is a chimeric mouse-human monoclonal antibody to human TNF-a that is described in more detail in Chapter 56.

Infliximab is administered as an intravenous infusion. The plasma concentration is linearly proportionate to dose and its elimination follows first-order kinetics. 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.

The biologic activity of TNF-a is mediated by binding of soluble or membrane-bound TNF-a trimers to cell-surface TNF-a receptors. Infliximab binds to soluble TNF-a trimers with high affinity, preventing the cytokine from binding to its receptors. Total serum TNF-a concentrations may actually increase because binding to infliximab slows TNF-a clearance. Infliximab also binds to membrane-bound TNF-a and neutralizes its activity. Furthermore, the Fc portion of human IgG₁ region of infliximab promotes complement activation and antibody-mediated apoptosis and cellular cytotoxicity of activated T lymphocytes and macrophages.

Clinical Uses

Infliximab is used in the acute and chronic treatment of patients with moderate to severe Crohn's disease and ulcerative colitis. It leads to symptomatic improvement in two thirds and disease remission in one third of patients with moderately severe or fistulizing 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. Infliximab induction therapy is generally given in a dosage of 5 mg/kg at 0, 2, and 6 weeks. Patients who respond may be treated with repeat infusions every 8 weeks to maintain remission with or without other therapies. Clinical response is maintained in more than 60% of patients with regularly scheduled infusions; however, one third of patients eventually lose response despite higher doses (10 mg/kg) or more frequent infusions. Loss of response in many patients may be due to development of antibodies to infliximab.

Infliximab was recently 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 had a clinical response and one third were in clinical remission. With continued maintenance infusions every 8 weeks, approximately one half of patients had continued clinical response.

Although infliximab currently is the only anti-TNF agent approved by the FDA for treatment of patients with inflammatory bowel disease, other anti-TNF agents have demonstrated efficacy in large controlled trials. These include adalimumab (a fully humanized IgG₁ antibody) and certolizumab (a polyethylene glycolated Fab fragment of humanized anti-TNF), both of which are administered by subcutaneous injection. It is unknown whether these agents will have similar efficacy to infliximab with reduced complications related to antibody formation.

Adverse Effects

Serious adverse events occur in 6% of patients with infliximab therapy. The most important adverse effect of infliximab therapy is infection due to suppression of the TH1 inflammatory response. Reactivation of latent tuberculosis, with dissemination, has occurred. Before administering infliximab, all patients must undergo purified protein derivative (PPD) testing; prophylactic therapy for tuberculosis is warranted for patients with positive test results. Other infections include pneumonia, sepsis, pneumocystosis, histoplasmosis, listeriosis, and reactivation of hepatitis B.

Antibodies directed at the murine epitope of infliximab develop in approximately one third of patients. These antibodies may attenuate or eliminate the clinical response and increase the likelihood of developing acute or delayed infusion reactions. Antibody development is less likely in patients who receive concomitant therapy with immunomodulators (ie, 6-MP or methotrexate), regularly scheduled infliximab infusions, or preinfusion treatment with corticosteroids (eg, hydrocortisone, 200 mg).

Infliximab 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 and diphenhydramine. Severe acute reactions, including significant hypotension, shortness of breath, muscle spasms, and chest discomfort, may require treatment with oxygen, epinephrine, and corticosteroids.

A delayed serum sickness-like infusion reaction, which occurs 1-2 weeks after infusion, develops in 1-2% patients who are retreated with infliximab, especially after a prolonged period. These reactions consist of myalgia, arthralgia, jaw tightness, fever, rash, urticaria, and edema. For patients with either acute severe or delayed infusion reactions, the risks and benefits of subsequent infusions must be weighed; pretreatment with acetaminophen, diphenhydramine, and corticosteroids is recommended. Positive antinuclear antibodies and anti-double-stranded DNA develop in a small number of patients. Development of a lupus-like syndrome has been reported that resolved after discontinuation of the drug.

Infliximab may cause severe hepatic reactions leading to acute hepatic failure. Liver enzymes should be monitored routinely.

Lymphoma has developed in patients who were treated with infliximab. However, the observed rates may be similar to those expected in patients with inflammatory bowel disease. Rare cases of multiple sclerosis have been reported. Infliximab may worsen congestive heart failure in patients with cardiac disease.

VIII. 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 maldigestion occur that 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 will be discussed here.

Pancrelipase is available in both nonenteric-coated and enteric-coated preparations. Pancrelipase enzymes are rapidly and permanently inactivated by gastric acids. Therefore, nonenteric-coated preparations (eg, Viokase) should be given concomitantly with acid suppression therapy (proton pump inhibitor or H₂ antagonist) in order 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 period¾a 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.

Pancreatic enzyme supplements are well tolerated. The capsules should be swallowed, not chewed, as 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.

IX. BILE ACID THERAPY FOR GALLSTONES

Introduction

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 half 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.

X. DRUGS USED TO TREAT VARICEAL HEMORRHAGE

INTRODUCTION

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 resistance to blood flow 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 collaterals¾especially 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, it causes splanchnic arterial vasoconstriction that leads to reduced splanchnic perfusion and lowered portal venous pressures. Prior to 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 infused¾to promote vasospasm¾into 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 is still undergoing clinical testing in the USA.

BETA-RECEPTOR-BLOCKING DRUGS

The pharmacology of these 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 (b₁ blockade) and to splanchnic vasoconstriction (b₂ blockade) caused by the unopposed effect of systemic catecholamines on a receptors. Thus, nonselective b blockers such as propranolol and nadolol are more effective than selective b₁ 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 b 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 b blockers significantly reduce the rate of recurrent bleeding, although a reduction in mortality is unproved.



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*; 10 mg tablet plus calcium carbonate 800 mg and magnesium hydroxide 165 mg*; 20, 40 mg tablets; powder to reconstitute for 40 mg/5 mL suspension
Parenteral: 10 mg/mL for injection
Nizatidine (Axid, Axid AR*)
Oral: 75 mg tablets*; 150, 300 mg capsules
Ranitidine (generic, Zantac, Zantac 75*)
Oral: 75*, 150, 300 mg tablets; 150 mg effervescent tablets; 150, 300 mg capsules; 15 mg/mL syrup
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
Methscopolamine (Pamine)
Oral: 2.5, 5 mg tablets
Propantheline (generic, Pro-Banthine)
Oral: 7.5, 15 mg tablets
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*; 20, 40 mg immediate-release powder containing 1680 mg NaHCO₃ for oral suspension
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/vial powder for IV injection
Pantoprazole (Protonix)
Oral: 20, 40 mg delayed release tablets
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-HT₃-Receptor Antagonists Alosetron (Lotronex)
Oral: 1 mg tablets
Dolasetron (Anzemet)
Oral: 50, 100 mg tablets
Parenteral: 20 mg/mL for injection
Granisetron (Kytril)
Oral: 1 mg tablets; 2 mg/10 mL oral solution
Parenteral: 0.1, 1 mg/mL for injection
Ondansetron (Zofran)
Oral: 4, 8, 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)
Parenteral: 0.05 mg/mL for injection
Other Motility and Antiemetic Agents Aprepitant (Emend)
Oral: 80, 125 mg capsules
Dronabinol (Marinol)
Oral: 2.5, 5, 10 mg capsules
Droperidol (Inapsine)
Parenteral: 2.5 mg/mL for IV injection
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 56)

Balsalazide (Colazal)
Oral: 750 mg capsules
Budesonide (Entocort)
Oral: 3 mg capsules
Hydrocortisone (Cortenema, 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, 500 mg suppositories; 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 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
Kaolin/pectin* (generic, Kaopectate, others)
Oral (typical): 5.85 g kaolin and 260 mg pectin per 30 mL suspension
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
Soluble dietary fiber (Benefiber)
Oral: bulk powder, tablets

OTHER SELECTED LAXATIVE DRUGS

Bisacodyl* (generic, Dulcolax, others)
Oral: 5 mg enteric-coated tablets
Rectal: 10 mg suppositories
Cascara sagrada* (generic)
Oral: 325 mg tablets; 5 mL per dose fluid extract (approximately 18% alcohol)
Castor oil* (generic, others)
Oral: liquid or liquid emulsion
Docusate* (generic, Colace, others)
Oral: 50, 100, 250 mg capsules; 100 mg tablets; 20, 50, 60, 150 mg/15 mL syrup
Glycerin liquid* (Fleet Babylax)
Rectal liquid: 4 mL per applicator
Glycerin suppository (generic, Sani-Supp)
Lactulose (Chronulac, Cephulac)
Oral: 10 g/15 mL syrup
Lubiprostone (Amitiza)
Oral: 24 mcg capsules
Magnesium hydroxide [milk of magnesia, Epsom Salt]* (generic)
Oral: 400, 800 mg/5 mL aqueous suspension
Mineral oil* (generic, others)
Oral: liquid or emulsion
Polycarbophil* (Equalactin, Mitrolan, FiberCon, Fiber-Lax)
Oral: 500, 625 mg tablets; 500 mg chewable tablets
Polyethylene glycol electrolyte solution (CoLyte, GoLYTELY, others)
Oral: Powder for oral solution, makes one gallon (approximately 4 L)
Senna* (Senokot, Ex·Lax, others)
Oral: 8.6, 15, 17, 25 mg tablets; 8.8, 15 mg/mL liquid

DRUGS THAT DISSOLVE GALLSTONES

Ursodiol (generic, Actigall, URSO)
Oral: 250, 500 mg tablets; 300 mg capsules

*Over-the-counter formulations.



REFERENCES


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Drugs Used for Irritable Bowel Syndrome

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Pancreatic Enzyme Supplements

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Bile Acids for Gallstone Therapy

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