PHARMACOTHERAPY OF NAUSEA, VOMITING, DIARRHEA, AND CONSTIPATIONVictor Nadler

Nausea and Vomiting

Physiology

Nausea subjectively describes gastrointestinal discomfort that often precedes vomiting. During nausea, gastric tone decreases, peristalsis is diminished, and the tone of the distal GI tract increases, hindering transit and promoting reflux of contents. Vomiting is a reflex that evacuates the gastrointestinal tract in a variety of conditions, such as pregnancy, postsurgery, excessive alcohol consumption, chemotherapy, GI infection, food poisoning, and motion sickness. Activation of the vomiting center initiates the reflex, during which the glottis closes to protect the lungs and the cardiac sphincter opens. Contents of the upper GI tract are expelled through the mouth due to powerful and sustained contractions of the abdominal and thoracic musculature coupled with downward contraction of the diaphragm. Contractions of the pharyngeal and GI muscles also contribute, and a reverse peristaltic wave ejects the stomach contents.

The vomiting reflex loop begins with receptors in the GI tract, which, when stimulated, send a signal through vagal afferents to the vomiting center or to the chemoreceptor trigger zone (CTZ). These brain regions are located in the area postrema of the medulla near the fourth ventricle. Several pathways provide input to the vomiting center, including the chemoreceptor trigger zone, the vestibular system, cortical regions, and visceral afferents from the GI tract. The blood-brain barrier is not well-developed around the area postrema, providing it access to the circulation.

The precise wiring of the vomiting center is unknown. Projections from the CTZ, cerebral cortex, vestibular system, and the GI tract activate the vomiting center. The CTZ is exposed to both cerebrospinal fluid and blood. It surveys these fluids for injurious substances and initiates vomiting to expel them from the body via its projection to the vomiting center. Receptors in the CTZ whose activation triggers vomiting include 5-HT3 (serotonin), D2 (dopamine), and NK1 (substance P). Projections from the vestibular system trigger vomiting associated with motion sickness. These projections are influenced by histamine and acetylcholine synapses that operate through H1 and

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muscarinic receptors. Visceral afferent fibers from the GI tract are part of the vagus nerve complex. Both peripheral and central terminals of these fibers express 5-HT3 and NK1 receptors. These innervation patterns and receptor distributions explain the efficacy of most drugs used to prevent or terminate nausea and vomiting triggered by different circumstances.

Stimuli and Pharmacotherapy

Three distinct circumstances trigger nausea and vomiting that can be treated with evidence-based pharmacotherapy: motion sickness, surgery/anesthesia, and chemotherapy/radiation. Each is treated with different drugs or drug combinations.

Motion sickness is most effectively ameliorated by muscarinic receptor antagonists. Scopolamine is by far the most widely-used drug of this type. Its superiority over other muscarinic receptor antagonists derives from its greater lipophilicity that allows for more expeditious transfer across the blood-brain barrier and for transdermal administration. Scopolamine blocks muscarinic receptors in the vestibular system, thereby reducing output to the vomiting center. It is formulated as an adhesive transdermal patch that is normally placed behind the ear. Because scopolamine’s onset of action is delayed for 2-4 hr after placement of the patch, it is used most effectively in anticipation of motion sickness (e.g., before a deep-sea fishing trip). Scopolamine produces typical antimuscarinic side affects (dry mouth, blurry vision, urinary retention, constipation), but to a lesser degree than most other such drugs.

First-generation antihistamines are more widely used than the scopolamine patch, because they are available from pharmacy shelves in generic form. All antihistamines used to treat motion sickness cross the blood-brain barrier and antagonize activation of both H1 and muscarinic receptors in the vestibular system. These drugs include dimenhydrinate (Dramamine®; a salt of diphenhydramine), diphenhydramine (Benadryl®), and meclizine (Bonine®, Antivert®). These agents are useful for motion sickness and vertigo, as well as in severe cases of nausea and vomiting associated with pregnancy. They are not useful for nausea associated with chemotherapy. In some cases, meclizine is effective for radiation-associated nausea and vomiting. The most common side effect, sometimes useful clinically, is drowsiness.

Nausea and vomiting are among the most feared side effects of treatment for patients with cancer about to begin chemotherapy and, in some cases, radiation therapy. Significant progress

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has been made since about 1990 in developing more effective and better-tolerated anti-emetic drugs to minimize chemotherapy-induced nausea and vomiting. The current standard of care is to combine a 5-HT3 receptor antagonist, such as ondansetron (Zofran®), with aprepitant (Emend®) and a glucocorticoid, such as dexamethasone.

Cytotoxic chemotherapeutic agents and radiation cause nausea and vomiting, at least partly, because damage to the GI mucosa releases serotonin from enterochromaffin cells. Serotonin can depolarize and activate vagal nerve terminals and also activate the CTZ via the circulation. These effects require the activation of 5-HT3 receptors. 5-HT3 receptor antagonists block this action of serotonin, both peripherally and centrally. Urinary levels of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) rise dramatically in individuals treated with highly emetogenic chemotherapy. Thus ondansetron and other drugs of this class (granisetron, dolasetron, tropisetron, palonosetron) may be more effective than older antiemetic drugs that work only in the brain because they block the vomiting signal at its source, before it has a chance to enter the vagus nerve. 5-HT3 antagonists are more efficacious against nausea and vomiting that occurs within hours after chemotherapy/radiation than against delayed (>24 hr) nausea and vomiting.

Aprepitant was the first drug that targets the neuropeptide substance P to be approved for use by the FDA. Substance P is an 11-amino acid peptide colocalized with glutamate or GABA in specific sets of synaptic terminals. Substance P is not released by single action potentials, but only by high-frequency activity or prolonged depolarization of the terminal. It then acts on the NK1 receptor, a G protein-coupled facilitatory receptor whose activation increases the excitability of the cell. NK1 receptors are expressed in the nucleus tractus solitarius, a region of the medulla that lies ventral to the area postrema, and on vagus nerve terminals. Aprepitant is a selective NK1 receptor antagonist. Thus it blocks the emetic action of substance P at both central and peripheral sites. Aprepitant has a broader spectrum of activity than 5-HT3

receptor antagonists and is more effective against delayed nausea and vomiting.Glucocorticoids, principally dexamethasone, have been used to prevent and terminate

chemotherapy- and radiation-induced nausea and vomiting for years. Their mechanism of action is not well understood. Theories include reduction in prostaglandin biosynthesis (due to indirect inhibition of phospholipase A2), release of endogenous opioids, and reduced synthesis and release of 5-HT in the GI tract.

Postoperative nausea and vomiting occurs in 30% of all surgical patients and in up to 70% of high-risk patients (see below). Patient-related risk factors include female gender, history of motion sickness or postoperative nausea and vomiting, non-smoking status, obesity, and use of narcotics in the postoperative period. Women have a 2- to 4-fold higher incidence than men. A previous history, negative smoking history, or postoperative narcotic use approximately doubles the risk. In addition, the risk of postoperative nausea and vomiting increases with abdominal, gynecological, orthopedic and ear, nose and throat surgeries, compared with other procedures. Inhaled general anesthetics are highly emetogenic. Lengthy surgeries are associated with a higher incidence of postoperative nausea and vomiting. The incidence of postoperative nausea and vomiting is 10-21% in patients with no more than one risk factor, but almost 80% in patients with two or more risk factors. As the number of risk factors increases, it is preferable to administer prophylactic anti-emetic drugs, rather than to wait until nausea becomes evident.

All classes of anti-emetic drugs are used to treat postoperative nausea and vomiting. One algorithm for using these drugs is shown in the figure below. In addition to muscarinic, H1, 5-HT 3 and NK1 receptor antagonists, and glucocorticoids, three chemical classes of D2 (dopamine) receptor antagonists are used. The phenothiazines, exemplified by prochlorperazine (Compazine®), and the butyrophenones, exemplified by droperidol (Inapsine®), act primarily by blocking dopamine signals in the CTZ. The substituted benzamide metoclopramide (Reglan®) is a complicated drug. It antagonizes D2 receptors in the CTZ and in the GI tract. It also exhibits muscarinic agonist activity, which increases the tone of the lower esophageal sphincter and promotes gastric motility. These drugs are also somewhat effective against chemotherapy- and radiation-induced nausea and vomiting, but have fallen out of favor

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for this use now that more effective drugs are available. All the D2 receptor antagonists cross the blood-brain barrier and produce Parkinson-like extrapyramidal side effects in some people. Droperidol prolongs the QT interval and can provoke torsade de pointes in susceptible individuals.

There is no evidence-based pharmacotherapy for the nausea and vomiting of pregnancy. Perhaps surprisingly, nausea and vomiting during pregnancy is associated with favorable pregnancy outcomes, specifically a reduced risk of miscarriage. Although this form of nausea and vomiting is usually self-limited, 1-3% of pregnant women experience severe symptoms. Severe nausea and vomiting is the third leading cause of hospitalization during pregnancy, due to dehydration, malnutrition, and electrolyte imbalances. The exact etiology and pathogenesis of this condition are poorly understood. Hypotheses include psychological predisposition, evolutionary adaptation, hormonal stimuli, and Helicobacter pylori infection.

It is unethical to perform randomized controlled clinical trials of antiemetic drugs during pregnancy. Furthermore, the placentas of other mammals differ significantly from the human placenta; animal studies are of limited value. Thus safety data on these drugs are based only on observational studies, and treatment choices remain largely empirical. In general, one should make every effort to avoid drug use and to begin pharmacotherapy with an antihistamine only if symptoms persist despite dietary changes, lifestyle modifications, and the use of complementary therapies. The use of other antiemetic drugs should be reserved for patients whose nausea and vomiting persists while on antihistamine therapy. One treatment algorithm is shown below. Note: pyridoxine-doxylamine (the latter a sedating antihistamine) is available in Canada but no longer in the US.

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Diarrhea

The causes of diarrhea are legion. Infectious diarrhea is common and kills 5 million people, mostly children, every year. We will not cover antibacterial treatment here. Most diarrhea is self-limiting, if dehydration and electrolyte imbalances are prevented by oral rehydration.The small intestine and colon are gigantic absorptive surfaces. On average, 9 liters of

Water movement out of GI tract

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fluid enters the small intestine every day (the vast majority from secretions). Only 1-1.5 liters of this fluid reaches the colon. Because the small intestine normally operates at 50% absorptive capacity and the colon can at most absorb only 4-5 liters/day, temporary loss of even 1% of absorptive capacity overloads the colon and diarrhea ensues.

Normally, water leaves the GI tract as nutrients (especially glucose) and electrolytes (sodium and potassium) are absorbed. The figure above shows the major transporter processes. Those that are most important to consider in treatment of diarrhea and constipation are the sodium-glucose cotransporter and the chloride secretory capacity. The former is important because this transport process tends to be maintained even after mucosal damage that limits activity of other transporter processes. Therefore providing electrolyte in combination with glucose causes significant water reabsorption. This forms the basis of the oral rehydration therapies that will be discussed below. Most enterotoxins cause secretion of anions, primarily HCO3

- and Cl-, as well as inhibiting Na+/H+ exchange in both small and large intestine. Bowel inflammation leads to diarrhea through loss of absorptive surface.

Diarrhea, or watery stools, is defined typically as excessive fluid weight in stools. The excess fluid:solid ratio is probably the most important consideration, but increased frequency (>3/day) in combination with excessive weight (>200 g) should also be considered in diagnosis. Most forms of infectious diarrhea result from bacterial or viral toxins that specifically interfere with electrolyte transport, and either prevent transport out of the intestine or promote secretion of electrolyte into the gut. These electrolytes draw water into the intestine which results in watery stools. Other causes include food malabsorption (lactose intolerance for example), inflammation of the bowel, disordered motility, endocrinopathies, including hyperthyroidism and Addison’s disease, inflammatory bowel disease, and some endocrine tumors that secrete peptides which stimulate GI motility and/or influence electrolyte reabsorption. Stress can influence GI motility and lead to decreased transit time and therefore decreased reabsorption of electrolytes and water; central corticotrophin-releasing factor (CRF) mechanisms have been implicated. Drugs that increase GI motility can also increase bowel frequency. Caffeine is a common cause that is easily eliminated.

Appropriate differential diagnosis is important before using these mainly nonselective therapies, because targeted approaches (e.g., appropriate antimicrobial therapies, identification of tumors, stress relief) should be used when a cause is known.

Approaches to therapy (in addition to treating the underlying disorder if possible) include the following:

1. Maintain hydration and electrolytes with oral or parenteral therapy. 2. Use bulk-forming or hygroscopic agents to absorb water, add solid matter to stool3. Slow motility: reduced transit time will permit more water reabsorption

Hydration and Electrolytes

A number of commercially-available rehydration solutions, including Pedialyte and Ricelyte, provide appropriate concentrations of sodium, potassium, and glucose. This facilitates Na+-glucose cotransport and water follows passively. An economical and effective rehydration solution can be made at home simply by dissolving one level teaspoon of salt and eight level teaspoons of sugar in a liter of clean water. A better balanced solution would be made by dissolving a half teaspoon of salt, a half teaspoon of baking soda, eight teaspoons of sugar and a quarter teaspoon of salt substitute (to add potassium) in a liter of clean water.

Bulk and Hygroscopic Agents

Bulk-forming agents can combat diarrhea or constipation, depending upon the situation. Commonly-available bulk-forming compounds include psyllium (Metamucil), polycarbophil (Fibercon) and semisynthetic celluloses (Citrucel). For diarrhea caused by excessive bile salts or some bacteria,

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cholestyramine (Questran) can be used. It binds bile salts and also some bacterial toxins.

Bismuth (Pepto-Bismol)

The bismuth subsalicylate in Pepto-Bismol is converted into bismuth oxychloride in the stomach. This active agent is antimicrobial, antisecretory, and anti-inflammatory. It can both prevent and treat mild cases of diarrhea.

Peripherally-Acting Narcotics

The mu receptors in the enteric nervous system mediate the decrease in GI motility and secretion produced by enkephalin release in the enteric parasympathetic ganglia. Slowing GI motility promotes fluid absorption. Loperamide (Imodium® and others) is a mu receptor agonist. A quaternary ammonium compound, it acts in the GI tract but is excluded from the CNS due to reverse transport by P-glycoprotein. Thus loperamide cannot be used for recreational purposes and is therefore available on pharmacy shelves. Loperamide-containing preparations are extremely effective in decreasing GI motility, as effective as morphine and other highly efficacious, centrally-acting narcotics. They are most useful when it is inconvenient to have diarrhea, such as when travelling, and to treat chronic diarrhea associated with inflammatory bowel disease.

Constipation

For the most part, constipation is an inconvenience and uncomfortable, but not life-threatening. Nonetheless, hospitalized patients are often constipated secondary to changes in environment, immobility, medications, or procedures (barium sulfate). In some cases (e.g., recent MI or GI surgery), one would simply like the patient to avoid straining.

The following factors can lead to constipation: low intake of non-digestible nutrients (i.e., bulk), low GI motility, which increases water reabsorption excessively due to prolonged transit time, and/or inadequate water intake. Physical activity also stimulates GI motility. Thus persons who are inactive can develop constipation.

The first approach to treating constipation in an outpatient is to modify lifestyle factors as much as possible. Immediate actions may include:

Increase bulk in diet - whole grains, vegetables, etc.Maintain adequate water intakeIncrease physical activity

These changes alone may be adequate and should usually be tried first in an ambulatory patient.

Bulk Agents

A number of commercial products provide indigestible plant material in liquid or granular form. Fiber products include Metamucil, Fibercon, or Citrucel. They are osmotically active, but metabolically inert. Thus they draw water into the lumen of the intestine.

Osmotic Cathartics

There are numerous preparations of non-absorbable salts or sugars that hold water in the intestinal lumen by the same mechanism as bulk agents, although they tend to act more quickly. Sugars include Mannitol, Lactulose, and Sorbitol. Salts include magnesium hydroxide (Milk of Magnesia), magnesium citrate, and sodium phosphate (Fleet). Polyethyleneglycol-electrolyte preparations, such

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as Golytely, are often used in hospital. Non-absorbable salts, with or without polyethyleneglycol, are most often used for bowel preps, because they act quickly and cause fairly complete bowel evacuation.

Emollient Surface Agents and Stimulant Cathartics

Surface agents soften the stool by allowing water and fat entry. The purpose is more to avoid straining than to relieve constipation per se. Products include docusate (Colace®, Dulcolax Stool Softener®). Stimulant cathartics, such as bisacodyl (Dulcolax® and others) or extracts of cascara sagrada or senna (Senecot®) stimulate peristalsis and electrolyte secretion into the GI lumen.

Timing of Different Agents

The choice of drug may depend upon how quickly and completely bowel evacuation is desired. The chart below indicates the relative speed with which each of these agents acts. Typically, slow-acting agents are also “gentler” in causing a less complete bowel evacuation.

1-3 days, softening of feces– Bulk– Surfactants– Lactulose

6-8 hours, semifluid stool– Bisacodyl– Senna, cascara

1-3 hours, watery evacuation– Osmotic laxatives

Drugs for Chronic Constipation

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In some individuals, constipation does not respond to fiber products or stimulant cathartics. It then becomes a chronic condition. This may occur without any apparent cause, in which case the condition is termed chronic idiopathic constipation. Chronic constipation can also result from surgery followed by a period of restricted activity and from long-term therapy with narcotics. Finally, chronic constipation is a major problem experienced by many persons with irritable bowel syndrome.

One drug currently available to treat chronic constipation is lubiprostone (Amitiza®). Lubiprostone is a derivative of prostaglandin E1 (PGE1), which has no activity upon prostaglandin receptors. It activates the ClC-2 chloride channels in the GI epithelium (see figure above). These channels are expressed in the apical membrane of the epithelial cells. Their activation produces a chloride-rich intestinal fluid secretion without altering plasma ion concentrations. More water is retained in the intestinal lumen, the stool softens, and intestinal motility increases.

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A newer option is linaclotide (Linzess®). Linaclotide is a guanylate cyclase-C (GC-C) receptor agonist (same mechanism as E. coli enterotoxins). Both linaclotide and its active metabolite bind to GC-C and act locally on the luminal surface of the intestinal epithelium. Activation of GC-C increases both intracellular and extracellular concentrations of cGMP. Elevation in intracellular cGMP stimulates secretion of chloride and bicarbonate into the intestinal lumen, mainly through activation of the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel, resulting in increased intestinal fluid and accelerated transit. It also inhibits luminal sodium absorption by a sodium proton exchanger. In animal models, linaclotide has been shown to both accelerate GI transit and reduce intestinal pain. The linaclotide-induced reduction in visceral pain in animals is thought to be mediated by increased extracellular cGMP, which was shown to decrease the activity of pain-sensing nerve endings.

Inflammatory Bowel Disease

Inflammatory bowel disease includes irritable bowel syndrome, Crohn’s disease, ulcerative colitis, and other syndromes. Although chronic diarrhea or constipation can be presenting symptoms, the underlying cause of the disorder, at least in Crohn’s disease and ulcerative colitis, is an autoimmune attack upon the GI mucosa. Damage to the GI mucosa interferes with absorption and secretion. Patients require chronic pharmacotherapy, which is helpful but not extremely successful. Ulcerative colitis affects the colon and rectum only, whereas Crohn’s disease can affect any part of the GI tract. The part of the GI tract most frequently involved in Crohn’s disease is the ileum.

Pharmacotherapy of ulcerative colitis, and of Crohn’s disease that involves the colon and/or rectum, begins with the use of mesalamine (5-aminosalicylic acid) or sulfasalazine. Mesalamine is an anti-inflammatory drug that acts, in part, by inhibiting both cyclooxygenase and 5-lipoxygenase, the enzymes responsible for the biosynthesis of prostaglandins and leukotrienes, respectively. Additional mechanisms of action have been suggested, including modulation of B-cell responses and angiogenesis. It is not well absorbed and is intended to act locally in the GI mucosa. Sulfasalazine is metabolized to mesalamine by bacteria in the colon. Therefore it is useful only when the lesions are in the colon or the terminal ileum. Mesalamine is formulated in capsules that break down and release drug at specific pH values. By matching the capsule to the pH of the intestinal segment where the lesions are located, mesalamine can be delivered to the area of the lesions. These drugs are more effective for ulcerative colitis than for Crohn’s disease. When mesalamine or sulfasalazine proves insufficient, the next drugs added are a glucocorticoid, such as prednisone, and an immunosuppressant, most commonly azathioprine. Glucocorticoids are used only to treat acute flares, whereas azathioprine is used for chronic therapy. Biologic agents are playing an increasing role in treating patients with serious complications of inflammatory bowel disease. The most widely used and most efficacious is infliximab (Remicade®), a humanized monoclonal antibody directed against TNFα. Because other anti-TNF-α treatments (adalimumab, etanercept) do not exert as great a therapeutic effect in inflammatory bowel diseases as infliximab does, infliximab must work by at least one other mechanism in addition to binding TNF-α. In fact, infliximab can induce apoptosis of inflammatory cells, including T cells and monocytes, by a caspase-dependent mechanism.

The newest treatment for Crohn’s disease and ulcerative colitis, approved by the FDA in May, 2014, is vedolizumab (Entyvio®). Vedolizumab is patterned after natalizumab (Tysabri®), a drug used in treating multiple sclerosis. Both are humanized monoclonal antibodies directed against integrins, adhesion molecules expressed by lymphocytes. Unlike natalizumab, vedolizumab is specific for the α 4β7

integrin subunit. Integrins having this subunit bind specifically to mucosal addressin cell adhesion molecule-1 (MAdCAM-1), which is expressed preferentially by blood vessels in the GI tract. Thus vedolizumab prevents lymphocytes from invading the GI tract. It is approved for use in patients inadequately treated by immunosuppressants and biologic agents.

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