Chapter 46: Treatment of Disorders of Bowel Motility and Water Flux; Anti-Emetics; Agents Used in Biliary and Pancreatic Disease

The longer I live, the more I am convinced that half the unhappiness in the world proceeds from little stoppages, from a duct choked up, from food pressing in the wrong place, from a vexed duodenum or an agitated pylorus.

—Sydney Smith (1771–1845)

Generation and Regulation of GI Activity

The ENS is responsible for the largely autonomous nature of most GI activity. This activity is organized into relatively distinct programs that respond to input from the local environment of the gut, as well as the ANS-CNS. Each program consists of a series of complex, but coordinated, patterns of secretion and movement that show regional and temporal variation. The fasting program of the gut is called the MMC (migrating myoelectric complex when referring to electrical activity and migrating motor complex when referring to the accompanying contractions) and consists of a series of four phasic activities. The most characteristic, phase III, consists of clusters of rhythmic contractions that occupy short segments of the intestine for a period of 6-10 minutes before proceeding caudally (toward the anus). Phase II of the MMC is associated with the release of the peptide hormone motilin. Agonists of motilin stimulate motility in the proximal gut and are used clinically (Sanger, 2008). One whole MMC cycle (i.e., all four phases) takes ~80-110 minutes. The migrating motor complex occurs in the fasting state, during which it helps sweep debris caudad in the gut and serves to limit the overgrowth of luminal bacteria. The migrating motor complex cycles continually in animals that feed constantly but is interrupted by another pattern of contractions—the fed program—in intermittently feeding animals such as humans. The fed program consists of high-frequency (12-15 per minute) contractions that are either propagated for short segments (propulsive) or are irregular and not propagated (mixing).

Reflex circuits within the ENS underlie the stereotyped behaviors of the gut, such as peristalsis. Physiologically, peristalsis is a series of reflex responses to a bolus in the lumen of a given segment of the intestine; the ascending excitatory reflex results in contraction of the circular muscle on the oral side of the bolus, whereas the descending inhibitory reflex results in relaxation on the anal side. The net pressure gradient moves the bolus caudad. Three neural elements, responsible for sensory, relay, and effector functions, are required to produce these reflexes. Luminal factors stimulate sensory elements in the mucosa, leading to a coordinated pattern of muscle activity that is directly controlled by the motor neurons of the myenteric plexus to provide the effector component of the peristaltic reflex. Motor neurons receive input from ascending and descending interneurons (which constitute the relay and programming systems) that are of two broad types, excitatory and inhibitory. The primary neurotransmitter of the excitatory motor neurons is acetylcholine (ACh), although tachykinins, co-released by these neurons, also play a role. The principal neurotransmitter in the inhibitory motor neurons appears to be NO, although important contributions may also be made by ATP, vasoactive intestinal peptide, and pituitary adenylyl cyclase–activating peptide (PACAP), all of which are variably coexpressed with NO synthase. Substantial progress has been made in elucidating the mucosal sensor for initiating peristalsis and other reflexes. Enterochromaffin cells, scattered throughout the epithelium of the intestine, release serotonin (5-HT) to initiate many gut reflexes (Gershon and Tack, 2007) by acting locally on enteric neurons. Excessive release of 5-HT from the gut wall (e.g., by chemotherapeutic agents) leads to vomiting by actions of 5-HT on vagal nerve endings in the proximal small intestine. Compounds targeting the 5-HT system are important modulators of motility, secretion, and emesis.

This view of nerve–muscle interaction within the GI tract is in many ways oversimplified, and other cell types are important. One of these is the interstitial cell of Cajal, distributed within the gut wall and responsible for setting the electrical rhythm, and hence the pace of contractions, in various regions of the gut. These cells also translate or modulate excitatory and inhibitory neuronal communication to the smooth muscle (Ward et al., 2004).

Excitation-Contraction Coupling in GI Smooth Muscle

Control of tension in GI smooth muscle is in large part dependent on the intracellular Ca²⁺ concentration. In general, there are two types of excitation-contraction coupling. Ionotropic receptors can mediate changes in membrane potential, which in turn activate voltage-dependent Ca²⁺ channels to trigger an influx of Ca²⁺ (electro-mechanical coupling); metabotropic receptors activate various signal transduction pathways to release Ca²⁺ from intracellular stores (pharmaco-mechanical coupling). Inhibitory receptors also exist on smooth muscle and generally act via PKA and PKG, whose kinase activities can lead to hyperpolarization, decreased cytosolic [Ca²⁺], and reduced interaction of actin and myosin. As an example, NO may induce relaxation via activation of guanylyl cyclase-cyclic GMP pathway, and the opening of several types of K⁺ channels.

The mechanisms of action of metoclopramide are complex and involve 5-HT₄ receptor agonism, vagal and central 5-HT₃ antagonism, and possible sensitization of muscarinic receptors on smooth muscle, in addition to DA receptor antagonism. Metoclopramide is one of the oldest true prokinetic agents; its administration results in coordinated contractions that enhance transit. Its effects are confined largely to the upper digestive tract, where it increases lower esophageal sphincter tone and stimulates antral and small intestinal contractions. Despite having in vitro effects on the contractility of colonic smooth muscle, metoclopramide has no clinically significant effects on large-bowel motility.

Pharmacokinetics. Metoclopramide is absorbed rapidly after oral ingestion, undergoes sulfation and glucuronide conjugation by the liver, and is excreted principally in the urine, with a t_1/2 of 4-6 hours. Peak concentrations occur within 1 hour after a single oral dose; the duration of action is 1-2 hours.

Therapeutic Use. Metoclopramide has been used in patients with gastroesophageal reflux disease to produce symptomatic relief of, but not healing of, associated esophagitis. It clearly is less effective than modern acid-suppressive medications, such as proton pump inhibitors or histamine H₂ receptor antagonists, and now rarely is used in this setting. Metoclopramide is indicated more often in symptomatic patients with gastroparesis, in whom it may cause mild to modest improvements of gastric emptying (Tonini et al., 2004). Metoclopramide injection is used as an adjunctive measure in medical or diagnostic procedures such as intestinal intubation or contrast radiography of the GI tract. Although it has been used in patients with postoperative ileus, its ability to improve transit in disorders of small-bowel motility appears to be limited. In general, its greatest utility lies in its ability to ameliorate the nausea and vomiting that often accompany GI dysmotility syndromes. Metoclopramide has also been used in the treatment of persistent hiccups, but its efficacy in this condition is equivocal at best.

Metoclopramide is available in oral dosage forms (tablets and solution) and as a parenteral preparation for intravenous or intramuscular use. The usual initial oral dose range is 10 mg, 30 minutes before each meal and at bedtime. The onset of action is within 30-60 minutes after an oral dose. In patients with severe nausea, an initial dose of 10 mg can be given intramuscularly (onset of action 10-15 minutes) or intravenously (onset of action 1-3 minutes). For prevention of chemotherapy-induced emesis, metoclopramide can be given as an infusion of 1-2 mg/kg administered over at least 15 minutes, beginning 30 minutes before the chemotherapy is begun and repeated as needed every 2 hours for two doses, then every 3 hours for three doses.

Adverse Effects. The major side effects of metoclopramide include extrapyramidal effects, such as those seen with the phenothiazines (Chapter 16). Dystonias, usually occurring acutely after intravenous administration, and parkinsonian-like symptoms that may occur several weeks after initiation of therapy generally respond to treatment with anticholinergic or antihistaminic drugs and are reversible upon discontinuation of metoclopramide. Tardive dyskinesia also can occur with chronic treatment (months to years) and may be irreversible. Extrapyramidal effects appear to occur more commonly in children and young adults and at higher doses. Like other DA antagonists, metoclopramide also can cause galactorrhea by blocking the inhibitory effect of dopamine on prolactin release, but this adverse effect is relatively infrequent in clinical practice. Methemoglobinemia has been reported occasionally in premature and full-term neonates receiving metoclopramide.

The availability of serotonergic prokinetic drugs has in recent years been restricted because of serious adverse cardiac events. Tegaserod maleate (zelnorm) was discontinued in 2007 and cisapride is available only via a restricted investigational drug protocol. A novel 5-HT₄ agonist, prucalopride (resolor), is approved for use in Europe for symptomatic treatment of chronic constipation in women in whom laxatives fail to provide adequate relief.

Cisapride. Cisapride (propulsid) is a substituted piperidinyl benzamide (Figure 46–2) that appears to stimulate 5-HT₄ receptors and increase adenylyl cyclase activity within neurons. It also has weak 5-HT₃ antagonistic properties and may directly stimulate smooth muscle. Cisapride was a commonly used prokinetic agent, particularly for gastroesophageal reflux disease and gastroparesis. However, it no longer is generally available in the U.S. because of its potential to induce serious and occasionally fatal cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsades de pointes. These arrhythmias result from a prolonged QT interval through an interaction with pore-forming subunits of the HERG K⁺ channel. HERG K⁺ channels conduct the rapid delayed rectifier K⁺ current that is important for normal repolarization of the ventricle (Chapter 29). Cisapride-induced ventricular arrhythmias occur most often when the drug is combined with other drugs that inhibit CYP3A4 (Chapter 6); such combinations inhibit the metabolism of cisapride and lead to high plasma concentrations of the drug. Due to its association with ventricular arrhythmias, cisapride is contraindicated in patients with a history of prolonged QT interval, renal failure, ventricular arrhythmias, ischemic heart disease, congestive heart failure, respiratory failure, uncorrected electrolyte abnormalities (e.g., hypokalemia and hypomagnesemia), or concomitant medications known to prolong the QT interval. At this time, cisapride is available only through an investigational, limited-access program for patients with GERD, gastroparesis, pseudo-obstruction, refractory severe chronic constipation, and neonatal enteral feeding intolerance who have failed all standard therapeutic modalities and who have undergone a thorough diagnostic evaluation, including an ECG.

Figure 46–2.

Ligands of 5-HT₃ and 5-HT₄ receptors modulating GI motility.

Graphic Jump Location

View Full Size||Download Slide (.ppt)

Prucalopride (reselor; Figure 46–2) is a benzofuran derivative and a specific 5-HT₄-receptor agonist that facilitates cholinergic neurotransmission. It acts throughout the length of the intestine, increasing oral-cecal transit and colonic transit without affecting gastric emptying in healthy volunteers. In patients with chronic idiopathic constipation, prucalopride was able to improve colonic transit and stool frequency. Given in doses of 2 and 4 mg orally, once daily, there were significant normalization of bowel habits including increased stool frequency and consistency (Gale, 2009). This drug recently gained approval in Europe for use in women with chronic constipation in whom laxatives fail to provide adequate relief.

Erythromycin induces phase III migrating motor complex activity in dogs and increases smooth muscle contractility. It has multiple effects on upper GI motility, increasing lower esophageal pressure and stimulating gastric and small-bowel contractility. By contrast, it has little or no effect on colonic motility. At doses higher than 3 mg/kg, it can produce a spastic type of contraction in the small bowel, resulting in cramps, impairment of transit, and vomiting.

Therapeutic Use. The best established use of erythromycin as a prokinetic agent is in patients with diabetic gastroparesis, where it can improve gastric emptying in the short term. Erythromycin-stimulated gastric contractions can be intense and result in "dumping" of relatively undigested food into the small bowel. This potential disadvantage can be exploited clinically to clear the stomach of undigestible residue such as plastic tubes or bezoars. Anecdotally, erythromycin also has been of benefit in patients with small-bowel dysmotility such as that seen in scleroderma, ileus, or pseudo-obstruction. Rapid development of tolerance to erythromycin, possibly by downregulation of the motilin receptor, and undesirable (in this context) antibiotic effects have limited the use of this drug as a prokinetic agent. Several non-antibiotic synthetic analogs of erythromycin and peptide analogs of motilin have been developed; to date, the clinical results have been disappointing.

A standard dose of erythromycin for gastric stimulation is 3 mg/kg intravenously or 200-250 mg orally every 8 hours. For small-bowel stimulation, a smaller dose (e.g., 40 mg intravenously) may be more useful, as higher doses may actually retard motility of this organ. Concerns about toxicity, pseudomembranous colitis, and the induction of resistant strains of bacteria, among other things, limit the use of erythromycin to acute situations or in circumstances where patients are resistant to other medications.

Motilin Receptor Agonists. A number of these drugs have been developed for the treatment of diabetic gastroparesis. Currently, mitemcinal (GM-611), a macrolide nonantibiotic, shows promise for the treatment of gastroparesis (Gale, 2009).

Miscellaneous Agents for Stimulating Motility

The GI hormone cholecystokinin (CCK) is released from the intestine in response to meals and delays gastric emptying, causes contraction of the gallbladder, stimulates pancreatic enzyme secretion, increases intestinal motility, promotes satiety, and has a host of other actions. The C-terminal octapeptide of CCK, sincalide (kinevac), is useful for stimulating the gallbladder and/or pancreas and may also be used for accelerating barium transit through the small bowel for diagnostic testing of these organs. This drug is administered intravenously 0.02-0.04 μg/kg over 30-60 seconds or up to 30-45 minutes depending on the test. Administration of this agent is frequently accompanied by nausea and abdominal pain, and much less frequently dizziness. Concerns that should be noted using this agent are related to the expulsion of small gallstones into the common bile duct or cystic duct. Dexloxiglumide is a CCK₁ (or CCK-A)–receptor antagonist that can improve gastric emptying and was investigated as a treatment for gastroparesis and for constipation-dominant IBS, but may also have uses in feeding intolerance in critically ill individuals. Clonidine also has been reported to be of benefit in patients with gastroparesis. Octreotide acetate (sandostatin, others), a somatostatin analogue, also is used in some patients with intestinal dysmotility.

In some disorders of motility, effective treatment does not necessarily require a "neuroenteric" approach. One such example is gastroesophageal reflux disease. Acid reflux is associated with transient lower esophageal sphincter relaxations that occur in the absence of a swallow. Because the damage to the esophagus ultimately is inflicted by acid, the most effective therapy for gastroesophageal reflux disease still is the suppression of acid production by the stomach (Chapter 45). Neither metoclopramide nor cisapride by itself is particularly effective in gastroesophageal reflux disease. However, a new approach under investigation relies on suppression of the transient lower esophageal sphincter relaxations, as achieved by CCK₁-receptor antagonists (such as dexloxiglumide), GABA agonists (such as baclofen), and inhibitors of NO synthesis.

Agents that Suppress Motility

Smooth muscle relaxants such as organic nitrates and Ca²⁺ channel antagonists (Chapters 27 and 28) often produce temporary, if partial, relief of symptoms in motility disorders such as achalasia, in which the lower esophageal sphincter fails to relax, resulting in a functional obstruction to the passage of food and severe difficulty in swallowing. A more recent approach relies on the use of preparations of botulinum toxin (botox, dysport, myobloc), injected directly into the lower esophageal sphincter via an endoscope, in doses of 80-100 units (Zhao and Pasricha, 2003). This potent agent inhibits ACh release from nerve endings (Chapter 11) and can produce partial paralysis of the sphincter muscle, with significant improvements in symptoms and esophageal clearance. However, its effects dissipate over a period of several months, requiring repeated injections; there is also some potential for post-administration "spread" of the toxin that can result in life-threatening consequences. Botulinum toxin preparations likely will be more widely used especially in the elderly and in those with other risks for pneumatic dilation. Other GI conditions in which botulinum toxin A has been used include gastroparesis, sphincter of Oddi dysfunction, and anal fissures, although currently there are not strong trial data to support its efficacy.

Constipation: General Principles of Pathophysiology and Treatment. Scientific definitions rely mostly on stool number; most surveys have found the normal stool frequency on a Western diet to be at least three times a week. However, patients use the term constipation not only for decreased frequency, but also for difficulty in initiation or passage, passage of firm or small-volume feces, or a feeling of incomplete evacuation. By questionnaire, 25% of the population of the U.S., more commonly women and elderly people, complain of constipation. A survey of bowel habits of adults in the U.S. showed that 18% of respondents used laxatives at least once a month, but nearly one-third of users did not have constipation. Approximately 2.5 million physician visits per year are attributed to constipation.

Constipation has many reversible or secondary causes, including lack of dietary fiber, drugs, hormonal disturbances, neurogenic disorders, and systemic illnesses. In most cases of chronic constipation, no specific cause is found. Up to 60% of patients presenting with constipation have normal colonic transit. These patients either have IBS or define constipation in terms other than stool frequency (e.g., changes in consistency, excessive straining, or a feeling of incomplete evacuation). In the rest, attempts usually are made to categorize the underlying pathophysiology either as a disorder of delayed colonic transit because of an underlying defect in colonic motility or, less commonly, as an isolated disorder of defecation or evacuation (outlet disorder) due to dysfunction of the neuromuscular apparatus of the rectoanal region. Colonic motility is responsible for mixing luminal contents to promote absorption of water and moving them from proximal to distal segments by means of propulsive contractions. Mixing in the colon is accomplished in a way similar to that in the small bowel: by short- or long-duration, stationary (nonpropulsive) contractions. Propulsive contractions in the colon include giant migrating contractions, also known as colonic mass actions or mass movements, which propagate caudally over extended lengths in the colon and evoke mass transfer of feces from the right to the left colon once or twice a day. Disturbances in motility therefore may have complex effects on bowel movements. "Decreased motility" of the mass action type and "increased motility" of the nonpropulsive type may lead to constipation. In any given patient, the predominant factor often is not obvious. Consequently, the pharmacological approach to constipation remains empirical and is based, in most cases, on nonspecific principles.

Bran, the residue left when flour is made from cereal grains, contains >40% dietary fiber. Wheat bran, with its high lignin content, is most effective at increasing stool weight. Fruits and vegetables contain more pectins and hemicelluloses, which are more readily fermentable and produce less effect on stool transit. Psyllium husk, derived from the seed of the plantago herb (Plantago ovata; known as ispaghula or isabgol in many parts of the world), is a component of many commercial products for constipation (metamucil, others). Psyllium husk contains a hydrophilic mucilloid that undergoes significant fermentation in the colon, leading to an increase in colonic bacterial mass. The usual dose is 2.5-4 g (1-3 teaspoonfuls in 250 mL of fruit juice), titrated upward until the desired goal is reached. A variety of semisynthetic celluloses—e.g., methylcellulose (citrucel, others) and the hydrophilic resin calcium polycarbophil (fibercon, fiberall, others), a polymer of acrylic acid resin—also are available. These poorly fermentable compounds absorb water and increase fecal bulk. Malt soup extract (malstsupex, others), an extract of malt from barley grains that contains small amounts of polymeric carbohydrates, proteins, electrolytes, and vitamins, is another orally administered bulk-forming agent.

Fiber is contraindicated in patients with obstructive symptoms and in those with megacolon or megarectum. Fecal impaction should be treated before initiating fiber supplementation. Bloating is the most common side effect of soluble fiber products (perhaps due to colonic fermentation), but it usually decreases with time. Calcium polycarbophil preparations release Ca²⁺ in the GI tract and thus should be avoided by patients who must restrict their intake of calcium or who are taking tetracycline. Sugar-free bulk laxatives may contain aspartame and are contraindicated in patients with phenylketonuria. Allergic reactions to psyllium have been reported.

Phosphate salts are better absorbed than magnesium-based agents and therefore need to be given in larger doses to induce catharsis. The most frequently employed preparations of sodium phosphate are an oral solution (fleet phospho-soda) and tablets (visicol, osmoprep). Over-the-counter oral sodium phosphate products for bowel cleansing were withdrawn from the market in 2008 following the determination by the FDA that only prescription medications should be available for this purpose. To reduce the likelihood of acute phosphate nephropathy, oral phosphates should be avoided in patients at risk (the elderly, patients with known bowel pathology or renal dysfunction, and patients on angiotensin-converting enzyme [ACE] inhibitors, angiotensin receptor blockers [ARBs], and nonsteroidal anti-inflammatory drugs [NSAIDs]) and the two-dose regimens should be split evenly with the first dose taken the evening before the exam and the second starting 3-5 hours before the exam. Adequate fluid intake (1-3 L) is essential for any oral sodium phosphate regimen used for colonic preparation.

Magnesium- and phosphate-containing preparations must be used with caution or avoided in patients with renal insufficiency, cardiac disease, or preexisting electrolyte abnormalities, and in patients on diuretic therapy. Patients taking >45 mL of oral sodium phosphate as a prescribed bowel preparation may experience electrolyte shifts that pose a risk for the development of symptomatic dehydration, renal failure, metabolic acidosis, tetany from hypocalcemia, and even death in vulnerable populations.

They are available as 70% solutions, which are given in doses of 15-30 mL at night, with increases as needed up to 60 mL per day in divided doses. Effects may not be seen for 24-48 hours after dosing is begun. Abdominal discomfort or distention and flatulence are relatively common in the first few days of treatment but usually subside with continued administration. A few patients dislike the sweet taste of the preparations; dilution with water or administering the preparation with fruit juice can mask the taste.

Lactulose also is used to treat hepatic encephalopathy. Patients with severe liver disease have an impaired capacity to detoxify ammonia coming from the colon, where it is produced by bacterial metabolism of fecal urea. The drop in luminal pH that accompanies hydrolysis to short-chain fatty acids in the colon results in "trapping" of the ammonia by its conversion to the polar ammonium ion. Combined with the increases in colonic transit, this therapy significantly lowers circulating ammonia levels. The therapeutic goal in this condition is to give sufficient amounts of lactulose (usually 20-30 g, three to four times per day) to produce two to three soft stools a day with a pH of 5-5.5.

PEGs (without electrolytes) are also increasingly being used in smaller doses (250-500 mL daily) for the treatment of constipation in difficult cases. A powder form of polyethylene glycol 3350 (miralax, others) is now available for the short-term treatment (≤2 weeks) of occasional constipation, although the agent has been prescribed safely for longer periods in clinical practice. The usual dose is 17 g of powder per day in 8 ounces of water. This preparation does not contain electrolytes, so larger volumes may represent a risk for ionic shifts. As with other laxatives, prolonged, frequent, or excessive use may result in dependence or electrolyte imbalance.

Mineral oil is a mixture of aliphatic hydrocarbons obtained from petrolatum. The oil is indigestible and absorbed only to a limited extent. When mineral oil is taken orally for 2-3 days, it penetrates and softens the stool and may interfere with resorption of water. The side effects of mineral oil preclude its regular use and include interference with absorption of fat-soluble substances (such as vitamins), elicitation of foreign-body reactions in the intestinal mucosa and other tissues, and leakage of oil past the anal sphincter. Rare complications such as lipid pneumonitis due to aspiration also can occur, so "heavy" mineral oil should not be taken at bedtime and "light" (topical) mineral oil should never be administered orally.

The usual oral daily dose of bisacodyl is 10-15 mg for adults and 5-10 mg for children ages 6-12 years old. The drug requires hydrolysis by endogenous esterases in the bowel for activation, and so the laxative effects after an oral dose usually are not produced in <6 hours; taken at bedtime, it will produce its effect the next morning. Suppositories work much more rapidly, within 30-60 minutes. Due to the possibility of developing an atonic nonfunctioning colon, bisacodyl should not be used for >10 consecutive days.

Bisacodyl is mainly excreted in the stool; ~5% is absorbed and excreted in the urine as a glucuronide. Overdosage can lead to catharsis and fluid and electrolyte deficits. The diphenylmethanes can damage the mucosa and initiate an inflammatory response in the small bowel and colon. To avoid drug activation in the stomach with consequent gastric irritation and cramping, patients should swallow tablets without chewing or crushing and avoid milk or antacid medications within 1 hour of the ingestion of bisacodyl.

Phenolphthalein, once among the most popular components of laxatives, has been withdrawn from the market in the U.S. because of potential carcinogenicity. Oxyphenisatin, another older drug, was withdrawn due to hepatotoxicity. Sodium picosulfate (lubrilax, sur-lax) is a diphenylmethane derivative widely available outside of the U.S. It is hydrolyzed by colonic bacteria to its active form, and hence acts locally only in the colon. Effective doses of the diphenylmethane derivatives vary as much as 4- to 8-fold in individual patients. Consequently, recommended doses may be ineffective in some patients but may produce cramps and excessive fluid secretion in others.

Senna (senokot, ex-lax, others) is obtained from the dried leaflets on pods of Cassia acutifolia or Cassia angustifolia and contains the rhein dianthrone glycosides sennoside A and B. Cascara sagrada is obtained from the bark of the buckthorn tree and contains the glycosides barbaloin and chrysaloin. Barbaloin is also found in aloe. The rhubarb plant also produces anthraquinone compounds that have been used as laxatives. Anthraquinones can also be synthesized; however, the synthetic monoanthrone danthron was withdrawn from the U.S. market because of concerns over possible carcinogenicity. In addition, all aloe and cascara sagrada products sold as laxatives have been categorized by FDA as not generally recognized as safe and effective for over-the-counter use because of a lack of scientific information about potential carcinogenicity.

Midway, his last resistance yielding, he allowed his bowels to ease themselves quietly as he read, reading still patiently that slight constipation of yesterday quite gone. Hope its not too big to bring on piles again. No, just right. So. Ah! Costive one tabloid of cascara sagrada. Life might be so. (Joyce, 1922)

Anthraquinone laxatives can produce giant migrating colonic contractions and induce water and electrolyte secretion. They are poorly absorbed in the small bowel, but because they require activation in the colon, the laxative effect is not noted until 6-12 hours after ingestion. Active compounds are absorbed to a variable degree from the colon and excreted in the bile, saliva, milk, and urine.

The adverse consequences of long-term use of these agents have limited their use. A melanotic pigmentation of the colonic mucosa (melanosis coli) has been observed in patients using anthraquinone laxatives for long periods (at least 4-9 months). Histologically, this is caused by the presence of pigment-laden macrophages within the lamina propria. The condition is benign and reversible on discontinuation of the laxative. These agents also have been associated with the development of "cathartic colon," which can be seen in patients (typically women) who have a long-standing history (typically years) of laxative abuse. Regardless of whether a definitive causal relationship can be demonstrated between the use of these agents and colonic pathology, it is clear that they should not be recommended for chronic or long-term use.

Castor Oil. A bane of childhood since the time of the ancient Egyptians, castor oil (purge, neoloid, others) is derived from the bean of the castor plant, Ricinus communis. The castor bean is the source of an extremely toxic protein, ricin, as well as the oil (chiefly of the triglyceride of ricinoleic acid). The triglyceride is hydrolyzed in the small bowel by the action of lipases into glycerol and the active agent, ricinoleic acid, which acts primarily in the small intestine to stimulate secretion of fluid and electrolytes and speed intestinal transit. When taken on an empty stomach, as little as 4 mL of castor oil may produce a laxative effect within 1-3 hours; however, the usual dose for a cathartic effect is 15-60 mL for adults. Because of its unpleasant taste and its potential toxic effects on intestinal epithelium and enteric neurons, castor oil is seldom recommended now.

Newer agents, such as the potent 5-HT₄-receptor agonist prucalopride, may be useful for the treatment of chronic constipation. Another potentially useful agent is misoprostol, a synthetic prostaglandin analog primarily used for protection against gastric ulcers resulting from the use of NSAIDs (Chapters 34 and 45). Prostaglandins can stimulate colonic contractions, particularly in the descending colon, and this may account for the diarrhea that limits the usefulness of misoprostol as a gastroprotectant. However, this property may be utilized for therapeutic gain in patients with intractable constipation. Colchicine, a microtubule formation inhibitor used for gout (Chapter 34), also has been shown to be effective in constipation (mechanism unknown), but its toxicity has limited widespread use. A novel biological agent, neurotrophin-3 (NT-3), recently was shown to be effective in improving frequency and stool consistency and decreasing straining, again by an unknown mechanism of action.

Enemas and Suppositories

Enemas commonly are employed, either by themselves or as adjuncts to bowel preparation regimens, to empty the distal colon or rectum of retained solid material. Bowel distention by any means will produce an evacuation reflex in most people, and almost any form of enema, including normal saline solution, can achieve this. Specialized enemas contain additional substances that are either osmotically active or irritant; however, their safety and efficacy have not been studied in a rigorous manner. Repeated enemas with tap water or other hypotonic solutions can cause hyponatremia; repeated enemas with sodium phosphate–containing solution can cause hypocalcemia. Phosphate-containing enemas also are known to alter the appearance of rectal mucosa and contribute to acute phosphate nephropathy in susceptible patients.

Glycerin is a trihydroxy alcohol that is absorbed orally but acts as a hygroscopic agent and lubricant when given rectally. The resultant water retention stimulates peristalsis and usually produces a bowel movement in less than an hour. Glycerin is for rectal use only and is given in a single daily dose as a 2- or 3-g rectal suppository or as 5-15 mL of an 80% solution in enema form. Rectal glycerin may cause local discomfort, burning, or hyperemia and (minimal) bleeding. Some glycerin suppositories contain sodium stearate, which can cause local irritation.

Another agent for occasional constipation makes use of rectal distension to initiate laxation. CEO-TWO suppositories contain sodium bicarbonate and potassium bitartrate. When administered rectally, the suppository produces CO₂, which initiates a bowel movement in 5-30 minutes.

An appreciation and knowledge of the underlying causative processes in diarrhea facilitates effective treatment. From a mechanistic perspective, diarrhea can be caused by an increased osmotic load within the intestine (resulting in retention of water within the lumen); excessive secretion of electrolytes and water into the intestinal lumen; exudation of protein and fluid from the mucosa; and altered intestinal motility resulting in rapid transit (and decreased fluid absorption). In most instances, multiple processes are affected simultaneously, leading to a net increase in stool volume and weight accompanied by increases in fractional water content.

In patients suspected of having bile salt–induced diarrhea, a trial of cholestyramine (questran, questran light, others) can be given at a dose of 4 g of the dried resin (four times a day). If successful, the dose may be titrated down to achieve the desired stool frequency.

Cholestyramine resin also is helpful for the relief of pruritus associated with partial biliary obstruction and in conditions such as primary biliary cirrhosis. In such conditions, excessive bile acids are thought to be deposited in the skin and cause irritation. Cholestyramine increases fecal excretion of bile acids and reduces circulating and eventually systemic levels with relief of pruritus in ~1-3 weeks.

Bismuth is thought to have anti-secretory, anti-inflammatory, and antimicrobial effects. Nausea and abdominal cramps also are relieved by bismuth. The clay in PEPTO-BISMOL and generic formulations also may have some additional benefits in diarrhea, but this is not clear. Bismuth subsalicylate has been used extensively for the prevention and treatment of traveler's diarrhea, but it also is effective in other forms of episodic diarrhea and in acute gastroenteritis. Today, the most common antibacterial use of this agent is in the treatment of Helicobacter pylori (Chapter 45). A recommended dose of the bismuth subsalicylate (30 mL of regular strength liquid or two tablets) contains approximately equal amounts of bismuth and salicylate (262 mg each). For control of indigestion, nausea, or diarrhea, the dose is repeated every 30-60 minutes, as needed, up to eight times a day. Bismuth products have a long track record of safety at recommended doses, although impaction may occur in infants and debilitated patients. Dark stools (sometimes mistaken for melena) and black staining of the tongue in association with bismuth compounds are caused by bismuth sulfide formed in a reaction between the drug and bacterial sulfides in the GI tract.

Probiotics. The GI tract contains a vast commensal microflora that is necessary for health. Alterations in the balance or composition of the microflora are responsible for antibiotic-associated diarrhea, and possibly other disease conditions. The administration of nonpathogenic bacteria to recolonize the gut is an area of intense investigation (Sartor, 2005). Probiotic preparations containing a variety of bacterial strains have shown some degree of benefit in acute diarrheal conditions, antibiotic-associated diarrhea, and infectious diarrhea, but most clinical studies have been small and conclusions are therefore limited. Because these agents are generally safe, their use continues despite mainly anecdotal evidence of efficacy.

Because of its effectiveness and safety, loperamide is marketed for over-the-counter distribution and is available in capsule, solution, and chewable tablet forms. It acts quickly after an oral dose, with peak plasma levels achieved within 3-5 hours. It has a t_1/2 of ~11 hours and undergoes extensive hepatic metabolism. The usual adult dose is 4 mg initially followed by 2 mg after each subsequent loose stool, up to 16 mg per day. If clinical improvement in acute diarrhea does not occur within 48 hours, loperamide should be discontinued. Recommended maximum daily doses for children are 3 mg for ages 2-5 years, 4 mg for ages 6-8 years, and 6 mg for ages 8-12 years. Loperamide is not recommended for use in children <2 years of age.

Loperamide has been shown to be effective against traveler's diarrhea, used either alone or in combination with antimicrobial agents (trimethoprim, trimethoprim-sulfamethoxazole, or a fluoroquinolone). Loperamide also has been used as adjunct treatment in almost all forms of chronic diarrheal disease, with few adverse effects. Loperamide lacks significant abuse potential and is more effective in treating diarrhea than diphenoxylate. Overdosage, however, can result in CNS depression (especially in children) and paralytic ileus. In patients with active inflammatory bowel disease involving the colon (Chapter 47), loperamide should be used with great caution, if at all, to prevent development of toxic megacolon.

Loperamide N-oxide, an investigational agent, is a site-specific prodrug; it is chemically designed for controlled release of loperamide in the intestinal lumen, thereby reducing systemic absorption.

Both compounds are extensively absorbed after oral administration, with peak levels achieved within 1-2 hours. Diphenoxylate is rapidly deesterified to difenoxin, which is eliminated with a t_1/2 of ~12 hours. Both drugs can produce CNS effects when used in higher doses (40-60 mg per day) and thus have a potential for abuse and/or addiction. They are available in preparations containing small doses of atropine (considered subtherapeutic) to discourage abuse and deliberate overdosage: 25 μg of atropine sulfate per tablet with either 2.5 mg diphenoxylate hydrochloride (lomotil) or 1 mg of difenoxin hydrochloride (motofen). The usual dosage is two tablets initially, then one tablet every 3-4 hours, not to exceed eight tablets per day. With excessive use or overdose, constipation and (in inflammatory conditions of the colon) toxic megacolon may develop. In high doses, these drugs cause CNS effects as well as anticholinergic effects from the atropine (dry mouth, blurred vision, etc.) (Chapter 9).

Other opioids used for diarrhea include codeine (in doses of 30 mg given three or four times daily) and opium-containing compounds. Paregoric (camphorated opium tincture) contains the equivalent of 2 mg of morphine per 5 mL (0.4 mg/mL); deodorized tincture of opium, which is 25 times stronger, contains the equivalent of 50 mg of morphine per 5 mL (10 mg/mL). The two tinctures sometimes are confused in prescribing and dispensing, resulting in dangerous overdoses. The anti-diarrheal dose of opium tincture for adults is 0.6 mL (equivalent to 6 mg morphine) four times daily; the adult dose of paregoric is 5-10 mL (equivalent to 2-4 mg morphine) one to four times daily. Paregoric is used in children at a dose of 0.25-0.5 mL/kg (equivalent to 0.1-0.2 mg morphine/kg) one to four times daily.

Enkephalins are endogenous opioids that are important enteric neurotransmitters. Enkephalins inhibit intestinal secretion without affecting motility. Racecadotril (acetorphan), a dipeptide inhibitor of enkephalinase, reinforces the effects of endogenous enkephalins on the δ-opioid receptor to produce an anti-diarrheal effect.

α₂ Adrenergic Receptor Agonists. α₂ Adrenergic receptor agonists such as clonidine can interact with specific receptors on enteric neurons and enterocytes, thereby stimulating absorption and inhibiting secretion of fluid and electrolytes and increasing intestinal transit time. These agents may have a special role in diabetics with chronic diarrhea, in whom autonomic neuropathy can lead to loss of noradrenergic innervation. Oral clonidine (beginning at 0.1 mg twice a day) has been used in these patients; the use of a topical preparation (e.g., catapres tts, two patches a week) may result in more steady plasma levels of the drug. Clonidine also may be useful in patients with diarrhea caused by opiate withdrawal. Side effects such as hypotension, depression, and perceived fatigue may be dose limiting in susceptible patients.

Octreotide has a t_1/2 of 1-2 hours and is administered either subcutaneously or intravenously as a bolus dose. Standard initial therapy with octreotide is 50-100 μg, given subcutaneously two or three times a day, with titration to a maximum dose of 500 μg three times a day based on clinical and biochemical responses. A long-acting preparation of octreotide acetate enclosed in biodegradable microspheres (sandostatin lar depot) is available for use in the treatment of diarrheas associated with carcinoid tumors and VIP–secreting tumors, as well as in the treatment of acromegaly (Chapter 44). This preparation is injected intramuscularly once per month in a dose of 20 or 30 mg. Side effects of octreotide depend on the duration of therapy. Short-term therapy leads to transient nausea, bloating, or pain at sites of injection. Long-term therapy can lead to gallstone formation and hypo- or hyperglycemia. Another long-acting SST analog, lanreotide (somatulin, others), is available in Europe but not in the U.S.; another, vapreotide, is under development. SST (stilamin) also is available in Europe.

Variceal Bleeding. Vasoactive agents have been used to control variceal bleeding. Traditionally, vasopressin has been used (Chapter 26), but its significant side effects—such as myocardial ischemia, peripheral vascular disease, and the release of plasminogen activator and factor VIII—have led to its decline. SST and octreotide are effective in reducing hepatic blood flow, hepatic venous wedge pressure, and azygos blood flow. These agents constrict the splanchnic arterioles by a direct action on vascular smooth muscle and by inhibiting the release of peptides contributing to the hyperdynamic circulatory syndrome of portal hypertension. Octreotide also may act through the autonomic nervous system. These agents can control bleeding acutely and decrease bleeding-related mortality, with an efficacy comparable to endoscopic therapy or balloon tamponade. The major advantage of somatostatin and octreotide over vasopressin is their safety. Because of its short t_1/2 (1-2 minutes), SST can be given only by intravenous infusion (a 250 μg bolus dose followed by 250 μg hourly for 5 days). Higher doses (up to 500 μg/hour) are more efficacious and can be used for patients who continue to bleed on the lower dose (Moitinho et al., 2001). For patients with variceal bleeding, therapy with octreotide usually is initiated while the patient is awaiting endoscopy.

Intestinal Dysmotility. Octreotide has complex and apparently conflicting effects on GI motility, including inhibition of antral motor activity and colonic tone. However, octreotide also can rapidly induce phase III activity of the migrating motor complex in the small bowel to produce longer and faster contractions than those occurring spontaneously. Its use has been shown to result in improvement in selected patients with scleroderma and small-bowel dysfunction.

Pancreatitis. Both SST and octreotide inhibit pancreatic secretion and have been used for the prophylaxis and treatment of acute pancreatitis. The rationale for their use is to "put the pancreas to rest" so as to not aggravate inflammation by the continuing production of proteolytic enzymes, to reduce intraductal pressures, and to ameliorate pain. Octreotide probably is less effective than SST in this regard because it may cause an increase in sphincter of Oddi pressure and perhaps also have a deleterious effect on pancreatic blood flow. Although some studies have suggested that these agents improve mortality in patients with acute pancreatitis, definitive data are lacking.

Other Agents

Calcium channel blockers such as verapamil and nifedipine (Chapters 25 and 27) reduce motility and may promote intestinal electrolyte and water absorption. Constipation, in fact, is a significant side effect of these drugs. However, because of their systemic effects and the availability of other agents, they seldom if ever are used for diarrheal illnesses.

Berberine is a plant alkaloid that has been used for millennia in traditional Indian and Chinese medicine. It is produced by several genera of the families Ranuculaceae and Berberidaceae (e.g., Berberis, Mahonia, and Coptis) and has complex pharmacological actions that include antimicrobial actions, stimulation of bile flow, inhibition of ventricular tachyarrhythmias, and possible antineoplastic activity. It is used most commonly in bacterial diarrhea and cholera, but is also apparently effective against intestinal parasites. The anti-diarrheal effects in part may be related to its antimicrobial activity, as well as its ability to inhibit smooth muscle contraction and delay intestinal transit by antagonizing the effects of ACh (by competitive and noncompetitive mechanisms) and blocking the entry of Ca²⁺ into cells. In addition, it inhibits intestinal secretion.

Chloride channel blockers are effective anti-secretory agents in vitro but are too toxic for human use and have not proven to be effective anti-diarrheal agents in vivo. Calmodulin inhibitors, which include chlorpromazine, also are anti-secretory. Zaldaride maleate, an investigational drug in this class, may be effective in traveler's diarrhea by reducing secretion without affecting intestinal motility.

Many patients can be managed satisfactorily with a strong patient-physician relationship, simple counseling, and adjunctive measures, including dietary restrictions and fiber supplementation; overt psychological abnormalities should be treated appropriately. Despite these measures, a significant proportion of patients remain plagued by severe symptoms, and drug therapy is attempted almost invariably. However, there are very few effective pharmacological options for these patients, a situation that in part reflects our limited understanding of the pathogenesis of this syndrome.

The pharmacological approach to IBS reflects its multifaceted nature. Treatment of bowel symptoms (either diarrhea or constipation) is predominantly symptomatic and nonspecific. Patients with mild symptoms often are started on fiber supplements; this approach may work for constipation and diarrhea (by binding water). Patients with episodic, discrete pain episodes often are treated with agents that may reduce smooth muscle contractility in the gut. These so-called antispasmodics include anticholinergic agents, Ca²⁺ channel antagonists, and peripheral opioid receptor antagonists. The use of most such drugs is hallowed by years of tradition but seldom has been subjected to critical assessment; however, these drugs may be modestly effective in a subset of patients and are useful adjuncts.

In recent years, an increasing emphasis is being placed on the pharmacological treatment of visceral sensitivity. Although the biological basis of visceral hyperalgesia in IBS patients is not known, a possible role for serotonin has been suggested based on its known involvement in sensitization of nociceptor neurons in inflammatory conditions. This has led to the development of specific receptor modulators, such as the 5-HT₃ antagonist alosetron (Figure 46–2). Buspirone and sumatriptan are 5-HT₁ receptor agonists (Chapter 13) that can reduce gastric and colonic sensitivity to distention and are being evaluated in clinical trials.

The most effective class of agents in this regard has been the tricyclic anti-depressants (Chapter 15), which can have neuromodulatory and analgesic properties independent of their anti-depressant effect. Tricyclic anti-depressants have a proven track record in the management of chronic "functional" visceral pain. Effective analgesic doses of these drugs (e.g., 25-75 mg per day of nortryptiline) are significantly lower than those required to treat depression. Although changes in mood usually do not occur at these doses, there may be some diminution of anxiety and restoration of sleep patterns, which can be considered desirable effects in this group of patients. Selective serotonin reuptake inhibitors have fewer side effects and have been advocated particularly for patients with functional constipation because they can increase bowel movements and even cause diarrhea. However, they probably are not as effective as tricyclic anti-depressants in the management of visceral pain.

a₂ Adrenergic agonists, such as clonidine (Chapter 12), also can increase visceral compliance and reduce distention-induced pain. The SST analog octreotide has selective inhibitory effects on peripheral afferent nerves projecting from the gut to the spinal cord in healthy human beings and has been shown to blunt the perception of rectal distention in patients with IBS. Fedotozine, an investigational opioid that appears to be a peripherally active, selective κ receptor antagonist, produces marginal improvement in symptoms in patients with IBS and functional dyspepsia. The lack of CNS effects is an advantage in such patients in whom chronic medication use is anticipated. Other agents of unproven value include leuprolide, a gonadotropin-releasing hormone analog (Chapter 42).

Alosetron and Other 5-HT₃ Antagonists

The 5-HT₃ receptor participates in several important processes in the gut, including sensitization of spinal sensory neurons, vagal signaling of nausea, and peristaltic reflexes. Some of these effects in experimental models are potentially conflicting, with release of excitatory and inhibitory neurotransmitters. However, the clinical effect of 5-HT₃ antagonism is a general reduction in GI contractility with decreased colonic transit, along with an increase in fluid absorption. In general, therefore, these antagonists produce the opposite effects seen with 5-HT₄ agonists. Although they also may blunt visceral sensation, a direct effect on spinal afferents has not been fully established. Alosetron (lotronex) was the first agent in this class specifically approved for the treatment of diarrhea-predominant IBS in women. Alosetron is a much more potent antagonist of the 5-HT₃ receptor than ondansetron and causes significant (although modest) improvements in abdominal pain as well as stool frequency, consistency, and urgency in these patients. Shortly after its initial release, alosetron was withdrawn from the U.S. market because of an unusually high incidence of ischemic colitis (up to 3 per 1000 patients), leading to surgery and even death in a small number of cases. The mechanism of this effect is not fully established but may result from the drug's ability to suppress intestinal relaxation, thereby causing severe spasm in segments of the colon in susceptible individuals. It is not clear whether this is a nonspecific effect or involves serotoninergic mechanisms. Nevertheless, the FDA has reapproved this drug for diarrhea-predominant IBS under a limited distribution system. However, concerns about the consequences of prescribing this drug are important, and the manufacturer requires a prescription program that includes physician certification and an elaborate patient education and consent protocol before dispensing.

Alosetron is rapidly absorbed from the GI tract; its duration of action (~10 hours) is longer than expected from its t_1/2 of 1.5 hours. It is metabolized by hepatic CYPs. The drug should be started at 1 mg per day for the first 4 weeks and advanced to a maximum of 1 mg twice daily if an adequate response is not achieved.

Other 5-HT₃ antagonists currently available in the U.S. are approved for nausea and vomiting (see later in this chapter and Chapter 13).

Dicyclomine is given in doses of 20 mg orally every 6 hours initially and increased to 40 mg every 6 hours unless limited by side effects. Doses <160 mg/day are not usually effective and should be discontinued after a 2-week trial period. Hyoscyamine is available as immediate-release oral capsules, tablets, elixir, drops, and a nonaerosol spray (all administered as 0.125-0.25 mg every 4 hours as needed), and extended-release forms for oral use (0.25-0.375 mg every 12 hours as needed). An injectable is available for subcutaneous, intravenous, or intramuscular administration. Regardless of the formulation, the adult dose of hyoscyamine usually should not exceed 1.5 mg in 24 hours. Glycopyrrolate is available as immediate-release tablets; the dose is 1-2 mg two or three times daily, not to exceed 8 mg/day. Methscopolamine is provided as 2.5-mg and 5-mg tablets; the dose is 2.5 mg a half hour before meals and 2.5-5 mg at bedtime.

There is evidence that effects at peripheral and central sites contribute to the efficacy of these agents. 5-HT₃ receptors are present in several critical sites involved in emesis, including vagal afferents, the STN (which receives signals from vagal afferents), and the area postrema itself (Figure 46–4). Serotonin is released by the enterochromaffin cells of the small intestine in response to chemotherapeutic agents and may stimulate vagal afferents (via 5-HT₃ receptors) to initiate the vomiting reflex. Experimentally, vagotomy has been shown to prevent cisplatin-induced emesis. However, the highest concentrations of 5-HT₃ receptors in the CNS are found in the STN and CTZ, and antagonists of 5-HT₃ receptors also may suppress nausea and vomiting by acting at these sites.

Pharmacokinetics. The anti-emetic effects of these drugs persist long after they disappear from the circulation, suggesting their continuing interaction at the receptor level. In fact, all of these drugs can be administered effectively just once a day.

These agents are absorbed well from the GI tract. Ondansetron is extensively metabolized in the liver by CYP1A2, CYP2D6, and CYP3A4, followed by glucuronide or sulfate conjugation. Patients with hepatic dysfunction have reduced plasma clearance, and some adjustment in the dosage is advisable. Although ondansetron clearance also is reduced in elderly patients, no adjustment in dosage for age is recommended. Granisetron also is metabolized predominantly by the liver, a process that appears to involve the CYP3A family, as it is inhibited by ketoconazole. Dolasetron is converted rapidly by plasma carbonyl reductase to its active metabolite, hydrodolasetron. A portion of this compound then undergoes subsequent biotransformation by CYP2D6 and CYP3A4 in the liver while about one-third of it is excreted unchanged in the urine. Palonosetron is metabolized principally by CYP2D6 and excreted in the urine as the metabolized and the unchanged forms in about equal proportions.

Therapeutic Use. These agents are most effective in treating chemotherapy-induced nausea and in treating nausea secondary to upper abdominal irradiation, where all three agents appear to be equally efficacious. They also are effective against hyperemesis of pregnancy, and to a lesser degree, postoperative nausea, but not against motion sickness. Unlike other agents in this class, palonosetron also may be helpful in delayed emesis, perhaps a reflection of its long t_1/2.

These agents are available as tablets, oral solution, and intravenous preparations for injection. For patients on cancer chemotherapy, these drugs can be given in a single intravenous dose (Table 46–8) infused over 15 minutes, beginning 30 minutes before chemotherapy, or in 2-3 divided doses, with the first usually given 30 minutes before and subsequent doses at various intervals after chemotherapy. The drugs also can be used intramuscularly (ondansetron only) or orally. Granisetron is available as a transdermal formulation that is applied 24-48 hours before chemotherapy and worn for up to 7 days.

Adverse Effects. In general, these drugs are very well tolerated, with the most common adverse effects being constipation or diarrhea, headache, and lightheadedness. As a class, these agents have been shown experimentally to induce minor electrocardiographic changes, but these are not expected to be clinically significant in most cases.

Dopamine-Receptor Antagonists

Phenothiazines such as prochlorperazine, thiethylperazine (discontinued in the U.S.), and chlorpromazine (Chapter 16) are among the most commonly used "general-purpose" anti-nauseants and anti-emetics. Their effects in this regard are complex, but their principal mechanism of action is D₂ receptor antagonism at the CTZ. Compared with metoclopramide or ondansetron, these drugs do not appear to be as uniformly effective in cancer chemotherapy–induced emesis. But they also possess antihistaminic and anticholinergic activities, which are of value in other forms of nausea, such as motion sickness.

Antihistamines

Histamine H₁ antagonists are primarily useful for motion sickness and postoperative emesis. They act on vestibular afferents and within the brainstem. Cyclizine, hydroxyzine, promethazine, and diphenhydramine are examples of this class of agents. Cyclizine has additional anticholinergic effects that may be useful for patients with abdominal cancer. For a detailed discussion of these drugs, see Chapter 32.

Anticholinergic Agents

The most commonly used muscarinic receptor antagonist is scopolamine (hyoscine), which can be injected as the hydrobromide, but usually is administered as the free base in the form of a transdermal patch (transderm-scop). Its principal utility is in the prevention and treatment of motion sickness, although it has been shown to have some activity in postoperative nausea and vomiting tool. In general, anticholinergic agents have no role in chemotherapy-induced nausea. For a detailed discussion of these drugs, see Chapter 9.

Substance P Receptor Antagonists

The nausea and vomiting associated with cisplatin (Chapter 61) have two components: an acute phase that universally is experienced (within 24 hours after chemotherapy) and a delayed phase that affects only some patients (on days 2-5). 5-HT₃ receptor antagonists are not very effective against delayed emesis. Antagonists of the NK₁ receptors for substance P, such as aprepitant (and its parenteral formulation, fosaprepitant; emend), have anti-emetic effects in delayed nausea and improve the efficacy of standard anti-emetic regimens in patients receiving multiple cycles of chemotherapy.

After absorption, aprepitant is bound extensively to plasma proteins (>95%); it is metabolized avidly, primarily by hepatic CYP3A4, and is excreted in the stools; its t_1/2 is 9-13 hours. Aprepitant has the potential to interact with other substrates of CYP3A4, requiring adjustment of other drugs, including dexamethasone, methylprednisolone (whose dose may need to be reduced by 50%), and warfarin. Aprepitant is contraindicated in patients on cisapride or pimozide, in whom life-threatening QT prolongation has been reported.

Aprepitant is supplied in 40-, 80- and 125-mg capsules and is administered for 3 days in conjunction with highly emetogenic chemotherapy, along with a 5-HT₃ antagonist and a corticosteroid. The recommended adult dosage of aprepitant is 125 mg administered 1 hour before chemotherapy on day 1, followed by 80 mg once daily in the morning on days 2 and 3 of the treatment regimen.

Cannabinoids

Dronabinol (Δ-9-tetrahydrocannabinol; marinol) is a naturally occurring cannabinoid that can be synthesized chemically or extracted from the marijuana plant, Cannabis sativa. The exact mechanism of the anti-emetic action of dronabinol is not known but probably relates to stimulation of the CB₁ subtype of cannabinoid receptors on neurons in and around the vomiting center in the brainstem (Van Sickle et al., 2001).

Pharmacokinetics. Dronabinol is a highly lipid-soluble compound that is absorbed readily after oral administration; its onset of action occurs within an hour, and peak levels are achieved within 2-4 hours. It undergoes extensive first-pass metabolism with limited systemic bioavailability after single doses (only 10-20%). Active and inactive metabolites are formed in the liver; the principal active metabolite is 11-OH-delta-9-tetrahydrocannabinol.

These metabolites are excreted primarily via the biliary-fecal route, with only 10-15% excreted in the urine. Both dronabinol and its metabolites are highly bound (>95%) to plasma proteins. Because of its large volume of distribution, a single dose of dronabinol can result in detectable levels of metabolites for several weeks.

Therapeutic Use. Dronabinol is a useful prophylactic agent in patients receiving cancer chemotherapy when other anti-emetic medications are not effective. It also can stimulate appetite and has been used in patients with acquired immunodeficiency syndrome (AIDS) and anorexia. As an anti-emetic agent, it is administered at an initial dose of 5 mg/m² given 1-3 hours before chemotherapy and then every 2-4 hours afterward for a total of four to six doses. If this is not adequate, incremental increases can be made up to a maximum of 15 mg/m² per dose. For other indications, the usual starting dose is 2.5 mg twice a day; this can be titrated up to a maximum of 20 mg per day.

Adverse Effects. Dronabinol has complex effects on the CNS, including a prominent central sympathomimetic activity. This can lead to palpitations, tachycardia, vasodilation, hypotension, and conjunctival injection (bloodshot eyes). Patient supervision is necessary because marijuana-like "highs" (e.g., euphoria, somnolence, detachment, dizziness, anxiety, nervousness, panic, etc.) can occur, as can more disturbing effects such as paranoid reactions and thinking abnormalities. After abrupt withdrawal of dronabinol, an abstinence syndrome (irritability, insomnia, and restlessness) can occur. Because of its high affinity for plasma proteins, dronabinol can displace other plasma protein-bound drugs, whose doses may have to be adjusted as a consequence. Dronabinol should be prescribed with great caution to persons with a history of substance abuse (alcohol, drugs) because it also may be abused by these patients.

Nabilone (cesamet) is a synthetic cannabinoid with a mode of action similar to that of dronabinol.

Pharmacokinetics. Nabilone, like dronabinol, is a highly lipid-soluble compound that is rapidly absorbed after oral administration; its onset of action occurs within an hour, and peak levels are achieved within 2 hours. The t_1/2 is ~2 hours for the parent compound and 35 hours for metabolites. The metabolites are excreted primarily via the biliary-fecal route (60%), with only ~25% excreted in the urine.

Therapeutic Use. Nabilone is a useful prophylactic agent in patients receiving cancer chemotherapy when other anti-emetic medications are not effective. A dose (1-2 mg) can be given the night before chemotherapy; usual dosing starts 1-3 hours before treatment and then every 8-12 hours during the course of chemotherapy and for 2 days following its cessation.

Adverse Effects. The adverse effects are largely the same as for dronabinol, with significant CNS actions in >10% of patients. Cardiovascular, GI, and other side effects are also common and together with the CNS actions limit the usefulness of this agent.

Glucocorticoids and Anti-Inflammatory Agents

Glucocorticoids such as dexamethasone can be useful adjuncts (Table 46–7) in the treatment of nausea in patients with widespread cancer, possibly by suppressing peritumoral inflammation and prostaglandin production. A similar mechanism has been invoked to explain beneficial effects of NSAIDs in the nausea and vomiting induced by systemic irradiation. For a detailed discussion of these drugs, see Chapters 34 and 42.

Benzodiazepines

Benzodiazepines, such as lorazepam and alprazolam, by themselves are not very effective anti-emetics, but their sedative, amnesic, and anti-anxiety effects can be helpful in reducing the anticipatory component of nausea and vomiting in patients. For a detailed discussion of these drugs, see Chapter 17.

Phosphorated Carbohydrate Solutions

Aqueous solutions of glucose, fructose, and phosphoric acid (emetrol, nausetrol) are available over the counter to relieve nausea. Their mechanism of action is not well established. They may be safely taken for a short period (1 hour with a dose every 15 minutes).

Enzyme Formulations. In the past, two preparations (and many brands thereof) of pancreatic enzymes were available for replacement therapy, pancreatin and pancrelipase. As of 2009, only pancrelipase (creon, zenpep) is licensed for sale in the U.S. Pancreatic enzymes are typically prescribed on the basis of the lipase content. Pancrelipase products contain various amounts of lipase, protease, and amylase and thus may not be interchangeable. Excess lipase administration has been implicated in the development of fibrosing colonopathy and adherence to published dosing guidelines is thought to minimize this risk (Borowitz et al., 2002).

Replacement Therapy for Malabsorption. Fat malabsorption (steatorrhea) and protein maldigestion occur when the pancreas loses >90% of its ability to produce digestive enzymes. The resultant diarrhea and malabsorption can be managed reasonably well if 30,000 USP units of pancreatic lipase are delivered to the duodenum during a 4-hour period with and after meals; this represents ~10% of the normal pancreatic output. Alternatively, one can titrate the dosage to the fat content of the diet, with ~8000 USP units of lipase activity required for each 17 g of dietary fat. Available preparations of pancreatic enzymes contain up to 20,000 units of lipase and 76,000 units of protease, and the typical dose of pancrelipase is one to three capsules or tablets with or just before meals and snacks, adjusted until a satisfactory symptomatic response is obtained. The loss of pancreatic amylase does not present a problem because of other sources of this enzyme (e.g., salivary glands). The commercially available products are formulated as delayed-release capsules to overcome the need to control gastric acid pharmacologically.

Enzymes for Pain. Pain is the other cardinal symptom of chronic pancreatitis. The rationale for its treatment with pancreatic enzymes is based on the principle of negative feedback inhibition of the pancreas by the presence of duodenal proteases. The release of cholecystokinin (CCK), the principal secretagogue for pancreatic enzymes, is triggered by CCK-releasing monitor peptide in the duodenum, which normally is denatured by pancreatic trypsin. In chronic pancreatitis, trypsin insufficiency leads to persistent activation of this peptide and an increased release of CCK, which is thought to cause pancreatic pain because of continuous stimulation of pancreatic enzyme output and increased intraductal pressure. Delivery of active proteases to the duodenum (which can be done reliably only with uncoated preparations) therefore is important for the interruption of this loop. Although enzymatic therapy has become firmly entrenched for the treatment of painful pancreatitis, the evidence supporting this practice is equivocal at best.

In general, pancreatic enzyme preparations are tolerated extremely well by patients. Hyperuricosuria in patients with cystic fibrosis can occur, and malabsorption of folate and iron has been reported.

Medium-chain triglycerides. Medium-chain triglycerides (MCTs) may provide an additional source of calories in patients with weight loss and a poor response to diet and pancreatic enzyme therapy. MCTs are readily degraded by gastric and pancreatic lipase, and they do not require bile for digestion. In addition, they can be directly absorbed in the intestine. Oral administration of an enteral formula such as PEPTAMEN, which is enriched in MCTs and hydrolyzed peptides, may be of benefit.

Octreotide. Octreotide (Chapter 38) also has been used, with questionable efficacy, to decrease refractory abdominal pain in patients with chronic pancreatitis.

Enzyme Deficiencies

Congenital or acquired deficiencies in digestive enzymes may lead to malabsorption and diarrhea as well as other GI symptoms. Most commonly seen are lactose intolerance, which occurs in the West (10-20%) but in some Asian populations may exceed 90%. Clinically, diarrhea, pain and flatulence occur. Treatment consists of reducing dietary intake of lactose, primarily by reducing consumption of milk and dairy products. Enzyme replacements are over the counter and can be added to meals. They are bacterial or yeast-derived β-galactosidases, with varying efficacy (lactaid, lactrase, dairyease, others). Because of considerable individual variation and the uncertain degree of efficacy of these preparations, patients must establish an effective dosing regime empirically. Because of the essential requirements to maintain protein, calcium, and vitamin D intake, these must be supplemented or alternative sources provided in the diet if dairy products are limited.

Congenital sucrase-isomaltase deficiency is less common. The symptoms include diarrhea, abdominal pain, and weight loss. This is a congenital disease and may be diagnosed in children who are failing to thrive and are susceptible to repeated infections. Treatment with enzyme replacement therapy is effective. Sacrosidase (sucraid) taken with meals reduces or attenuates symptoms in most cases. Elimination of sugars and carbohydrates from the diet is not practical.

Dried bile from the Himalayan bear (Yutan) has been used for centuries in China to treat liver disease. Ursodeoxycholic acid (UDCA; ursodiol, actigall, others) (Figure 46–5) is a hydrophilic, dehydroxylated bile acid that is formed by epimerization of the bile acid chenodeoxycholic acid (CDCA; chenodiol) in the gut by intestinal bacteria; it comprises ~1-3% of the total bile acid pool in human beings but is present at much higher concentrations in bears. When administered orally, litholytic bile acids such as chenodiol and ursodiol can alter relative concentrations of bile acids, decrease biliary lipid secretion, and reduce the cholesterol content of the bile so that it is less lithogenic. Ursodiol also may have cytoprotective effects on hepatocytes and effects on the immune system that account for some of its beneficial effects in cholestatic liver diseases.

Bile acids were first used therapeutically for gallstone dissolution; use for this indication requires a functional gallbladder because the modified bile must enter the gallbladder to interact with gallstones. To be amenable to dissolution, the gallstones must be composed of cholesterol monohydrate crystals and generally must be <15 mm in diameter to provide a favorable ratio of surface to size. For these reasons, the overall efficacy of litholytic bile acids in the treatment of gallstones has been disappointing (partial dissolution occurs in 40-60% of patients completing therapy and is complete in only 33-50% of these). Although a combination of chenodiol and ursodiol probably is better than either agent alone, ursodiol is preferred as a single agent because of its greater efficacy and less-frequent side effects (e.g., hepatotoxicity).

Primary biliary cirrhosis is a chronic, progressive, cholestatic liver disease of unknown etiology that typically affects middle-aged to elderly women. Ursodiol (administered at 13-15 mg/kg per day in two divided doses) reduces the concentration of primary bile acids and improves biochemical and histological features of primary biliary cirrhosis, especially in early disease. Patients with advanced primary biliary cirrhosis and complications such as ascites do not benefit from this treatment. Ursodiol also has been used in a variety of other cholestatic liver diseases, including primary sclerosing cholangitis, and in cystic fibrosis; in general, it is less effective in these conditions than in primary biliary cirrhosis.

Simethicone is an inert, non-toxic insoluble liquid. Because of its ability to collapse bubbles by forming a thin layer on their surface, it is an effective anti-foaming agent. Although it may be effective in diminishing gas volumes in the GI tract, it is not clear whether this accomplishes a therapeutic effect. Simethicone is available in chewable tablets, liquid-filled capsules, suspensions, and orally disintegrating strips, either by itself or in combination with other over-the-counter medications including antacids and other digestants. The usual dosage in adults is 40-25 mg four times daily. Activated charcoal may also be used alone or in combination with simethicone, but has not been shown conclusively to have much benefit.

An alpha-galactosidase preparation (beano) is available over-the-counter to reduce gas from baked beans.