Goodman and Gilman Manual of Pharmacology and Therapeutics

Section VI
Drugs Affecting Gastrointestinal Function

chapter 46
Gastrointestinal Motility and Water Flux; Emesis; Biliary and Pancreatic Disease


The gastrointestinal (GI) tract is in a continuous contractile, absorptive, and secretory state. The control of this state is complex, with contributions by the muscle and epithelium, local nerves of the enteric nervous system (ENS), the autonomic nervous system (ANS), and circulating hormones. Of these, perhaps the most important regulator of physiological gut function is the ENS (Figure 46–1).


Figure 46–1 The neuronal network that initiates and generates the peristaltic response. Mucosal stimulation leads to release of serotonin by enterochromaffin cells (8), which excites the intrinsic primary afferent neurons (1), which then communicate with ascending (2) and descending (3) interneurons in the local reflex pathways. The reflex results in contraction at the oral end via the excitatory motor neuron (6) and aboral relaxation via the inhibitory motor neuron (5). The migratory myoelectric complex (see text) is shown here as being conducted by a different chain of interneurons (4). Another intrinsic primary afferent neuron with its cell body in the submucosa also is shown (7). MP, myenteric plexus; CM, circular muscle; LM, longitudinal muscle; SM, submucosa; Muc, mucosa. (Adapted with permission of Annual Reviews, from Kunze WA, Furness JB. The enteric nervous system and regulation of intestinal motility. Annu Rev Physiol, 1999;61:117–142. Permission conveyed through Copyright Clearance Center, Inc.)

The ENS is an extensive collection of nerves that constitutes the third division of the ANS. It is the only part of the ANS truly capable of autonomous function if separated from the central nervous system (CNS). The ENS lies within the wall of the GI tract organized into 2 connected networks of neurons and nerve fibers: the myenteric (Auerbach) plexus, found between the circular and longitudinal muscle layers, and the submucosal (Meissner) plexus, located in the submucosa. The former is largely responsible for motor control, whereas the latter regulates secretion, fluid transport, and blood flow. The ENS and the ANS are also involved in host defense and innervate organs and cells of the immune system.


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 4 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 min before proceeding caudally (toward the anus). Phase II of the MMC is associated with the release of the peptide hormone motilin. Motilin agonists stimulate motility in the proximal gut. One whole MMC cycle (i.e., all 4 phases) takes ~80-110 min. The MMC occurs in the fasting state, helping to sweep debris caudad in the gut and limiting the overgrowth of luminal bacteria. The MMC is interrupted by the fed program in intermittently feeding animals such as humans. The fed program consists of high-frequency (12-15/min) contractions that are either propagated for short segments (propulsive) or are irregular and not propagated (mixing).

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. Motor neurons receive input from ascending and descending interneurons (which constitute the relay and programming systems) that are of 2 broad types, excitatory and inhibitory. The primary neurotransmitter of the excitatory motor neurons is acetylcholine (ACh). The principal neurotransmitter in the inhibitory motor neurons appears to be NO, although important contributions may also be made by ATP, vasoactive intestinal peptide (VIP), and pituitary adenylyl cyclase–activating peptide (PACAP). Enterochromaffin cells, scattered throughout the epithelium of the intestine, release serotonin (5HT) to initiate many gut reflexes by acting locally on enteric neurons. Excessive release of 5HT from the gut wall (e.g., by chemotherapeutic agents) leads to vomiting by actions of 5HT on vagal nerve endings in the proximal small intestine. Compounds targeting the 5HT system are important modulators of motility, secretion, and emesis.

Other cell types are important, including the interstitial cells of Cajal, distributed within the gut wall and responsible for setting the electrical rhythm and 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.


Control of tension in GI smooth muscle is dependent on the intracellular Ca2+ concentration. There are basically 2 types of excitation-contraction coupling in these cells. Ionotropic receptors can mediate changes in membrane potential, which in turn activate voltage-dependent Ca2+ channels to trigger an influx of Ca2+ (electromechanical coupling); metabotropic receptors activate various signal transduction pathways to release Ca2+ from intracellular stores (pharmaco-mechanical coupling). Inhibitory receptors act via PKA and PKG and 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 cause the opening of several types of K+ channels.


GI motility disorders are a heterogeneous group of syndromes. Typical motility disorders include achalasia of the esophagus (impaired relaxation of the lower esophageal sphincter associated with defective esophageal peristalsis that results in dysphagia and regurgitation), gastroparesis (delayed gastric emptying), myopathic and neuropathic forms of intestinal dysmotility, and others. These disorders can be congenital, idiopathic, or secondary to systemic diseases (e.g., diabetes mellitus or scleroderma). This term also has traditionally included disorders such as irritable bowel syndrome (IBS) and noncardiac chest pain. For most of these disorders, treatment remains empirical and symptom based, reflecting ignorance of the pathophysiology involved.


Prokinetic agents are medications that enhance coordinated GI motility and transit of material in the GI tract. These agents appear to enhance the release of excitatory neurotransmitter at the nerve-muscle junction without interfering with the normal physiological pattern and rhythm of motility. By contrast, activation of muscarinic receptors with the older cholinomimetic agents (see Chapter 9) or AChE inhibitors (see Chapter 10) enhances contractions in a relatively uncoordinated fashion that produces little or no net propulsive activity.


Dopamine (DA) is present in significant amounts in the GI tract and has several inhibitory effects on motility, including reduction of lower esophageal sphincter and intragastric pressures. These effects, which result from suppression of ACh release from myenteric motor neurons, are mediated by D2 dopaminergic receptors. DA receptor antagonists are effective as prokinetic agents; they have the additional advantage of relieving nausea and vomiting by antagonism of DA receptors in the chemoreceptor trigger zone. Examples aremetoclopramide and domperidone.

METOCLOPRAMIDE. Metoclopramide (RSCEGLAN, others) and other substituted benzamides are derivatives of para-aminobenzoic acid and are structurally related to procainamide.

The mechanisms of action of metoclopramide are complex and involve 5HT4 receptor agonism, vagal and central 5HT3 antagonism, and possible sensitization of muscarinic receptors on smooth muscle, in addition to DA receptor antagonism. Administration of metoclopramide 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. Metoclopramide has no clinically significant effects on large-bowel motility.

ADME. Metoclopramide is absorbed rapidly after oral ingestion, undergoes sulfation and glucuronide conjugation by the liver, and is excreted principally in the urine, with a t1/2 of 4-6 h. Peak concentrations occur within 1 h after a single oral dose; the duration of action is 1-2 h.

Therapeutic Use. Metoclopramide is indicated in symptomatic patients with gastroparesis, in whom it may cause modest improvements of gastric emptying. Metoclopramide injection is used as an adjunctive measure in medical or diagnostic procedures such as intestinal intubation or contrast radiography of the GI tract. Its greatest utility lies in its ability to ameliorate the nausea and vomiting that often accompany GI dysmotility syndromes. Metoclopramide is available in oral dosage forms (tablets and solution) and as a parenteral preparation for intravenous or intramuscular use. The initial regimen is 10 mg orally, 30 min before each meal and at bedtime. The onset of action is within 30-60 min. In patients with severe nausea, an initial dose of 10 mg can be given intramuscularly (onset of action 10-15 min) or intravenously (onset of action 1-3 min). For prevention of chemotherapy-induced emesis, metoclopramide can be given as an infusion of 1-2 mg/kg administered over at least 15 min, beginning 30 min before the chemotherapy is begun and repeated as needed every 2 h for 2 doses, then every 3 h for 3 doses.

Adverse Effects. The major side effects of metoclopramide include extrapyramidal effects. 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 reverse 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. Metoclopramide also can cause galactorrhea by blocking the inhibitory effect of dopamine on prolactin release (seen infrequently in clinical practice). Methemoglobinemia has been reported occasionally in premature and full-term neonates receiving metoclopramide.

DOMPERIDONE, A D2 RECEPTOR ANTAGONIST. In contrast to metoclopramide, domperidone predominantly antagonizes the D2 receptor without major involvement of other receptors.

Domperidone (MOTILIUM, others) is not available for use in the U.S. but is used elsewhere and has modest prokinetic activity in doses of 10-20 mg 3 times a day. Although it does not readily cross the blood-brain barrier to cause extrapyramidal side effects, domperidone exerts effects in the parts of the CNS that lack this barrier, such as those regulating emesis, temperature, and prolactin release. Domperidone does not appear to have any significant effects on lower GI motility.


5HT plays an important role in the normal motor and secretory function of the gut (see Chapter 13). Indeed, >90% of the total 5HT in the body exists in the GI tract. The enterochromaffin cell produces most of this 5HT and rapidly releases 5HT in response to chemical and mechanical stimulation (e.g., food boluses; noxious agents such as cisplatin; certain microbial toxins; adrenergic, cholinergic, and purinergic receptor agonists). 5HT triggers the peristaltic reflex (see Figure 46–1) by stimulating intrinsic sensory neurons in the myenteric plexus (via 5HT1p and 5HT4 receptors), as well as extrinsic vagal and spinal sensory neurons (via 5HT3 receptors). Additionally, stimulation of submucosal intrinsic afferent neurons activates secretomotor reflexes resulting in epithelial secretion.

5HT receptors also are found on other neurons in the ENS, where they can be either stimulatory (5HT3 and 5HT4) or inhibitory (5HT1). In addition, serotonin also stimulates the release of other neurotransmitters. Thus, 5HT1 stimulation of the gastric fundus results in release of NO and reduces smooth muscle tone. 5HT4 stimulation of excitatory motor neurons enhances ACh release at the neuromuscular junction, and both 5HT3 and 5HT4 receptors facilitate interneuronal signaling. Developmentally, 5HT acts as a neurotrophic factor for enteric neurons via the 5HT2B and 5HT4 receptors. Reuptake of serotonin by enteric neurons and epithelium is mediated by the same transporter (SERT; see Chapters 5 and 13) as 5HT reuptake by serotonergic neurons in the CNS. This reuptake also is blocked by selective serotonin reuptake inhibitors (SSRIs; see Figure 15–1 and Table 15–1), which explains the common side effect of diarrhea that accompanies the use of these agents. Modulation of the multiple, complex, and sometimes opposing effects of 5HT on gut motor function has become a major target for drug development. The availability of serotonergic prokinetic drugs has in recent years been restricted because of serious adverse cardiac events. Tegaserod maleate (ZELNORM) has been discontinued; cisapride is available only via a restricted investigational drug protocol. A novel 5HT4 agonist, prucalopride (RESOLOR), is approved in Europe for symptomatic treatment of chronic constipation in women in whom laxatives fail to provide adequate relief.

CISAPRIDE. Cisapride (PROPULSID; Figure 46–2) is a 5HT4 agonist that stimulates adenylyl cyclase activity in neurons. It also has weak 5HT3 antagonistic properties and may directly stimulate smooth muscle. Cisapride was a commonly used prokinetic agent, however, it no longer is available in the U.S. because of its potential to induce serious and occasionally fatal cardiac arrhythmias that result from a prolonged QT interval. Cisapride is metabolized by CYP3A4 (see Chapter 6). 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, or concomitant medications known to prolong the QT interval. 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 Serotonergic agents modulating GI motility.

PRUCALOPRIDE. Prucalopride (RESELOR; see Figure 46–2) is a specific 5HT4 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. Given in doses of 2 and 4 mg orally, once daily, the drug improves bowel habits. Prucalopride is approved in Europe for use in women with chronic constipation in whom laxatives fail to provide adequate relief.


MACROLIDES AND ERYTHROMYCIN. Motilin, a 22–amino acid peptide hormone found in the M cells and in some enterochromaffin cells of the upper small bowel, is a potent contractile agent of the upper GI tract. Motilin levels fluctuate in association with the migrating motor complex and appear to be responsible for the amplification, if not the actual induction, of phase III activity. In addition, motilin receptors are found on smooth muscle cells and enteric neurons.

The effects of motilin can be mimicked by erythromycin, a property shared to varying extents by other macrolide antibiotics (e.g., oleandomycin, azithromycin, and clarithromycin; see Chapter 55). In addition to its motilin-like effects, which are most pronounced at higher doses (250-500 mg), erythromycin at lower doses (e.g., 40-80 mg) also may act by other poorly defined mechanisms that may involve cholinergic facilitation. Erythromycin 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. Erythromycin is used as a prokinetic agent 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. Rapid development of tolerance to erythromycin, possibly by downregulation of the motilin receptor, and antibiotic effects (undesirable in this context) limit the use of this drug as a prokinetic agent. A standard dose of erythromycin for gastric stimulation is 3 mg/kg intravenously or 200-250 mg orally every 8 h. For small-bowel stimulation, a smaller dose (e.g., 40 mg intravenously) may be more useful; higher doses may actually retard the motility. 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.

Mitemcinal (GM-611), a macrolide non-antibiotic, shows promise for the treatment of gastroparesis.


The 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, and promotes satiety. The C-terminal octapeptide of CCK, sincalide (KINEVAC), is useful for stimulating the gallbladder and/or pancreas and for accelerating barium transit through the small bowel for diagnostic testing of these organs. Dexloxiglumide is a CCK1 (or CCK-A) receptor antagonist that can improve gastric emptying and has been investigated as a treatment for gastroparesis and for constipation-dominant IBS and 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.


Smooth muscle relaxants such as organic nitrates and Ca2+ channel antagonists 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 severe difficulty in swallowing. Preparations of botulinum toxin (BOTOX, DYSPORT, MYOBLOC), injected directly into the lower esophageal sphincter via an endoscope, in doses of 80-100 units, inhibit ACh release from nerve endings and can produce partial paralysis of the sphincter muscle, with significant improvements in symptoms and esophageal clearance.


OVERVIEW OF GI WATER AND ELECTROLYTE FLUX. Water normally accounts for 70-85% of total stool weight. Net stool fluid content reflects a balance between luminal input (ingestion and secretion of water and electrolytes) and output (absorption) along the length of the GI tract. The daily challenge for the gut is to extract water, minerals, and nutrients from the luminal contents, leaving behind a manageable pool of fluid for proper expulsion of waste material via the process of defecation.

Normally ~8-9 L of fluid enter the small intestine daily from exogenous and endogenous sources (Figure 46–3). Net absorption of the water occurs in the small intestine in response to osmotic gradients that result from the uptake and secretion of ions and the absorption of nutrients (mainly sugars and amino acids), with only ~1-1.5 L crossing the ileocecal valve. The colon then extracts most of the remaining fluid, leaving ~100 mL of fecal water daily. Under normal circumstances, these quantities are within the range of the total absorptive capacity of the small bowel (~16 L) and colon (4-5 L). Neurohumoral mechanisms, pathogens, and drugs can alter secretion and absorption of fluid by the intestinal epithelium. Altered motility also contributes in a general way to this process. With decreased motility and excess fluid removal, feces can become inspissated and impacted, leading to constipation. When the capacity of the colon to absorb fluid is exceeded, diarrhea occurs.


Figure 46–3 The approximate volume and composition of fluid that traverses the small and large intestines daily. Of the 9 L of fluid typically presented to the small intestine each day, 2 L are from the diet and 7 L are from secretions (salivary, gastric, pancreatic, and biliary). The absorptive capacity of the colon is 4-5 L per day.

CONSTIPATION: GENERAL PRINCIPLES OF PATHOPHYSIOLOGY AND TREATMENT. 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.

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. 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. 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.

Constipation generally may be corrected by adherence to a fiber-rich (20-35 g daily) diet, adequate fluid intake, appropriate bowel habits and training, and avoidance of constipating drugs. Constipation related to medications can be corrected by use of alternative drugs where possible, or adjustment of dosage. If nonpharmacological measures alone are inadequate, they may be supplemented with bulk-forming agents or osmotic laxatives.

When stimulant laxatives are used, they should be administered at the lowest effective dosage and for the shortest period of time to avoid abuse. In addition to perpetuating dependence on drugs, the laxative habit may lead to excessive loss of water and electrolytes; secondary aldosteronism may occur if volume depletion is prominent. Steatorrhea, protein-losing enteropathy with hypoalbuminemia, and osteomalacia due to excessive loss of calcium in the stool have been reported. Laxatives frequently are employed before surgical, radiological, and endoscopic procedures where an empty colon is desirable. The terms laxatives, cathartics, purgatives, aperients, and evacuants often are used interchangeably. There is a distinction, however, between laxation (the evacuation of formed fecal material from the rectum) and catharsis (the evacuation of unformed, usually watery fecal material from the entire colon). Most of the commonly used agents promote laxation, but some are actually cathartics that act as laxatives at low doses.

Laxatives relieve constipation and promote evacuation of the bowel via:

• Enhancing retention of intraluminal fluid by hydrophilic or osmotic mechanisms

• Decreasing net absorption of fluid by effects on small- and large-bowel fluid and electrolyte transport

• Altering motility by either inhibiting segmenting (nonpropulsive) contractions or stimulating propulsive contractions

Laxatives can be classified based on their actions (Table 46–1) or by the pattern of effects produced by the usual clinical dosage (Table 46–2), with some overlap between classifications.

Table 46–1

Classification of Laxatives


Table 46–2

Classification and Comparison of Representative Laxatives


A variety of laxatives, both osmotic agents and stimulants, increase the activity of NO synthase and the biosynthesis of platelet-activating factor in the gut. Platelet-activating factor is a phospholipid proinflammatory mediator that stimulates colonic secretion and GI motility. NO also may stimulate intestinal secretion and inhibit segmenting contractions in the colon, thereby promoting laxation. Agents that reduce the expression of NO synthase or its activity can prevent the laxative effects of castor oil, cascara, and bisacodyl (but not senna), as well as magnesium sulfate.


Bulk, softness, and hydration of feces depend on the fiber content of the diet. Fiber is defined as that part of food that resists enzymatic digestion and reaches the colon largely unchanged. Colonic bacteria ferment fiber to varying degrees, depending on its chemical nature and water solubility. Fermentation of fiber has 2 important effects: (1) it produces short-chain fatty acids that are trophic for colonic epithelium; (2) it increases bacterial mass. Although fermentation of fiber generally decreases stool water, short-chain fatty acids may have a prokinetic effect, and increased bacterial mass may contribute to increased stool volume. However, fiber that is not fermented can attract water and increase stool bulk. The net effect on bowel movement therefore varies with different compositions of dietary fiber (Table 46–3). In general, insoluble, poorly fermentable fibers, such as lignin, are most effective in increasing stool bulk and transit.

Table 46–3

Properties of Different Dietary Fibers


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, 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 (FIBER CSCON, FIBERALL, others), a polymer of acrylic acid resin—also are available. These poorly fermentable compounds absorb water and increase fecal bulk. Malt soup extract (MALTSUPEX, others), an extract of malt, is another orally administered bulk-forming agent. Bloating is the most common side effect of soluble fiber products (perhaps due to colonic fermentation), but it usually decreases with time.


POLYETHYLENE GLYCOL–ELECTROLYTE SOLUTIONS. Long-chain polyethylene glycols (PEGs; MW ~3350 Da) are poorly absorbed and retain water via their high osmotic nature. When used in high volume, aqueous solutions of PEGs with electrolytes (COLYTE, GOLYTELY, others) produce an effective catharsis and have replaced oral sodium phosphates as the most widely used preparations for colonic cleansing prior to radiological, surgical, and endoscopic procedures.

Usually 240 mL of this solution is taken every 10 min until 4 L is consumed or the rectal effluent is clear. To avoid net transfer of ions across the intestinal wall, these preparations contain an isotonic mixture of sodium sulfate, sodium bicarbonate, sodium chloride, and potassium chloride. The osmotic activity of the PEG molecules retains the added water and the electrolyte concentration assures little or no net ionic shifts. A powder form of polyethylene glycol 3350 (MIRALAX, others) is now available for the short-term treatment (≤2 weeks) of occasional constipation. The usual dose is 17 g of powder per day in 8 ounces of water.

SALINE LAXATIVES. Laxatives containing magnesium cations or phosphate anions commonly are called saline laxatives: magnesium sulfate, magnesium hydroxide, magnesium citrate, sodium phosphate. Their cathartic action is believed to result from osmotic water retention, which then stimulates peristalsis. Other mechanisms may contribute, including the production of inflammatory mediators.

Magnesium-containing laxatives may stimulate the release of cholecystokinin, which leads to intraluminal fluid and electrolyte accumulation and to increased intestinal motility. For every additional mEq of Mg2+ in the intestinal lumen, fecal weight increases by ~7 g. The usual dose of magnesium salts contains 40-120 mEq of Mg2+ and produces 300-600 mL of stool within 6 h.

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). The FDA has ruled 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 2-dose regimens should be split evenly with the first dose taken the evening before the exam and the second starting 3-5 h 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.

NONDIGESTIBLE SUGARS AND ALCOHOLS. Lactulose (CEPHULAC, CHRONULAC, others) is a synthetic disaccharide of galactose and fructose that resists intestinal disaccharidase activity. This and other nonabsorbable sugars such as sorbitol and mannitol are hydrolyzed in the colon to short-chain fatty acids, which stimulate colonic propulsive motility by osmotically drawing water into the lumen. Sorbitol and lactulose are equally efficacious in the treatment of constipation caused by opioids and vincristine, of constipation in the elderly, and of idiopathic chronic constipation. 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 h after dosing is begun. Abdominal discomfort or distention and flatulence are relatively common but usually subside with continued administration.

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, 3 to 4 times per day) to produce 2 to 3 soft stools a day with a pH of 5-5.5.


Docusate salts are anionic surfactants that lower the surface tension of the stool to allow mixing of aqueous and fatty substances, softening the stool and permitting easier defecation. These agents also stimulate intestinal fluid and electrolyte secretion (possibly by increasing mucosal cyclic AMP) and alter intestinal mucosal permeability. Docusate sodium (dioctyl sodium sulfosuccinate; COLACE, DOXINATE, others) and docusate calcium (dioctyl calcium sulfosuccinate; SURFAK, others) are available in several dosage forms. These agents have marginal efficacy in most cases of constipation.

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.


Stimulant laxatives have direct effects on enterocytes, enteric neurons, and GI smooth muscle and probably induce a limited low-grade inflammation in the small and large bowel to promote accumulation of water and electrolytes and stimulate intestinal motility. This group incudes: diphenylmethane derivatives, anthraquinones, and ricinoleic acid.

DIPHENYLMETHANE DERIVATIVES. Bisacodyl (DULCOLAX, CORRECTOL, others) is marketed as enteric-coated and regular tablets and as a suppository for rectal administration. 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 h. Suppositories work within 30-60 min. 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.

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 acts locally only in the colon. Effective doses of the diphenylmethane derivatives vary as much as 4- to 8-fold in individual patients. Phenolphthalein, once among the most popular components of laxatives, has been withdrawn from the market in the U.S. because of potential carcinogenicity. Oxyphenisatin was withdrawn due to hepatotoxicity.

ANTHRAQUINONE LAXATIVES. These derivatives of plants such as aloe, cascara, and senna share a tricyclic anthracene nucleus modified with hydroxyl, methyl, or carboxyl groups to form monoanthrones, such as rhein and frangula. For use, monoanthrones (oral mucosal irritants) are converted to more innocuous dimeric (dianthrones) or glycoside forms. This process is reversed by bacterial action in the colon to generate the active forms.

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. The synthetic monoanthrone danthron was withdrawn from the U.S. market because of concerns over possible carcinogenicity. 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. These ingredients may still be sold over-the-counter in the U.S., but legally they cannot be labeled for use as laxatives. This judgment is medically prudent but may provoke a longing for times past amongst Joyceans, who recall that cascara sagrada, the sacred bark, worked well for Leopold Bloom, in Dublin, on the morning of June 16, 1904:

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. (Ulysses, James Joyce, 1922)

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 h; 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.


The term prokinetic generally is reserved for agents that enhance GI transit via interaction with specific receptors involved in the regulation of motility.

The potent 5HT4 receptor agonist prucalopride may be useful for the treatment of chronic constipation. Misoprostol, a synthetic prostaglandin analog, is primarily used for protection against gastric ulcers resulting from the use of NSAIDs (see Chapters 34 and 45). Prostaglandins can stimulate colonic contractions, particularly in the descending colon; this may account for the diarrhea that limits the usefulness of misoprostol as a gastroprotectant and find utility in patients with intractable constipation. Colchicine, a microtubule formation inhibitor used for gout (see Chapter 34), also has been shown to be effective in constipation, but its toxicity has limited widespread use. Neurotrophin-3 (NT-3) recently was shown to be effective in improving frequency and stool consistency by an unknown mechanism of action.

Lubiprostone (AMITIZA) is a prostanoid activator of Cl channels. The drug appears to bind to EP4 receptors linked to activation of adenylyl cyclase, leading to enhanced apical Cl conductance. The drug promotes the secretion of a chloride-rich fluid, thereby improving stool consistency and promoting increased frequency by reflexly activating motility. A dose of 8 μg twice daily was found to be effective in IBS-C, though higher doses (24 μg twice daily) are given for chronic constipation. The drug is poorly bioavailable, acting only in the lumen of the bowel. Side effects of lubiprostone include nausea, headache, diarrhea, allergic reactions, and dyspnea.

Another class of secretory agent is represented by linaclotide (LINZESS), a 14–amino acid peptide agonist of guanylate cyclase C that stimulates secretion and motility. This compound is approved in the treatment of IBS-C and chronic constipation. Common side effects include gas, abdominal pain, and diarrhea.


Opioid analgesics can cause severe constipation. Laxatives and dietary strategies are frequently ineffective in the management of opioid-induced constipation. A promising strategy is the prevention of opioid-induced constipation with peripherally acting μ opioid receptor (MOR) antagonists that specifically target the underlying reason for this condition, without limiting centrally produced analgesia.Methylnaltrexone (RELISTOR), a peripherally restricted MOR antagonist, is approved for the treatment of opioid-induced constipation. In multicenter trials, when methylnaltrexone (0.15-0.3 mg/kg) was administered repeatedly every other day for 2 weeks, bowel movements occurred in 50% of the patients, compared with 8-15% of patients receiving placebo. Another MOR antagonist, alvimopan (ENTEREG, 0.5-1 mg twice daily for 6 weeks), increased spontaneous bowel movements and improved other symptoms of opioid-induced constipation without compromising analgesia.


Postoperative ileus refers to the intolerance to oral intake and nonmechanical obstruction of the bowel that occurs after abdominal and nonabdominal surgery. The pathogenesis is complex and is a combination of activation of neural inhibitory reflexes involving enteric MOR and the activation of local inflammatory mechanisms that reduce smooth muscle contractility. The condition is exacerbated by opioids, which are the mainstay of postoperative analgesia. Prokinetic agents typically do not have much effect in this condition, but recently, 2 new therapeutic agents have been introduced that have benefit in reducing GI recovery time after surgery.

Alvimopan (ENTEREG) is an orally active peripherally restricted μ opioid receptor antagonist that is approved for limited indications following surgery (12 mg prior to surgery and then once daily for up to 7 days or until discharge; not to exceed 15 doses total). Methylnaltrexone (see above) is FDA-approved for the treatment of opioid-induced constipation in patients receiving palliative care when laxative therapy is insufficient. Dexpanthenol (ILOPAN, others) is the alcohol of pantothenic acid (vitamin B5). The drug is a congener of pantothenic acid, a precursor of coenzyme A, which serves as a cofactor in the synthesis of ACh by choline acetyl transferase. It is proposed to act by enhancing synthesis of ACh, major excitatory transmitter of the gut. Dexpanthenol is used as an injection immediately postoperatively after major abdominal surgery to minimize the occurrence of paralytic ileus. It is given by intramuscular injection (200-500 mg) immediately and then 2 h later and every 6 h after that until the situation has resolved. It may cause mild hypotension and shortness of breath as well as local irritation.


Enemas 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. Repeated enemas with hypotonic solutions can cause hyponatremia; repeated enemas with sodium phosphate–containing solution can cause hypocalcemia.

Glycerin is absorbed when given 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. CEO-TWO suppositories contain sodium bicarbonate and potassium bitartrate and make use of rectal distension to initiate laxation. When administered rectally, the suppository produces CO2, which initiates a bowel movement in 5-30 min.


DIARRHEA: GENERAL PRINCIPLES AND APPROACH TO TREATMENT. 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.

Many patients with sudden onset of diarrhea have a benign, self-limited illness requiring no treatment or evaluation. In severe cases of diarrhea, dehydration and electrolyte imbalances are the principal risk.Oral rehydration therapy therefore is a cornerstone for patients with acute illnesses resulting in significant diarrhea. This therapy exploits the fact that nutrient-linked cotransport of water and electrolytes remains intact in the small bowel in most cases of acute diarrhea. Na+ and Cl absorption links to glucose uptake by the enterocyte; this is followed by movement of water in the same direction. A balanced mixture of glucose and electrolytes in volumes matched to losses therefore can prevent dehydration. This can be provided by many commercial premixed formulas using glucose-electrolyte or rice-based physiological solutions.

Pharmacotherapy of diarrhea in adults should be reserved for patients with significant or persistent symptoms. Nonspecific anti-diarrheal agents typically do not address the underlying pathophysiology responsible for the diarrhea. Many of these agents act by decreasing intestinal motility and should be avoided in acute diarrheal illnesses caused by invasive organisms. In such cases, these agents may mask the clinical picture, delay clearance of organisms, and increase the risk of systemic invasion by the infectious organisms.

BULK-FORMING AND HYDROSCOPIC AGENTS. Hydrophilic and poorly fermentable colloids or polymers such as carboxymethylcellulose and calcium polycarbophil absorb water and increase stool bulk (calcium polycarbophil absorbs 60 times its weight in water). They usually are used for constipation but are sometimes useful in acute episodic diarrhea and in mild chronic diarrheas in patients suffering with IBS. Some of these agents also may bind bacterial toxins and bile salts. Clays such as kaolin (a hydrated aluminum silicate) and other silicates such as attapulgite (magnesium aluminum disilicate; DIASORB, others) bind water avidly and also may bind enterotoxins. However, binding is not selective and may involve other drugs and nutrients; hence these agents are best avoided within 2-3 h of taking other medications. A mixture of kaolin and pectin (a plant polysaccharide) is a popular over-the-counter remedy (KAOPECTOLIN, others) and may provide useful symptomatic relief of mild diarrhea.

BILE ACID SEQUESTRANTS. Cholestyramine, colestipol, and colesevelam effectively bind bile acids and some bacterial toxins. Cholestyramine is useful in the treatment of bile salt-induced diarrhea, as in patients with resection of the distal ileum. In these patients, excessive concentrations of bile salts reach the colon and stimulate water and electrolyte secretion. Patients with extensive ileal resection (usually >100 cm) eventually develop net bile salt depletion, which can produce steatorrhea because of inadequate micellar formation required for fat absorption. In such patients, the use of cholestyramine aggravates the diarrhea. In patients having bile salt-induced diarrhea, cholestyramine (QUESTRAN, QUESTRAN LIGHT, others) can be given at a dose of 4 g of the dried resin (4 times a day). If successful, the dose may be titrated down to achieve the desired stool frequency.

BISMUTH. Bismuth compounds are used to treat a variety of GI diseases, although their mechanism of action remains poorly understood. PEPTO-BISMOL is a popular over-the-counter preparation that consists of trivalent bismuth and salicylate suspended in a mixture of magnesium aluminum silicate clay. In the low pH of the stomach, the bismuth subsalicylate reacts with hydrochloric acid to form bismuth oxychloride and salicylic acid. Although 99% of the bismuth passes unaltered and unabsorbed into the feces, the salicylate is absorbed in the stomach and small intestine. Thus, the product carries the same warning regarding Reye syndrome as other salicylates.

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 is used 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 (see Chapter 45). A recommended dose of the bismuth subsalicylate (30 mL of regular strength liquid or 2 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 min, as needed, up to 8 times a day. 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. 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.


OPIOIDS. Opioids continue to be widely used in the treatment of diarrhea. They act by several different mechanisms, mediated principally through either μ- or δ-opioid receptors on enteric nerves, epithelial cells, and muscle (see Chapter 18). These mechanisms include effects on intestinal motility (μ receptors), intestinal secretion (δ receptors), or absorption (μ and δ receptors). Commonly used anti-diarrheals such as diphenoxylate, difenoxin, and loperamide act principally via peripheral μ opioid receptors and are preferred over opioids that penetrate the CNS.

Loperamide. Loperamide (IMODIUM, IMODIUM A-D, others), a compound with MOR activity, is an orally active anti-diarrheal agent. The drug is 40-50 times more potent than morphine as an anti-diarrheal agent and penetrates the CNS poorly. It increases small intestinal and mouth-to-cecum transit times. Loperamide also increases anal sphincter tone. In addition, loperamide has anti-secretory activity against cholera toxin and some forms of Escherichia coli toxin, presumably by acting on Gi-linked receptors to counter the stimulation of adenylyl cyclase activity by the toxins.

Loperamide is available OTC in capsule, solution, and chewable tablet forms. It acts quickly after an oral dose, with peak plasma levels achieved within 3-5 h. It has a t1/2 of ~11 h 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 h, 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 is effective against traveler’s diarrhea, used alone or in combination with antimicrobial agents (trimethoprim, trimethoprim-sulfamethoxazole, or a fluoroquinolone). Loperamide is used as adjunct treatment in most 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 (seeChapter 47), loperamide should be used with great caution, if at all, to avoid development of toxic megacolon.

Diphenoxylate and Difenoxin. Diphenoxylate and its active metabolite difenoxin (diphenoxylic acid) are related structurally to meperidine. As anti-diarrheal agents, diphenoxylate and difenoxin are somewhat more potent than morphine. Both compounds are extensively absorbed after oral administration, with peak levels achieved within 1-2 h. Diphenoxylate is rapidly de-esterified to difenoxin, which is eliminated with a t1/2 of ~12 h. 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 sub-therapeutic) 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 2 tablets initially, then 1 tablet every 3-4 h, not to exceed 8 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.) (seeChapter 9).

OTHER OPIOIDS. Opioids used for diarrhea include codeine (in doses of 30 mg given 3 or 4 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 2 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) 4 times daily; the adult dose of paregoric is 5-10 mL (equivalent to 2-4 mg morphine) 1 to 4 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) 1 to 4 times daily.

Enkephalins are endogenous opioids that are important enteric neurotransmitters; they can inhibit intestinal secretion without affecting motility. Racecadotril (acetorphan), a dipeptide inhibitor of enkephalinase, potentiates 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.

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, 2 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 AND SOMATOSTATIN. Octreotide (SANDOSTATIN, others) (see Chapter 43) is an octapeptide analog of somatostatin (SST) that is effective in inhibiting the severe secretory diarrhea brought about by hormone-secreting tumors of the pancreas and the GI tract.

Octreotide inhibits secretion of 5HT and various GI peptides. Its greatest utility may be in the “dumping syndrome” seen in some patients after gastric surgery and pyloroplasty, in whom octreotide inhibits the release of hormones (triggered by rapid passage of food into the small intestine) that are responsible for distressing local and systemic effects. Octreotide has a t1/2 of 1-2 h and is administered either subcutaneously or intravenously as a bolus dose. Standard initial therapy with octreotide is 50-100 μg, given subcutaneously 2 or 3 times a day, with titration to a maximum dose of 500 μg 3 times a day based on clinical and biochemical responses. A long-acting preparation of octreotide acetate enclosed in biodegradable microspheres (SANDOSTATIN LAR DSCEPOT) 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 (see Chapter 38). 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; transient nausea, bloating, or pain at sites of injection in the short term, gallstone formation and hypo- or hyperglycemia in the long term. A long-acting SST analog, lanreotide (SOMATULIN, others), is available in Europe; another, vapreotide, is under development. SST (STILAMIN) also is available in Europe.

Variceal Bleeding. 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 ANS. Because of its short t1/2 (1-2 min), 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/h) are more efficacious and can be used for patients who continue to bleed on the lower dose. 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 rest the pancreas 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.


Berberine is a plant alkaloid that has complex pharmacological actions that include antimicrobial effects, 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.


IBS affects up to 15% of the population in the U.S. Patients may complain of a variety of symptoms, the most characteristic of which is recurrent abdominal pain associated with altered bowel movements. IBS appears to result from a varying combination of disturbances in visceral motor and sensory function, often associated with significant affective disorders. The disturbances in bowel function can be either constipation or diarrhea or both at different times. Considerable evidence suggests a specific enhancement of visceral (as opposed to somatic) sensitivity to noxious, as well as physiological stimuli in this syndrome.

Many patients can be managed with dietary restrictions and fiber supplementation; many cannot. Treatment of bowel symptoms (either diarrhea or constipation) is predominantly symptomatic and nonspecific using agents discussed above. A possible role for serotonin in IBS 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 5HT3 antagonist alosetron (see Figure 46–2).

An effective class of agents for IBS has been the tricyclic antidepressants (see Chapter 15), which can have neuromodulatory and analgesic properties independent of their antidepressant effect. Tricyclic antidepressants 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 nortriptyline) 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. 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 antidepressants in the management of visceral pain.

α2 Adrenergic agonists, such as clonidine (see 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.


The 5HT3 receptor participates in sensitization of spinal sensory neurons, vagal signaling of nausea, and peristaltic reflexes. The clinical effect of 5HT3 antagonism is a general reduction in GI contractility with decreased colonic transit, along with an increase in fluid absorption. Alosetron (LOTRONEX), a potent antagonist of the 5HT3 receptor, was initially 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. Nevertheless, the FDA has reapproved this drug for diarrhea-predominant IBS under a limited distribution system. 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 h) is longer than expected from its t1/2 of 1.5 h. 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. Other 5HT3 antagonists currently available in the U.S. are approved for nausea and vomiting (see later in this chapter and Chapter 13).


Anticholinergic agents (“spasmolytics” or “anti-spasmodics”) often are used in patients with IBS. The most common agents of this class available in the U.S. are nonspecific antagonists of the muscarinic receptor (see Chapter 9) and include the tertiary amines dicyclomine (BENTYL, others) and hyoscyamine (LEVSIN, others) and the quaternary ammonium compounds glycopyrrolate (ROBINUL, others) andmethscopolamine (PAMINE, others). The advantage of the latter 2 compounds is that they have a limited propensity to cross the blood-brain barrier and hence a lower risk for neurological side effects such as lightheadedness, drowsiness, or nervousness. These agents typically are given either on an as-needed basis or before meals to prevent the pain and fecal urgency that occur in some patients with IBS.

Dicyclomine is given in doses of 20 mg orally every 6 h initially and increased to 40 mg every 6 h unless limited by side effects. 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 h as needed), and extended-release forms for oral use (0.25-0.375 mg every 12 h as needed). Glycopyrrolate is available as immediate-release tablets; the dose is 1-2 mg 2 or 3 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.

OTHER DRUGS. Cimetropium, an antimuscarinic compound that is effective in patients with IBS, is not available in the U.S. Otilonium bromide is a quaternary ammonium salt with antimuscarinic effects that also appears to block Ca2+ channels and neurokinin NK2 receptors; it is not available in the U.S. Mebeverine hydrochloride, a derivative of hydroxybenzamide, appears to have a direct effect on the smooth muscle cell, blocking K+ Na+, and Ca2+ channels, and is used outside of the U.S. as an anti-spasmodic agent.



Emesis and the sensation of nausea that accompanies it generally are viewed as protective reflexes that serve to rid the stomach and intestine of toxic substances and prevent their further ingestion. Vomiting is a complex process that appears to be coordinated by a central emesis center in the lateral reticular formation of the mid-brainstem adjacent to both the chemoreceptor trigger zone (CTZ) in the area postrema (AP) at the bottom of the fourth ventricle and the solitary tract nucleus (STN). The lack of a blood-brain barrier allows the CTZ to monitor blood and cerebrospinal fluid constantly for toxic substances and to relay information to the emesis center to trigger nausea and vomiting. The emesis center also receives information from the gut, principally by the vagus nerve (via the STN) but also by splanchnic afferents via the spinal cord. Two other important inputs to the emesis center come from the cerebral cortex (particularly in anticipatory nausea or vomiting) and the vestibular apparatus (in motion sickness). The CTZ has high concentrations of receptors for serotonin (5HT3), dopamine (D2), and opioids; the STN is rich in receptors for enkephalin, histamine, and ACh, and also contains 5HT3 receptors. A variety of these neurotransmitters are involved in nausea and vomiting (Figure 46–4). Anti-emetics generally are classified according to the predominant receptor on which they are proposed to act (Table 46–4). For treatment and prevention of the nausea and emesis associated with cancer chemotherapy, several anti-emetic agents from different pharmacological classes may be used in combination (Table 46–5).


Figure 46–4 Pharmacologists view of emetic stimuli. Myriad signaling pathways lead from the periphery to the emetic center. Stimulants of these pathways are noted in italics. These pathways involve specific neurotransmitters and their receptors (bold type). Receptors are shown for dopamine (D2), acetylcholine (muscarinic, M), histamine (H1), cannabinoids (CB1), substance P (NK1), and 5-hydroxytryptamine (5HT3). Some of these receptors also may mediate signaling in the emetic center.

Table 46–4

General Classification of Anti-emetic Agents


Table 46–5

Anti-emetic Agents in Cancer Chemotherapya



Ondansetron (ZOFRAN, others) is the prototypical drug in this class. The 5HT3 receptor antagonists (Table 46–6) are the most widely used drugs for chemotherapy-induced emesis. Other agents in this class include granisetron (KYTRIL, others), dolasetron (ANZEMET), palonosetron (ALOXI), and tropisetron (not available in the U.S.).

Table 46–6

5HT3 Antagonists in Chemotherapy-Induced Nausea/Emesis


5HT3 receptors are present in several critical sites involved in emesis, including vagal afferents, the STN (which receives signals from vagal afferents), and the AP itself (see 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 5HT3 receptors) to initiate the vomiting reflex. The highest concentrations of 5HT3 receptors in the CNS are found in the STN and CTZ, and antagonists of 5HT3 receptors also may suppress nausea and vomiting by acting at these sites.

ADME. 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. Granisetron also is metabolized predominantly by the liver by the CYP3A family. 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. The anti-emetic effects of these drugs persist long after they disappear from the circulation, suggesting their continuing interaction at the receptor level; these drugs can be administered effectively just once a day.

Therapeutic Use. These agents are most effective in treating chemotherapy-induced nausea and in treating nausea secondary to upper abdominal irradiation. 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 may be helpful in delayed emesis, perhaps reflecting its long t1/2. 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 (see Table 46–6) infused over 15 min, beginning 30 min before chemotherapy, or in 2-3 divided doses, with the first usually given 30 min 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 h 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.


Phenothiazines such as prochlorperazine, thiethylperazine (discontinued in the U.S.), and chlorpromazine (see Chapter 16) are among the most commonly used “general-purpose” anti-nauseants and anti-emetics. Their principal mechanism of action is D2 receptor antagonism at the CTZ. These drugs are not uniformly effective in cancer chemotherapy-induced emesis but they possess antihistaminic and anticholinergic activities that are of value in other forms of nausea, such as motion sickness.


Histamine H1 antagonists are primarily useful for motion sickness and postoperative emesis. They act on vestibular afferents and within the brainstem. Cyclizine, hydroxyzine, promethazine, anddiphenhydramine 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, seeChapter 32.


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, with some activity in postoperative nausea and vomiting. In general, however, anticholinergic agents have no role in chemotherapy-induced nausea.


The nausea and vomiting associated with cisplatin (see Chapter 61) have 2 components: an acute phase that universally is experienced (within 24 h after chemotherapy) and a delayed phase that affects only some patients (on days 2-5). 5HT3 receptor antagonists are not very effective against delayed emesis. Antagonists of the NK1 receptors for substance P, such asaprepitant (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 primarily by hepatic CYP3A4, and is excreted in the stools; its t1/2 is 9-13 h. 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 5HT3 antagonist and a corticosteroid. The recommended adult dosage of aprepitant is 125 mg administered 1 h before chemotherapy on day 1, followed by 80 mg once daily in the morning on days 2 and 3 of the treatment regimen.


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 CTZ and emetic center (see Figure 46–4).


ADME. 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 h. It undergoes extensive first-pass metabolism with limited systemic bioavailability after single doses (only 10-20%). 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 h before chemotherapy and then every 2-4 h afterward for a total of 4 to 6 doses. If this is inadequate, 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, too, may be abused by these patients.

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

ADME. Nabilone 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 h. The t1/2 is ~2 h for the parent compound and 35 h for metabolites. The metabolites are excreted primarily via the biliary-fecal route (60%), with only ~l25% 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 h before treatment and then every 8-12 h 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 such as dexamethasone can be useful adjuncts (see Table 46–5) 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, such as lorazepam and alprazolam, by themselves are not very effective anti-emetics, but their sedative, amnesic, and antianxiety 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.


Aqueous solutions of glucose, fructose, and phosphoric acid (EMETROL, NAUSETROL) are available over the counter to relieve nausea. Their mechanisms of action are unclear.



PANCREATIC ENZYMES. Chronic pancreatitis is a debilitating syndrome that results in symptoms from loss of glandular function (exocrine and endocrine) and inflammation (pain). The goals of pharmacological therapy are prevention of malabsorption and palliation of pain.

Enzyme Formulations. Pancreatic enzymes are typically prescribed on the basis of the lipase content. Only pancrelipase (CREON, ZENPEP, PANCREAZE, PERTZYE) is licensed for sale in the U.S. Pancrelipase products contain various amounts of lipase, protease, and amylase and thus may not be interchangeable.

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 well if 30,000 USP units of pancreatic lipase are delivered to the duodenum during a 4-h period with and after meals. 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 1-3 capsules with or just before meals. The loss of pancreatic amylase does not present a problem because of other sources of this enzyme (e.g., salivary glands).

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 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.

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.


Bile acids and their conjugates are synthesized from cholesterol in the liver. Bile acids induce bile flow, feedback-inhibit cholesterol synthesis, promote intestinal excretion of cholesterol, and facilitate the dispersion and absorption of lipids and fat-soluble vitamins. After secretion into the biliary tract, bile acids are largely (95%) reabsorbed in the intestine, returned to the liver, and then again secreted in bile (enterohepatic circulation). Cholic acid, chenodeoxycholic acid, and deoxycholic acid constitute 95% of bile acids; lithocholic acid and ursodeoxycholic acid are minor constituents. The bile acids exist largely as glycine and taurine conjugates, the salts of which are called bile salts. 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. When administered orally, litholytic bile acids such as chenodiol and ursodiol 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.


Figure 46–5 Major bile acids in adults.


“Gas” is a common but relatively vague GI complaint, used in reference not only to flatulence and eructation but also bloating or fullness. Over-the-counter and herbal preparations are popular. Simethicone(MYLICON, GAS-X, others), a mixture of siloxane polymers stabilized with silicon dioxide, is an inert nontoxic insoluble liquid. Because of its capacity to collapse bubbles by forming a thin layer on their surface, it is an effective anti-foaming agent; whether this accomplishes a therapeutic effect in the GI tract is not clear. 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 4 times daily. Activated charcoal may be used alone or in combination with simethicone, but has not been shown conclusively to have much benefit. An alphagalactosidase preparation (BEANO) is available over the counter to reduce gas from baked beans.


GLP-2 Receptor Agonist

Teduglutide (GATTEX) is a 33-amino acid GLP-2 analog approved for the treatment of short-bowel syndrome. Teduglutide injection is administered by subcutaneously once daily to help improve intestinal absorption of nutrients to reduce the need of parenteral support. Common side effects include abdominal pain, nausea, headache, and flu-like symptoms. Teduglutide may cause serious side effects including cancer of the bowel, blockage of the bowel, and inflammation of the gallbladder or pancreas. Teduglutide has orphan drug status.